Federal Practitioner

SAN DIEGO — Two proposed new multiple myeloma staging systems offer similar prognostic accuracy compared with the standard staging system, but the new systems provide more refined risk classifications across different disease stages. 

The findings should encourage greater use of these newer staging systems in routine clinical practice, first author Manni Mohyuddin, MD, said during a presentation at the American Society of Hematology annual meeting.

Dr. Mohyuddin and his colleagues retrospectively compared the standard Revised International Staging System (R-ISS) with two newer systems, the Second Revision of the R-ISS (R2-ISS) and the Mayo Additive Staging System (MASS), using real-world data from nearly 500 patients with newly diagnosed multiple myeloma.

The R-ISS, the most common multiple myeloma staging system, incorporates a range of prognostic features, including high-risk genetic markers assessed using fluorescence in situ hybridization as well as levels of lactate dehydrogenase, albumin, and beta-2 microglobulin, explained Dr. Mohyuddin, assistant professor at the Huntsman Cancer Institute, University of Utah, Salt Lake City.

R2-ISS and MASS include additional factors that reflect experts’ growing understanding of multiple myeloma. Specifically, the systems also evaluate a gain of chromosome 1q, in which patients have an extra copy of chromosome 1q, as well as the additive effects of multiple high-risk cytogenetic abnormalities, both of which indicate worse prognosis in multiple myeloma, Dr. Mohyuddin said in an interview.

To compare the three staging systems, the investigators used information on newly diagnosed patients in the Flatiron Health EHR–derived deidentified database, which includes data from cancer clinics across the United States. Patients were followed from first-line treatment initiation until death, the end of the study period, or last recorded activity.

The patients from the database had a median age of 70 years, and most had not received a transplant. The most common cytogenetic abnormality was gain 1q, present in about one third of patients. 

Given that the R2-ISS originated from patients in clinical trials, Dr. Mohyuddin noted the importance of assessing how the system would perform in a real-world setting. 

Of the 497 patients in the analysis, the R-ISS staging system classified 24% as stage I, 63% as stage II, and 13% as stage III. Overall survival differed across these R-ISS stages, indicating the system was prognostic for survival. Median overall survival was not reached for those with stage I disease, was 62.9 months for those with stage II disease, and 37.6 months for those with stage III disease.

Because the R-ISS doesn’t consider the additive effect of multiple cytogenetic abnormalities, many patients end up in the R-ISS stage II category but ultimately may have vastly different outcomes, Dr. Mohyuddin said.

The R2-ISS includes four risk categories, which provide more granularity to the stage II classification: Stage I is low risk, stage II is low-intermediate, stage III is intermediate, and stage IV is high risk. Using this staging system, 20% of patients were stage I, 25% were stage II, 46% were stage III, and 9% were stage IV.

The R2-ISS was also prognostic for survival, which generally worsened from stage I to stage IV: Median overall survival was not reached in stage I patients, was 69.3 months for stage II, 50.0 months for stage III, and 50.6 months for stage IV patients. However, Dr. Mohyuddin noted that there was some overlap in the survival curves for stages I and II and for stages III and IV.

When applying MASS, 34% of patients were categorized as stage I, 35% as stage II, and 31% as stage III disease. This system was prognostic for survival as well, with median overall survival of 76.9 months for stage I, 61.2 months for stage II, and 45.0 months for stage III.

With R2-ISS, many of those in R-ISS stage II are moved into stage I and III. With MASS, the R-ISS stage II patients are more evenly distributed across stages I, II, and III.

In other words, “we show that both these newer staging systems basically recategorize patients into different stages,” essentially “decreasing the number of people in the large, ambiguous (R-ISS) stage II category,” said Dr. Mohyuddin. 

Dr. Mohyuddin and colleagues also evaluated the staging systems in fully adjusted analyses that controlled for age, race/ethnicity, sex, practice type, and diagnosis year. 

Using R2-ISS, stage I patients had a similar risk for death compared with stage II patients (hazard ratio [HR], 1.2). Compared with stage I patients, stage III and IV patients had comparable risks for death, both about 2.5-fold higher than in those with stage I disease (HR, 2.4 and 2.6, respectively). 

Compared with stage I MASS patients, those with stage II had a twofold higher risk for death (HR, 2.0), and those with stage III had an almost threefold higher risk (HR, 2.7). 

Although no system considers all factors associated with myeloma outcomes, R2-ISS and MASS do offer a benefit over R-ISS, Dr. Mohyuddin said.

He added that the R2-ISS and MASS are similar from a statistical standpoint, but he gave MASS a slight edge for use in clinical practice.

MASS “more cleanly demarcated [patients] into prognostic subsets,” plus it is “a little easier to remember by heart,” he explained. MASS also puts more emphasis on the presence of multiple high-risk cytogenetic abnormalities, which is a worse prognostic in this era of quadruplet therapy for multiple myeloma, he added.

Because the study largely took place in an era when triplet therapy dominated, “we would be curious to see, with longer follow-up and more use of quadruplets, how these staging systems would perform,” he said. 

Despite the benefits of these newer staging systems, many factors play a role in multiple myeloma outcomes, Dr. Mohyuddin explained. Staging systems are “only a piece of the puzzle.”

Dr. Mohyuddin reported having no financial interests to disclose.
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Two proposed new multiple myeloma staging systems offer similar prognostic accuracy compared with the standard staging system, but the new systems provide more refined risk classifications across different disease stages. 

The findings should encourage greater use of these newer staging systems in routine clinical practice, first author Manni Mohyuddin, MD, said during a presentation at the American Society of Hematology annual meeting.

Dr. Mohyuddin and his colleagues retrospectively compared the standard Revised International Staging System (R-ISS) with two newer systems, the Second Revision of the R-ISS (R2-ISS) and the Mayo Additive Staging System (MASS), using real-world data from nearly 500 patients with newly diagnosed multiple myeloma.

The R-ISS, the most common multiple myeloma staging system, incorporates a range of prognostic features, including high-risk genetic markers assessed using fluorescence in situ hybridization as well as levels of lactate dehydrogenase, albumin, and beta-2 microglobulin, explained Dr. Mohyuddin, assistant professor at the Huntsman Cancer Institute, University of Utah, Salt Lake City.

R2-ISS and MASS include additional factors that reflect experts’ growing understanding of multiple myeloma. Specifically, the systems also evaluate a gain of chromosome 1q, in which patients have an extra copy of chromosome 1q, as well as the additive effects of multiple high-risk cytogenetic abnormalities, both of which indicate worse prognosis in multiple myeloma, Dr. Mohyuddin said in an interview.

To compare the three staging systems, the investigators used information on newly diagnosed patients in the Flatiron Health EHR–derived deidentified database, which includes data from cancer clinics across the United States. Patients were followed from first-line treatment initiation until death, the end of the study period, or last recorded activity.

The patients from the database had a median age of 70 years, and most had not received a transplant. The most common cytogenetic abnormality was gain 1q, present in about one third of patients. 

Given that the R2-ISS originated from patients in clinical trials, Dr. Mohyuddin noted the importance of assessing how the system would perform in a real-world setting. 

Of the 497 patients in the analysis, the R-ISS staging system classified 24% as stage I, 63% as stage II, and 13% as stage III. Overall survival differed across these R-ISS stages, indicating the system was prognostic for survival. Median overall survival was not reached for those with stage I disease, was 62.9 months for those with stage II disease, and 37.6 months for those with stage III disease.

Because the R-ISS doesn’t consider the additive effect of multiple cytogenetic abnormalities, many patients end up in the R-ISS stage II category but ultimately may have vastly different outcomes, Dr. Mohyuddin said.

The R2-ISS includes four risk categories, which provide more granularity to the stage II classification: Stage I is low risk, stage II is low-intermediate, stage III is intermediate, and stage IV is high risk. Using this staging system, 20% of patients were stage I, 25% were stage II, 46% were stage III, and 9% were stage IV.

The R2-ISS was also prognostic for survival, which generally worsened from stage I to stage IV: Median overall survival was not reached in stage I patients, was 69.3 months for stage II, 50.0 months for stage III, and 50.6 months for stage IV patients. However, Dr. Mohyuddin noted that there was some overlap in the survival curves for stages I and II and for stages III and IV.

When applying MASS, 34% of patients were categorized as stage I, 35% as stage II, and 31% as stage III disease. This system was prognostic for survival as well, with median overall survival of 76.9 months for stage I, 61.2 months for stage II, and 45.0 months for stage III.

With R2-ISS, many of those in R-ISS stage II are moved into stage I and III. With MASS, the R-ISS stage II patients are more evenly distributed across stages I, II, and III.

In other words, “we show that both these newer staging systems basically recategorize patients into different stages,” essentially “decreasing the number of people in the large, ambiguous (R-ISS) stage II category,” said Dr. Mohyuddin. 

Dr. Mohyuddin and colleagues also evaluated the staging systems in fully adjusted analyses that controlled for age, race/ethnicity, sex, practice type, and diagnosis year. 

Using R2-ISS, stage I patients had a similar risk for death compared with stage II patients (hazard ratio [HR], 1.2). Compared with stage I patients, stage III and IV patients had comparable risks for death, both about 2.5-fold higher than in those with stage I disease (HR, 2.4 and 2.6, respectively). 

Compared with stage I MASS patients, those with stage II had a twofold higher risk for death (HR, 2.0), and those with stage III had an almost threefold higher risk (HR, 2.7). 

Although no system considers all factors associated with myeloma outcomes, R2-ISS and MASS do offer a benefit over R-ISS, Dr. Mohyuddin said.

He added that the R2-ISS and MASS are similar from a statistical standpoint, but he gave MASS a slight edge for use in clinical practice.

MASS “more cleanly demarcated [patients] into prognostic subsets,” plus it is “a little easier to remember by heart,” he explained. MASS also puts more emphasis on the presence of multiple high-risk cytogenetic abnormalities, which is a worse prognostic in this era of quadruplet therapy for multiple myeloma, he added.

Because the study largely took place in an era when triplet therapy dominated, “we would be curious to see, with longer follow-up and more use of quadruplets, how these staging systems would perform,” he said. 

Despite the benefits of these newer staging systems, many factors play a role in multiple myeloma outcomes, Dr. Mohyuddin explained. Staging systems are “only a piece of the puzzle.”

Dr. Mohyuddin reported having no financial interests to disclose.
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Two proposed new multiple myeloma staging systems offer similar prognostic accuracy compared with the standard staging system, but the new systems provide more refined risk classifications across different disease stages. 

The findings should encourage greater use of these newer staging systems in routine clinical practice, first author Manni Mohyuddin, MD, said during a presentation at the American Society of Hematology annual meeting.

Dr. Mohyuddin and his colleagues retrospectively compared the standard Revised International Staging System (R-ISS) with two newer systems, the Second Revision of the R-ISS (R2-ISS) and the Mayo Additive Staging System (MASS), using real-world data from nearly 500 patients with newly diagnosed multiple myeloma.

The R-ISS, the most common multiple myeloma staging system, incorporates a range of prognostic features, including high-risk genetic markers assessed using fluorescence in situ hybridization as well as levels of lactate dehydrogenase, albumin, and beta-2 microglobulin, explained Dr. Mohyuddin, assistant professor at the Huntsman Cancer Institute, University of Utah, Salt Lake City.

R2-ISS and MASS include additional factors that reflect experts’ growing understanding of multiple myeloma. Specifically, the systems also evaluate a gain of chromosome 1q, in which patients have an extra copy of chromosome 1q, as well as the additive effects of multiple high-risk cytogenetic abnormalities, both of which indicate worse prognosis in multiple myeloma, Dr. Mohyuddin said in an interview.

To compare the three staging systems, the investigators used information on newly diagnosed patients in the Flatiron Health EHR–derived deidentified database, which includes data from cancer clinics across the United States. Patients were followed from first-line treatment initiation until death, the end of the study period, or last recorded activity.

The patients from the database had a median age of 70 years, and most had not received a transplant. The most common cytogenetic abnormality was gain 1q, present in about one third of patients. 

Given that the R2-ISS originated from patients in clinical trials, Dr. Mohyuddin noted the importance of assessing how the system would perform in a real-world setting. 

Of the 497 patients in the analysis, the R-ISS staging system classified 24% as stage I, 63% as stage II, and 13% as stage III. Overall survival differed across these R-ISS stages, indicating the system was prognostic for survival. Median overall survival was not reached for those with stage I disease, was 62.9 months for those with stage II disease, and 37.6 months for those with stage III disease.

Because the R-ISS doesn’t consider the additive effect of multiple cytogenetic abnormalities, many patients end up in the R-ISS stage II category but ultimately may have vastly different outcomes, Dr. Mohyuddin said.

The R2-ISS includes four risk categories, which provide more granularity to the stage II classification: Stage I is low risk, stage II is low-intermediate, stage III is intermediate, and stage IV is high risk. Using this staging system, 20% of patients were stage I, 25% were stage II, 46% were stage III, and 9% were stage IV.

The R2-ISS was also prognostic for survival, which generally worsened from stage I to stage IV: Median overall survival was not reached in stage I patients, was 69.3 months for stage II, 50.0 months for stage III, and 50.6 months for stage IV patients. However, Dr. Mohyuddin noted that there was some overlap in the survival curves for stages I and II and for stages III and IV.

When applying MASS, 34% of patients were categorized as stage I, 35% as stage II, and 31% as stage III disease. This system was prognostic for survival as well, with median overall survival of 76.9 months for stage I, 61.2 months for stage II, and 45.0 months for stage III.

With R2-ISS, many of those in R-ISS stage II are moved into stage I and III. With MASS, the R-ISS stage II patients are more evenly distributed across stages I, II, and III.

In other words, “we show that both these newer staging systems basically recategorize patients into different stages,” essentially “decreasing the number of people in the large, ambiguous (R-ISS) stage II category,” said Dr. Mohyuddin. 

Dr. Mohyuddin and colleagues also evaluated the staging systems in fully adjusted analyses that controlled for age, race/ethnicity, sex, practice type, and diagnosis year. 

Using R2-ISS, stage I patients had a similar risk for death compared with stage II patients (hazard ratio [HR], 1.2). Compared with stage I patients, stage III and IV patients had comparable risks for death, both about 2.5-fold higher than in those with stage I disease (HR, 2.4 and 2.6, respectively). 

Compared with stage I MASS patients, those with stage II had a twofold higher risk for death (HR, 2.0), and those with stage III had an almost threefold higher risk (HR, 2.7). 

Although no system considers all factors associated with myeloma outcomes, R2-ISS and MASS do offer a benefit over R-ISS, Dr. Mohyuddin said.

He added that the R2-ISS and MASS are similar from a statistical standpoint, but he gave MASS a slight edge for use in clinical practice.

MASS “more cleanly demarcated [patients] into prognostic subsets,” plus it is “a little easier to remember by heart,” he explained. MASS also puts more emphasis on the presence of multiple high-risk cytogenetic abnormalities, which is a worse prognostic in this era of quadruplet therapy for multiple myeloma, he added.

Because the study largely took place in an era when triplet therapy dominated, “we would be curious to see, with longer follow-up and more use of quadruplets, how these staging systems would perform,” he said. 

Despite the benefits of these newer staging systems, many factors play a role in multiple myeloma outcomes, Dr. Mohyuddin explained. Staging systems are “only a piece of the puzzle.”

Dr. Mohyuddin reported having no financial interests to disclose.
 

A version of this article appeared on Medscape.com.

Human microbiome research has progressed in leaps and bounds over the past decades, from pivotal studies begun in the 1970s to the launch of the Human Microbiome Project in 2007. Breakthroughs have laid the groundwork for more recent clinical applications, such as fecal microbiota transplantation (FMT), and advanced techniques to explore new therapeutic pathways. Yet the “microbiome revolution” is just getting started, according to professor Martin J. Blaser, MD, one of the field’s pioneers.

The ongoing research and clinical trials into the microbiome’s link to the major causes of death in the United States hold the promise of interventions that manipulate the microbiome to prevent, slow, or perhaps even cure these conditions, says Dr. Blaser, who holds the Henry Rutgers Chair of the Human Microbiome and is director of the Center for Advanced Biotechnology and Medicine at Rutgers University in New Brunswick, New Jersey.

Dr. Blaser is the author of Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues, serves as chair of the Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria and is a member of the scientific advisory board of the biotech startup Micronoma.

In this interview, which has been condensed and edited for clarity, Dr. Blaser discusses where we’re at now and where he sees the microbiome field evolving in the coming years.

Highlighting the Most Promising Applications

Which recent studies on the link between the human microbiome and disease have you found particularly promising?

There have been a number of studies, including our own, focusing on the gut-kidney axis. The gut microbiome produces, or detoxifies, metabolites that are toxic to the kidney: for example, those involved in the formation of kidney stones and in the worsening of uremia. 

Altering the microbiome to reduce the uremic toxins and the nidus for stone formation is a very promising field of research. 

What other disease states may be amenable to microbiome-based interventions?

There are diseases that are caused by known genetic mutations. Yet, for nearly all of them, there is great variation in clinical outcomes, which might be classed as genes multiplied by environment interactions. 

It seems likely to me that microbiome variation could account for some proportion of those differences for some genetic diseases. 

It’s now well established that altering the microbiome with FMT is a successful intervention for recurrent  Clostridioides difficile  infections. What do you see as the next disease states where FMT could prove successful?

If you go to ClinicalTrials.gov, you will find that that there are 471 trials registered using FMT. This is across a broad range of illnesses, including metabolic, immunological, autoimmune, inflammatory, degenerative, and neoplastic diseases. 

Which will be the next condition showing marked efficacy is anyone’s guess. That is why we must do clinical trials to assess what works and what does not, regardless of specific illness. 

The donor’s microbiome appears to be vital to engraftment success, with “superdonors” even being identified. What factors do you think primarily influence microbiome engraftment?

There is an emerging science about this question, driven in part by classical ecological theory. 

Right now, we are using FMT as if one size fits all. But this probably would not provide optimal treatment for all. Just as we type blood donors and recipients before the blood transfusion, one could easily imagine a parallel kind of procedure. 

Are there any diseases where it’s just too far-fetched to think altering the microbiome could make a difference?

The link between the microbiome and human health is so pervasive that there are few conditions that are out of the realm of possibility. It really is a frontier. 

Not that the microbiome causes everything, but by understanding and manipulating the microbiome, we could at least palliate, or slow down, particular pathologic processes. 

For all the major causes of death in the United States — cardiovascular disease, cancer, dementia and neurogenerative diseases, diabetes, and lung, liver, and kidney diseases — there is ongoing investigation of the microbiome. A greater promise would be to prevent or cure these illnesses. 

Predicting the Next Stages of the ‘Microbiome Revolution’

Do you believe we are at a turning point with the microbiome in terms of being able to manipulate or engineer it?

The microbiome is a scientific frontier that has an impact across the biosphere. It is a broad frontier involving human and veterinary medicine, agriculture, and the environment. Knowledge is increasing incrementally, as expected. 

Are we at the point yet where doctors should be incorporating microbiome-related lifestyle changes for people with or at risk for cancer, heart disease, Alzheimer’s disease, or other chronic conditions?

Although we are still in the early stages of the “microbiome revolution,” which I first wrote about in EMBO Reports  in 2006 and then again in the Journal of Clinical Investigation in 2014, I think important advances for all of these conditions are coming our way in the next 5-10 years. 

How are prebiotics, probiotics, and postbiotics being used to shape the microbiome?

This is a very important and active area in clinical investigation, which needs to be ramped up. 

Tens of millions of people are using probiotics and prebiotics every day for vague indications, and which have only infrequently been tested in robust clinical trials. So, there is a disconnect between what’s being claimed with the bulk of the probiotics at present and what we’ll actually know in the future. 

How do you think the microbiome will stack up to other factors influencing health, such as genetics, exercise, and nutrition?

All are important, but unlike genetics, the microbiome is tractable, like diet and exercise. 

It is essentially impossible to change one’s genome, but that might become more likely before too long. However, we can easily change someone’s microbiome through dietary means, for example. Once we know the ground rules, there will be many options. Right now, it is mostly one-offs, but as the scientific basis broadens, much more will be possible. 

In the future, do you think we’ll be able to look at a person’s microbiome and tell what his or her risk of developing disease is, similar to the way we use gene panels now?

Yes, but we will need scientific advances to teach us what are the important biomarkers in general and in particular people. This will be one area of precision medicine. 

Lessons From Decades at the Forefront

You’ve been involved in this research for over 30 years, and the majority has focused on the human microbiome and its role in disease. When did it become apparent to you that this research had unique therapeutic promise?

From the very start, there was always the potential to harness the microbiome to improve human health. In fact, I wrote a perspective in PNAS on that theme in 2010. 

The key is to understand the biology of the microbiome, and from the scientific study comes new preventives and new treatments. Right now, there are many “probiotic” products on the market. Probiotics have a great future, but most of what is out there has not been rigorously tested for effectiveness. 

Was there a particular series of studies that occurred before the launch of the Human Microbiome Project and brought us to the current era?

The studies in the 1970s-1980s by Carl Woese using 16S rRNA genes to understand phylogeny and evolution opened up the field of DNA sequencing to consider bacterial evolution and issues of ancestry. 

A key subject of your research and the focus of your book is antibiotic-resistant bacteria. What did this work teach you about describing the science of antibiotic resistance to the general public?

People don’t care very much about antibiotic resistance. They think that affects other people, mostly. In contrast, they care about their own health and their children’s health. 

The more that the data show that using antibiotics can be harmful to health in some circumstances, the more that use will diminish. We need more transparency about benefits and costs. 

Are there any common misconceptions about the microbiome that you hear from the general public, or even clinicians, that you would like to see greater efforts to dispel?

The public and the medical profession are in love with probiotics, buying them by the tens of millions. But as stated before, they are very diverse and mostly untested for efficacy. 

The next step is to test specific formulations to see which ones work, and for whom, and which ones don’t. That would be a big advance. 

A version of this article appeared on Medscape.com.

Human microbiome research has progressed in leaps and bounds over the past decades, from pivotal studies begun in the 1970s to the launch of the Human Microbiome Project in 2007. Breakthroughs have laid the groundwork for more recent clinical applications, such as fecal microbiota transplantation (FMT), and advanced techniques to explore new therapeutic pathways. Yet the “microbiome revolution” is just getting started, according to professor Martin J. Blaser, MD, one of the field’s pioneers.

The ongoing research and clinical trials into the microbiome’s link to the major causes of death in the United States hold the promise of interventions that manipulate the microbiome to prevent, slow, or perhaps even cure these conditions, says Dr. Blaser, who holds the Henry Rutgers Chair of the Human Microbiome and is director of the Center for Advanced Biotechnology and Medicine at Rutgers University in New Brunswick, New Jersey.

Dr. Blaser is the author of Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues, serves as chair of the Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria and is a member of the scientific advisory board of the biotech startup Micronoma.

In this interview, which has been condensed and edited for clarity, Dr. Blaser discusses where we’re at now and where he sees the microbiome field evolving in the coming years.

Highlighting the Most Promising Applications

Which recent studies on the link between the human microbiome and disease have you found particularly promising?

There have been a number of studies, including our own, focusing on the gut-kidney axis. The gut microbiome produces, or detoxifies, metabolites that are toxic to the kidney: for example, those involved in the formation of kidney stones and in the worsening of uremia. 

Altering the microbiome to reduce the uremic toxins and the nidus for stone formation is a very promising field of research. 

What other disease states may be amenable to microbiome-based interventions?

There are diseases that are caused by known genetic mutations. Yet, for nearly all of them, there is great variation in clinical outcomes, which might be classed as genes multiplied by environment interactions. 

It seems likely to me that microbiome variation could account for some proportion of those differences for some genetic diseases. 

It’s now well established that altering the microbiome with FMT is a successful intervention for recurrent  Clostridioides difficile  infections. What do you see as the next disease states where FMT could prove successful?

If you go to ClinicalTrials.gov, you will find that that there are 471 trials registered using FMT. This is across a broad range of illnesses, including metabolic, immunological, autoimmune, inflammatory, degenerative, and neoplastic diseases. 

Which will be the next condition showing marked efficacy is anyone’s guess. That is why we must do clinical trials to assess what works and what does not, regardless of specific illness. 

The donor’s microbiome appears to be vital to engraftment success, with “superdonors” even being identified. What factors do you think primarily influence microbiome engraftment?

There is an emerging science about this question, driven in part by classical ecological theory. 

Right now, we are using FMT as if one size fits all. But this probably would not provide optimal treatment for all. Just as we type blood donors and recipients before the blood transfusion, one could easily imagine a parallel kind of procedure. 

Are there any diseases where it’s just too far-fetched to think altering the microbiome could make a difference?

The link between the microbiome and human health is so pervasive that there are few conditions that are out of the realm of possibility. It really is a frontier. 

Not that the microbiome causes everything, but by understanding and manipulating the microbiome, we could at least palliate, or slow down, particular pathologic processes. 

For all the major causes of death in the United States — cardiovascular disease, cancer, dementia and neurogenerative diseases, diabetes, and lung, liver, and kidney diseases — there is ongoing investigation of the microbiome. A greater promise would be to prevent or cure these illnesses. 

Predicting the Next Stages of the ‘Microbiome Revolution’

Do you believe we are at a turning point with the microbiome in terms of being able to manipulate or engineer it?

The microbiome is a scientific frontier that has an impact across the biosphere. It is a broad frontier involving human and veterinary medicine, agriculture, and the environment. Knowledge is increasing incrementally, as expected. 

Are we at the point yet where doctors should be incorporating microbiome-related lifestyle changes for people with or at risk for cancer, heart disease, Alzheimer’s disease, or other chronic conditions?

Although we are still in the early stages of the “microbiome revolution,” which I first wrote about in EMBO Reports  in 2006 and then again in the Journal of Clinical Investigation in 2014, I think important advances for all of these conditions are coming our way in the next 5-10 years. 

How are prebiotics, probiotics, and postbiotics being used to shape the microbiome?

This is a very important and active area in clinical investigation, which needs to be ramped up. 

Tens of millions of people are using probiotics and prebiotics every day for vague indications, and which have only infrequently been tested in robust clinical trials. So, there is a disconnect between what’s being claimed with the bulk of the probiotics at present and what we’ll actually know in the future. 

How do you think the microbiome will stack up to other factors influencing health, such as genetics, exercise, and nutrition?

All are important, but unlike genetics, the microbiome is tractable, like diet and exercise. 

It is essentially impossible to change one’s genome, but that might become more likely before too long. However, we can easily change someone’s microbiome through dietary means, for example. Once we know the ground rules, there will be many options. Right now, it is mostly one-offs, but as the scientific basis broadens, much more will be possible. 

In the future, do you think we’ll be able to look at a person’s microbiome and tell what his or her risk of developing disease is, similar to the way we use gene panels now?

Yes, but we will need scientific advances to teach us what are the important biomarkers in general and in particular people. This will be one area of precision medicine. 

Lessons From Decades at the Forefront

You’ve been involved in this research for over 30 years, and the majority has focused on the human microbiome and its role in disease. When did it become apparent to you that this research had unique therapeutic promise?

From the very start, there was always the potential to harness the microbiome to improve human health. In fact, I wrote a perspective in PNAS on that theme in 2010. 

The key is to understand the biology of the microbiome, and from the scientific study comes new preventives and new treatments. Right now, there are many “probiotic” products on the market. Probiotics have a great future, but most of what is out there has not been rigorously tested for effectiveness. 

Was there a particular series of studies that occurred before the launch of the Human Microbiome Project and brought us to the current era?

The studies in the 1970s-1980s by Carl Woese using 16S rRNA genes to understand phylogeny and evolution opened up the field of DNA sequencing to consider bacterial evolution and issues of ancestry. 

A key subject of your research and the focus of your book is antibiotic-resistant bacteria. What did this work teach you about describing the science of antibiotic resistance to the general public?

People don’t care very much about antibiotic resistance. They think that affects other people, mostly. In contrast, they care about their own health and their children’s health. 

The more that the data show that using antibiotics can be harmful to health in some circumstances, the more that use will diminish. We need more transparency about benefits and costs. 

Are there any common misconceptions about the microbiome that you hear from the general public, or even clinicians, that you would like to see greater efforts to dispel?

The public and the medical profession are in love with probiotics, buying them by the tens of millions. But as stated before, they are very diverse and mostly untested for efficacy. 

The next step is to test specific formulations to see which ones work, and for whom, and which ones don’t. That would be a big advance. 

A version of this article appeared on Medscape.com.

Human microbiome research has progressed in leaps and bounds over the past decades, from pivotal studies begun in the 1970s to the launch of the Human Microbiome Project in 2007. Breakthroughs have laid the groundwork for more recent clinical applications, such as fecal microbiota transplantation (FMT), and advanced techniques to explore new therapeutic pathways. Yet the “microbiome revolution” is just getting started, according to professor Martin J. Blaser, MD, one of the field’s pioneers.

The ongoing research and clinical trials into the microbiome’s link to the major causes of death in the United States hold the promise of interventions that manipulate the microbiome to prevent, slow, or perhaps even cure these conditions, says Dr. Blaser, who holds the Henry Rutgers Chair of the Human Microbiome and is director of the Center for Advanced Biotechnology and Medicine at Rutgers University in New Brunswick, New Jersey.

Dr. Blaser is the author of Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues, serves as chair of the Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria and is a member of the scientific advisory board of the biotech startup Micronoma.

In this interview, which has been condensed and edited for clarity, Dr. Blaser discusses where we’re at now and where he sees the microbiome field evolving in the coming years.

Highlighting the Most Promising Applications

Which recent studies on the link between the human microbiome and disease have you found particularly promising?

There have been a number of studies, including our own, focusing on the gut-kidney axis. The gut microbiome produces, or detoxifies, metabolites that are toxic to the kidney: for example, those involved in the formation of kidney stones and in the worsening of uremia. 

Altering the microbiome to reduce the uremic toxins and the nidus for stone formation is a very promising field of research. 

What other disease states may be amenable to microbiome-based interventions?

There are diseases that are caused by known genetic mutations. Yet, for nearly all of them, there is great variation in clinical outcomes, which might be classed as genes multiplied by environment interactions. 

It seems likely to me that microbiome variation could account for some proportion of those differences for some genetic diseases. 

It’s now well established that altering the microbiome with FMT is a successful intervention for recurrent  Clostridioides difficile  infections. What do you see as the next disease states where FMT could prove successful?

If you go to ClinicalTrials.gov, you will find that that there are 471 trials registered using FMT. This is across a broad range of illnesses, including metabolic, immunological, autoimmune, inflammatory, degenerative, and neoplastic diseases. 

Which will be the next condition showing marked efficacy is anyone’s guess. That is why we must do clinical trials to assess what works and what does not, regardless of specific illness. 

The donor’s microbiome appears to be vital to engraftment success, with “superdonors” even being identified. What factors do you think primarily influence microbiome engraftment?

There is an emerging science about this question, driven in part by classical ecological theory. 

Right now, we are using FMT as if one size fits all. But this probably would not provide optimal treatment for all. Just as we type blood donors and recipients before the blood transfusion, one could easily imagine a parallel kind of procedure. 

Are there any diseases where it’s just too far-fetched to think altering the microbiome could make a difference?

The link between the microbiome and human health is so pervasive that there are few conditions that are out of the realm of possibility. It really is a frontier. 

Not that the microbiome causes everything, but by understanding and manipulating the microbiome, we could at least palliate, or slow down, particular pathologic processes. 

For all the major causes of death in the United States — cardiovascular disease, cancer, dementia and neurogenerative diseases, diabetes, and lung, liver, and kidney diseases — there is ongoing investigation of the microbiome. A greater promise would be to prevent or cure these illnesses. 

Predicting the Next Stages of the ‘Microbiome Revolution’

Do you believe we are at a turning point with the microbiome in terms of being able to manipulate or engineer it?

The microbiome is a scientific frontier that has an impact across the biosphere. It is a broad frontier involving human and veterinary medicine, agriculture, and the environment. Knowledge is increasing incrementally, as expected. 

Are we at the point yet where doctors should be incorporating microbiome-related lifestyle changes for people with or at risk for cancer, heart disease, Alzheimer’s disease, or other chronic conditions?

Although we are still in the early stages of the “microbiome revolution,” which I first wrote about in EMBO Reports  in 2006 and then again in the Journal of Clinical Investigation in 2014, I think important advances for all of these conditions are coming our way in the next 5-10 years. 

How are prebiotics, probiotics, and postbiotics being used to shape the microbiome?

This is a very important and active area in clinical investigation, which needs to be ramped up. 

Tens of millions of people are using probiotics and prebiotics every day for vague indications, and which have only infrequently been tested in robust clinical trials. So, there is a disconnect between what’s being claimed with the bulk of the probiotics at present and what we’ll actually know in the future. 

How do you think the microbiome will stack up to other factors influencing health, such as genetics, exercise, and nutrition?

All are important, but unlike genetics, the microbiome is tractable, like diet and exercise. 

It is essentially impossible to change one’s genome, but that might become more likely before too long. However, we can easily change someone’s microbiome through dietary means, for example. Once we know the ground rules, there will be many options. Right now, it is mostly one-offs, but as the scientific basis broadens, much more will be possible. 

In the future, do you think we’ll be able to look at a person’s microbiome and tell what his or her risk of developing disease is, similar to the way we use gene panels now?

Yes, but we will need scientific advances to teach us what are the important biomarkers in general and in particular people. This will be one area of precision medicine. 

Lessons From Decades at the Forefront

You’ve been involved in this research for over 30 years, and the majority has focused on the human microbiome and its role in disease. When did it become apparent to you that this research had unique therapeutic promise?

From the very start, there was always the potential to harness the microbiome to improve human health. In fact, I wrote a perspective in PNAS on that theme in 2010. 

The key is to understand the biology of the microbiome, and from the scientific study comes new preventives and new treatments. Right now, there are many “probiotic” products on the market. Probiotics have a great future, but most of what is out there has not been rigorously tested for effectiveness. 

Was there a particular series of studies that occurred before the launch of the Human Microbiome Project and brought us to the current era?

The studies in the 1970s-1980s by Carl Woese using 16S rRNA genes to understand phylogeny and evolution opened up the field of DNA sequencing to consider bacterial evolution and issues of ancestry. 

A key subject of your research and the focus of your book is antibiotic-resistant bacteria. What did this work teach you about describing the science of antibiotic resistance to the general public?

People don’t care very much about antibiotic resistance. They think that affects other people, mostly. In contrast, they care about their own health and their children’s health. 

The more that the data show that using antibiotics can be harmful to health in some circumstances, the more that use will diminish. We need more transparency about benefits and costs. 

Are there any common misconceptions about the microbiome that you hear from the general public, or even clinicians, that you would like to see greater efforts to dispel?

The public and the medical profession are in love with probiotics, buying them by the tens of millions. But as stated before, they are very diverse and mostly untested for efficacy. 

The next step is to test specific formulations to see which ones work, and for whom, and which ones don’t. That would be a big advance. 

A version of this article appeared on Medscape.com.

SAN ANTONIO — Low-dose tamoxifen, sometimes called “baby TAM,” is gaining traction as an alternative to full-dose tamoxifen for use in breast cancer prevention. The drug can reduce incidence of breast cancer in high-risk individuals, but side effects that mimic menopause have led to low rates of uptake. Lower-dose tamoxifen aims to reduce those side effects, but there remains some uncertainty about the minimum dose required to maintain efficacy.

The TAM-01 study, first published in 2019, demonstrated that a 5-mg dose of tamoxifen led to a reduction in recurrence of invasive breast cancer or ductal carcinoma in situ (DCIS). At the San Antonio Breast Cancer Symposium, two studies were presented that provided insight into dose efficacy and likelihood of medication adherence in women taking baby TAM.

“We all know that women who are at increased risk for breast cancer may benefit from the use of tamoxifen to help lower their risk, although historical uptake to tamoxifen in the prevention setting has been quite low,” said Lauren Cornell, MD, during a presentation. Her team investigated the impact of patient counseling on how well they understood their risk, as well as their likelihood of adherence to the medication.

The study included 41 women, and 31 completed follow-up at 1 year. “We saw that 90% of our patients reported good or complete understanding of their breast cancer risk after the consultation, emphasizing the benefit of that consult, and 73% reported that the availability of baby tamoxifen helped in their decision to consider a preventative medication,” said Dr. Cornell during her presentation. After 1 year of follow-up, 74% said that they had initiated baby tamoxifen, and 78% of those who started taking the drug were still taking it at 1 year.

Participants who continued to take baby TAM at 1 year had a higher estimated breast cancer risk (IBIS 10-year risk, 12.7% vs 7.6%; P = .027) than those who discontinued. “We saw that uptake to baby TAM after informed discussion in patients who qualify is high, especially in those patients with high risk and intraepithelial lesions or DCIS, and adherence and tolerability at 1 year follow up is improved, compared to what we would expect with traditional dosing of tamoxifen. It’s important to note that the NCCN guidelines and the ASCO clinical practice update now include low-dose tamoxifen as an option for select women, and future randomized control trials on de-escalation of tamoxifen and high-risk patients based on their risk model assessment still need to be done. Future study should also focus on markers to identify candidates best suited for low versus standard dose of tamoxifen,” said Dr. Cornell, who is an assistant professor of medicine at Mayo Clinic Florida in Jacksonville.

At another SABCS session, Per Hall, MD, PhD, discussed findings from the previously published KARISMA-2 study, which examined efficacy of various doses of tamoxifen. A total of 1440 participants, 240 in each arm, received tamoxifen doses of 20 mg, 10 mg, 5 mg, 2.5 mg, 1 mg, or placebo. During his talk, Dr. Hall pointed out that measuring outcomes would take a very large number of participants to identify small differences in breast cancer rates. Therefore, the researchers examined breast density changes as a proxy. As a noninferiority outcome, the researchers used the proportion of women in each arm who achieved the median decrease in breast density seen at 20 mg of tamoxifen, which is 10.1%.

The women underwent mammograms at baseline and again at 6 months to determine change in breast density. Among all women in the study, the proportion of patients who had a similar breast density reduction as the 20-mg dose were very similar in the 10 mg (50.0%; P = .002), 5 mg (49.3%; P < .001), and 2.5 mg (52.5%; P < .001) groups. The 1 mg group had a proportion of 39.5% (P = .138), while the placebo group had 38.9% (P = .161). However, the results were driven by premenopausal women, where the values were 63.3%, 70.7%, 74.4%, and 69.7% in the 20-mg, 10-mg, 5-mg, and 2.5-mg groups, respectively, and 32.9% at 1 mg and 29.7% on placebo. In postmenopausal women, the values were 41.9%, 36.7%, 33.3%, and 41.9% in the 20-mg, 10-mg, 5-mg, and 2.5-mg groups, with values of 44.2% in the 1-mg group and 43.8% in the placebo group.

The median density change was 18.5% in premenopausal women and 4.0% in postmenopausal women.

“We didn’t see anything in the postmenopausal women. The decrease for those on 20 milligrams and those on placebo were exactly the same. Why this is, we still don’t know because we do know that tamoxifen in the adjuvant setting could be used for postmenopausal women. It could be that 6 months is too short of a time [to see a benefit]. We don’t know,” said Dr. Hall, who is a medical epidemiologist and biostatistician at Karolinska Institutet, Stockholm, Sweden.

Severe vasomotor side effects like hot flashes, cold flashes, and night sweats were reduced by about 50% in the lower tamoxifen doses, compared with 20 mg.

Dr. Hall also pointed out that tamoxifen is a prodrug. The CYP2D6 enzyme produces a range of metabolites, with endoxifen having the strongest affinity to the estrogen receptor and being present at the highest plasma concentration. He showed a table of endoxifen plasma levels at various tamoxifen doses in women of various metabolizer status, ranging from poor to ultrafast. Among intermediate, normal, and ultrarapid metabolizers, 5- and 10-mg doses produced plasma endoxifen levels ranging from 2.4 to 6.2 ng/mL, which represents a good therapeutic window. “For intermediate and normal metabolizers, it could be that 5 mg [of tamoxifen] is enough, but I want to underline that we didn’t use breast cancer incidence or recurrence in this study, we used density change, so we should be careful when we use these results,” said Dr. Hall. His group is now conducting the KARISMA Endoxifen trial, which will test endoxifen directly at doses of 1 and 2 mg.

Dr. Cornell has no relevant financial disclosures. Dr. Hall is a member of the scientific advisory board for Atossa Therapeutics.

SAN ANTONIO — Low-dose tamoxifen, sometimes called “baby TAM,” is gaining traction as an alternative to full-dose tamoxifen for use in breast cancer prevention. The drug can reduce incidence of breast cancer in high-risk individuals, but side effects that mimic menopause have led to low rates of uptake. Lower-dose tamoxifen aims to reduce those side effects, but there remains some uncertainty about the minimum dose required to maintain efficacy.

The TAM-01 study, first published in 2019, demonstrated that a 5-mg dose of tamoxifen led to a reduction in recurrence of invasive breast cancer or ductal carcinoma in situ (DCIS). At the San Antonio Breast Cancer Symposium, two studies were presented that provided insight into dose efficacy and likelihood of medication adherence in women taking baby TAM.

“We all know that women who are at increased risk for breast cancer may benefit from the use of tamoxifen to help lower their risk, although historical uptake to tamoxifen in the prevention setting has been quite low,” said Lauren Cornell, MD, during a presentation. Her team investigated the impact of patient counseling on how well they understood their risk, as well as their likelihood of adherence to the medication.

The study included 41 women, and 31 completed follow-up at 1 year. “We saw that 90% of our patients reported good or complete understanding of their breast cancer risk after the consultation, emphasizing the benefit of that consult, and 73% reported that the availability of baby tamoxifen helped in their decision to consider a preventative medication,” said Dr. Cornell during her presentation. After 1 year of follow-up, 74% said that they had initiated baby tamoxifen, and 78% of those who started taking the drug were still taking it at 1 year.

Participants who continued to take baby TAM at 1 year had a higher estimated breast cancer risk (IBIS 10-year risk, 12.7% vs 7.6%; P = .027) than those who discontinued. “We saw that uptake to baby TAM after informed discussion in patients who qualify is high, especially in those patients with high risk and intraepithelial lesions or DCIS, and adherence and tolerability at 1 year follow up is improved, compared to what we would expect with traditional dosing of tamoxifen. It’s important to note that the NCCN guidelines and the ASCO clinical practice update now include low-dose tamoxifen as an option for select women, and future randomized control trials on de-escalation of tamoxifen and high-risk patients based on their risk model assessment still need to be done. Future study should also focus on markers to identify candidates best suited for low versus standard dose of tamoxifen,” said Dr. Cornell, who is an assistant professor of medicine at Mayo Clinic Florida in Jacksonville.

At another SABCS session, Per Hall, MD, PhD, discussed findings from the previously published KARISMA-2 study, which examined efficacy of various doses of tamoxifen. A total of 1440 participants, 240 in each arm, received tamoxifen doses of 20 mg, 10 mg, 5 mg, 2.5 mg, 1 mg, or placebo. During his talk, Dr. Hall pointed out that measuring outcomes would take a very large number of participants to identify small differences in breast cancer rates. Therefore, the researchers examined breast density changes as a proxy. As a noninferiority outcome, the researchers used the proportion of women in each arm who achieved the median decrease in breast density seen at 20 mg of tamoxifen, which is 10.1%.

The women underwent mammograms at baseline and again at 6 months to determine change in breast density. Among all women in the study, the proportion of patients who had a similar breast density reduction as the 20-mg dose were very similar in the 10 mg (50.0%; P = .002), 5 mg (49.3%; P < .001), and 2.5 mg (52.5%; P < .001) groups. The 1 mg group had a proportion of 39.5% (P = .138), while the placebo group had 38.9% (P = .161). However, the results were driven by premenopausal women, where the values were 63.3%, 70.7%, 74.4%, and 69.7% in the 20-mg, 10-mg, 5-mg, and 2.5-mg groups, respectively, and 32.9% at 1 mg and 29.7% on placebo. In postmenopausal women, the values were 41.9%, 36.7%, 33.3%, and 41.9% in the 20-mg, 10-mg, 5-mg, and 2.5-mg groups, with values of 44.2% in the 1-mg group and 43.8% in the placebo group.

The median density change was 18.5% in premenopausal women and 4.0% in postmenopausal women.

“We didn’t see anything in the postmenopausal women. The decrease for those on 20 milligrams and those on placebo were exactly the same. Why this is, we still don’t know because we do know that tamoxifen in the adjuvant setting could be used for postmenopausal women. It could be that 6 months is too short of a time [to see a benefit]. We don’t know,” said Dr. Hall, who is a medical epidemiologist and biostatistician at Karolinska Institutet, Stockholm, Sweden.

Severe vasomotor side effects like hot flashes, cold flashes, and night sweats were reduced by about 50% in the lower tamoxifen doses, compared with 20 mg.

Dr. Hall also pointed out that tamoxifen is a prodrug. The CYP2D6 enzyme produces a range of metabolites, with endoxifen having the strongest affinity to the estrogen receptor and being present at the highest plasma concentration. He showed a table of endoxifen plasma levels at various tamoxifen doses in women of various metabolizer status, ranging from poor to ultrafast. Among intermediate, normal, and ultrarapid metabolizers, 5- and 10-mg doses produced plasma endoxifen levels ranging from 2.4 to 6.2 ng/mL, which represents a good therapeutic window. “For intermediate and normal metabolizers, it could be that 5 mg [of tamoxifen] is enough, but I want to underline that we didn’t use breast cancer incidence or recurrence in this study, we used density change, so we should be careful when we use these results,” said Dr. Hall. His group is now conducting the KARISMA Endoxifen trial, which will test endoxifen directly at doses of 1 and 2 mg.

Dr. Cornell has no relevant financial disclosures. Dr. Hall is a member of the scientific advisory board for Atossa Therapeutics.

SAN ANTONIO — Low-dose tamoxifen, sometimes called “baby TAM,” is gaining traction as an alternative to full-dose tamoxifen for use in breast cancer prevention. The drug can reduce incidence of breast cancer in high-risk individuals, but side effects that mimic menopause have led to low rates of uptake. Lower-dose tamoxifen aims to reduce those side effects, but there remains some uncertainty about the minimum dose required to maintain efficacy.

The TAM-01 study, first published in 2019, demonstrated that a 5-mg dose of tamoxifen led to a reduction in recurrence of invasive breast cancer or ductal carcinoma in situ (DCIS). At the San Antonio Breast Cancer Symposium, two studies were presented that provided insight into dose efficacy and likelihood of medication adherence in women taking baby TAM.

“We all know that women who are at increased risk for breast cancer may benefit from the use of tamoxifen to help lower their risk, although historical uptake to tamoxifen in the prevention setting has been quite low,” said Lauren Cornell, MD, during a presentation. Her team investigated the impact of patient counseling on how well they understood their risk, as well as their likelihood of adherence to the medication.

The study included 41 women, and 31 completed follow-up at 1 year. “We saw that 90% of our patients reported good or complete understanding of their breast cancer risk after the consultation, emphasizing the benefit of that consult, and 73% reported that the availability of baby tamoxifen helped in their decision to consider a preventative medication,” said Dr. Cornell during her presentation. After 1 year of follow-up, 74% said that they had initiated baby tamoxifen, and 78% of those who started taking the drug were still taking it at 1 year.

Participants who continued to take baby TAM at 1 year had a higher estimated breast cancer risk (IBIS 10-year risk, 12.7% vs 7.6%; P = .027) than those who discontinued. “We saw that uptake to baby TAM after informed discussion in patients who qualify is high, especially in those patients with high risk and intraepithelial lesions or DCIS, and adherence and tolerability at 1 year follow up is improved, compared to what we would expect with traditional dosing of tamoxifen. It’s important to note that the NCCN guidelines and the ASCO clinical practice update now include low-dose tamoxifen as an option for select women, and future randomized control trials on de-escalation of tamoxifen and high-risk patients based on their risk model assessment still need to be done. Future study should also focus on markers to identify candidates best suited for low versus standard dose of tamoxifen,” said Dr. Cornell, who is an assistant professor of medicine at Mayo Clinic Florida in Jacksonville.

At another SABCS session, Per Hall, MD, PhD, discussed findings from the previously published KARISMA-2 study, which examined efficacy of various doses of tamoxifen. A total of 1440 participants, 240 in each arm, received tamoxifen doses of 20 mg, 10 mg, 5 mg, 2.5 mg, 1 mg, or placebo. During his talk, Dr. Hall pointed out that measuring outcomes would take a very large number of participants to identify small differences in breast cancer rates. Therefore, the researchers examined breast density changes as a proxy. As a noninferiority outcome, the researchers used the proportion of women in each arm who achieved the median decrease in breast density seen at 20 mg of tamoxifen, which is 10.1%.

The women underwent mammograms at baseline and again at 6 months to determine change in breast density. Among all women in the study, the proportion of patients who had a similar breast density reduction as the 20-mg dose were very similar in the 10 mg (50.0%; P = .002), 5 mg (49.3%; P < .001), and 2.5 mg (52.5%; P < .001) groups. The 1 mg group had a proportion of 39.5% (P = .138), while the placebo group had 38.9% (P = .161). However, the results were driven by premenopausal women, where the values were 63.3%, 70.7%, 74.4%, and 69.7% in the 20-mg, 10-mg, 5-mg, and 2.5-mg groups, respectively, and 32.9% at 1 mg and 29.7% on placebo. In postmenopausal women, the values were 41.9%, 36.7%, 33.3%, and 41.9% in the 20-mg, 10-mg, 5-mg, and 2.5-mg groups, with values of 44.2% in the 1-mg group and 43.8% in the placebo group.

The median density change was 18.5% in premenopausal women and 4.0% in postmenopausal women.

“We didn’t see anything in the postmenopausal women. The decrease for those on 20 milligrams and those on placebo were exactly the same. Why this is, we still don’t know because we do know that tamoxifen in the adjuvant setting could be used for postmenopausal women. It could be that 6 months is too short of a time [to see a benefit]. We don’t know,” said Dr. Hall, who is a medical epidemiologist and biostatistician at Karolinska Institutet, Stockholm, Sweden.

Severe vasomotor side effects like hot flashes, cold flashes, and night sweats were reduced by about 50% in the lower tamoxifen doses, compared with 20 mg.

Dr. Hall also pointed out that tamoxifen is a prodrug. The CYP2D6 enzyme produces a range of metabolites, with endoxifen having the strongest affinity to the estrogen receptor and being present at the highest plasma concentration. He showed a table of endoxifen plasma levels at various tamoxifen doses in women of various metabolizer status, ranging from poor to ultrafast. Among intermediate, normal, and ultrarapid metabolizers, 5- and 10-mg doses produced plasma endoxifen levels ranging from 2.4 to 6.2 ng/mL, which represents a good therapeutic window. “For intermediate and normal metabolizers, it could be that 5 mg [of tamoxifen] is enough, but I want to underline that we didn’t use breast cancer incidence or recurrence in this study, we used density change, so we should be careful when we use these results,” said Dr. Hall. His group is now conducting the KARISMA Endoxifen trial, which will test endoxifen directly at doses of 1 and 2 mg.

Dr. Cornell has no relevant financial disclosures. Dr. Hall is a member of the scientific advisory board for Atossa Therapeutics.

This transcript has been edited for clarity.

In 1986, in Britain, cattle started dying.

The condition, quickly nicknamed “mad cow disease,” was clearly infectious, but the particular pathogen was difficult to identify. By 1993, 120,000 cattle in Britain were identified as being infected. As yet, no human cases had occurred and the UK government insisted that cattle were a dead-end host for the pathogen. By the mid-1990s, however, multiple human cases, attributable to ingestion of meat and organs from infected cattle, were discovered. In humans, variant Creutzfeldt-Jakob disease (CJD) was a media sensation — a nearly uniformly fatal, untreatable condition with a rapid onset of dementia, mobility issues characterized by jerky movements, and autopsy reports finding that the brain itself had turned into a spongy mess.

The United States banned UK beef imports in 1996 and only lifted the ban in 2020.

The disease was made all the more mysterious because the pathogen involved was not a bacterium, parasite, or virus, but a protein — or a proteinaceous infectious particle, shortened to “prion.”

Prions are misfolded proteins that aggregate in cells — in this case, in nerve cells. But what makes prions different from other misfolded proteins is that the misfolded protein catalyzes the conversion of its non-misfolded counterpart into the misfolded configuration. It creates a chain reaction, leading to rapid accumulation of misfolded proteins and cell death.

Courtesy Dr. F. Perry Wilson

Courtesy Dr. F. Perry Wilson

Courtesy Dr. F. Perry Wilson

This transcript has been edited for clarity.

In 1986, in Britain, cattle started dying.

The condition, quickly nicknamed “mad cow disease,” was clearly infectious, but the particular pathogen was difficult to identify. By 1993, 120,000 cattle in Britain were identified as being infected. As yet, no human cases had occurred and the UK government insisted that cattle were a dead-end host for the pathogen. By the mid-1990s, however, multiple human cases, attributable to ingestion of meat and organs from infected cattle, were discovered. In humans, variant Creutzfeldt-Jakob disease (CJD) was a media sensation — a nearly uniformly fatal, untreatable condition with a rapid onset of dementia, mobility issues characterized by jerky movements, and autopsy reports finding that the brain itself had turned into a spongy mess.

The United States banned UK beef imports in 1996 and only lifted the ban in 2020.

The disease was made all the more mysterious because the pathogen involved was not a bacterium, parasite, or virus, but a protein — or a proteinaceous infectious particle, shortened to “prion.”

Prions are misfolded proteins that aggregate in cells — in this case, in nerve cells. But what makes prions different from other misfolded proteins is that the misfolded protein catalyzes the conversion of its non-misfolded counterpart into the misfolded configuration. It creates a chain reaction, leading to rapid accumulation of misfolded proteins and cell death.

Courtesy Dr. F. Perry Wilson

Courtesy Dr. F. Perry Wilson

Courtesy Dr. F. Perry Wilson

This transcript has been edited for clarity.

In 1986, in Britain, cattle started dying.

The condition, quickly nicknamed “mad cow disease,” was clearly infectious, but the particular pathogen was difficult to identify. By 1993, 120,000 cattle in Britain were identified as being infected. As yet, no human cases had occurred and the UK government insisted that cattle were a dead-end host for the pathogen. By the mid-1990s, however, multiple human cases, attributable to ingestion of meat and organs from infected cattle, were discovered. In humans, variant Creutzfeldt-Jakob disease (CJD) was a media sensation — a nearly uniformly fatal, untreatable condition with a rapid onset of dementia, mobility issues characterized by jerky movements, and autopsy reports finding that the brain itself had turned into a spongy mess.

The United States banned UK beef imports in 1996 and only lifted the ban in 2020.

The disease was made all the more mysterious because the pathogen involved was not a bacterium, parasite, or virus, but a protein — or a proteinaceous infectious particle, shortened to “prion.”

Prions are misfolded proteins that aggregate in cells — in this case, in nerve cells. But what makes prions different from other misfolded proteins is that the misfolded protein catalyzes the conversion of its non-misfolded counterpart into the misfolded configuration. It creates a chain reaction, leading to rapid accumulation of misfolded proteins and cell death.

Courtesy Dr. F. Perry Wilson

Courtesy Dr. F. Perry Wilson

Courtesy Dr. F. Perry Wilson

TOPLINE:

People who are extroverted and conscientious and have a positive outlook may be at lower dementia risk, whereas those who score highly for neuroticism and have a negative outlook may be at increased risk, new research suggests. 

METHODOLOGY: 

• Researchers examined the link between the “big five” personality traits (conscientiousness, extraversion, openness to experience, neuroticism, and agreeableness) and subjective well-being (positive and negative affect and life satisfaction) and clinical symptoms of dementia (cognitive test performance) and neuropathology at autopsy. 
• Data for the meta-analysis came from eight longitudinal studies with 44,531 adults (aged 49-81 years at baseline; 26%-61% women) followed for up to 21 years, during which 1703 incident cases of dementia occurred. 
• Bayesian multilevel models tested whether personality traits and subjective well-being differentially predicted neuropsychological and neuropathologic characteristics of dementia. 

TAKEAWAY:

• High neuroticism, negative affect, and low conscientiousness were risk factors for dementia, whereas conscientiousness, extraversion, and positive affect were protective.
• Across all analyses, there was directional consistency in estimates across samples, which is noteworthy given between-study differences in sociodemographic and design characteristics. 
• No consistent associations were found between psychological factors and neuropathology. 
• However, individuals higher in conscientiousness who did not receive a clinical diagnosis tended to have a lower Braak stage at autopsy, suggesting the possibility that conscientiousness is related to cognitive resilience. 

IN PRACTICE:

“These results replicate and extend evidence that personality traits may assist in early identification and dementia-care planning strategies, as well as risk stratification for dementia diagnosis. Moreover, our findings provide further support for recommendations to incorporate psychological trait measures into clinical screening or diagnosis criteria,” the authors write. SOURCE:

The study, with first author Emorie Beck, PhD, Department of Psychology, University of California, Davis, was published online on November 29, 2023, in Alzheimer’s & Dementia.

 LIMITATIONS:

Access to autopsy data was limited. The findings may not generalize across racial groups. The analysis did not examine dynamic associations between changing personality and cognition and neuropathology over time.

DISCLOSURES:

The study was supported by grants from the National Institute on Aging. The authors have declared no conflicts of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

People who are extroverted and conscientious and have a positive outlook may be at lower dementia risk, whereas those who score highly for neuroticism and have a negative outlook may be at increased risk, new research suggests. 

METHODOLOGY: 

• Researchers examined the link between the “big five” personality traits (conscientiousness, extraversion, openness to experience, neuroticism, and agreeableness) and subjective well-being (positive and negative affect and life satisfaction) and clinical symptoms of dementia (cognitive test performance) and neuropathology at autopsy. 
• Data for the meta-analysis came from eight longitudinal studies with 44,531 adults (aged 49-81 years at baseline; 26%-61% women) followed for up to 21 years, during which 1703 incident cases of dementia occurred. 
• Bayesian multilevel models tested whether personality traits and subjective well-being differentially predicted neuropsychological and neuropathologic characteristics of dementia. 

TAKEAWAY:

• High neuroticism, negative affect, and low conscientiousness were risk factors for dementia, whereas conscientiousness, extraversion, and positive affect were protective.
• Across all analyses, there was directional consistency in estimates across samples, which is noteworthy given between-study differences in sociodemographic and design characteristics. 
• No consistent associations were found between psychological factors and neuropathology. 
• However, individuals higher in conscientiousness who did not receive a clinical diagnosis tended to have a lower Braak stage at autopsy, suggesting the possibility that conscientiousness is related to cognitive resilience. 

IN PRACTICE:

“These results replicate and extend evidence that personality traits may assist in early identification and dementia-care planning strategies, as well as risk stratification for dementia diagnosis. Moreover, our findings provide further support for recommendations to incorporate psychological trait measures into clinical screening or diagnosis criteria,” the authors write. SOURCE:

The study, with first author Emorie Beck, PhD, Department of Psychology, University of California, Davis, was published online on November 29, 2023, in Alzheimer’s & Dementia.

 LIMITATIONS:

Access to autopsy data was limited. The findings may not generalize across racial groups. The analysis did not examine dynamic associations between changing personality and cognition and neuropathology over time.

DISCLOSURES:

The study was supported by grants from the National Institute on Aging. The authors have declared no conflicts of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

People who are extroverted and conscientious and have a positive outlook may be at lower dementia risk, whereas those who score highly for neuroticism and have a negative outlook may be at increased risk, new research suggests. 

METHODOLOGY: 

• Researchers examined the link between the “big five” personality traits (conscientiousness, extraversion, openness to experience, neuroticism, and agreeableness) and subjective well-being (positive and negative affect and life satisfaction) and clinical symptoms of dementia (cognitive test performance) and neuropathology at autopsy. 
• Data for the meta-analysis came from eight longitudinal studies with 44,531 adults (aged 49-81 years at baseline; 26%-61% women) followed for up to 21 years, during which 1703 incident cases of dementia occurred. 
• Bayesian multilevel models tested whether personality traits and subjective well-being differentially predicted neuropsychological and neuropathologic characteristics of dementia. 

TAKEAWAY:

• High neuroticism, negative affect, and low conscientiousness were risk factors for dementia, whereas conscientiousness, extraversion, and positive affect were protective.
• Across all analyses, there was directional consistency in estimates across samples, which is noteworthy given between-study differences in sociodemographic and design characteristics. 
• No consistent associations were found between psychological factors and neuropathology. 
• However, individuals higher in conscientiousness who did not receive a clinical diagnosis tended to have a lower Braak stage at autopsy, suggesting the possibility that conscientiousness is related to cognitive resilience. 

IN PRACTICE:

“These results replicate and extend evidence that personality traits may assist in early identification and dementia-care planning strategies, as well as risk stratification for dementia diagnosis. Moreover, our findings provide further support for recommendations to incorporate psychological trait measures into clinical screening or diagnosis criteria,” the authors write. SOURCE:

The study, with first author Emorie Beck, PhD, Department of Psychology, University of California, Davis, was published online on November 29, 2023, in Alzheimer’s & Dementia.

 LIMITATIONS:

Access to autopsy data was limited. The findings may not generalize across racial groups. The analysis did not examine dynamic associations between changing personality and cognition and neuropathology over time.

DISCLOSURES:

The study was supported by grants from the National Institute on Aging. The authors have declared no conflicts of interest.

A version of this article first appeared on Medscape.com.

SAN ANTONIO – Women aged 50 and over who have undergone curative treatment for breast cancer and remain cancer free after 3 years may safely de-escalate mammogram surveillance from the recommended annual schedule, according to results from a new randomized trial.

In the UK study, researchers found similar recurrence rates and overall survival between patients who continued to undergo annual screening versus women who underwent screening every 2 years after breast-conserving surgery or every 3 years after a mastectomy.

Current US guidelines recommend annual screening with no stopping point, while UK guidelines recommend annual screening for 5 years, followed by every 3 years after that.

The study was commissioned by the UK government after a previously commissioned systematic review showed lack of evidence for the existing frequency and duration of mammograms in this patient population, and a survey showed wide-ranging clinical practices. In response, the UK government funded the new study to evaluate whether it would be safe to reduce screening, according to Janet Dunn, PhD, who presented the study at the San Antonio Breast Cancer Symposium.

“Ladies are going back for years and years and years [for mammograms], and it’s inappropriate, it’s not necessary,” Dr. Dunn, professor of clinical trials and head of cancer trials at University of Warwick in the UK, said in an interview.

The lower frequency schedule requires that the patient be cancer free at 3 years following curative treatment. “We know for anybody going through breast cancer there are a couple of peaks of recurrence. One peak is 2 to 3 years [after curative treatment] for high-risk patients. The other peak is when they start hormone therapy, so at 5 to 6 years you get the peak. But this particular set of patients are at low to moderate risk, so they’re not the high-risk patients going into treatment trials,” said Dr. Dunn.

When asked if the findings should change practice, Dr. Dunn suggested that they could. “We would say that this is providing clinical evidence and probably changing guidance for the management of these patients: Instead of giving annual mammograms for years and years and years, after three years post curative surgery, and having gone through treatment with a baseline mammogram that’s clear, in the UK we can manage these patients back within the screening program, certainly for the mastectomy patients,” said Dr. Dunn.

She emphasized the potential mental health impact. “Women who are going through mammograms waiting for the results are much more anxious if they’ve had breast cancer before than those who were who were just going through normal screening. So [deescalation] is reducing anxiety. It’s also reducing the cost. It’s just reducing the burden on the whole health care system,” said Dr. Dunn.

During the Q&A session after the talk, Bruce Mann, MBBS, PhD, asked if there were differences in the pathology of the cancers that occurred in the less frequent group than those that arose in the annual group. If more frequent screening leads to earlier diagnosis of a tumor, “you would expect that those who have less [frequent screening] may be diagnosed with more advanced recurrences or new cancers, and that would eventually lead to a difference in outcome,” Dr. Mann said in an interview. He is director of breast cancer services at the Royal Melbourne Hospital in Australia.

He acknowledged the need to reconsider screening frequency, and complimented the researchers. “This is a nice pragmatic study. It’s interesting. It’s provocative. I think it’s a bit too early [to change practice]. I think we do need to see more information,” he said.

The researchers randomized 5235 women aged 50 and older to annual or less frequent mammography. The disease type was invasive in 87% of women, while 13% had ductal carcinoma in situ.

Over a median follow-up of 8.7 years, 7% experienced a recurrence. At 5 years, breast cancer–specific survival was 98.1% and 98.3% in the annual and less frequent groups, respectively (hazard ratio [HR], 0.92; 95% CI, 0.64-1.32). There was also no difference in recurrence-free survival or overall survival.

Analyses showed noninferiority of less frequent mammograms at a 3% margin (P < .0001) and a 1% margin (P = .003).

The researchers found that 83% of women were compliant with the mammogram schedule in the annual group, versus 69% in the less frequent arm. The COVID-19 pandemic was responsible for 35% of missed mammograms overall.

Quality of life measures showed that levels of distress over mammograms was similar across time and between the two groups, with 24% of women reporting medium or high levels of distress.

Dr. Dunn and Dr. Mann have no relevant financial disclosures.

SAN ANTONIO – Women aged 50 and over who have undergone curative treatment for breast cancer and remain cancer free after 3 years may safely de-escalate mammogram surveillance from the recommended annual schedule, according to results from a new randomized trial.

In the UK study, researchers found similar recurrence rates and overall survival between patients who continued to undergo annual screening versus women who underwent screening every 2 years after breast-conserving surgery or every 3 years after a mastectomy.

Current US guidelines recommend annual screening with no stopping point, while UK guidelines recommend annual screening for 5 years, followed by every 3 years after that.

The study was commissioned by the UK government after a previously commissioned systematic review showed lack of evidence for the existing frequency and duration of mammograms in this patient population, and a survey showed wide-ranging clinical practices. In response, the UK government funded the new study to evaluate whether it would be safe to reduce screening, according to Janet Dunn, PhD, who presented the study at the San Antonio Breast Cancer Symposium.

“Ladies are going back for years and years and years [for mammograms], and it’s inappropriate, it’s not necessary,” Dr. Dunn, professor of clinical trials and head of cancer trials at University of Warwick in the UK, said in an interview.

The lower frequency schedule requires that the patient be cancer free at 3 years following curative treatment. “We know for anybody going through breast cancer there are a couple of peaks of recurrence. One peak is 2 to 3 years [after curative treatment] for high-risk patients. The other peak is when they start hormone therapy, so at 5 to 6 years you get the peak. But this particular set of patients are at low to moderate risk, so they’re not the high-risk patients going into treatment trials,” said Dr. Dunn.

When asked if the findings should change practice, Dr. Dunn suggested that they could. “We would say that this is providing clinical evidence and probably changing guidance for the management of these patients: Instead of giving annual mammograms for years and years and years, after three years post curative surgery, and having gone through treatment with a baseline mammogram that’s clear, in the UK we can manage these patients back within the screening program, certainly for the mastectomy patients,” said Dr. Dunn.

She emphasized the potential mental health impact. “Women who are going through mammograms waiting for the results are much more anxious if they’ve had breast cancer before than those who were who were just going through normal screening. So [deescalation] is reducing anxiety. It’s also reducing the cost. It’s just reducing the burden on the whole health care system,” said Dr. Dunn.

During the Q&A session after the talk, Bruce Mann, MBBS, PhD, asked if there were differences in the pathology of the cancers that occurred in the less frequent group than those that arose in the annual group. If more frequent screening leads to earlier diagnosis of a tumor, “you would expect that those who have less [frequent screening] may be diagnosed with more advanced recurrences or new cancers, and that would eventually lead to a difference in outcome,” Dr. Mann said in an interview. He is director of breast cancer services at the Royal Melbourne Hospital in Australia.

He acknowledged the need to reconsider screening frequency, and complimented the researchers. “This is a nice pragmatic study. It’s interesting. It’s provocative. I think it’s a bit too early [to change practice]. I think we do need to see more information,” he said.

The researchers randomized 5235 women aged 50 and older to annual or less frequent mammography. The disease type was invasive in 87% of women, while 13% had ductal carcinoma in situ.

Over a median follow-up of 8.7 years, 7% experienced a recurrence. At 5 years, breast cancer–specific survival was 98.1% and 98.3% in the annual and less frequent groups, respectively (hazard ratio [HR], 0.92; 95% CI, 0.64-1.32). There was also no difference in recurrence-free survival or overall survival.

Analyses showed noninferiority of less frequent mammograms at a 3% margin (P < .0001) and a 1% margin (P = .003).

The researchers found that 83% of women were compliant with the mammogram schedule in the annual group, versus 69% in the less frequent arm. The COVID-19 pandemic was responsible for 35% of missed mammograms overall.

Quality of life measures showed that levels of distress over mammograms was similar across time and between the two groups, with 24% of women reporting medium or high levels of distress.

Dr. Dunn and Dr. Mann have no relevant financial disclosures.

SAN ANTONIO – Women aged 50 and over who have undergone curative treatment for breast cancer and remain cancer free after 3 years may safely de-escalate mammogram surveillance from the recommended annual schedule, according to results from a new randomized trial.

In the UK study, researchers found similar recurrence rates and overall survival between patients who continued to undergo annual screening versus women who underwent screening every 2 years after breast-conserving surgery or every 3 years after a mastectomy.

Current US guidelines recommend annual screening with no stopping point, while UK guidelines recommend annual screening for 5 years, followed by every 3 years after that.

The study was commissioned by the UK government after a previously commissioned systematic review showed lack of evidence for the existing frequency and duration of mammograms in this patient population, and a survey showed wide-ranging clinical practices. In response, the UK government funded the new study to evaluate whether it would be safe to reduce screening, according to Janet Dunn, PhD, who presented the study at the San Antonio Breast Cancer Symposium.

“Ladies are going back for years and years and years [for mammograms], and it’s inappropriate, it’s not necessary,” Dr. Dunn, professor of clinical trials and head of cancer trials at University of Warwick in the UK, said in an interview.

The lower frequency schedule requires that the patient be cancer free at 3 years following curative treatment. “We know for anybody going through breast cancer there are a couple of peaks of recurrence. One peak is 2 to 3 years [after curative treatment] for high-risk patients. The other peak is when they start hormone therapy, so at 5 to 6 years you get the peak. But this particular set of patients are at low to moderate risk, so they’re not the high-risk patients going into treatment trials,” said Dr. Dunn.

When asked if the findings should change practice, Dr. Dunn suggested that they could. “We would say that this is providing clinical evidence and probably changing guidance for the management of these patients: Instead of giving annual mammograms for years and years and years, after three years post curative surgery, and having gone through treatment with a baseline mammogram that’s clear, in the UK we can manage these patients back within the screening program, certainly for the mastectomy patients,” said Dr. Dunn.

She emphasized the potential mental health impact. “Women who are going through mammograms waiting for the results are much more anxious if they’ve had breast cancer before than those who were who were just going through normal screening. So [deescalation] is reducing anxiety. It’s also reducing the cost. It’s just reducing the burden on the whole health care system,” said Dr. Dunn.

During the Q&A session after the talk, Bruce Mann, MBBS, PhD, asked if there were differences in the pathology of the cancers that occurred in the less frequent group than those that arose in the annual group. If more frequent screening leads to earlier diagnosis of a tumor, “you would expect that those who have less [frequent screening] may be diagnosed with more advanced recurrences or new cancers, and that would eventually lead to a difference in outcome,” Dr. Mann said in an interview. He is director of breast cancer services at the Royal Melbourne Hospital in Australia.

He acknowledged the need to reconsider screening frequency, and complimented the researchers. “This is a nice pragmatic study. It’s interesting. It’s provocative. I think it’s a bit too early [to change practice]. I think we do need to see more information,” he said.

The researchers randomized 5235 women aged 50 and older to annual or less frequent mammography. The disease type was invasive in 87% of women, while 13% had ductal carcinoma in situ.

Over a median follow-up of 8.7 years, 7% experienced a recurrence. At 5 years, breast cancer–specific survival was 98.1% and 98.3% in the annual and less frequent groups, respectively (hazard ratio [HR], 0.92; 95% CI, 0.64-1.32). There was also no difference in recurrence-free survival or overall survival.

Analyses showed noninferiority of less frequent mammograms at a 3% margin (P < .0001) and a 1% margin (P = .003).

The researchers found that 83% of women were compliant with the mammogram schedule in the annual group, versus 69% in the less frequent arm. The COVID-19 pandemic was responsible for 35% of missed mammograms overall.

Quality of life measures showed that levels of distress over mammograms was similar across time and between the two groups, with 24% of women reporting medium or high levels of distress.

Dr. Dunn and Dr. Mann have no relevant financial disclosures.

SAN DIEGO — A newly approved gene therapy product for sickle cell disease, lovotibeglogene autotemcel (lovo-cel, marketed as Lyfgenia), led to durable disease remissions for up to 5 years and almost complete elimination of dangerous and debilitating vaso-occlusive events, according to results of a long-term follow-up study.

More specifically, a single infusion of lovo-cel led to complete resolution of vaso-occlusive events in 88% of patients, with 94% achieving complete resolution of severe events. All 10 adolescents in the study achieved complete resolution of vaso-occlusive events. Most patients remained free of vaso-occlusive events at their last follow-up.

“This is a one-time, truly transformative treatment with lovo-cel,” lead author Julie Kanter, MD, director of the adult sickle cell clinic at the University of Alabama in Birmingham, said in a media briefing at the annual meeting of the American Society of Hematology. The gene therapy can essentially eliminate vaso-occlusive events in patients with sickle cell disease and lead to normal hemoglobin levels, Dr. Kanter added. 

For “anybody who has rounded on the inpatient floor and taken care of adolescents admitted with a pain crisis multiple times a year,” seeing these results “is so compelling,” commented Sarah O’Brien, MD, a pediatric hematologist at Nationwide Children’s Hospital in Columbus, Ohio, who moderated the briefing but was not involved in the study.
 

One and Done

Sickle cell disease, a debilitating and potentially life-threatening blood disorder, affects an estimated 100,000 people in the US. 

People with the condition have a mutation in hemoglobin, which causes red blood cells to develop an abnormal sickle shape. These sickled cells block the flow of blood, ultimately depriving tissues of oxygen and leading to organ damage and severe pain, known as vaso-occlusive events. 

On Dec. 8, the U.S. Food and Drug Administration (FDA) approved lovo-cel for patients aged 12 years or older with severe sickle cell disease alongside another gene-editing therapy called exagamglogene autotemcel or exa-cel (Casgevy, Vertex Pharmaceuticals and Crispr Therapeutics). The two therapies use different gene-editing approaches — exa-cel is the first to use the gene-editing tool CRISPR while lovo-cel uses a lentiviral vector.

Both are one-time, single-dose cell-based gene therapies.

With lovo-cel, patients first undergo a transfusion regimen and myeloablative conditioning with busulfan to collect cells that can then be genetically modified. A patient’s harvested cells are modified with an anti-sickling version of hemoglobin A, HbAT87Q. Patients then receive an infusion of these edited cells and remain in the hospital during engraftment and reconstitution.

Dr. Kanter presented long-term follow-up data on 47 patients enrolled in phase 1/2 and phase 3 studies of lovo-cel. 

All patients had stable HbAT87Q levels from 6 months to their last follow-up at a median of 35.5 months. 

Most patients achieved a durable globin response through their final follow-up visit.

Among the 34 evaluable patients, 88% had complete resolution of vaso-occlusive events 6 to 18 months after their infusion, including all 10 adolescent patients. Almost all patients (94%) achieved complete resolution of serious vaso-occlusive events. 

In the few patients who experienced posttreatment vaso-occlusive events, these individuals still achieved major reductions in hospital admissions and hospital days.

Among 20 patients followed for at least 3 years, more than half had clinically meaningful improvements in pain intensity, pain interference, and fatigue.

Most treatment-related adverse events occurred within 1 year of lovo-cel infusions and were primarily related to busulfan conditioning. No cases of veno-occlusive liver disease, graft failure, or graft vs host disease occurred, and patients did not have complications related to the viral vector. No patients who had a history of stroke prior to lovo-cel therapy experienced a post-therapy stroke. 

One patient died at baseline from significant cardiopulmonary disease related to sickle cell disease, but the death was considered unrelated to lovo-cel therapy.

To see a one-time treatment that essentially eradicates vaso-occlusive events is “really unparalleled,” said Steven Pipe, MD, from the University of Michigan School of Medicine in Ann Arbor, who presented data on a different study at the briefing.

However, Dr. Kanter noted, “it’s important to highlight that many of these individuals come into this therapy with significant disease and end-organ complications, and this will be something we will really need to follow long-term to understand how much this therapy can stabilize or reverse these complications.”

The studies were funded by bluebird bio. Dr. Kanter disclosed honoraria from the company and consulting/advising activities and receipt of research funding from multiple other entities. Dr. O’Brien disclosed consultancy for AstraZeneca, honoraria from Pharmacosmos, and research funding from Bristol Myers Squibb. Dr. Pipe disclosed consulting activities from multiple companies, not including bluebird bio. 

A version of this article appeared on Medscape.com.

SAN DIEGO — A newly approved gene therapy product for sickle cell disease, lovotibeglogene autotemcel (lovo-cel, marketed as Lyfgenia), led to durable disease remissions for up to 5 years and almost complete elimination of dangerous and debilitating vaso-occlusive events, according to results of a long-term follow-up study.

More specifically, a single infusion of lovo-cel led to complete resolution of vaso-occlusive events in 88% of patients, with 94% achieving complete resolution of severe events. All 10 adolescents in the study achieved complete resolution of vaso-occlusive events. Most patients remained free of vaso-occlusive events at their last follow-up.

“This is a one-time, truly transformative treatment with lovo-cel,” lead author Julie Kanter, MD, director of the adult sickle cell clinic at the University of Alabama in Birmingham, said in a media briefing at the annual meeting of the American Society of Hematology. The gene therapy can essentially eliminate vaso-occlusive events in patients with sickle cell disease and lead to normal hemoglobin levels, Dr. Kanter added. 

For “anybody who has rounded on the inpatient floor and taken care of adolescents admitted with a pain crisis multiple times a year,” seeing these results “is so compelling,” commented Sarah O’Brien, MD, a pediatric hematologist at Nationwide Children’s Hospital in Columbus, Ohio, who moderated the briefing but was not involved in the study.
 

One and Done

Sickle cell disease, a debilitating and potentially life-threatening blood disorder, affects an estimated 100,000 people in the US. 

People with the condition have a mutation in hemoglobin, which causes red blood cells to develop an abnormal sickle shape. These sickled cells block the flow of blood, ultimately depriving tissues of oxygen and leading to organ damage and severe pain, known as vaso-occlusive events. 

On Dec. 8, the U.S. Food and Drug Administration (FDA) approved lovo-cel for patients aged 12 years or older with severe sickle cell disease alongside another gene-editing therapy called exagamglogene autotemcel or exa-cel (Casgevy, Vertex Pharmaceuticals and Crispr Therapeutics). The two therapies use different gene-editing approaches — exa-cel is the first to use the gene-editing tool CRISPR while lovo-cel uses a lentiviral vector.

Both are one-time, single-dose cell-based gene therapies.

With lovo-cel, patients first undergo a transfusion regimen and myeloablative conditioning with busulfan to collect cells that can then be genetically modified. A patient’s harvested cells are modified with an anti-sickling version of hemoglobin A, HbAT87Q. Patients then receive an infusion of these edited cells and remain in the hospital during engraftment and reconstitution.

Dr. Kanter presented long-term follow-up data on 47 patients enrolled in phase 1/2 and phase 3 studies of lovo-cel. 

All patients had stable HbAT87Q levels from 6 months to their last follow-up at a median of 35.5 months. 

Most patients achieved a durable globin response through their final follow-up visit.

Among the 34 evaluable patients, 88% had complete resolution of vaso-occlusive events 6 to 18 months after their infusion, including all 10 adolescent patients. Almost all patients (94%) achieved complete resolution of serious vaso-occlusive events. 

In the few patients who experienced posttreatment vaso-occlusive events, these individuals still achieved major reductions in hospital admissions and hospital days.

Among 20 patients followed for at least 3 years, more than half had clinically meaningful improvements in pain intensity, pain interference, and fatigue.

Most treatment-related adverse events occurred within 1 year of lovo-cel infusions and were primarily related to busulfan conditioning. No cases of veno-occlusive liver disease, graft failure, or graft vs host disease occurred, and patients did not have complications related to the viral vector. No patients who had a history of stroke prior to lovo-cel therapy experienced a post-therapy stroke. 

One patient died at baseline from significant cardiopulmonary disease related to sickle cell disease, but the death was considered unrelated to lovo-cel therapy.

To see a one-time treatment that essentially eradicates vaso-occlusive events is “really unparalleled,” said Steven Pipe, MD, from the University of Michigan School of Medicine in Ann Arbor, who presented data on a different study at the briefing.

However, Dr. Kanter noted, “it’s important to highlight that many of these individuals come into this therapy with significant disease and end-organ complications, and this will be something we will really need to follow long-term to understand how much this therapy can stabilize or reverse these complications.”

The studies were funded by bluebird bio. Dr. Kanter disclosed honoraria from the company and consulting/advising activities and receipt of research funding from multiple other entities. Dr. O’Brien disclosed consultancy for AstraZeneca, honoraria from Pharmacosmos, and research funding from Bristol Myers Squibb. Dr. Pipe disclosed consulting activities from multiple companies, not including bluebird bio. 

A version of this article appeared on Medscape.com.

SAN DIEGO — A newly approved gene therapy product for sickle cell disease, lovotibeglogene autotemcel (lovo-cel, marketed as Lyfgenia), led to durable disease remissions for up to 5 years and almost complete elimination of dangerous and debilitating vaso-occlusive events, according to results of a long-term follow-up study.

More specifically, a single infusion of lovo-cel led to complete resolution of vaso-occlusive events in 88% of patients, with 94% achieving complete resolution of severe events. All 10 adolescents in the study achieved complete resolution of vaso-occlusive events. Most patients remained free of vaso-occlusive events at their last follow-up.

“This is a one-time, truly transformative treatment with lovo-cel,” lead author Julie Kanter, MD, director of the adult sickle cell clinic at the University of Alabama in Birmingham, said in a media briefing at the annual meeting of the American Society of Hematology. The gene therapy can essentially eliminate vaso-occlusive events in patients with sickle cell disease and lead to normal hemoglobin levels, Dr. Kanter added. 

For “anybody who has rounded on the inpatient floor and taken care of adolescents admitted with a pain crisis multiple times a year,” seeing these results “is so compelling,” commented Sarah O’Brien, MD, a pediatric hematologist at Nationwide Children’s Hospital in Columbus, Ohio, who moderated the briefing but was not involved in the study.
 

One and Done

Sickle cell disease, a debilitating and potentially life-threatening blood disorder, affects an estimated 100,000 people in the US. 

People with the condition have a mutation in hemoglobin, which causes red blood cells to develop an abnormal sickle shape. These sickled cells block the flow of blood, ultimately depriving tissues of oxygen and leading to organ damage and severe pain, known as vaso-occlusive events. 

On Dec. 8, the U.S. Food and Drug Administration (FDA) approved lovo-cel for patients aged 12 years or older with severe sickle cell disease alongside another gene-editing therapy called exagamglogene autotemcel or exa-cel (Casgevy, Vertex Pharmaceuticals and Crispr Therapeutics). The two therapies use different gene-editing approaches — exa-cel is the first to use the gene-editing tool CRISPR while lovo-cel uses a lentiviral vector.

Both are one-time, single-dose cell-based gene therapies.

With lovo-cel, patients first undergo a transfusion regimen and myeloablative conditioning with busulfan to collect cells that can then be genetically modified. A patient’s harvested cells are modified with an anti-sickling version of hemoglobin A, HbAT87Q. Patients then receive an infusion of these edited cells and remain in the hospital during engraftment and reconstitution.

Dr. Kanter presented long-term follow-up data on 47 patients enrolled in phase 1/2 and phase 3 studies of lovo-cel. 

All patients had stable HbAT87Q levels from 6 months to their last follow-up at a median of 35.5 months. 

Most patients achieved a durable globin response through their final follow-up visit.

Among the 34 evaluable patients, 88% had complete resolution of vaso-occlusive events 6 to 18 months after their infusion, including all 10 adolescent patients. Almost all patients (94%) achieved complete resolution of serious vaso-occlusive events. 

In the few patients who experienced posttreatment vaso-occlusive events, these individuals still achieved major reductions in hospital admissions and hospital days.

Among 20 patients followed for at least 3 years, more than half had clinically meaningful improvements in pain intensity, pain interference, and fatigue.

Most treatment-related adverse events occurred within 1 year of lovo-cel infusions and were primarily related to busulfan conditioning. No cases of veno-occlusive liver disease, graft failure, or graft vs host disease occurred, and patients did not have complications related to the viral vector. No patients who had a history of stroke prior to lovo-cel therapy experienced a post-therapy stroke. 

One patient died at baseline from significant cardiopulmonary disease related to sickle cell disease, but the death was considered unrelated to lovo-cel therapy.

To see a one-time treatment that essentially eradicates vaso-occlusive events is “really unparalleled,” said Steven Pipe, MD, from the University of Michigan School of Medicine in Ann Arbor, who presented data on a different study at the briefing.

However, Dr. Kanter noted, “it’s important to highlight that many of these individuals come into this therapy with significant disease and end-organ complications, and this will be something we will really need to follow long-term to understand how much this therapy can stabilize or reverse these complications.”

The studies were funded by bluebird bio. Dr. Kanter disclosed honoraria from the company and consulting/advising activities and receipt of research funding from multiple other entities. Dr. O’Brien disclosed consultancy for AstraZeneca, honoraria from Pharmacosmos, and research funding from Bristol Myers Squibb. Dr. Pipe disclosed consulting activities from multiple companies, not including bluebird bio. 

A version of this article appeared on Medscape.com.

SAN DIEGO — CD19-directed chimeric antigen receptor (CAR) T-cell therapy, which has transformed the treatment landscape for B-cell malignancies, is now showing great promise in at least three distinct autoantibody-dependent autoimmune diseases.

A single infusion of autologous CD19-directed CAR T-cell therapy led to persistent, drug-free remission in 15 patients with life-threatening systemic lupus erythematosus, idiopathic inflammatory myositis, or systemic sclerosis, according to research presented at the American Society of Hematology annual meeting.

The responses persisted at 15 months median follow-up, with all patients achieving complete remission, reported Fabian Mueller, MD, of the Bavarian Cancer Research Center and Friedrich-Alexander University of Erlangen-Nuremberg, Bavaria, Germany.

The CAR T-cell treatment appears to provide an “entire reset of B cells,” possibly even a cure, for these 15 patients who had run out of treatment options and had short life expectancies, Dr. Mueller said. “It’s impressive that we have treated these patients.”

Some of the cases have been described previously — including in Annals of the Rheumatic Diseases earlier this year, Nature Medicine in 2022, and the New England Journal of Medicine in 2021. 

Now with substantially longer follow-up, the investigators have gained a greater understanding of “the B-cell biology behind our treatment,” Dr. Mueller said. However, “we need longer follow-up to establish how effective the treatment is going to be in the long run.” 

All 15 patients included in the analysis were heavily pretreated and had multi-organ involvement. Prior to CAR T-cell therapy, patients had a median disease duration of 3 years, ranging from 1 to as many as 20 years, and had failed a median of five previous treatments. Patients were young — a median age of 36 years — which is much younger than most oncology patients who undergo CAR T-cell therapy, Dr. Mueller said. 

The 15 patients underwent typical lymphodepletion and were apheresed and treated with a single infusion of 1 x 10⁶ CD19 CAR T cells per kg of body weight — an established safe dose used in a phase 1 trial of B cell malignancies. 

The CAR T cells, manufactured in-house, expanded rapidly, peaking around day 9. B cells disappeared within 7 days and began to reoccur in peripheral blood in all patients between 60 and 180 days. However, no disease flares occurred, Dr. Mueller said.

After 3 months, eight patients with systemic lupus erythematosus showed no sign of disease activity and dramatic improvement in symptoms. Three patients with idiopathic inflammatory myositis experienced major improvements in symptoms and normalization of creatinine kinase levels, the most clinically relevant marker for muscle inflammation. And three of four patients with systemic sclerosis demonstrated major improvements in symptoms and no new disease activity. These responses lasted for a median of 15 months, and all patients stopped taking immunosuppressive drugs. 

Patients also tolerated the CAR T-cell treatment well, especially compared with the adverse event profile in oncology patients. Only low-grade inflammatory CAR T-related side effects occurred, and few patients required support for B-cell-derived immune deficiency. 

However, infectious complications occurred in 14 patients, including urinary tract and respiratory infections, over the 12-month follow-up. One patient was hospitalized for severe pneumonia a few weeks after CAR T therapy, and two patients experienced herpes zoster reactivations, including one at 6 months and one at 12 months following treatment. 

During a press briefing at the ASH conference, Dr. Mueller addressed the “critical question” of patient selection for CAR T-cell therapy, especially in light of the recently announced US Food and Drug Administration investigation exploring whether CAR T cells can cause secondary blood cancers. 

Although the T-cell malignancy risk complicates matters, CAR T cells appear to behave differently in patients with autoimmune diseases than those with cancer, he said.

“We don’t understand the biology” related to the malignancy risk yet, Dr. Mueller said, but the benefit for end-of-life patients with no other treatment option likely outweighs the risk. That risk-benefit assessment, however, is more uncertain for those with less severe autoimmune diseases.

For now, it’s important to conduct individual assessments and inform patients about the risk, Dr. Mueller said.

Dr. Mueller disclosed relationships with BMS, AstraZeneca, Gilead, Janssen, Miltenyi Biomedicine, Novartis, Incyte, Abbvie, Sobi, and BeiGene.
 

A version of this article appeared on Medscape.com.

SAN DIEGO — CD19-directed chimeric antigen receptor (CAR) T-cell therapy, which has transformed the treatment landscape for B-cell malignancies, is now showing great promise in at least three distinct autoantibody-dependent autoimmune diseases.

A single infusion of autologous CD19-directed CAR T-cell therapy led to persistent, drug-free remission in 15 patients with life-threatening systemic lupus erythematosus, idiopathic inflammatory myositis, or systemic sclerosis, according to research presented at the American Society of Hematology annual meeting.

The responses persisted at 15 months median follow-up, with all patients achieving complete remission, reported Fabian Mueller, MD, of the Bavarian Cancer Research Center and Friedrich-Alexander University of Erlangen-Nuremberg, Bavaria, Germany.

The CAR T-cell treatment appears to provide an “entire reset of B cells,” possibly even a cure, for these 15 patients who had run out of treatment options and had short life expectancies, Dr. Mueller said. “It’s impressive that we have treated these patients.”

Some of the cases have been described previously — including in Annals of the Rheumatic Diseases earlier this year, Nature Medicine in 2022, and the New England Journal of Medicine in 2021. 

Now with substantially longer follow-up, the investigators have gained a greater understanding of “the B-cell biology behind our treatment,” Dr. Mueller said. However, “we need longer follow-up to establish how effective the treatment is going to be in the long run.” 

All 15 patients included in the analysis were heavily pretreated and had multi-organ involvement. Prior to CAR T-cell therapy, patients had a median disease duration of 3 years, ranging from 1 to as many as 20 years, and had failed a median of five previous treatments. Patients were young — a median age of 36 years — which is much younger than most oncology patients who undergo CAR T-cell therapy, Dr. Mueller said. 

The 15 patients underwent typical lymphodepletion and were apheresed and treated with a single infusion of 1 x 10⁶ CD19 CAR T cells per kg of body weight — an established safe dose used in a phase 1 trial of B cell malignancies. 

The CAR T cells, manufactured in-house, expanded rapidly, peaking around day 9. B cells disappeared within 7 days and began to reoccur in peripheral blood in all patients between 60 and 180 days. However, no disease flares occurred, Dr. Mueller said.

After 3 months, eight patients with systemic lupus erythematosus showed no sign of disease activity and dramatic improvement in symptoms. Three patients with idiopathic inflammatory myositis experienced major improvements in symptoms and normalization of creatinine kinase levels, the most clinically relevant marker for muscle inflammation. And three of four patients with systemic sclerosis demonstrated major improvements in symptoms and no new disease activity. These responses lasted for a median of 15 months, and all patients stopped taking immunosuppressive drugs. 

Patients also tolerated the CAR T-cell treatment well, especially compared with the adverse event profile in oncology patients. Only low-grade inflammatory CAR T-related side effects occurred, and few patients required support for B-cell-derived immune deficiency. 

However, infectious complications occurred in 14 patients, including urinary tract and respiratory infections, over the 12-month follow-up. One patient was hospitalized for severe pneumonia a few weeks after CAR T therapy, and two patients experienced herpes zoster reactivations, including one at 6 months and one at 12 months following treatment. 

During a press briefing at the ASH conference, Dr. Mueller addressed the “critical question” of patient selection for CAR T-cell therapy, especially in light of the recently announced US Food and Drug Administration investigation exploring whether CAR T cells can cause secondary blood cancers. 

Although the T-cell malignancy risk complicates matters, CAR T cells appear to behave differently in patients with autoimmune diseases than those with cancer, he said.

“We don’t understand the biology” related to the malignancy risk yet, Dr. Mueller said, but the benefit for end-of-life patients with no other treatment option likely outweighs the risk. That risk-benefit assessment, however, is more uncertain for those with less severe autoimmune diseases.

For now, it’s important to conduct individual assessments and inform patients about the risk, Dr. Mueller said.

Dr. Mueller disclosed relationships with BMS, AstraZeneca, Gilead, Janssen, Miltenyi Biomedicine, Novartis, Incyte, Abbvie, Sobi, and BeiGene.
 

A version of this article appeared on Medscape.com.

SAN DIEGO — CD19-directed chimeric antigen receptor (CAR) T-cell therapy, which has transformed the treatment landscape for B-cell malignancies, is now showing great promise in at least three distinct autoantibody-dependent autoimmune diseases.

A single infusion of autologous CD19-directed CAR T-cell therapy led to persistent, drug-free remission in 15 patients with life-threatening systemic lupus erythematosus, idiopathic inflammatory myositis, or systemic sclerosis, according to research presented at the American Society of Hematology annual meeting.

The responses persisted at 15 months median follow-up, with all patients achieving complete remission, reported Fabian Mueller, MD, of the Bavarian Cancer Research Center and Friedrich-Alexander University of Erlangen-Nuremberg, Bavaria, Germany.

The CAR T-cell treatment appears to provide an “entire reset of B cells,” possibly even a cure, for these 15 patients who had run out of treatment options and had short life expectancies, Dr. Mueller said. “It’s impressive that we have treated these patients.”

Some of the cases have been described previously — including in Annals of the Rheumatic Diseases earlier this year, Nature Medicine in 2022, and the New England Journal of Medicine in 2021. 

Now with substantially longer follow-up, the investigators have gained a greater understanding of “the B-cell biology behind our treatment,” Dr. Mueller said. However, “we need longer follow-up to establish how effective the treatment is going to be in the long run.” 

All 15 patients included in the analysis were heavily pretreated and had multi-organ involvement. Prior to CAR T-cell therapy, patients had a median disease duration of 3 years, ranging from 1 to as many as 20 years, and had failed a median of five previous treatments. Patients were young — a median age of 36 years — which is much younger than most oncology patients who undergo CAR T-cell therapy, Dr. Mueller said. 

The 15 patients underwent typical lymphodepletion and were apheresed and treated with a single infusion of 1 x 10⁶ CD19 CAR T cells per kg of body weight — an established safe dose used in a phase 1 trial of B cell malignancies. 

The CAR T cells, manufactured in-house, expanded rapidly, peaking around day 9. B cells disappeared within 7 days and began to reoccur in peripheral blood in all patients between 60 and 180 days. However, no disease flares occurred, Dr. Mueller said.

After 3 months, eight patients with systemic lupus erythematosus showed no sign of disease activity and dramatic improvement in symptoms. Three patients with idiopathic inflammatory myositis experienced major improvements in symptoms and normalization of creatinine kinase levels, the most clinically relevant marker for muscle inflammation. And three of four patients with systemic sclerosis demonstrated major improvements in symptoms and no new disease activity. These responses lasted for a median of 15 months, and all patients stopped taking immunosuppressive drugs. 

Patients also tolerated the CAR T-cell treatment well, especially compared with the adverse event profile in oncology patients. Only low-grade inflammatory CAR T-related side effects occurred, and few patients required support for B-cell-derived immune deficiency. 

However, infectious complications occurred in 14 patients, including urinary tract and respiratory infections, over the 12-month follow-up. One patient was hospitalized for severe pneumonia a few weeks after CAR T therapy, and two patients experienced herpes zoster reactivations, including one at 6 months and one at 12 months following treatment. 

During a press briefing at the ASH conference, Dr. Mueller addressed the “critical question” of patient selection for CAR T-cell therapy, especially in light of the recently announced US Food and Drug Administration investigation exploring whether CAR T cells can cause secondary blood cancers. 

Although the T-cell malignancy risk complicates matters, CAR T cells appear to behave differently in patients with autoimmune diseases than those with cancer, he said.

“We don’t understand the biology” related to the malignancy risk yet, Dr. Mueller said, but the benefit for end-of-life patients with no other treatment option likely outweighs the risk. That risk-benefit assessment, however, is more uncertain for those with less severe autoimmune diseases.

For now, it’s important to conduct individual assessments and inform patients about the risk, Dr. Mueller said.

Dr. Mueller disclosed relationships with BMS, AstraZeneca, Gilead, Janssen, Miltenyi Biomedicine, Novartis, Incyte, Abbvie, Sobi, and BeiGene.
 

A version of this article appeared on Medscape.com.

SAN DIEGO — In the real world, outcomes for patients with multiple myeloma who received standard regimens were dramatically worse than those reported in clinical trials, a new study found. 

The analysis, which included nearly 4,000 patients with multiple myeloma, revealed that patients in a real-world setting demonstrated worse progression-free and overall survival on six of seven standard treatments compared with patients evaluated in randomized controlled trials.

Lead author Alissa Visram, MD, MPH, who spoke about the study at the annual meeting of the American Society of Hematology, said the findings will likely change the way she speaks to patients about their potential outcomes. 

“I’ll probably present both numbers [from real-life and clinical-trial data] and give them a sense of the best-case scenario,” Dr. Visram said during an ASH media briefing. But she said she will also caution her patients that the real-world numbers reflect how people on these drugs actually fare. 

The effectiveness of multiple myeloma drugs remains unclear outside the clinical trial setting, explained Dr. Visram, of the Division of Hematology at the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. Outcomes from randomized controlled trials form the basis of drug approvals but many patients in the real world do not meet the “stringent” trial inclusion criteria. 

Dr. Visram and colleagues launched the current study to better understand the potential differences between real-world and clinical trial outcomes. In the analysis, the researchers compared real-world outcomes among patients receiving seven standard multiple myeloma regimens covered by Ontario’s public health plan with patient outcomes reported in phase 3 randomized controlled trials. 

The retrospective study included 3951 patients with newly diagnosed and refractory multiple myeloma treated from 2007 to 2020 in Ontario. Regimens for newly diagnosed transplant ineligible patients included lenalidomide plus dexamethasone and triple therapy with bortezomib, lenalidomide, and dexamethasone. Regimens for patients with relapsed disease included pomalidomide plus dexamethasone or carfilzomib plus dexamethasone as well as triple combinations including carfilzomib, lenalidomide, and dexamethasone.

Overall, Dr. Visram and colleagues found that patients in the real-world setting demonstrated worse overall survival for six of the seven regimens evaluated (pooled hazard ratio [HR], 1.75; P = .010). 

The real-world patients also had worse progression-free survival for six of the seven regimens (pooled HR, 1.44; P = .034). 

For these regimens, progression-free survival was at least 3-18 months longer in the clinical trial cohort, while median overall survival was at least 19 months longer compared with real-world patients, Dr. Visram explained. 

The only regimen with comparable outcomes in the clinical trial and real-world settings was pomalidomide and dexamethasone, she said. One reason could be that patients receiving pomalidomide plus dexamethasone in the clinical trial setting had similar or more advanced disease than those in the real-world setting.

The study also found that adverse effects were similar between the clinical and real-world groups. 

The next step, Dr. Visram said, would be to explore what’s driving the differences in outcomes. 

Are patients in the real-world setting older or frailer? Do they have more advanced disease? Are providers using these regimens differently? 

Mikkael A. Sekeres, MD, MS, explained that the difference likely comes down to the health of the patient. 

Patients in these types of clinical trials “are just these pristine specimens of human beings except for the cancer that’s being treated,” Dr. Sekeres, of the Sylvester Comprehensive Cancer Center at the University of Miami, Florida, said in an earlier ASH press briefing.

Cynthia E. Dunbar, MD, noted that patients in clinical trials have other advantages as well.

“Patients who are able to enroll in clinical trials are more likely to be able to show up at the treatment center at the right time and for every dose, have transportation, and afford drugs to prevent side effects,” said Dr. Dunbar, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute and secretary of ASH. These patients also “might stay on the drug for longer, or they have nurses who are always encouraging them on how to make it through a toxicity.”

Dr. Dunbar said hematologists and patients should consider randomized controlled trials to be “the best possible outcome, and perhaps adjust their thinking if an individual patient is older, sicker, or less able to follow a regimen exactly.” 

No study funding was reported. Dr. Visram reported consulting and honoraria relationships with Apotex, Janssen, and Sanofi. Other study authors reported multiple relationships with industry. Disclosures for Dr. Dunbar and Dr. Sekeres were unavailable. 

A version of this article appeared on Medscape.com.

SAN DIEGO — In the real world, outcomes for patients with multiple myeloma who received standard regimens were dramatically worse than those reported in clinical trials, a new study found. 

The analysis, which included nearly 4,000 patients with multiple myeloma, revealed that patients in a real-world setting demonstrated worse progression-free and overall survival on six of seven standard treatments compared with patients evaluated in randomized controlled trials.

Lead author Alissa Visram, MD, MPH, who spoke about the study at the annual meeting of the American Society of Hematology, said the findings will likely change the way she speaks to patients about their potential outcomes. 

“I’ll probably present both numbers [from real-life and clinical-trial data] and give them a sense of the best-case scenario,” Dr. Visram said during an ASH media briefing. But she said she will also caution her patients that the real-world numbers reflect how people on these drugs actually fare. 

The effectiveness of multiple myeloma drugs remains unclear outside the clinical trial setting, explained Dr. Visram, of the Division of Hematology at the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. Outcomes from randomized controlled trials form the basis of drug approvals but many patients in the real world do not meet the “stringent” trial inclusion criteria. 

Dr. Visram and colleagues launched the current study to better understand the potential differences between real-world and clinical trial outcomes. In the analysis, the researchers compared real-world outcomes among patients receiving seven standard multiple myeloma regimens covered by Ontario’s public health plan with patient outcomes reported in phase 3 randomized controlled trials. 

The retrospective study included 3951 patients with newly diagnosed and refractory multiple myeloma treated from 2007 to 2020 in Ontario. Regimens for newly diagnosed transplant ineligible patients included lenalidomide plus dexamethasone and triple therapy with bortezomib, lenalidomide, and dexamethasone. Regimens for patients with relapsed disease included pomalidomide plus dexamethasone or carfilzomib plus dexamethasone as well as triple combinations including carfilzomib, lenalidomide, and dexamethasone.

Overall, Dr. Visram and colleagues found that patients in the real-world setting demonstrated worse overall survival for six of the seven regimens evaluated (pooled hazard ratio [HR], 1.75; P = .010). 

The real-world patients also had worse progression-free survival for six of the seven regimens (pooled HR, 1.44; P = .034). 

For these regimens, progression-free survival was at least 3-18 months longer in the clinical trial cohort, while median overall survival was at least 19 months longer compared with real-world patients, Dr. Visram explained. 

The only regimen with comparable outcomes in the clinical trial and real-world settings was pomalidomide and dexamethasone, she said. One reason could be that patients receiving pomalidomide plus dexamethasone in the clinical trial setting had similar or more advanced disease than those in the real-world setting.

The study also found that adverse effects were similar between the clinical and real-world groups. 

The next step, Dr. Visram said, would be to explore what’s driving the differences in outcomes. 

Are patients in the real-world setting older or frailer? Do they have more advanced disease? Are providers using these regimens differently? 

Mikkael A. Sekeres, MD, MS, explained that the difference likely comes down to the health of the patient. 

Patients in these types of clinical trials “are just these pristine specimens of human beings except for the cancer that’s being treated,” Dr. Sekeres, of the Sylvester Comprehensive Cancer Center at the University of Miami, Florida, said in an earlier ASH press briefing.

Cynthia E. Dunbar, MD, noted that patients in clinical trials have other advantages as well.

“Patients who are able to enroll in clinical trials are more likely to be able to show up at the treatment center at the right time and for every dose, have transportation, and afford drugs to prevent side effects,” said Dr. Dunbar, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute and secretary of ASH. These patients also “might stay on the drug for longer, or they have nurses who are always encouraging them on how to make it through a toxicity.”

Dr. Dunbar said hematologists and patients should consider randomized controlled trials to be “the best possible outcome, and perhaps adjust their thinking if an individual patient is older, sicker, or less able to follow a regimen exactly.” 

No study funding was reported. Dr. Visram reported consulting and honoraria relationships with Apotex, Janssen, and Sanofi. Other study authors reported multiple relationships with industry. Disclosures for Dr. Dunbar and Dr. Sekeres were unavailable. 

A version of this article appeared on Medscape.com.

SAN DIEGO — In the real world, outcomes for patients with multiple myeloma who received standard regimens were dramatically worse than those reported in clinical trials, a new study found. 

The analysis, which included nearly 4,000 patients with multiple myeloma, revealed that patients in a real-world setting demonstrated worse progression-free and overall survival on six of seven standard treatments compared with patients evaluated in randomized controlled trials.

Lead author Alissa Visram, MD, MPH, who spoke about the study at the annual meeting of the American Society of Hematology, said the findings will likely change the way she speaks to patients about their potential outcomes. 

“I’ll probably present both numbers [from real-life and clinical-trial data] and give them a sense of the best-case scenario,” Dr. Visram said during an ASH media briefing. But she said she will also caution her patients that the real-world numbers reflect how people on these drugs actually fare. 

The effectiveness of multiple myeloma drugs remains unclear outside the clinical trial setting, explained Dr. Visram, of the Division of Hematology at the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. Outcomes from randomized controlled trials form the basis of drug approvals but many patients in the real world do not meet the “stringent” trial inclusion criteria. 

Dr. Visram and colleagues launched the current study to better understand the potential differences between real-world and clinical trial outcomes. In the analysis, the researchers compared real-world outcomes among patients receiving seven standard multiple myeloma regimens covered by Ontario’s public health plan with patient outcomes reported in phase 3 randomized controlled trials. 

The retrospective study included 3951 patients with newly diagnosed and refractory multiple myeloma treated from 2007 to 2020 in Ontario. Regimens for newly diagnosed transplant ineligible patients included lenalidomide plus dexamethasone and triple therapy with bortezomib, lenalidomide, and dexamethasone. Regimens for patients with relapsed disease included pomalidomide plus dexamethasone or carfilzomib plus dexamethasone as well as triple combinations including carfilzomib, lenalidomide, and dexamethasone.

Overall, Dr. Visram and colleagues found that patients in the real-world setting demonstrated worse overall survival for six of the seven regimens evaluated (pooled hazard ratio [HR], 1.75; P = .010). 

The real-world patients also had worse progression-free survival for six of the seven regimens (pooled HR, 1.44; P = .034). 

For these regimens, progression-free survival was at least 3-18 months longer in the clinical trial cohort, while median overall survival was at least 19 months longer compared with real-world patients, Dr. Visram explained. 

The only regimen with comparable outcomes in the clinical trial and real-world settings was pomalidomide and dexamethasone, she said. One reason could be that patients receiving pomalidomide plus dexamethasone in the clinical trial setting had similar or more advanced disease than those in the real-world setting.

The study also found that adverse effects were similar between the clinical and real-world groups. 

The next step, Dr. Visram said, would be to explore what’s driving the differences in outcomes. 

Are patients in the real-world setting older or frailer? Do they have more advanced disease? Are providers using these regimens differently? 

Mikkael A. Sekeres, MD, MS, explained that the difference likely comes down to the health of the patient. 

Patients in these types of clinical trials “are just these pristine specimens of human beings except for the cancer that’s being treated,” Dr. Sekeres, of the Sylvester Comprehensive Cancer Center at the University of Miami, Florida, said in an earlier ASH press briefing.

Cynthia E. Dunbar, MD, noted that patients in clinical trials have other advantages as well.

“Patients who are able to enroll in clinical trials are more likely to be able to show up at the treatment center at the right time and for every dose, have transportation, and afford drugs to prevent side effects,” said Dr. Dunbar, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute and secretary of ASH. These patients also “might stay on the drug for longer, or they have nurses who are always encouraging them on how to make it through a toxicity.”

Dr. Dunbar said hematologists and patients should consider randomized controlled trials to be “the best possible outcome, and perhaps adjust their thinking if an individual patient is older, sicker, or less able to follow a regimen exactly.” 

No study funding was reported. Dr. Visram reported consulting and honoraria relationships with Apotex, Janssen, and Sanofi. Other study authors reported multiple relationships with industry. Disclosures for Dr. Dunbar and Dr. Sekeres were unavailable.