Multiple Myeloma

Study authors Qinghai Zhang

(right) and Sung Chang Lee

Photo courtesy of

The Scripps Research Institute

Scientists have discovered how the primary protein responsible for multidrug chemotherapy resistance changes shape and reacts to drugs.

They believe this information will aid the design of better molecules to inhibit or evade multidrug resistance.

The researchers noted that the proteins at work in multidrug resistance are ABC transporters. An important ABC transporter, P-glycoprotein (P-gp), catches harmful toxins in a “binding pocket” and expels them from cells.

The problem is that, in cancer patients, P-gp sometimes begins recognizing chemotherapy drugs and expelling them too. Over time, more and more cancer cells can develop multidrug resistance, eliminating all possible treatments.

“Virtually all cancer deaths can be attributed to the failure of chemotherapy,” said study author Qinghai Zhang, PhD, of The Scripps Research Institute in La Jolla, California.

He and his colleagues theorized that scientists might be able to design more effective cancer drugs if they had a better understanding of P-gp and how it binds to molecules.

A better look at transporters

For their first study, published in Structure, the researchers looked at P-gp and MsbA, a similar transporter protein found in bacteria, under an electron microscope. This helped them solve a major problem in transporter research.

Until recently, scientists could only compare images of crystal structures made from transporter proteins. These crystallography images showed single snapshots of the transporter but didn’t show how the shape of the transporters could change.

Using electron microscopy, however, a whole range of different conformations of the structures could be visualized, essentially capturing P-gp and MsbA in action.

The research was also aided by the development of new chemical tools. The team used a solution of lipids and peptides to mimic natural conditions in the cell membrane. They used a novel chemical called beta-sheet peptide to stabilize the protein and provide enough stability for a new perspective.

Together with electron microscopy, this technique enabled the researchers to capture a series of images showing how transporter proteins change shape in response to drug and nucleotide binding. They found that transporter proteins have an open binding pocket that constantly switches to face different sides of membranes.

“The transporter goes through many steps,” Dr Zhang said. “It’s like a machine.”

A closer look at binding

In a second study, published in Acta Crystallographica Section D, the scientists investigated the drug binding sites of P-gp using higher-resolution X-ray crystallography. And they discovered how P-gp interacts with ligands.

The researchers studied crystals of the transporter bound to 4 different ligands to see how the transporters reacted. They found that when certain ligands bind to P-gp, they trigger local conformational changes in the transporter.

Binding also increased the rate of ATP hydrolysis, which provides mechanical energy and may be the first step in the process by which the binding pocket closes.

The team also discovered that ligands could bind to different areas of the transporter, leaving nearby slots open for other molecules. This suggests it may be difficult to completely halt the drug expulsion process.

Dr Zhang said the next step for this research is to develop molecules to evade P-gp binding.

Study authors Qinghai Zhang

(right) and Sung Chang Lee

Photo courtesy of

The Scripps Research Institute

Scientists have discovered how the primary protein responsible for multidrug chemotherapy resistance changes shape and reacts to drugs.

They believe this information will aid the design of better molecules to inhibit or evade multidrug resistance.

The researchers noted that the proteins at work in multidrug resistance are ABC transporters. An important ABC transporter, P-glycoprotein (P-gp), catches harmful toxins in a “binding pocket” and expels them from cells.

The problem is that, in cancer patients, P-gp sometimes begins recognizing chemotherapy drugs and expelling them too. Over time, more and more cancer cells can develop multidrug resistance, eliminating all possible treatments.

“Virtually all cancer deaths can be attributed to the failure of chemotherapy,” said study author Qinghai Zhang, PhD, of The Scripps Research Institute in La Jolla, California.

He and his colleagues theorized that scientists might be able to design more effective cancer drugs if they had a better understanding of P-gp and how it binds to molecules.

A better look at transporters

For their first study, published in Structure, the researchers looked at P-gp and MsbA, a similar transporter protein found in bacteria, under an electron microscope. This helped them solve a major problem in transporter research.

Until recently, scientists could only compare images of crystal structures made from transporter proteins. These crystallography images showed single snapshots of the transporter but didn’t show how the shape of the transporters could change.

Using electron microscopy, however, a whole range of different conformations of the structures could be visualized, essentially capturing P-gp and MsbA in action.

The research was also aided by the development of new chemical tools. The team used a solution of lipids and peptides to mimic natural conditions in the cell membrane. They used a novel chemical called beta-sheet peptide to stabilize the protein and provide enough stability for a new perspective.

Together with electron microscopy, this technique enabled the researchers to capture a series of images showing how transporter proteins change shape in response to drug and nucleotide binding. They found that transporter proteins have an open binding pocket that constantly switches to face different sides of membranes.

“The transporter goes through many steps,” Dr Zhang said. “It’s like a machine.”

A closer look at binding

In a second study, published in Acta Crystallographica Section D, the scientists investigated the drug binding sites of P-gp using higher-resolution X-ray crystallography. And they discovered how P-gp interacts with ligands.

The researchers studied crystals of the transporter bound to 4 different ligands to see how the transporters reacted. They found that when certain ligands bind to P-gp, they trigger local conformational changes in the transporter.

Binding also increased the rate of ATP hydrolysis, which provides mechanical energy and may be the first step in the process by which the binding pocket closes.

The team also discovered that ligands could bind to different areas of the transporter, leaving nearby slots open for other molecules. This suggests it may be difficult to completely halt the drug expulsion process.

Dr Zhang said the next step for this research is to develop molecules to evade P-gp binding.

Study authors Qinghai Zhang

(right) and Sung Chang Lee

Photo courtesy of

The Scripps Research Institute

Scientists have discovered how the primary protein responsible for multidrug chemotherapy resistance changes shape and reacts to drugs.

They believe this information will aid the design of better molecules to inhibit or evade multidrug resistance.

The researchers noted that the proteins at work in multidrug resistance are ABC transporters. An important ABC transporter, P-glycoprotein (P-gp), catches harmful toxins in a “binding pocket” and expels them from cells.

The problem is that, in cancer patients, P-gp sometimes begins recognizing chemotherapy drugs and expelling them too. Over time, more and more cancer cells can develop multidrug resistance, eliminating all possible treatments.

“Virtually all cancer deaths can be attributed to the failure of chemotherapy,” said study author Qinghai Zhang, PhD, of The Scripps Research Institute in La Jolla, California.

He and his colleagues theorized that scientists might be able to design more effective cancer drugs if they had a better understanding of P-gp and how it binds to molecules.

A better look at transporters

For their first study, published in Structure, the researchers looked at P-gp and MsbA, a similar transporter protein found in bacteria, under an electron microscope. This helped them solve a major problem in transporter research.

Until recently, scientists could only compare images of crystal structures made from transporter proteins. These crystallography images showed single snapshots of the transporter but didn’t show how the shape of the transporters could change.

Using electron microscopy, however, a whole range of different conformations of the structures could be visualized, essentially capturing P-gp and MsbA in action.

The research was also aided by the development of new chemical tools. The team used a solution of lipids and peptides to mimic natural conditions in the cell membrane. They used a novel chemical called beta-sheet peptide to stabilize the protein and provide enough stability for a new perspective.

Together with electron microscopy, this technique enabled the researchers to capture a series of images showing how transporter proteins change shape in response to drug and nucleotide binding. They found that transporter proteins have an open binding pocket that constantly switches to face different sides of membranes.

“The transporter goes through many steps,” Dr Zhang said. “It’s like a machine.”

A closer look at binding

In a second study, published in Acta Crystallographica Section D, the scientists investigated the drug binding sites of P-gp using higher-resolution X-ray crystallography. And they discovered how P-gp interacts with ligands.

The researchers studied crystals of the transporter bound to 4 different ligands to see how the transporters reacted. They found that when certain ligands bind to P-gp, they trigger local conformational changes in the transporter.

Binding also increased the rate of ATP hydrolysis, which provides mechanical energy and may be the first step in the process by which the binding pocket closes.

The team also discovered that ligands could bind to different areas of the transporter, leaving nearby slots open for other molecules. This suggests it may be difficult to completely halt the drug expulsion process.

Dr Zhang said the next step for this research is to develop molecules to evade P-gp binding.

Cancer patient receives therapy

Photo by Rhoda Baer

Interim results of the phase 3 ENDEAVOR trial suggest that carfilzomib given in combination with low-dose dexamethasone may be more effective than bortezomib plus low-dose dexamethasone for certain patients with relapsed multiple myeloma (MM).

Patients who received the carfilzomib combination had a higher overall response rate and nearly twice the median progression-free survival (PFS) of patients who received the bortezomib combination.

Those who received carfilzomib had higher rates of cardiac and renal failure but lower rates of neuropathy. And rates of treatment discontinuation and on-study death were similar between the treatment arms.

Onyx Pharmaceuticals, the company developing carfilzomib (as Kyprolis), announced these results yesterday. The company plans to submit complete trial data for presentation at the 2015 ASCO Annual Meeting.

The ENDEAVOR trial included 929 MM patients who had relapsed after at least 1, but not more than 3, prior treatment regimens. They were randomized to receive carfilzomib or bortezomib, both in combination with low-dose dexamethasone.

Patients received carfilzomib as a 30-minute infusion, along with low-dose dexamethasone (20 mg). For cycle 1 only, carfilzomib was given at 20 mg/m² on days 1 and 2, followed by escalation to 56 mg/m² on days 8, 9, 15, and 16. Patients who tolerated 56 mg/m² in cycle 1 remained at this dose for subsequent cycles on days 1, 2, 8, 9, 15, and 16 on a 28-day cycle.

Patients who received bortezomib (1.3 mg/m²) with low-dose dexamethasone (20 mg) received bortezomib subcutaneously or intravenously at the discretion of the investigator and in accordance with the regulatory approval of bortezomib. More than 75% of the patients in the control arm received bortezomib subcutaneously.

The primary endpoint of the trial was PFS, defined as the time from treatment initiation to disease progression or death. The median PFS in the carfilzomib arm was roughly double that of the bortezomib arm—18.7 months and 9.4 months, respectively (hazard ratio=0.53).

The carfilzomib combination also demonstrated superiority over the bortezomib combination for secondary endpoints of higher overall response rate and lower neuropathy events.

However, the rates for cardiac and renal failure were higher in the carfilzomib arm than the bortezomib arm. The same was true for hypertension and dyspnea.

Rates of cardiac and renal failure with carfilzomib in this trial were similar to those observed in the phase 3 ASPIRE trial, but rates of hypertension and dyspnea were higher in ENDEAVOR than ASPIRE.

Cancer patient receives therapy

Photo by Rhoda Baer

Interim results of the phase 3 ENDEAVOR trial suggest that carfilzomib given in combination with low-dose dexamethasone may be more effective than bortezomib plus low-dose dexamethasone for certain patients with relapsed multiple myeloma (MM).

Patients who received the carfilzomib combination had a higher overall response rate and nearly twice the median progression-free survival (PFS) of patients who received the bortezomib combination.

Those who received carfilzomib had higher rates of cardiac and renal failure but lower rates of neuropathy. And rates of treatment discontinuation and on-study death were similar between the treatment arms.

Onyx Pharmaceuticals, the company developing carfilzomib (as Kyprolis), announced these results yesterday. The company plans to submit complete trial data for presentation at the 2015 ASCO Annual Meeting.

The ENDEAVOR trial included 929 MM patients who had relapsed after at least 1, but not more than 3, prior treatment regimens. They were randomized to receive carfilzomib or bortezomib, both in combination with low-dose dexamethasone.

Patients received carfilzomib as a 30-minute infusion, along with low-dose dexamethasone (20 mg). For cycle 1 only, carfilzomib was given at 20 mg/m² on days 1 and 2, followed by escalation to 56 mg/m² on days 8, 9, 15, and 16. Patients who tolerated 56 mg/m² in cycle 1 remained at this dose for subsequent cycles on days 1, 2, 8, 9, 15, and 16 on a 28-day cycle.

Patients who received bortezomib (1.3 mg/m²) with low-dose dexamethasone (20 mg) received bortezomib subcutaneously or intravenously at the discretion of the investigator and in accordance with the regulatory approval of bortezomib. More than 75% of the patients in the control arm received bortezomib subcutaneously.

The primary endpoint of the trial was PFS, defined as the time from treatment initiation to disease progression or death. The median PFS in the carfilzomib arm was roughly double that of the bortezomib arm—18.7 months and 9.4 months, respectively (hazard ratio=0.53).

The carfilzomib combination also demonstrated superiority over the bortezomib combination for secondary endpoints of higher overall response rate and lower neuropathy events.

However, the rates for cardiac and renal failure were higher in the carfilzomib arm than the bortezomib arm. The same was true for hypertension and dyspnea.

Rates of cardiac and renal failure with carfilzomib in this trial were similar to those observed in the phase 3 ASPIRE trial, but rates of hypertension and dyspnea were higher in ENDEAVOR than ASPIRE.

Cancer patient receives therapy

Photo by Rhoda Baer

Interim results of the phase 3 ENDEAVOR trial suggest that carfilzomib given in combination with low-dose dexamethasone may be more effective than bortezomib plus low-dose dexamethasone for certain patients with relapsed multiple myeloma (MM).

Patients who received the carfilzomib combination had a higher overall response rate and nearly twice the median progression-free survival (PFS) of patients who received the bortezomib combination.

Those who received carfilzomib had higher rates of cardiac and renal failure but lower rates of neuropathy. And rates of treatment discontinuation and on-study death were similar between the treatment arms.

Onyx Pharmaceuticals, the company developing carfilzomib (as Kyprolis), announced these results yesterday. The company plans to submit complete trial data for presentation at the 2015 ASCO Annual Meeting.

The ENDEAVOR trial included 929 MM patients who had relapsed after at least 1, but not more than 3, prior treatment regimens. They were randomized to receive carfilzomib or bortezomib, both in combination with low-dose dexamethasone.

Patients received carfilzomib as a 30-minute infusion, along with low-dose dexamethasone (20 mg). For cycle 1 only, carfilzomib was given at 20 mg/m² on days 1 and 2, followed by escalation to 56 mg/m² on days 8, 9, 15, and 16. Patients who tolerated 56 mg/m² in cycle 1 remained at this dose for subsequent cycles on days 1, 2, 8, 9, 15, and 16 on a 28-day cycle.

Patients who received bortezomib (1.3 mg/m²) with low-dose dexamethasone (20 mg) received bortezomib subcutaneously or intravenously at the discretion of the investigator and in accordance with the regulatory approval of bortezomib. More than 75% of the patients in the control arm received bortezomib subcutaneously.

The primary endpoint of the trial was PFS, defined as the time from treatment initiation to disease progression or death. The median PFS in the carfilzomib arm was roughly double that of the bortezomib arm—18.7 months and 9.4 months, respectively (hazard ratio=0.53).

The carfilzomib combination also demonstrated superiority over the bortezomib combination for secondary endpoints of higher overall response rate and lower neuropathy events.

However, the rates for cardiac and renal failure were higher in the carfilzomib arm than the bortezomib arm. The same was true for hypertension and dyspnea.

Rates of cardiac and renal failure with carfilzomib in this trial were similar to those observed in the phase 3 ASPIRE trial, but rates of hypertension and dyspnea were higher in ENDEAVOR than ASPIRE.

Micrograph showing MM

The US Food and Drug Administration (FDA) has granted accelerated approval for panobinostat (Farydak) to treat patients with multiple myeloma (MM).

Panobinostat is the first histone deacetylase (HDAC) inhibitor approved to treat MM.

The drug can now be used in combination with bortezomib and dexamethasone to treat patients who have received at least 2 prior standard therapies, including bortezomib and an immunomodulatory agent (IMiD).

Panobinostat was approved with a boxed warning alerting patients and healthcare professionals that severe diarrhea and severe and fatal cardiac events, arrhythmias, and electrocardiogram changes have occurred in patients receiving the drug.

Panobinostat was approved with a Risk Evaluation and Mitigation Strategy as well, which consists of a communication plan to inform healthcare professionals of these risks and how to minimize them.

Data supporting approval

In November 2014, the FDA’s Oncologic Drugs Advisory Committee advised the agency that, based on the data reviewed, the benefits of panobinostat did not outweigh its risks for patients with relapsed MM.

After the meeting, Novartis, the company developing the HDAC inhibitor, submitted additional information supporting the use of panobinostat for a different indication: MM patients who have received at least 2 prior standard therapies, including bortezomib and an IMiD.

The FDA’s accelerated approval of panobinostat is based on that data—efficacy and safety results in a subgroup analysis of 193 patients enrolled in the phase 3 PANORAMA-1 trial. These patients had received prior treatment with both bortezomib and an IMiD.

In these patients, treatment with panobinostat, bortezomib, and dexamethasone resulted in superior progression-free survival, when compared to treatment with bortezomib, dexamethasone, and placebo—10.6 months and 5.8 months, respectively (hazard ratio=0.52).

The most common adverse events (incidence ≥ 20%) in clinical studies of panobinostat have been diarrhea, fatigue, nausea, peripheral edema, decreased appetite, pyrexia, and vomiting.

The most common non-hematologic laboratory abnormalities (incidence ≥ 40%) were hypophosphatemia, hypokalemia, hyponatremia, and increased creatinine. The most common hematologic laboratory abnormalities (incidence ≥ 60%) were thrombocytopenia, lymphopenia, leukopenia, neutropenia, and anemia.

Panobinostat can cause fatal and serious toxicities, including severe diarrhea and cardiac toxicities.

The most frequent (≥ 5%) treatment-emergent serious adverse events for patients treated with the HDAC inhibitor were pneumonia (18%), diarrhea (11%), thrombocytopenia (7%), fatigue (6%), and sepsis (6%). Additional serious adverse events included hemorrhage, myelosuppression, infections, hepatotoxicity, and embryo-fetal toxicity.

Panobinostat development

The FDA previously granted panobinostat priority review and orphan product designation. Priority review provides an expedited review of drugs that are intended to treat a serious disease or condition and may provide a significant improvement over available therapy. Orphan product designation is given to drugs intended to treat rare diseases.

Now, the FDA has granted panobinostat accelerated approval, which allows for conditional approval of a drug based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients.

Continued approval of panobinostat may be contingent upon verification of a clinical benefit in confirmatory trials conducted by Novartis. An improvement in overall survival or disease-related symptoms has not yet been established for the HDAC inhibitor.

For more details on panobinostat, see the full prescribing information.

Micrograph showing MM

The US Food and Drug Administration (FDA) has granted accelerated approval for panobinostat (Farydak) to treat patients with multiple myeloma (MM).

Panobinostat is the first histone deacetylase (HDAC) inhibitor approved to treat MM.

The drug can now be used in combination with bortezomib and dexamethasone to treat patients who have received at least 2 prior standard therapies, including bortezomib and an immunomodulatory agent (IMiD).

Panobinostat was approved with a boxed warning alerting patients and healthcare professionals that severe diarrhea and severe and fatal cardiac events, arrhythmias, and electrocardiogram changes have occurred in patients receiving the drug.

Panobinostat was approved with a Risk Evaluation and Mitigation Strategy as well, which consists of a communication plan to inform healthcare professionals of these risks and how to minimize them.

Data supporting approval

In November 2014, the FDA’s Oncologic Drugs Advisory Committee advised the agency that, based on the data reviewed, the benefits of panobinostat did not outweigh its risks for patients with relapsed MM.

After the meeting, Novartis, the company developing the HDAC inhibitor, submitted additional information supporting the use of panobinostat for a different indication: MM patients who have received at least 2 prior standard therapies, including bortezomib and an IMiD.

The FDA’s accelerated approval of panobinostat is based on that data—efficacy and safety results in a subgroup analysis of 193 patients enrolled in the phase 3 PANORAMA-1 trial. These patients had received prior treatment with both bortezomib and an IMiD.

In these patients, treatment with panobinostat, bortezomib, and dexamethasone resulted in superior progression-free survival, when compared to treatment with bortezomib, dexamethasone, and placebo—10.6 months and 5.8 months, respectively (hazard ratio=0.52).

The most common adverse events (incidence ≥ 20%) in clinical studies of panobinostat have been diarrhea, fatigue, nausea, peripheral edema, decreased appetite, pyrexia, and vomiting.

The most common non-hematologic laboratory abnormalities (incidence ≥ 40%) were hypophosphatemia, hypokalemia, hyponatremia, and increased creatinine. The most common hematologic laboratory abnormalities (incidence ≥ 60%) were thrombocytopenia, lymphopenia, leukopenia, neutropenia, and anemia.

Panobinostat can cause fatal and serious toxicities, including severe diarrhea and cardiac toxicities.

The most frequent (≥ 5%) treatment-emergent serious adverse events for patients treated with the HDAC inhibitor were pneumonia (18%), diarrhea (11%), thrombocytopenia (7%), fatigue (6%), and sepsis (6%). Additional serious adverse events included hemorrhage, myelosuppression, infections, hepatotoxicity, and embryo-fetal toxicity.

Panobinostat development

The FDA previously granted panobinostat priority review and orphan product designation. Priority review provides an expedited review of drugs that are intended to treat a serious disease or condition and may provide a significant improvement over available therapy. Orphan product designation is given to drugs intended to treat rare diseases.

Now, the FDA has granted panobinostat accelerated approval, which allows for conditional approval of a drug based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients.

Continued approval of panobinostat may be contingent upon verification of a clinical benefit in confirmatory trials conducted by Novartis. An improvement in overall survival or disease-related symptoms has not yet been established for the HDAC inhibitor.

For more details on panobinostat, see the full prescribing information.

Micrograph showing MM

The US Food and Drug Administration (FDA) has granted accelerated approval for panobinostat (Farydak) to treat patients with multiple myeloma (MM).

Panobinostat is the first histone deacetylase (HDAC) inhibitor approved to treat MM.

The drug can now be used in combination with bortezomib and dexamethasone to treat patients who have received at least 2 prior standard therapies, including bortezomib and an immunomodulatory agent (IMiD).

Panobinostat was approved with a boxed warning alerting patients and healthcare professionals that severe diarrhea and severe and fatal cardiac events, arrhythmias, and electrocardiogram changes have occurred in patients receiving the drug.

Panobinostat was approved with a Risk Evaluation and Mitigation Strategy as well, which consists of a communication plan to inform healthcare professionals of these risks and how to minimize them.

Data supporting approval

In November 2014, the FDA’s Oncologic Drugs Advisory Committee advised the agency that, based on the data reviewed, the benefits of panobinostat did not outweigh its risks for patients with relapsed MM.

After the meeting, Novartis, the company developing the HDAC inhibitor, submitted additional information supporting the use of panobinostat for a different indication: MM patients who have received at least 2 prior standard therapies, including bortezomib and an IMiD.

The FDA’s accelerated approval of panobinostat is based on that data—efficacy and safety results in a subgroup analysis of 193 patients enrolled in the phase 3 PANORAMA-1 trial. These patients had received prior treatment with both bortezomib and an IMiD.

In these patients, treatment with panobinostat, bortezomib, and dexamethasone resulted in superior progression-free survival, when compared to treatment with bortezomib, dexamethasone, and placebo—10.6 months and 5.8 months, respectively (hazard ratio=0.52).

The most common adverse events (incidence ≥ 20%) in clinical studies of panobinostat have been diarrhea, fatigue, nausea, peripheral edema, decreased appetite, pyrexia, and vomiting.

The most common non-hematologic laboratory abnormalities (incidence ≥ 40%) were hypophosphatemia, hypokalemia, hyponatremia, and increased creatinine. The most common hematologic laboratory abnormalities (incidence ≥ 60%) were thrombocytopenia, lymphopenia, leukopenia, neutropenia, and anemia.

Panobinostat can cause fatal and serious toxicities, including severe diarrhea and cardiac toxicities.

The most frequent (≥ 5%) treatment-emergent serious adverse events for patients treated with the HDAC inhibitor were pneumonia (18%), diarrhea (11%), thrombocytopenia (7%), fatigue (6%), and sepsis (6%). Additional serious adverse events included hemorrhage, myelosuppression, infections, hepatotoxicity, and embryo-fetal toxicity.

Panobinostat development

The FDA previously granted panobinostat priority review and orphan product designation. Priority review provides an expedited review of drugs that are intended to treat a serious disease or condition and may provide a significant improvement over available therapy. Orphan product designation is given to drugs intended to treat rare diseases.

Now, the FDA has granted panobinostat accelerated approval, which allows for conditional approval of a drug based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients.

Continued approval of panobinostat may be contingent upon verification of a clinical benefit in confirmatory trials conducted by Novartis. An improvement in overall survival or disease-related symptoms has not yet been established for the HDAC inhibitor.

For more details on panobinostat, see the full prescribing information.

Doctor consults with a cancer

patient and her father

Photo by Rhoda Baer

A survey of more than 5000 cancer patients suggests there are a number of factors that might make a patient more likely to involve family members in treatment decisions.

A patient’s gender, age, marital status, native language, insurance status, and even past military service all appeared to impact family involvement in care decisions.

Gabriela Hobbs, MD, of Harvard Medical School in Boston, Massachusetts, and her colleagues conducted this research and reported the results in Cancer.

The researchers surveyed 5284 patients with a new diagnosis of lung or colon cancer, asking patients how they involved their families in treatment decisions.

Only 1.5% of patients reported complete family control over decisions. Nearly half of patients (49.4%) said they and family members shared decision-making responsibilities equally, 22.1% of patients reported some family input, and 28.5% reported little or no input from their families.

Asian and Hispanic patients who did not speak English were more likely than their peers to report equally shared decisions with their families. Likewise, patients who were married, female, older, and insured were more likely to share decision-making equally with their families.

Veterans were the least likely to share decision-making with their families, even when the researchers adjusted for marital status and social support.

“Understanding how patients vary in their inclusion of family members in decisions—by ethnicity, language spoken, marital status, sex, age, insurance status, and veteran status—may help physicians to better assess their patients’ preferences for engaging family members in decisions,” Dr Hobbs said.

“As we move to more patient-centered models of care, such assessments may help doctors personalize the care they offer their patients.”

Dr Hobbs noted that as therapies for cancer patients improve, they are also becoming increasingly complex, making it challenging for patients and providers to determine the optimal therapy for each patient. Therefore, knowing how patients make decisions and understanding the role families play in decision-making is crucial for optimizing patient participation in treatment decisions.

“Our study suggests that not all patients wish to include family in the same way,” Dr Hobbs said. “By raising awareness of these preferences, we hope that physicians will be aware of these variations and elicit their patient’s preference on how they wish to include, or not to include, families in decision-making.”

Doctor consults with a cancer

patient and her father

Photo by Rhoda Baer

A survey of more than 5000 cancer patients suggests there are a number of factors that might make a patient more likely to involve family members in treatment decisions.

A patient’s gender, age, marital status, native language, insurance status, and even past military service all appeared to impact family involvement in care decisions.

Gabriela Hobbs, MD, of Harvard Medical School in Boston, Massachusetts, and her colleagues conducted this research and reported the results in Cancer.

The researchers surveyed 5284 patients with a new diagnosis of lung or colon cancer, asking patients how they involved their families in treatment decisions.

Only 1.5% of patients reported complete family control over decisions. Nearly half of patients (49.4%) said they and family members shared decision-making responsibilities equally, 22.1% of patients reported some family input, and 28.5% reported little or no input from their families.

Asian and Hispanic patients who did not speak English were more likely than their peers to report equally shared decisions with their families. Likewise, patients who were married, female, older, and insured were more likely to share decision-making equally with their families.

Veterans were the least likely to share decision-making with their families, even when the researchers adjusted for marital status and social support.

“Understanding how patients vary in their inclusion of family members in decisions—by ethnicity, language spoken, marital status, sex, age, insurance status, and veteran status—may help physicians to better assess their patients’ preferences for engaging family members in decisions,” Dr Hobbs said.

“As we move to more patient-centered models of care, such assessments may help doctors personalize the care they offer their patients.”

Dr Hobbs noted that as therapies for cancer patients improve, they are also becoming increasingly complex, making it challenging for patients and providers to determine the optimal therapy for each patient. Therefore, knowing how patients make decisions and understanding the role families play in decision-making is crucial for optimizing patient participation in treatment decisions.

“Our study suggests that not all patients wish to include family in the same way,” Dr Hobbs said. “By raising awareness of these preferences, we hope that physicians will be aware of these variations and elicit their patient’s preference on how they wish to include, or not to include, families in decision-making.”

Doctor consults with a cancer

patient and her father

Photo by Rhoda Baer

A survey of more than 5000 cancer patients suggests there are a number of factors that might make a patient more likely to involve family members in treatment decisions.

A patient’s gender, age, marital status, native language, insurance status, and even past military service all appeared to impact family involvement in care decisions.

Gabriela Hobbs, MD, of Harvard Medical School in Boston, Massachusetts, and her colleagues conducted this research and reported the results in Cancer.

The researchers surveyed 5284 patients with a new diagnosis of lung or colon cancer, asking patients how they involved their families in treatment decisions.

Only 1.5% of patients reported complete family control over decisions. Nearly half of patients (49.4%) said they and family members shared decision-making responsibilities equally, 22.1% of patients reported some family input, and 28.5% reported little or no input from their families.

Asian and Hispanic patients who did not speak English were more likely than their peers to report equally shared decisions with their families. Likewise, patients who were married, female, older, and insured were more likely to share decision-making equally with their families.

Veterans were the least likely to share decision-making with their families, even when the researchers adjusted for marital status and social support.

“Understanding how patients vary in their inclusion of family members in decisions—by ethnicity, language spoken, marital status, sex, age, insurance status, and veteran status—may help physicians to better assess their patients’ preferences for engaging family members in decisions,” Dr Hobbs said.

“As we move to more patient-centered models of care, such assessments may help doctors personalize the care they offer their patients.”

Dr Hobbs noted that as therapies for cancer patients improve, they are also becoming increasingly complex, making it challenging for patients and providers to determine the optimal therapy for each patient. Therefore, knowing how patients make decisions and understanding the role families play in decision-making is crucial for optimizing patient participation in treatment decisions.

“Our study suggests that not all patients wish to include family in the same way,” Dr Hobbs said. “By raising awareness of these preferences, we hope that physicians will be aware of these variations and elicit their patient’s preference on how they wish to include, or not to include, families in decision-making.”

Revlimid (lenalidomide)

Photo courtesy of Celgene

The European Commission (EC) has expanded the marketing authorization for lenalidomide (Revlimid), just 2 days after the US Food and Drug Administration did the same.

Lenalidomide is now approved in the European Union (EU) to treat adults with previously untreated multiple myeloma (MM) who are not eligible for hematopoietic stem cell transplant. These patients can receive the drug continuously until

disease progression.

Lenalidomide was already approved in the EU for use in combination with dexamethasone to treat adults with MM who have received at least 1 prior therapy.

Lenalidomide is also approved in the EU to treat patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with 5q deletion when other therapeutic options are insufficient or inadequate.

“Having a new treatment option now available for patients newly diagnosed with multiple myeloma is a real step forward,” said Thierry Facon, MD, of CHRU Lille in France.

“Treating patients continuously until disease progression is supported by several clinical studies and will have an important impact on how we manage the disease over the long-term.”

The EC’s decision to extend the approved use of lenalidomide was based on the results of 2 studies: MM-015 and MM-020, also known as FIRST.

The FIRST trial

In the phase 3 FIRST trial, researchers enrolled 1623 patients who were newly diagnosed with MM and not eligible for transplant.

Patients were randomized to receive lenalidomide and dexamethasone (Rd) in 28-day cycles until disease progression (n=535), 18 cycles of lenalidomide and dexamethasone (Rd18) for 72 weeks (n=541), or melphalan, prednisone, and thalidomide (MPT) for 72 weeks (n=547).

Response rates were significantly better with continuous Rd (75%) and Rd18 (73%) than with MPT (62%, P<0.001 for both comparisons). Complete response rates were 15%, 14%, and 9%, respectively.

The median progression-free survival was 25.5 months with continuous Rd, 20.7 months with Rd18, and 21.2 months with MPT.

This resulted in a 28% reduction in the risk of progression or death for patients treated with continuous Rd compared with those treated with MPT (hazard ratio[HR]=0.72, P<0.001) and a 30% reduction compared with Rd18 (HR=0.70, P<0.001).

The pre-planned interim analysis of overall survival showed a 22% reduction in the risk of death for continuous Rd vs MPT (HR=0.78, P=0.02), but the difference did not cross the pre-specified superiority boundary (P<0.0096).

Adverse events reported in 20% or more of patients in the continuous Rd, Rd18, or MPT arms included diarrhea (45.5%, 38.5%, 16.5%), anemia (43.8%, 35.7%, 42.3%), neutropenia (35.0%, 33.0%, 60.6%), fatigue (32.5%, 32.8%, 28.5%), back pain (32.0%, 26.9%, 21.4%), insomnia (27.6%, 23.5%, 9.8%), asthenia (28.2%, 22.8%, 22.9%), rash (26.1%, 28.0%, 19.4%), decreased appetite (23.1%, 21.3%, 13.3%), cough (22.7%, 17.4%, 12.6%), pyrexia (21.4%, 18.9%, 14.0%), muscle spasms (20.5%, 18.9%, 11.3%), and abdominal pain (20.5%, 14.4%, 11.1%).

The incidence of invasive second primary malignancies was 3% in patients taking continuous Rd, 6% in patients taking Rd18, and 5% in those taking MPT. The overall incidence of solid tumors was identical in the continuous Rd and MPT arms (3%) and 5% in the Rd18 arm.

The MM-015 trial

In the phase 3 MM-015 study, researchers enrolled 459 patients who were 65 or older and newly diagnosed with MM.

The team compared melphalan-prednisone-lenalidomide induction followed by lenalidomide maintenance (MPR-R) with melphalan-prednisone-lenalidomide (MPR) or melphalan-prednisone (MP) followed by placebo maintenance.

Patients who received MPR-R or MPR had significantly better response rates than patients who received MP, at 77%, 68%, and 50%, respectively (P<0.001 and P=0.002, respectively, for the comparison with MP).

And the median progression-free survival was significantly longer with MPR-R (31 months) than with MPR (14 months, HR=0.49, P<0.001) or MP (13 months, HR=0.40, P<0.001).

During induction, the most frequent adverse events were hematologic. Grade 4 neutropenia occurred in 35% of patients in the MPR-R arm, 32% in the MPR arm, and 8% in the MP arm. The 3-year rate of second primary malignancies was 7%, 7%, and 3%, respectively.

Revlimid (lenalidomide)

Photo courtesy of Celgene

The European Commission (EC) has expanded the marketing authorization for lenalidomide (Revlimid), just 2 days after the US Food and Drug Administration did the same.

Lenalidomide is now approved in the European Union (EU) to treat adults with previously untreated multiple myeloma (MM) who are not eligible for hematopoietic stem cell transplant. These patients can receive the drug continuously until

disease progression.

Lenalidomide was already approved in the EU for use in combination with dexamethasone to treat adults with MM who have received at least 1 prior therapy.

Lenalidomide is also approved in the EU to treat patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with 5q deletion when other therapeutic options are insufficient or inadequate.

“Having a new treatment option now available for patients newly diagnosed with multiple myeloma is a real step forward,” said Thierry Facon, MD, of CHRU Lille in France.

“Treating patients continuously until disease progression is supported by several clinical studies and will have an important impact on how we manage the disease over the long-term.”

The EC’s decision to extend the approved use of lenalidomide was based on the results of 2 studies: MM-015 and MM-020, also known as FIRST.

The FIRST trial

In the phase 3 FIRST trial, researchers enrolled 1623 patients who were newly diagnosed with MM and not eligible for transplant.

Patients were randomized to receive lenalidomide and dexamethasone (Rd) in 28-day cycles until disease progression (n=535), 18 cycles of lenalidomide and dexamethasone (Rd18) for 72 weeks (n=541), or melphalan, prednisone, and thalidomide (MPT) for 72 weeks (n=547).

Response rates were significantly better with continuous Rd (75%) and Rd18 (73%) than with MPT (62%, P<0.001 for both comparisons). Complete response rates were 15%, 14%, and 9%, respectively.

The median progression-free survival was 25.5 months with continuous Rd, 20.7 months with Rd18, and 21.2 months with MPT.

This resulted in a 28% reduction in the risk of progression or death for patients treated with continuous Rd compared with those treated with MPT (hazard ratio[HR]=0.72, P<0.001) and a 30% reduction compared with Rd18 (HR=0.70, P<0.001).

The pre-planned interim analysis of overall survival showed a 22% reduction in the risk of death for continuous Rd vs MPT (HR=0.78, P=0.02), but the difference did not cross the pre-specified superiority boundary (P<0.0096).

Adverse events reported in 20% or more of patients in the continuous Rd, Rd18, or MPT arms included diarrhea (45.5%, 38.5%, 16.5%), anemia (43.8%, 35.7%, 42.3%), neutropenia (35.0%, 33.0%, 60.6%), fatigue (32.5%, 32.8%, 28.5%), back pain (32.0%, 26.9%, 21.4%), insomnia (27.6%, 23.5%, 9.8%), asthenia (28.2%, 22.8%, 22.9%), rash (26.1%, 28.0%, 19.4%), decreased appetite (23.1%, 21.3%, 13.3%), cough (22.7%, 17.4%, 12.6%), pyrexia (21.4%, 18.9%, 14.0%), muscle spasms (20.5%, 18.9%, 11.3%), and abdominal pain (20.5%, 14.4%, 11.1%).

The incidence of invasive second primary malignancies was 3% in patients taking continuous Rd, 6% in patients taking Rd18, and 5% in those taking MPT. The overall incidence of solid tumors was identical in the continuous Rd and MPT arms (3%) and 5% in the Rd18 arm.

The MM-015 trial

In the phase 3 MM-015 study, researchers enrolled 459 patients who were 65 or older and newly diagnosed with MM.

The team compared melphalan-prednisone-lenalidomide induction followed by lenalidomide maintenance (MPR-R) with melphalan-prednisone-lenalidomide (MPR) or melphalan-prednisone (MP) followed by placebo maintenance.

Patients who received MPR-R or MPR had significantly better response rates than patients who received MP, at 77%, 68%, and 50%, respectively (P<0.001 and P=0.002, respectively, for the comparison with MP).

And the median progression-free survival was significantly longer with MPR-R (31 months) than with MPR (14 months, HR=0.49, P<0.001) or MP (13 months, HR=0.40, P<0.001).

During induction, the most frequent adverse events were hematologic. Grade 4 neutropenia occurred in 35% of patients in the MPR-R arm, 32% in the MPR arm, and 8% in the MP arm. The 3-year rate of second primary malignancies was 7%, 7%, and 3%, respectively.

Revlimid (lenalidomide)

Photo courtesy of Celgene

The European Commission (EC) has expanded the marketing authorization for lenalidomide (Revlimid), just 2 days after the US Food and Drug Administration did the same.

Lenalidomide is now approved in the European Union (EU) to treat adults with previously untreated multiple myeloma (MM) who are not eligible for hematopoietic stem cell transplant. These patients can receive the drug continuously until

disease progression.

Lenalidomide was already approved in the EU for use in combination with dexamethasone to treat adults with MM who have received at least 1 prior therapy.

Lenalidomide is also approved in the EU to treat patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with 5q deletion when other therapeutic options are insufficient or inadequate.

“Having a new treatment option now available for patients newly diagnosed with multiple myeloma is a real step forward,” said Thierry Facon, MD, of CHRU Lille in France.

“Treating patients continuously until disease progression is supported by several clinical studies and will have an important impact on how we manage the disease over the long-term.”

The EC’s decision to extend the approved use of lenalidomide was based on the results of 2 studies: MM-015 and MM-020, also known as FIRST.

The FIRST trial

In the phase 3 FIRST trial, researchers enrolled 1623 patients who were newly diagnosed with MM and not eligible for transplant.

Patients were randomized to receive lenalidomide and dexamethasone (Rd) in 28-day cycles until disease progression (n=535), 18 cycles of lenalidomide and dexamethasone (Rd18) for 72 weeks (n=541), or melphalan, prednisone, and thalidomide (MPT) for 72 weeks (n=547).

Response rates were significantly better with continuous Rd (75%) and Rd18 (73%) than with MPT (62%, P<0.001 for both comparisons). Complete response rates were 15%, 14%, and 9%, respectively.

The median progression-free survival was 25.5 months with continuous Rd, 20.7 months with Rd18, and 21.2 months with MPT.

This resulted in a 28% reduction in the risk of progression or death for patients treated with continuous Rd compared with those treated with MPT (hazard ratio[HR]=0.72, P<0.001) and a 30% reduction compared with Rd18 (HR=0.70, P<0.001).

The pre-planned interim analysis of overall survival showed a 22% reduction in the risk of death for continuous Rd vs MPT (HR=0.78, P=0.02), but the difference did not cross the pre-specified superiority boundary (P<0.0096).

Adverse events reported in 20% or more of patients in the continuous Rd, Rd18, or MPT arms included diarrhea (45.5%, 38.5%, 16.5%), anemia (43.8%, 35.7%, 42.3%), neutropenia (35.0%, 33.0%, 60.6%), fatigue (32.5%, 32.8%, 28.5%), back pain (32.0%, 26.9%, 21.4%), insomnia (27.6%, 23.5%, 9.8%), asthenia (28.2%, 22.8%, 22.9%), rash (26.1%, 28.0%, 19.4%), decreased appetite (23.1%, 21.3%, 13.3%), cough (22.7%, 17.4%, 12.6%), pyrexia (21.4%, 18.9%, 14.0%), muscle spasms (20.5%, 18.9%, 11.3%), and abdominal pain (20.5%, 14.4%, 11.1%).

The incidence of invasive second primary malignancies was 3% in patients taking continuous Rd, 6% in patients taking Rd18, and 5% in those taking MPT. The overall incidence of solid tumors was identical in the continuous Rd and MPT arms (3%) and 5% in the Rd18 arm.

The MM-015 trial

In the phase 3 MM-015 study, researchers enrolled 459 patients who were 65 or older and newly diagnosed with MM.

The team compared melphalan-prednisone-lenalidomide induction followed by lenalidomide maintenance (MPR-R) with melphalan-prednisone-lenalidomide (MPR) or melphalan-prednisone (MP) followed by placebo maintenance.

Patients who received MPR-R or MPR had significantly better response rates than patients who received MP, at 77%, 68%, and 50%, respectively (P<0.001 and P=0.002, respectively, for the comparison with MP).

And the median progression-free survival was significantly longer with MPR-R (31 months) than with MPR (14 months, HR=0.49, P<0.001) or MP (13 months, HR=0.40, P<0.001).

During induction, the most frequent adverse events were hematologic. Grade 4 neutropenia occurred in 35% of patients in the MPR-R arm, 32% in the MPR arm, and 8% in the MP arm. The 3-year rate of second primary malignancies was 7%, 7%, and 3%, respectively.

Capsules

The US Food and Drug Administration (FDA) has expanded the existing indication for lenalidomide (Revlimid)—in combination with dexamethasone—to include patients with newly diagnosed multiple myeloma (MM).

The FDA previously approved lenalidomide in combination with dexamethasone to treat MM patients who had received at least 1 prior therapy.

Lenalidomide is also FDA-approved to treat mantle cell lymphoma patients who have failed 2 prior therapies, including bortezomib.

And the drug is approved to treat patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with 5q deletion, with or without additional cytogenetic abnormalities.

“The approval of Revlimid as an option for use in all patients with multiple myeloma represents a new paradigm in the management of this disease,” said Kenneth Anderson, MD, of Dana-Farber/Brigham and Women’s Cancer Center in Boston, Massachusetts.

“We now have clinical evidence demonstrating that starting and keeping newly diagnosed multiple myeloma patients on Revlimid significantly improves progression-free survival.”

The FDA’s latest approval of lenalidomide was based on safety and efficacy results from phase 3 studies, particularly the FIRST trial.

The FIRST trial

In this phase 3 trial, researchers enrolled 1623 patients who were newly diagnosed with MM and not eligible for stem cell transplant.

Patients were randomized to receive lenalidomide and dexamethasone (Rd) in 28-day cycles until disease progression (n=535), 18 cycles of lenalidomide and dexamethasone (Rd18) for 72 weeks (n=541), or melphalan, prednisone, and thalidomide (MPT) for 72 weeks (n=547).

Response rates were significantly better with continuous Rd (75%) and Rd18 (73%) than with MPT (62%, P<0.001 for both comparisons). Complete response rates were 15%, 14%, and 9%, respectively.

The median progression-free survival was 25.5 months with continuous Rd, 20.7 months with Rd18, and 21.2 months with MPT.

This resulted in a 28% reduction in the risk of progression or death for patients treated with continuous Rd compared with those treated with MPT (hazard ratio[HR]=0.72, P<0.001) and a 30% reduction compared with Rd18 (HR=0.70, P<0.001).

The pre-planned interim analysis of overall survival showed a 22% reduction in the risk of death for continuous Rd vs MPT (HR=0.78, P=0.02), but the difference did not cross the pre-specified superiority boundary (P<0.0096).

Adverse events reported in 20% or more of patients in the continuous Rd, Rd18, or MPT arms included diarrhea (45.5%, 38.5%, 16.5%), anemia (43.8%, 35.7%, 42.3%), neutropenia (35.0%, 33.0%, 60.6%), fatigue (32.5%, 32.8%, 28.5%), back pain (32.0%, 26.9%, 21.4%), insomnia (27.6%, 23.5%, 9.8%), asthenia (28.2%, 22.8%, 22.9%), rash (26.1%, 28.0%, 19.4%), decreased appetite (23.1%, 21.3%, 13.3%), cough (22.7%, 17.4%, 12.6%), pyrexia (21.4%, 18.9%, 14.0%), muscle spasms (20.5%, 18.9%, 11.3%) and abdominal pain (20.5%, 14.4%, 11.1%).

The most frequently reported grade 3/4 events in the continuous Rd arm (until disease progression) were neutropenia (27.8%), anemia (18.2%), thrombocytopenia (8.3%), pneumonia (11.3%), asthenia (7.7%), fatigue (7.3%), back pain (7%), hypokalemia (6.6%), rash (7.3%), cataract (5.8%), dyspnea (5.6%), deep vein thrombosis (5.6%), and hyperglycemia (5.3%).

The incidence of invasive second primary malignancies was 3% in the continuous Rd arm, 6% in the Rd18 arm, and 5% in the MPT arm. The overall incidence of solid tumors was identical in the continuous Rd and MPT arms (3%) and 5% in the Rd18 arm.

Capsules

The US Food and Drug Administration (FDA) has expanded the existing indication for lenalidomide (Revlimid)—in combination with dexamethasone—to include patients with newly diagnosed multiple myeloma (MM).

The FDA previously approved lenalidomide in combination with dexamethasone to treat MM patients who had received at least 1 prior therapy.

Lenalidomide is also FDA-approved to treat mantle cell lymphoma patients who have failed 2 prior therapies, including bortezomib.

And the drug is approved to treat patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with 5q deletion, with or without additional cytogenetic abnormalities.

“The approval of Revlimid as an option for use in all patients with multiple myeloma represents a new paradigm in the management of this disease,” said Kenneth Anderson, MD, of Dana-Farber/Brigham and Women’s Cancer Center in Boston, Massachusetts.

“We now have clinical evidence demonstrating that starting and keeping newly diagnosed multiple myeloma patients on Revlimid significantly improves progression-free survival.”

The FDA’s latest approval of lenalidomide was based on safety and efficacy results from phase 3 studies, particularly the FIRST trial.

The FIRST trial

In this phase 3 trial, researchers enrolled 1623 patients who were newly diagnosed with MM and not eligible for stem cell transplant.

Patients were randomized to receive lenalidomide and dexamethasone (Rd) in 28-day cycles until disease progression (n=535), 18 cycles of lenalidomide and dexamethasone (Rd18) for 72 weeks (n=541), or melphalan, prednisone, and thalidomide (MPT) for 72 weeks (n=547).

Response rates were significantly better with continuous Rd (75%) and Rd18 (73%) than with MPT (62%, P<0.001 for both comparisons). Complete response rates were 15%, 14%, and 9%, respectively.

The median progression-free survival was 25.5 months with continuous Rd, 20.7 months with Rd18, and 21.2 months with MPT.

This resulted in a 28% reduction in the risk of progression or death for patients treated with continuous Rd compared with those treated with MPT (hazard ratio[HR]=0.72, P<0.001) and a 30% reduction compared with Rd18 (HR=0.70, P<0.001).

The pre-planned interim analysis of overall survival showed a 22% reduction in the risk of death for continuous Rd vs MPT (HR=0.78, P=0.02), but the difference did not cross the pre-specified superiority boundary (P<0.0096).

Adverse events reported in 20% or more of patients in the continuous Rd, Rd18, or MPT arms included diarrhea (45.5%, 38.5%, 16.5%), anemia (43.8%, 35.7%, 42.3%), neutropenia (35.0%, 33.0%, 60.6%), fatigue (32.5%, 32.8%, 28.5%), back pain (32.0%, 26.9%, 21.4%), insomnia (27.6%, 23.5%, 9.8%), asthenia (28.2%, 22.8%, 22.9%), rash (26.1%, 28.0%, 19.4%), decreased appetite (23.1%, 21.3%, 13.3%), cough (22.7%, 17.4%, 12.6%), pyrexia (21.4%, 18.9%, 14.0%), muscle spasms (20.5%, 18.9%, 11.3%) and abdominal pain (20.5%, 14.4%, 11.1%).

The most frequently reported grade 3/4 events in the continuous Rd arm (until disease progression) were neutropenia (27.8%), anemia (18.2%), thrombocytopenia (8.3%), pneumonia (11.3%), asthenia (7.7%), fatigue (7.3%), back pain (7%), hypokalemia (6.6%), rash (7.3%), cataract (5.8%), dyspnea (5.6%), deep vein thrombosis (5.6%), and hyperglycemia (5.3%).

The incidence of invasive second primary malignancies was 3% in the continuous Rd arm, 6% in the Rd18 arm, and 5% in the MPT arm. The overall incidence of solid tumors was identical in the continuous Rd and MPT arms (3%) and 5% in the Rd18 arm.

Capsules

The US Food and Drug Administration (FDA) has expanded the existing indication for lenalidomide (Revlimid)—in combination with dexamethasone—to include patients with newly diagnosed multiple myeloma (MM).

The FDA previously approved lenalidomide in combination with dexamethasone to treat MM patients who had received at least 1 prior therapy.

Lenalidomide is also FDA-approved to treat mantle cell lymphoma patients who have failed 2 prior therapies, including bortezomib.

And the drug is approved to treat patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with 5q deletion, with or without additional cytogenetic abnormalities.

“The approval of Revlimid as an option for use in all patients with multiple myeloma represents a new paradigm in the management of this disease,” said Kenneth Anderson, MD, of Dana-Farber/Brigham and Women’s Cancer Center in Boston, Massachusetts.

“We now have clinical evidence demonstrating that starting and keeping newly diagnosed multiple myeloma patients on Revlimid significantly improves progression-free survival.”

The FDA’s latest approval of lenalidomide was based on safety and efficacy results from phase 3 studies, particularly the FIRST trial.

The FIRST trial

In this phase 3 trial, researchers enrolled 1623 patients who were newly diagnosed with MM and not eligible for stem cell transplant.

Patients were randomized to receive lenalidomide and dexamethasone (Rd) in 28-day cycles until disease progression (n=535), 18 cycles of lenalidomide and dexamethasone (Rd18) for 72 weeks (n=541), or melphalan, prednisone, and thalidomide (MPT) for 72 weeks (n=547).

Response rates were significantly better with continuous Rd (75%) and Rd18 (73%) than with MPT (62%, P<0.001 for both comparisons). Complete response rates were 15%, 14%, and 9%, respectively.

The median progression-free survival was 25.5 months with continuous Rd, 20.7 months with Rd18, and 21.2 months with MPT.

This resulted in a 28% reduction in the risk of progression or death for patients treated with continuous Rd compared with those treated with MPT (hazard ratio[HR]=0.72, P<0.001) and a 30% reduction compared with Rd18 (HR=0.70, P<0.001).

The pre-planned interim analysis of overall survival showed a 22% reduction in the risk of death for continuous Rd vs MPT (HR=0.78, P=0.02), but the difference did not cross the pre-specified superiority boundary (P<0.0096).

Adverse events reported in 20% or more of patients in the continuous Rd, Rd18, or MPT arms included diarrhea (45.5%, 38.5%, 16.5%), anemia (43.8%, 35.7%, 42.3%), neutropenia (35.0%, 33.0%, 60.6%), fatigue (32.5%, 32.8%, 28.5%), back pain (32.0%, 26.9%, 21.4%), insomnia (27.6%, 23.5%, 9.8%), asthenia (28.2%, 22.8%, 22.9%), rash (26.1%, 28.0%, 19.4%), decreased appetite (23.1%, 21.3%, 13.3%), cough (22.7%, 17.4%, 12.6%), pyrexia (21.4%, 18.9%, 14.0%), muscle spasms (20.5%, 18.9%, 11.3%) and abdominal pain (20.5%, 14.4%, 11.1%).

The most frequently reported grade 3/4 events in the continuous Rd arm (until disease progression) were neutropenia (27.8%), anemia (18.2%), thrombocytopenia (8.3%), pneumonia (11.3%), asthenia (7.7%), fatigue (7.3%), back pain (7%), hypokalemia (6.6%), rash (7.3%), cataract (5.8%), dyspnea (5.6%), deep vein thrombosis (5.6%), and hyperglycemia (5.3%).

The incidence of invasive second primary malignancies was 3% in the continuous Rd arm, 6% in the Rd18 arm, and 5% in the MPT arm. The overall incidence of solid tumors was identical in the continuous Rd and MPT arms (3%) and 5% in the Rd18 arm.

Patient receives chemotherapy

Photo by Rhoda Baer

SAN DIGEO—A phase 3 study comparing conditioning regimens in multiple myeloma patients undergoing autologous transplant has yielded counterintuitive results.

Patients who received busulfan plus melphalan (bu-mel) had a lower complete response (CR) rate at 90 days and a higher rate of grade 3-4 non-hematologic

toxicity, compared to patients who received melphalan (mel) alone.

However, patients in the bu-mel arm enjoyed significantly longer progression-free survival (PFS).

These results suggest the rate of CR at 90 days is not a good endpoint for trials of autologous hematopoietic stem cell transplant (auto-HSCT), said Muzaffar H.

Qazilbash, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Qazilbash presented these and other findings at the 2015 BMT Tandem Meetings as abstract 83.*

“High-dose melphalan at 200 mg/m² is considered the standard of care for autologous stem cell transplantation for multiple myeloma,” he said. “However, most patients have disease recurrence or progression after an autologous transplant, even with the use of post-transplant maintenance.”

A recent retrospective study suggested that bu-mel might be associated with a longer PFS compared to mel alone. So Dr Qazilbash and his colleagues decided to

investigate that possibility in a randomized, phase 3 trial.

The trial included 92 patients with symptomatic multiple myeloma who had received at least 2 cycles of induction therapy. They were all within 12 months of the start of induction, and all had adequate cardiac, pulmonary, renal, and liver function.

Forty-nine patients received bu-mel—a 130 mg/m² daily infusion of busulfan for 4 days, followed by 2 daily doses of melphalan at 70 mg/m². All patients in this arm also received phenytoin for seizure prophylaxis. The 43 patients in the mel-only arm received a single dose of melphalan at 200 mg/m².

Baseline characteristics were similar between the 2 arms. The patients’ median ages were 58 in the bu-mel arm and 59 in the mel arm. At the time of transplant, 18% of patients in the bu-mel arm were in CR or near CR, as were 28% of patients in the mel arm.

Adverse events

At 100 days post-transplant, the transplant-related mortality was 0% in both arms.

“There was a significantly higher rate of grade 3-4 non-hematologic adverse events in the busulfan-plus-melphalan arm—78% vs 47% [P=0.002],” Dr Qazilbash noted. “And these adverse events were mostly infectious events.”

Grade 3 infection occurred in 71% of bu-mel-treated patients and 39% of mel-treated patients (P=0.003). Grade 2 gastrointestinal toxicities occurred in 69% and 48%, respectively (P=0.05).

There were no significant differences between the arms with regard to other adverse events. And there were no second primary malignancies in either arm.

Response

At 90 days, the CR rate was 16% in the bu-mel arm and 35% in the mel arm (P=0.05). The rates of CR plus very good partial response were 63% and 81%, respectively (P=0.06).

“The trial was stopped early, based on a prescribed rule in the trial design, because of a significantly higher CR rate in the control arm,” Dr Qazilbash said.

Still, he noted that, at 180 days, the CR rate was 26% in the bu-mel arm and 37% in the mel arm (P=0.36). And the 180-day rates of CR plus very good

partial response were 69% and 86%, respectively (P=0.65).

Maintenance

A majority of patients received maintenance therapy post-transplant—84% of patients in the bu-mel arm and 88% in the mel arm.

The median interval between auto-HSCT and maintenance was 4.6 months and 4.5 months, respectively. And the median duration of maintenance was 16 months and 14.2 months, respectively.

Maintenance largely consisted of lenalidomide. Sixty-five percent of patients in the bu-mel arm and 63% in the mel arm received the drug. Fewer patients received bortezomib—8% and 16%, respectively—or lenalidomide plus ixazomib—10% and 9%, respectively.

Survival

At a median follow-up of 19.5 months, bu-mel was associated with significantly longer PFS than mel alone (P=0.047). And a multivariate analysis showed that bu-mel was an independent predictor of PFS.

Dr Qazilbash noted that there was no significant difference in overall survival between the bu-mel and mel arms (P=0.97), but the follow-up is less than 2 years, so this is expected.

“Bu-mel was associated with a significantly lower day 90 CR rate, a significantly higher rate of grade 3-4 non-hematologic toxicity, no significant difference in transplant-related mortality . . . , and a significantly longer PFS,” Dr Qazilbash summarized.

He therefore concluded that, based on this study, day 90 CR is not an adequate endpoint for auto-HSCT trials. This trial was amended to change the primary

endpoint from day 90 CR to PFS, and accrual has been increased to 205 patients.

Dr Qazilbash and others involved in this study received research funding from Otsuka, makers of busulfan. Dr Qazilbash also reported relationships (advisory

board, honoraria) with Celgene, Millennium, and Onyx.

*Information in the abstract differs from that presented at the meeting.

Patient receives chemotherapy

Photo by Rhoda Baer

SAN DIGEO—A phase 3 study comparing conditioning regimens in multiple myeloma patients undergoing autologous transplant has yielded counterintuitive results.

Patients who received busulfan plus melphalan (bu-mel) had a lower complete response (CR) rate at 90 days and a higher rate of grade 3-4 non-hematologic

toxicity, compared to patients who received melphalan (mel) alone.

However, patients in the bu-mel arm enjoyed significantly longer progression-free survival (PFS).

These results suggest the rate of CR at 90 days is not a good endpoint for trials of autologous hematopoietic stem cell transplant (auto-HSCT), said Muzaffar H.

Qazilbash, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Qazilbash presented these and other findings at the 2015 BMT Tandem Meetings as abstract 83.*

“High-dose melphalan at 200 mg/m² is considered the standard of care for autologous stem cell transplantation for multiple myeloma,” he said. “However, most patients have disease recurrence or progression after an autologous transplant, even with the use of post-transplant maintenance.”

A recent retrospective study suggested that bu-mel might be associated with a longer PFS compared to mel alone. So Dr Qazilbash and his colleagues decided to

investigate that possibility in a randomized, phase 3 trial.

The trial included 92 patients with symptomatic multiple myeloma who had received at least 2 cycles of induction therapy. They were all within 12 months of the start of induction, and all had adequate cardiac, pulmonary, renal, and liver function.

Forty-nine patients received bu-mel—a 130 mg/m² daily infusion of busulfan for 4 days, followed by 2 daily doses of melphalan at 70 mg/m². All patients in this arm also received phenytoin for seizure prophylaxis. The 43 patients in the mel-only arm received a single dose of melphalan at 200 mg/m².

Baseline characteristics were similar between the 2 arms. The patients’ median ages were 58 in the bu-mel arm and 59 in the mel arm. At the time of transplant, 18% of patients in the bu-mel arm were in CR or near CR, as were 28% of patients in the mel arm.

Adverse events

At 100 days post-transplant, the transplant-related mortality was 0% in both arms.

“There was a significantly higher rate of grade 3-4 non-hematologic adverse events in the busulfan-plus-melphalan arm—78% vs 47% [P=0.002],” Dr Qazilbash noted. “And these adverse events were mostly infectious events.”

Grade 3 infection occurred in 71% of bu-mel-treated patients and 39% of mel-treated patients (P=0.003). Grade 2 gastrointestinal toxicities occurred in 69% and 48%, respectively (P=0.05).

There were no significant differences between the arms with regard to other adverse events. And there were no second primary malignancies in either arm.

Response

At 90 days, the CR rate was 16% in the bu-mel arm and 35% in the mel arm (P=0.05). The rates of CR plus very good partial response were 63% and 81%, respectively (P=0.06).

“The trial was stopped early, based on a prescribed rule in the trial design, because of a significantly higher CR rate in the control arm,” Dr Qazilbash said.

Still, he noted that, at 180 days, the CR rate was 26% in the bu-mel arm and 37% in the mel arm (P=0.36). And the 180-day rates of CR plus very good

partial response were 69% and 86%, respectively (P=0.65).

Maintenance

A majority of patients received maintenance therapy post-transplant—84% of patients in the bu-mel arm and 88% in the mel arm.

The median interval between auto-HSCT and maintenance was 4.6 months and 4.5 months, respectively. And the median duration of maintenance was 16 months and 14.2 months, respectively.

Maintenance largely consisted of lenalidomide. Sixty-five percent of patients in the bu-mel arm and 63% in the mel arm received the drug. Fewer patients received bortezomib—8% and 16%, respectively—or lenalidomide plus ixazomib—10% and 9%, respectively.

Survival

At a median follow-up of 19.5 months, bu-mel was associated with significantly longer PFS than mel alone (P=0.047). And a multivariate analysis showed that bu-mel was an independent predictor of PFS.

Dr Qazilbash noted that there was no significant difference in overall survival between the bu-mel and mel arms (P=0.97), but the follow-up is less than 2 years, so this is expected.

“Bu-mel was associated with a significantly lower day 90 CR rate, a significantly higher rate of grade 3-4 non-hematologic toxicity, no significant difference in transplant-related mortality . . . , and a significantly longer PFS,” Dr Qazilbash summarized.

He therefore concluded that, based on this study, day 90 CR is not an adequate endpoint for auto-HSCT trials. This trial was amended to change the primary

endpoint from day 90 CR to PFS, and accrual has been increased to 205 patients.

Dr Qazilbash and others involved in this study received research funding from Otsuka, makers of busulfan. Dr Qazilbash also reported relationships (advisory

board, honoraria) with Celgene, Millennium, and Onyx.

*Information in the abstract differs from that presented at the meeting.

Patient receives chemotherapy

Photo by Rhoda Baer

SAN DIGEO—A phase 3 study comparing conditioning regimens in multiple myeloma patients undergoing autologous transplant has yielded counterintuitive results.

Patients who received busulfan plus melphalan (bu-mel) had a lower complete response (CR) rate at 90 days and a higher rate of grade 3-4 non-hematologic

toxicity, compared to patients who received melphalan (mel) alone.

However, patients in the bu-mel arm enjoyed significantly longer progression-free survival (PFS).

These results suggest the rate of CR at 90 days is not a good endpoint for trials of autologous hematopoietic stem cell transplant (auto-HSCT), said Muzaffar H.

Qazilbash, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Qazilbash presented these and other findings at the 2015 BMT Tandem Meetings as abstract 83.*

“High-dose melphalan at 200 mg/m² is considered the standard of care for autologous stem cell transplantation for multiple myeloma,” he said. “However, most patients have disease recurrence or progression after an autologous transplant, even with the use of post-transplant maintenance.”

A recent retrospective study suggested that bu-mel might be associated with a longer PFS compared to mel alone. So Dr Qazilbash and his colleagues decided to

investigate that possibility in a randomized, phase 3 trial.

The trial included 92 patients with symptomatic multiple myeloma who had received at least 2 cycles of induction therapy. They were all within 12 months of the start of induction, and all had adequate cardiac, pulmonary, renal, and liver function.

Forty-nine patients received bu-mel—a 130 mg/m² daily infusion of busulfan for 4 days, followed by 2 daily doses of melphalan at 70 mg/m². All patients in this arm also received phenytoin for seizure prophylaxis. The 43 patients in the mel-only arm received a single dose of melphalan at 200 mg/m².

Baseline characteristics were similar between the 2 arms. The patients’ median ages were 58 in the bu-mel arm and 59 in the mel arm. At the time of transplant, 18% of patients in the bu-mel arm were in CR or near CR, as were 28% of patients in the mel arm.

Adverse events

At 100 days post-transplant, the transplant-related mortality was 0% in both arms.

“There was a significantly higher rate of grade 3-4 non-hematologic adverse events in the busulfan-plus-melphalan arm—78% vs 47% [P=0.002],” Dr Qazilbash noted. “And these adverse events were mostly infectious events.”

Grade 3 infection occurred in 71% of bu-mel-treated patients and 39% of mel-treated patients (P=0.003). Grade 2 gastrointestinal toxicities occurred in 69% and 48%, respectively (P=0.05).

There were no significant differences between the arms with regard to other adverse events. And there were no second primary malignancies in either arm.

Response

At 90 days, the CR rate was 16% in the bu-mel arm and 35% in the mel arm (P=0.05). The rates of CR plus very good partial response were 63% and 81%, respectively (P=0.06).

“The trial was stopped early, based on a prescribed rule in the trial design, because of a significantly higher CR rate in the control arm,” Dr Qazilbash said.

Still, he noted that, at 180 days, the CR rate was 26% in the bu-mel arm and 37% in the mel arm (P=0.36). And the 180-day rates of CR plus very good

partial response were 69% and 86%, respectively (P=0.65).

Maintenance

A majority of patients received maintenance therapy post-transplant—84% of patients in the bu-mel arm and 88% in the mel arm.

The median interval between auto-HSCT and maintenance was 4.6 months and 4.5 months, respectively. And the median duration of maintenance was 16 months and 14.2 months, respectively.

Maintenance largely consisted of lenalidomide. Sixty-five percent of patients in the bu-mel arm and 63% in the mel arm received the drug. Fewer patients received bortezomib—8% and 16%, respectively—or lenalidomide plus ixazomib—10% and 9%, respectively.

Survival

At a median follow-up of 19.5 months, bu-mel was associated with significantly longer PFS than mel alone (P=0.047). And a multivariate analysis showed that bu-mel was an independent predictor of PFS.

Dr Qazilbash noted that there was no significant difference in overall survival between the bu-mel and mel arms (P=0.97), but the follow-up is less than 2 years, so this is expected.

“Bu-mel was associated with a significantly lower day 90 CR rate, a significantly higher rate of grade 3-4 non-hematologic toxicity, no significant difference in transplant-related mortality . . . , and a significantly longer PFS,” Dr Qazilbash summarized.

He therefore concluded that, based on this study, day 90 CR is not an adequate endpoint for auto-HSCT trials. This trial was amended to change the primary

endpoint from day 90 CR to PFS, and accrual has been increased to 205 patients.

Dr Qazilbash and others involved in this study received research funding from Otsuka, makers of busulfan. Dr Qazilbash also reported relationships (advisory

board, honoraria) with Celgene, Millennium, and Onyx.

*Information in the abstract differs from that presented at the meeting.