Multiple Myeloma

Prescription medications

Credit: Steven Harbour

The European Medicines Agency (EMA) has recommended suspending a number of drugs that were approved in the European Union (EU) based on clinical studies conducted at GVK Biosciences in Hyderabad, India.

An inspection of the site suggested GVK Bio employees may have manipulated data from trials that took place there.

So the EMA compiled a list of drugs—which includes clopidogrel, dexamethasone, and tacrolimus, among others—that should be suspended.

However, the EMA said there is no evidence of harm or lack of effectiveness linked to the conduct of studies by GVK Bio, and patients should continue taking their medicines as prescribed.

The EMA’s opinion has been forwarded to the European Commission (EC), which will adopt a legally binding decision.

It was at the request of the EC that the EMA’s Committee for Medicinal Products for Human Use (CHMP) reviewed the drugs set to be suspended.

An inspection by the French medicines agency, Agence nationale de sécurité du médicament et des produits de santé (ANSM), in May 2014 uncovered “non-compliance with good clinical practice” at the GVK Bio site in Hyderabad.

The ANSM inspector analyzed 9 studies conducted there from 2008 to 2013 and found evidence suggesting that data from electrocardiograms (ECGs) had been manipulated. It appeared that GVK Bio employees were taking multiple ECGs of one volunteer and presenting them as ECGs of other volunteers.

The EMA said the systematic nature of these data manipulations, the extended period of time during which they took place, and the number of staff members involved casts doubt on the integrity of the way trials were performed at the Hyderabad facility and on the reliability of data generated there.

With this in mind, the CHMP looked at more than 1000 pharmaceutical forms and strengths of medicines studied at the site. For more than 300 of the medications, there was sufficient data from other sources to support the drugs’ authorization, so these will remain on the market in the EU.

For drugs that lack data from other studies, the CHMP recommended suspension unless they are of critical importance for patients because alternatives will not be able to meet patients’ needs.

Whether a medicine is critical for patients will be determined by the national authorities of EU member states, depending on the situation in their country. For drugs that are considered critical, companies developing those drugs will be given 12 months to submit additional data.

The CHMP’s recommendation will be sent to the EC for a legally binding decision that will apply to all EU member states whether or not they have taken interim measures to suspend medicines.

GVK Bio responds

GVK Bio said an internal audit conducted following the ANSM inspection suggested that standard operating procedures were followed for the 9 trials analyzed. The organization also sought the opinion of 4 independent cardiologists, who said it was difficult to determine if the ECGs belong to the same volunteer or more than one person.

GVK Bio presented this information to the ANSM, but the agency concluded that the studies did not meet good clinical practice guidelines and should be rejected.

Following subsequent meetings and analyses, the EMA came to a similar conclusion—that the overall findings cast doubt on the results of trials conducted at the Hyderabad facility from 2008 to 2014.

GVK Bio said it respects the EMA’s decision, but their recommended suspension of drugs is “unprecedented and highly disproportional” for a few reasons.

First, the ANSM said the ECGs in question were not essential to demonstrate the bioequivalence of the drugs tested, and the agency’s recommendation to reject the 9 studies was a “precautionary” measure.

The ANSM also said the observations made during the inspection should not be extrapolated to other trial-related activities at the Hyderabad site or GVK Bio’s other site in Ahmedabad.

And finally, the EMA itself said there is no evidence proving that the drugs in question are ineffective or pose a risk to human health.

Prescription medications

Credit: Steven Harbour

The European Medicines Agency (EMA) has recommended suspending a number of drugs that were approved in the European Union (EU) based on clinical studies conducted at GVK Biosciences in Hyderabad, India.

An inspection of the site suggested GVK Bio employees may have manipulated data from trials that took place there.

So the EMA compiled a list of drugs—which includes clopidogrel, dexamethasone, and tacrolimus, among others—that should be suspended.

However, the EMA said there is no evidence of harm or lack of effectiveness linked to the conduct of studies by GVK Bio, and patients should continue taking their medicines as prescribed.

The EMA’s opinion has been forwarded to the European Commission (EC), which will adopt a legally binding decision.

It was at the request of the EC that the EMA’s Committee for Medicinal Products for Human Use (CHMP) reviewed the drugs set to be suspended.

An inspection by the French medicines agency, Agence nationale de sécurité du médicament et des produits de santé (ANSM), in May 2014 uncovered “non-compliance with good clinical practice” at the GVK Bio site in Hyderabad.

The ANSM inspector analyzed 9 studies conducted there from 2008 to 2013 and found evidence suggesting that data from electrocardiograms (ECGs) had been manipulated. It appeared that GVK Bio employees were taking multiple ECGs of one volunteer and presenting them as ECGs of other volunteers.

The EMA said the systematic nature of these data manipulations, the extended period of time during which they took place, and the number of staff members involved casts doubt on the integrity of the way trials were performed at the Hyderabad facility and on the reliability of data generated there.

With this in mind, the CHMP looked at more than 1000 pharmaceutical forms and strengths of medicines studied at the site. For more than 300 of the medications, there was sufficient data from other sources to support the drugs’ authorization, so these will remain on the market in the EU.

For drugs that lack data from other studies, the CHMP recommended suspension unless they are of critical importance for patients because alternatives will not be able to meet patients’ needs.

Whether a medicine is critical for patients will be determined by the national authorities of EU member states, depending on the situation in their country. For drugs that are considered critical, companies developing those drugs will be given 12 months to submit additional data.

The CHMP’s recommendation will be sent to the EC for a legally binding decision that will apply to all EU member states whether or not they have taken interim measures to suspend medicines.

GVK Bio responds

GVK Bio said an internal audit conducted following the ANSM inspection suggested that standard operating procedures were followed for the 9 trials analyzed. The organization also sought the opinion of 4 independent cardiologists, who said it was difficult to determine if the ECGs belong to the same volunteer or more than one person.

GVK Bio presented this information to the ANSM, but the agency concluded that the studies did not meet good clinical practice guidelines and should be rejected.

Following subsequent meetings and analyses, the EMA came to a similar conclusion—that the overall findings cast doubt on the results of trials conducted at the Hyderabad facility from 2008 to 2014.

GVK Bio said it respects the EMA’s decision, but their recommended suspension of drugs is “unprecedented and highly disproportional” for a few reasons.

First, the ANSM said the ECGs in question were not essential to demonstrate the bioequivalence of the drugs tested, and the agency’s recommendation to reject the 9 studies was a “precautionary” measure.

The ANSM also said the observations made during the inspection should not be extrapolated to other trial-related activities at the Hyderabad site or GVK Bio’s other site in Ahmedabad.

And finally, the EMA itself said there is no evidence proving that the drugs in question are ineffective or pose a risk to human health.

Prescription medications

Credit: Steven Harbour

The European Medicines Agency (EMA) has recommended suspending a number of drugs that were approved in the European Union (EU) based on clinical studies conducted at GVK Biosciences in Hyderabad, India.

An inspection of the site suggested GVK Bio employees may have manipulated data from trials that took place there.

So the EMA compiled a list of drugs—which includes clopidogrel, dexamethasone, and tacrolimus, among others—that should be suspended.

However, the EMA said there is no evidence of harm or lack of effectiveness linked to the conduct of studies by GVK Bio, and patients should continue taking their medicines as prescribed.

The EMA’s opinion has been forwarded to the European Commission (EC), which will adopt a legally binding decision.

It was at the request of the EC that the EMA’s Committee for Medicinal Products for Human Use (CHMP) reviewed the drugs set to be suspended.

An inspection by the French medicines agency, Agence nationale de sécurité du médicament et des produits de santé (ANSM), in May 2014 uncovered “non-compliance with good clinical practice” at the GVK Bio site in Hyderabad.

The ANSM inspector analyzed 9 studies conducted there from 2008 to 2013 and found evidence suggesting that data from electrocardiograms (ECGs) had been manipulated. It appeared that GVK Bio employees were taking multiple ECGs of one volunteer and presenting them as ECGs of other volunteers.

The EMA said the systematic nature of these data manipulations, the extended period of time during which they took place, and the number of staff members involved casts doubt on the integrity of the way trials were performed at the Hyderabad facility and on the reliability of data generated there.

With this in mind, the CHMP looked at more than 1000 pharmaceutical forms and strengths of medicines studied at the site. For more than 300 of the medications, there was sufficient data from other sources to support the drugs’ authorization, so these will remain on the market in the EU.

For drugs that lack data from other studies, the CHMP recommended suspension unless they are of critical importance for patients because alternatives will not be able to meet patients’ needs.

Whether a medicine is critical for patients will be determined by the national authorities of EU member states, depending on the situation in their country. For drugs that are considered critical, companies developing those drugs will be given 12 months to submit additional data.

The CHMP’s recommendation will be sent to the EC for a legally binding decision that will apply to all EU member states whether or not they have taken interim measures to suspend medicines.

GVK Bio responds

GVK Bio said an internal audit conducted following the ANSM inspection suggested that standard operating procedures were followed for the 9 trials analyzed. The organization also sought the opinion of 4 independent cardiologists, who said it was difficult to determine if the ECGs belong to the same volunteer or more than one person.

GVK Bio presented this information to the ANSM, but the agency concluded that the studies did not meet good clinical practice guidelines and should be rejected.

Following subsequent meetings and analyses, the EMA came to a similar conclusion—that the overall findings cast doubt on the results of trials conducted at the Hyderabad facility from 2008 to 2014.

GVK Bio said it respects the EMA’s decision, but their recommended suspension of drugs is “unprecedented and highly disproportional” for a few reasons.

First, the ANSM said the ECGs in question were not essential to demonstrate the bioequivalence of the drugs tested, and the agency’s recommendation to reject the 9 studies was a “precautionary” measure.

The ANSM also said the observations made during the inspection should not be extrapolated to other trial-related activities at the Hyderabad site or GVK Bio’s other site in Ahmedabad.

And finally, the EMA itself said there is no evidence proving that the drugs in question are ineffective or pose a risk to human health.

Prescription drugs

Credit: CDC

Several hematology drugs approved by the US Food and Drug Administration (FDA) have recently undergone label changes to reflect newly reported adverse events.

Changes have been made to the labels for the JAK1/2 inhibitor ruxolitinib (Jakafi), the anti-CD20 monoclonal antibody obinutuzumab (Gazyva), the factor Xa inhibitor rivaroxaban (Xarelto), and the hematopoietic stem cell mobilizer plerixafor (Mozobil).

Plerixafor

Plerixafor is FDA-approved for use in combination with granulocyte-colony stimulating factor to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin lymphoma and multiple myeloma.

The product’s label was changed to include a new entry under the “Adverse Reactions” heading. Postmarketing experience suggested the drug may cause abnormal dreams and nightmares.

Rivaroxaban

Rivaroxaban is a factor Xa inhibitor that’s FDA-approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), to reduce the risk of recurrent DVT and PE, and to prevent DVT, which may lead to PE, in patients undergoing knee or hip replacement surgery.

Postmarketing experience has led to two changes to the “Adverse Reactions” section of rivaroxaban’s label. Thrombocytopenia has been added as an adverse reaction, and the term “cytolytic hepatitis” has been replaced with “hepatitis (including hepatocellular injury).”

Obinutuzumab

Obinutuzumab is a CD20-directed cytolytic antibody that is FDA-approved in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia.

The “Warnings and Precautions” section of obinutuzumab’s label has been changed to reflect that fatal infections have been reported in patients who received the drug.

The label has also been changed to coincide with changes in trial data. The label now states that obinutuzumab caused grade 3 or 4 neutropenia in 33% of patients and grade 3 or 4 thrombocytopenia in 10% of patients.

Ruxolitinib

Ruxolitinib is a JAK1/JAK2 inhibitor that’s FDA-approved to treat patients with polycythemia vera (PV) who cannot tolerate or don’t respond to hydroxyurea, as well as patients with intermediate or high-risk myelofibrosis.

Ruxolitinib’s label now includes a warning that symptoms of myeloproliferative neoplasms may return about a week after discontinuing treatment. The label also advises healthcare professionals to discourage patients form interrupting or discontinuing ruxolitinib without consulting their physician.

In addition, a warning about the risk of non-melanoma skin cancer associated with ruxolitinib, as well as advice for informing patients of this risk, have been added to ruxolitinib’s label.

The label has undergone significant changes in sections 6.1, “Clinical Trials Experience in Myelofibrosis” and 6.2 “Clinical Trial Experience in Polycythemia Vera.” It now includes additional information on the risk of thrombocytopenia, anemia, and neutropenia.

Under the “Special Populations” heading, recommendations were added to reduce the drug’s dose in patients with PV and moderate or severe renal impairment, as well as PV patients with hepatic impairment.

Prescription drugs

Credit: CDC

Several hematology drugs approved by the US Food and Drug Administration (FDA) have recently undergone label changes to reflect newly reported adverse events.

Changes have been made to the labels for the JAK1/2 inhibitor ruxolitinib (Jakafi), the anti-CD20 monoclonal antibody obinutuzumab (Gazyva), the factor Xa inhibitor rivaroxaban (Xarelto), and the hematopoietic stem cell mobilizer plerixafor (Mozobil).

Plerixafor

Plerixafor is FDA-approved for use in combination with granulocyte-colony stimulating factor to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin lymphoma and multiple myeloma.

The product’s label was changed to include a new entry under the “Adverse Reactions” heading. Postmarketing experience suggested the drug may cause abnormal dreams and nightmares.

Rivaroxaban

Rivaroxaban is a factor Xa inhibitor that’s FDA-approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), to reduce the risk of recurrent DVT and PE, and to prevent DVT, which may lead to PE, in patients undergoing knee or hip replacement surgery.

Postmarketing experience has led to two changes to the “Adverse Reactions” section of rivaroxaban’s label. Thrombocytopenia has been added as an adverse reaction, and the term “cytolytic hepatitis” has been replaced with “hepatitis (including hepatocellular injury).”

Obinutuzumab

Obinutuzumab is a CD20-directed cytolytic antibody that is FDA-approved in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia.

The “Warnings and Precautions” section of obinutuzumab’s label has been changed to reflect that fatal infections have been reported in patients who received the drug.

The label has also been changed to coincide with changes in trial data. The label now states that obinutuzumab caused grade 3 or 4 neutropenia in 33% of patients and grade 3 or 4 thrombocytopenia in 10% of patients.

Ruxolitinib

Ruxolitinib is a JAK1/JAK2 inhibitor that’s FDA-approved to treat patients with polycythemia vera (PV) who cannot tolerate or don’t respond to hydroxyurea, as well as patients with intermediate or high-risk myelofibrosis.

Ruxolitinib’s label now includes a warning that symptoms of myeloproliferative neoplasms may return about a week after discontinuing treatment. The label also advises healthcare professionals to discourage patients form interrupting or discontinuing ruxolitinib without consulting their physician.

In addition, a warning about the risk of non-melanoma skin cancer associated with ruxolitinib, as well as advice for informing patients of this risk, have been added to ruxolitinib’s label.

The label has undergone significant changes in sections 6.1, “Clinical Trials Experience in Myelofibrosis” and 6.2 “Clinical Trial Experience in Polycythemia Vera.” It now includes additional information on the risk of thrombocytopenia, anemia, and neutropenia.

Under the “Special Populations” heading, recommendations were added to reduce the drug’s dose in patients with PV and moderate or severe renal impairment, as well as PV patients with hepatic impairment.

Prescription drugs

Credit: CDC

Several hematology drugs approved by the US Food and Drug Administration (FDA) have recently undergone label changes to reflect newly reported adverse events.

Changes have been made to the labels for the JAK1/2 inhibitor ruxolitinib (Jakafi), the anti-CD20 monoclonal antibody obinutuzumab (Gazyva), the factor Xa inhibitor rivaroxaban (Xarelto), and the hematopoietic stem cell mobilizer plerixafor (Mozobil).

Plerixafor

Plerixafor is FDA-approved for use in combination with granulocyte-colony stimulating factor to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin lymphoma and multiple myeloma.

The product’s label was changed to include a new entry under the “Adverse Reactions” heading. Postmarketing experience suggested the drug may cause abnormal dreams and nightmares.

Rivaroxaban

Rivaroxaban is a factor Xa inhibitor that’s FDA-approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), to reduce the risk of recurrent DVT and PE, and to prevent DVT, which may lead to PE, in patients undergoing knee or hip replacement surgery.

Postmarketing experience has led to two changes to the “Adverse Reactions” section of rivaroxaban’s label. Thrombocytopenia has been added as an adverse reaction, and the term “cytolytic hepatitis” has been replaced with “hepatitis (including hepatocellular injury).”

Obinutuzumab

Obinutuzumab is a CD20-directed cytolytic antibody that is FDA-approved in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia.

The “Warnings and Precautions” section of obinutuzumab’s label has been changed to reflect that fatal infections have been reported in patients who received the drug.

The label has also been changed to coincide with changes in trial data. The label now states that obinutuzumab caused grade 3 or 4 neutropenia in 33% of patients and grade 3 or 4 thrombocytopenia in 10% of patients.

Ruxolitinib

Ruxolitinib is a JAK1/JAK2 inhibitor that’s FDA-approved to treat patients with polycythemia vera (PV) who cannot tolerate or don’t respond to hydroxyurea, as well as patients with intermediate or high-risk myelofibrosis.

Ruxolitinib’s label now includes a warning that symptoms of myeloproliferative neoplasms may return about a week after discontinuing treatment. The label also advises healthcare professionals to discourage patients form interrupting or discontinuing ruxolitinib without consulting their physician.

In addition, a warning about the risk of non-melanoma skin cancer associated with ruxolitinib, as well as advice for informing patients of this risk, have been added to ruxolitinib’s label.

The label has undergone significant changes in sections 6.1, “Clinical Trials Experience in Myelofibrosis” and 6.2 “Clinical Trial Experience in Polycythemia Vera.” It now includes additional information on the risk of thrombocytopenia, anemia, and neutropenia.

Under the “Special Populations” heading, recommendations were added to reduce the drug’s dose in patients with PV and moderate or severe renal impairment, as well as PV patients with hepatic impairment.

Prescription medications

Credit: Steven Harbour

The National Health Service (NHS) has increased the budget for England’s Cancer Drugs Fund (CDF) and  added a new drug to treat 2 hematologic malignancies, but 5 other blood cancer drugs will be removed from the fund in March.

The budget for the CDF will grow from £200 million in 2013/14 to £280 million in 2014/15.

However, 16 drugs (for 25 different indications) will no longer be offered through the fund as of March 12, 2015.

Still, the NHS said it has taken steps to ensure patients can receive appropriate treatment.

Review leads to cuts

A national panel of oncologists, pharmacists, and patient representatives independently reviewed the drug indications currently available through the CDF, plus new applications.

They evaluated the clinical benefit, survival, quality of life, toxicity, and safety associated with each treatment, as well as the level of unmet need and the median cost per patient. In cases where the high cost of a drug would lead to its exclusion from CDF, manufacturers were given an opportunity to reduce prices.

The result of the review is that 59 of the 84 most effective currently approved indications of drugs will rollover into the CDF next year, creating room for new drug indications that will be funded for the first time.

These are panitumumab for bowel cancer, ibrutinib for mantle cell lymphoma, and ibrutinib for chronic lymphocytic leukemia.

However, 16 drugs, including 5 blood cancer drugs—bendamustine, bortezomib, bosutinib, dasatinib, and ofatumumab—will no longer be offered through the CDF.

Following these changes, the NHS will put 4 measures in place to ensure patients can receive appropriate treatment. First, any patient currently receiving a drug through the CDF will continue to receive it, regardless of whether it remains in the CDF.

Second, drugs that are the only therapy for the cancer in question will remain available through the CDF. Third, if the CDF panel removes a drug for a particular indication, some patients may instead be able to receive it in another line of therapy or receive an alternative CDF-approved drug.

And finally, clinicians can apply for their patient to receive a drug not available through the CDF on an exceptional basis.

Cuts to blood cancer drugs

The full list of cuts to the CDF is available on the NHS website, but the following list includes all drugs for hematologic malignancies that will no longer be available. These drugs will still be available for other indications, however.

1. Bendamustine for the treatment of low-grade lymphoma that is refractory to rituximab alone or in combination.
2. Bortezomib for the treatment of:

   • relapsed/refractory mantle cell lymphoma after 1 or more prior chemotherapies or stem cell transplant
   • relapsed multiple myeloma patients with a previous partial response or complete response of 6 months or more with bortezomib
   • relapsed Waldenstrom’s macroglobulinemia patients who received previous treatment with alkylating agents and purine analogues.

3. Bosutinib for the treatment of:

   • blast crisis chronic myeloid leukemia (CML) that is refractory to nilotinib or dasatinib if dasatinib was accessed via a clinical trial or via its current approved CDF indication
   • blast crisis CML where there is treatment intolerance, specifically, significant intolerance to dasatinib (grade 3 or 4 adverse events) if dasatinib was accessed via its current approved CDF indication.

4. Dasatinib for the treatment of lymphoid, blast crisis CML that is refractory to, significantly intolerant of, or resistant to prior therapy including imatinib (grade 3 or 4 adverse events); also when used as the 2nd- or 3rd-line treatment.
5. Ofatumumab for the treatment of CML as the 2nd- or 3rd-line indication and if the patient is refractory to treatment with fludarabine in combination and/or alemtuzumab or if treatment with fludarabine in combination and/or alemtuzumab is contraindicated.

More about the CDF and the NHS

The CDF—set up in 2010 and currently due to run until March 2016—is money the government has set aside to pay for cancer drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the NHS in England. Most cancer drugs are routinely funded outside of the CDF.

NHS England said it is working with cancer charities, the pharmaceutical industry, and NICE to create a sustainable model for the commissioning of chemotherapy. The agency has also updated its procedures for evaluating drugs in the CDF, in an effort to ensure sustainability.

In addition, NHS England has set up an appeals process by which pharmaceutical companies can challenge the decision-making process.

And a newly assembled national taskforce, headed by Harpal Kumar, chief executive of Cancer Research UK, is set to produce a refreshed, 5-year cancer plan for the NHS.

Prescription medications

Credit: Steven Harbour

The National Health Service (NHS) has increased the budget for England’s Cancer Drugs Fund (CDF) and  added a new drug to treat 2 hematologic malignancies, but 5 other blood cancer drugs will be removed from the fund in March.

The budget for the CDF will grow from £200 million in 2013/14 to £280 million in 2014/15.

However, 16 drugs (for 25 different indications) will no longer be offered through the fund as of March 12, 2015.

Still, the NHS said it has taken steps to ensure patients can receive appropriate treatment.

Review leads to cuts

A national panel of oncologists, pharmacists, and patient representatives independently reviewed the drug indications currently available through the CDF, plus new applications.

They evaluated the clinical benefit, survival, quality of life, toxicity, and safety associated with each treatment, as well as the level of unmet need and the median cost per patient. In cases where the high cost of a drug would lead to its exclusion from CDF, manufacturers were given an opportunity to reduce prices.

The result of the review is that 59 of the 84 most effective currently approved indications of drugs will rollover into the CDF next year, creating room for new drug indications that will be funded for the first time.

These are panitumumab for bowel cancer, ibrutinib for mantle cell lymphoma, and ibrutinib for chronic lymphocytic leukemia.

However, 16 drugs, including 5 blood cancer drugs—bendamustine, bortezomib, bosutinib, dasatinib, and ofatumumab—will no longer be offered through the CDF.

Following these changes, the NHS will put 4 measures in place to ensure patients can receive appropriate treatment. First, any patient currently receiving a drug through the CDF will continue to receive it, regardless of whether it remains in the CDF.

Second, drugs that are the only therapy for the cancer in question will remain available through the CDF. Third, if the CDF panel removes a drug for a particular indication, some patients may instead be able to receive it in another line of therapy or receive an alternative CDF-approved drug.

And finally, clinicians can apply for their patient to receive a drug not available through the CDF on an exceptional basis.

Cuts to blood cancer drugs

The full list of cuts to the CDF is available on the NHS website, but the following list includes all drugs for hematologic malignancies that will no longer be available. These drugs will still be available for other indications, however.

1. Bendamustine for the treatment of low-grade lymphoma that is refractory to rituximab alone or in combination.
2. Bortezomib for the treatment of:

   • relapsed/refractory mantle cell lymphoma after 1 or more prior chemotherapies or stem cell transplant
   • relapsed multiple myeloma patients with a previous partial response or complete response of 6 months or more with bortezomib
   • relapsed Waldenstrom’s macroglobulinemia patients who received previous treatment with alkylating agents and purine analogues.

3. Bosutinib for the treatment of:

   • blast crisis chronic myeloid leukemia (CML) that is refractory to nilotinib or dasatinib if dasatinib was accessed via a clinical trial or via its current approved CDF indication
   • blast crisis CML where there is treatment intolerance, specifically, significant intolerance to dasatinib (grade 3 or 4 adverse events) if dasatinib was accessed via its current approved CDF indication.

4. Dasatinib for the treatment of lymphoid, blast crisis CML that is refractory to, significantly intolerant of, or resistant to prior therapy including imatinib (grade 3 or 4 adverse events); also when used as the 2nd- or 3rd-line treatment.
5. Ofatumumab for the treatment of CML as the 2nd- or 3rd-line indication and if the patient is refractory to treatment with fludarabine in combination and/or alemtuzumab or if treatment with fludarabine in combination and/or alemtuzumab is contraindicated.

More about the CDF and the NHS

The CDF—set up in 2010 and currently due to run until March 2016—is money the government has set aside to pay for cancer drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the NHS in England. Most cancer drugs are routinely funded outside of the CDF.

NHS England said it is working with cancer charities, the pharmaceutical industry, and NICE to create a sustainable model for the commissioning of chemotherapy. The agency has also updated its procedures for evaluating drugs in the CDF, in an effort to ensure sustainability.

In addition, NHS England has set up an appeals process by which pharmaceutical companies can challenge the decision-making process.

And a newly assembled national taskforce, headed by Harpal Kumar, chief executive of Cancer Research UK, is set to produce a refreshed, 5-year cancer plan for the NHS.

Prescription medications

Credit: Steven Harbour

The National Health Service (NHS) has increased the budget for England’s Cancer Drugs Fund (CDF) and  added a new drug to treat 2 hematologic malignancies, but 5 other blood cancer drugs will be removed from the fund in March.

The budget for the CDF will grow from £200 million in 2013/14 to £280 million in 2014/15.

However, 16 drugs (for 25 different indications) will no longer be offered through the fund as of March 12, 2015.

Still, the NHS said it has taken steps to ensure patients can receive appropriate treatment.

Review leads to cuts

A national panel of oncologists, pharmacists, and patient representatives independently reviewed the drug indications currently available through the CDF, plus new applications.

They evaluated the clinical benefit, survival, quality of life, toxicity, and safety associated with each treatment, as well as the level of unmet need and the median cost per patient. In cases where the high cost of a drug would lead to its exclusion from CDF, manufacturers were given an opportunity to reduce prices.

The result of the review is that 59 of the 84 most effective currently approved indications of drugs will rollover into the CDF next year, creating room for new drug indications that will be funded for the first time.

These are panitumumab for bowel cancer, ibrutinib for mantle cell lymphoma, and ibrutinib for chronic lymphocytic leukemia.

However, 16 drugs, including 5 blood cancer drugs—bendamustine, bortezomib, bosutinib, dasatinib, and ofatumumab—will no longer be offered through the CDF.

Following these changes, the NHS will put 4 measures in place to ensure patients can receive appropriate treatment. First, any patient currently receiving a drug through the CDF will continue to receive it, regardless of whether it remains in the CDF.

Second, drugs that are the only therapy for the cancer in question will remain available through the CDF. Third, if the CDF panel removes a drug for a particular indication, some patients may instead be able to receive it in another line of therapy or receive an alternative CDF-approved drug.

And finally, clinicians can apply for their patient to receive a drug not available through the CDF on an exceptional basis.

Cuts to blood cancer drugs

The full list of cuts to the CDF is available on the NHS website, but the following list includes all drugs for hematologic malignancies that will no longer be available. These drugs will still be available for other indications, however.

1. Bendamustine for the treatment of low-grade lymphoma that is refractory to rituximab alone or in combination.
2. Bortezomib for the treatment of:

   • relapsed/refractory mantle cell lymphoma after 1 or more prior chemotherapies or stem cell transplant
   • relapsed multiple myeloma patients with a previous partial response or complete response of 6 months or more with bortezomib
   • relapsed Waldenstrom’s macroglobulinemia patients who received previous treatment with alkylating agents and purine analogues.

3. Bosutinib for the treatment of:

   • blast crisis chronic myeloid leukemia (CML) that is refractory to nilotinib or dasatinib if dasatinib was accessed via a clinical trial or via its current approved CDF indication
   • blast crisis CML where there is treatment intolerance, specifically, significant intolerance to dasatinib (grade 3 or 4 adverse events) if dasatinib was accessed via its current approved CDF indication.

4. Dasatinib for the treatment of lymphoid, blast crisis CML that is refractory to, significantly intolerant of, or resistant to prior therapy including imatinib (grade 3 or 4 adverse events); also when used as the 2nd- or 3rd-line treatment.
5. Ofatumumab for the treatment of CML as the 2nd- or 3rd-line indication and if the patient is refractory to treatment with fludarabine in combination and/or alemtuzumab or if treatment with fludarabine in combination and/or alemtuzumab is contraindicated.

More about the CDF and the NHS

The CDF—set up in 2010 and currently due to run until March 2016—is money the government has set aside to pay for cancer drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the NHS in England. Most cancer drugs are routinely funded outside of the CDF.

NHS England said it is working with cancer charities, the pharmaceutical industry, and NICE to create a sustainable model for the commissioning of chemotherapy. The agency has also updated its procedures for evaluating drugs in the CDF, in an effort to ensure sustainability.

In addition, NHS England has set up an appeals process by which pharmaceutical companies can challenge the decision-making process.

And a newly assembled national taskforce, headed by Harpal Kumar, chief executive of Cancer Research UK, is set to produce a refreshed, 5-year cancer plan for the NHS.

Doctor consults with cancer

patient and her father

Credit: Rhoda Baer

New research shows that, even decades after being cured, many cancer survivors face challenges resulting from their disease and its treatment.

A survey of more than 1500 cancer survivors revealed 16 themes of challenges or unmet needs, such as physical dysfunction, financial problems, a lack of education about cancer survival, and anxiety about cancer recurrence.

Mary Ann Burg, PhD, of the University of Central Florida in Orlando, and her colleagues reported these findings in Cancer.

To assess the unmet needs of cancer survivors, the researchers evaluated responses from an American Cancer Society survey in which subjects responded to the open-ended question, “Please tell us about any needs you have now as a cancer survivor that are not being met to your satisfaction.”

There were a total of 1514 respondents who were 2, 5, or 10 years from cancer diagnosis. They were 24 to 97 years of age, 65.4% were female, and 24.8% were racial/ethnic minorities (black and Hispanic/Latino).

“This study was unique in that it gave a very large sample of cancer survivors a real voice to express their needs and concerns,” Dr Burg said.

The researchers found that the number and type of challenges/unmet needs were not associated with a subject’s time since cancer treatment, although older cancer survivors tended to report fewer unmet needs than younger survivors.

Sixteen themes of challenges/unmet needs emerged from respondents’ answers, with physical issues being the most common. About 38% of respondents reported physical issues, such as pain, symptoms, and sexual dysfunction.

About 20% reported financial problems, such as issues with insurance and the affordability of needed services and products. About 20% also said they had needs related to unanswered questions and a lack of knowledge about what to expect as a cancer survivor, including guidance on follow-up care and cancer risks, causes, and prevention.

About 16% of respondents cited issues relating to personal control (a lack of physical and social autonomy). And about 16% described flaws and constraints in the healthcare system that affected early detection, diagnosis, treatment, follow-up care, and continuity of care.

About 14% of respondents reported a lack of resources (such as supplies, equipment, and medications), and about 14% cited emotional and mental health issues (such as fear of cancer recurrence, depression, and anxiety).

About 13% of respondents said they lacked social support (such as access to support groups), and 10% reported issues relating to societal perceptions of cancer survivors (such as discrimination and misinformation).

About 9% of respondents expressed the need to talk about or explain the cancer experience with their physician, friends, and family. And about 9% cited a lack of trust in healthcare providers.

Other themes included the wish for more effective cancer treatments (3.5%), body image issues such as feeling unattractive or losing trust in the body (3.5%), issues with the “survivor” identity (3.1%), trouble obtaining or maintaining appropriate employment (2.3%), and existential issues, such as finding meaning in the cancer experience (0.6%).

“Overall, we found that cancer survivors are often caught off guard by the lingering problems they experience after cancer treatment,” Dr Burg said. “In the wake of cancer, many survivors feel they have lost a sense of personal control, have reduced quality of life, and are frustrated that these problems are not sufficiently addressed within the medical care system.”

She added that this study points to several areas in which we might work to improve the situation, including raising public awareness of cancer survivors’ problems, promoting honest professional communication about the side effects of cancer and its treatment, and coordinating medical care resources to help survivors and their families cope with lingering challenges.

Doctor consults with cancer

patient and her father

Credit: Rhoda Baer

New research shows that, even decades after being cured, many cancer survivors face challenges resulting from their disease and its treatment.

A survey of more than 1500 cancer survivors revealed 16 themes of challenges or unmet needs, such as physical dysfunction, financial problems, a lack of education about cancer survival, and anxiety about cancer recurrence.

Mary Ann Burg, PhD, of the University of Central Florida in Orlando, and her colleagues reported these findings in Cancer.

To assess the unmet needs of cancer survivors, the researchers evaluated responses from an American Cancer Society survey in which subjects responded to the open-ended question, “Please tell us about any needs you have now as a cancer survivor that are not being met to your satisfaction.”

There were a total of 1514 respondents who were 2, 5, or 10 years from cancer diagnosis. They were 24 to 97 years of age, 65.4% were female, and 24.8% were racial/ethnic minorities (black and Hispanic/Latino).

“This study was unique in that it gave a very large sample of cancer survivors a real voice to express their needs and concerns,” Dr Burg said.

The researchers found that the number and type of challenges/unmet needs were not associated with a subject’s time since cancer treatment, although older cancer survivors tended to report fewer unmet needs than younger survivors.

Sixteen themes of challenges/unmet needs emerged from respondents’ answers, with physical issues being the most common. About 38% of respondents reported physical issues, such as pain, symptoms, and sexual dysfunction.

About 20% reported financial problems, such as issues with insurance and the affordability of needed services and products. About 20% also said they had needs related to unanswered questions and a lack of knowledge about what to expect as a cancer survivor, including guidance on follow-up care and cancer risks, causes, and prevention.

About 16% of respondents cited issues relating to personal control (a lack of physical and social autonomy). And about 16% described flaws and constraints in the healthcare system that affected early detection, diagnosis, treatment, follow-up care, and continuity of care.

About 14% of respondents reported a lack of resources (such as supplies, equipment, and medications), and about 14% cited emotional and mental health issues (such as fear of cancer recurrence, depression, and anxiety).

About 13% of respondents said they lacked social support (such as access to support groups), and 10% reported issues relating to societal perceptions of cancer survivors (such as discrimination and misinformation).

About 9% of respondents expressed the need to talk about or explain the cancer experience with their physician, friends, and family. And about 9% cited a lack of trust in healthcare providers.

Other themes included the wish for more effective cancer treatments (3.5%), body image issues such as feeling unattractive or losing trust in the body (3.5%), issues with the “survivor” identity (3.1%), trouble obtaining or maintaining appropriate employment (2.3%), and existential issues, such as finding meaning in the cancer experience (0.6%).

“Overall, we found that cancer survivors are often caught off guard by the lingering problems they experience after cancer treatment,” Dr Burg said. “In the wake of cancer, many survivors feel they have lost a sense of personal control, have reduced quality of life, and are frustrated that these problems are not sufficiently addressed within the medical care system.”

She added that this study points to several areas in which we might work to improve the situation, including raising public awareness of cancer survivors’ problems, promoting honest professional communication about the side effects of cancer and its treatment, and coordinating medical care resources to help survivors and their families cope with lingering challenges.

Doctor consults with cancer

patient and her father

Credit: Rhoda Baer

New research shows that, even decades after being cured, many cancer survivors face challenges resulting from their disease and its treatment.

A survey of more than 1500 cancer survivors revealed 16 themes of challenges or unmet needs, such as physical dysfunction, financial problems, a lack of education about cancer survival, and anxiety about cancer recurrence.

Mary Ann Burg, PhD, of the University of Central Florida in Orlando, and her colleagues reported these findings in Cancer.

To assess the unmet needs of cancer survivors, the researchers evaluated responses from an American Cancer Society survey in which subjects responded to the open-ended question, “Please tell us about any needs you have now as a cancer survivor that are not being met to your satisfaction.”

There were a total of 1514 respondents who were 2, 5, or 10 years from cancer diagnosis. They were 24 to 97 years of age, 65.4% were female, and 24.8% were racial/ethnic minorities (black and Hispanic/Latino).

“This study was unique in that it gave a very large sample of cancer survivors a real voice to express their needs and concerns,” Dr Burg said.

The researchers found that the number and type of challenges/unmet needs were not associated with a subject’s time since cancer treatment, although older cancer survivors tended to report fewer unmet needs than younger survivors.

Sixteen themes of challenges/unmet needs emerged from respondents’ answers, with physical issues being the most common. About 38% of respondents reported physical issues, such as pain, symptoms, and sexual dysfunction.

About 20% reported financial problems, such as issues with insurance and the affordability of needed services and products. About 20% also said they had needs related to unanswered questions and a lack of knowledge about what to expect as a cancer survivor, including guidance on follow-up care and cancer risks, causes, and prevention.

About 16% of respondents cited issues relating to personal control (a lack of physical and social autonomy). And about 16% described flaws and constraints in the healthcare system that affected early detection, diagnosis, treatment, follow-up care, and continuity of care.

About 14% of respondents reported a lack of resources (such as supplies, equipment, and medications), and about 14% cited emotional and mental health issues (such as fear of cancer recurrence, depression, and anxiety).

About 13% of respondents said they lacked social support (such as access to support groups), and 10% reported issues relating to societal perceptions of cancer survivors (such as discrimination and misinformation).

About 9% of respondents expressed the need to talk about or explain the cancer experience with their physician, friends, and family. And about 9% cited a lack of trust in healthcare providers.

Other themes included the wish for more effective cancer treatments (3.5%), body image issues such as feeling unattractive or losing trust in the body (3.5%), issues with the “survivor” identity (3.1%), trouble obtaining or maintaining appropriate employment (2.3%), and existential issues, such as finding meaning in the cancer experience (0.6%).

“Overall, we found that cancer survivors are often caught off guard by the lingering problems they experience after cancer treatment,” Dr Burg said. “In the wake of cancer, many survivors feel they have lost a sense of personal control, have reduced quality of life, and are frustrated that these problems are not sufficiently addressed within the medical care system.”

She added that this study points to several areas in which we might work to improve the situation, including raising public awareness of cancer survivors’ problems, promoting honest professional communication about the side effects of cancer and its treatment, and coordinating medical care resources to help survivors and their families cope with lingering challenges.

Syringe

A study of more than 2000 patients refutes the idea that biopsies cause cancer to spread.

In a study published in Gut, researchers showed that patients who received a biopsy had better overall survival and similar cancer-free survival rates as patients who did not have a biopsy.

The team studied pancreatic cancer but said their findings likely apply to other cancers because the diagnostic technique used in this study—fine needle aspiration—is commonly used across tumor types.

“This study shows that physicians and patients should feel reassured that a biopsy is very safe,” said study author Michael Wallace, MD, of the Mayo Clinic in Jacksonville, Florida.

“We do millions of biopsies of cancer a year in the US, but one or two case studies have led to this common myth that biopsies spread cancer.”

This is the second study Dr Wallace and his team have conducted to examine the risk of biopsy.

In a 2013 study published in Endoscopy, the researchers examined outcomes in 256 pancreatic cancer patients treated at the Mayo Clinic in Jacksonville. The team found no difference in cancer recurrence between 208 patients who had ultrasound-guided fine needle aspiration (EUS-FNA) and the 48 patients who did not have a biopsy.

In the current study, the researchers examined 11 years (1998-2009) of Medicare data on patients with non-metastatic pancreatic cancer who underwent surgery. The team examined overall survival and pancreatic cancer-specific survival in 498 patients who had EUS-FNA and in 1536 patients who did not have a biopsy.

During a mean follow-up time of 21 months, 285 patients (57%) in the EUS-FNA group and 1167 patients (76%) in the non-EUS-FNA group died. Pancreatic cancer was identified as the cause of death for 251 patients (50%) in the EUS-FNA group and 980 patients (64%) in the non-EUS-FNA group.

The median overall survival in the EUS-FNA group was 22 months, compared to 15 months in the non-EUS-FNA group. Multivariate analysis showed that receipt of EUS-FNA had a borderline significant association with improved overall survival (hazard ratio=0.84, P=0.03).

The median cancer-specific survival was 24 months in the EUS-FNA group and 18 months in the non-EUS-FNA group. Multivariate analysis revealed no significant difference between the two groups (hazard ratio=0.87, P=0.12).

“[Biopsies provide] very valuable information that allow us to tailor treatment,” Dr Wallace noted. “In some cases, we can offer chemotherapy and radiation before surgery for a better outcome, and, in other cases, we can avoid surgery and other therapy altogether.”

Syringe

A study of more than 2000 patients refutes the idea that biopsies cause cancer to spread.

In a study published in Gut, researchers showed that patients who received a biopsy had better overall survival and similar cancer-free survival rates as patients who did not have a biopsy.

The team studied pancreatic cancer but said their findings likely apply to other cancers because the diagnostic technique used in this study—fine needle aspiration—is commonly used across tumor types.

“This study shows that physicians and patients should feel reassured that a biopsy is very safe,” said study author Michael Wallace, MD, of the Mayo Clinic in Jacksonville, Florida.

“We do millions of biopsies of cancer a year in the US, but one or two case studies have led to this common myth that biopsies spread cancer.”

This is the second study Dr Wallace and his team have conducted to examine the risk of biopsy.

In a 2013 study published in Endoscopy, the researchers examined outcomes in 256 pancreatic cancer patients treated at the Mayo Clinic in Jacksonville. The team found no difference in cancer recurrence between 208 patients who had ultrasound-guided fine needle aspiration (EUS-FNA) and the 48 patients who did not have a biopsy.

In the current study, the researchers examined 11 years (1998-2009) of Medicare data on patients with non-metastatic pancreatic cancer who underwent surgery. The team examined overall survival and pancreatic cancer-specific survival in 498 patients who had EUS-FNA and in 1536 patients who did not have a biopsy.

During a mean follow-up time of 21 months, 285 patients (57%) in the EUS-FNA group and 1167 patients (76%) in the non-EUS-FNA group died. Pancreatic cancer was identified as the cause of death for 251 patients (50%) in the EUS-FNA group and 980 patients (64%) in the non-EUS-FNA group.

The median overall survival in the EUS-FNA group was 22 months, compared to 15 months in the non-EUS-FNA group. Multivariate analysis showed that receipt of EUS-FNA had a borderline significant association with improved overall survival (hazard ratio=0.84, P=0.03).

The median cancer-specific survival was 24 months in the EUS-FNA group and 18 months in the non-EUS-FNA group. Multivariate analysis revealed no significant difference between the two groups (hazard ratio=0.87, P=0.12).

“[Biopsies provide] very valuable information that allow us to tailor treatment,” Dr Wallace noted. “In some cases, we can offer chemotherapy and radiation before surgery for a better outcome, and, in other cases, we can avoid surgery and other therapy altogether.”

Syringe

A study of more than 2000 patients refutes the idea that biopsies cause cancer to spread.

In a study published in Gut, researchers showed that patients who received a biopsy had better overall survival and similar cancer-free survival rates as patients who did not have a biopsy.

The team studied pancreatic cancer but said their findings likely apply to other cancers because the diagnostic technique used in this study—fine needle aspiration—is commonly used across tumor types.

“This study shows that physicians and patients should feel reassured that a biopsy is very safe,” said study author Michael Wallace, MD, of the Mayo Clinic in Jacksonville, Florida.

“We do millions of biopsies of cancer a year in the US, but one or two case studies have led to this common myth that biopsies spread cancer.”

This is the second study Dr Wallace and his team have conducted to examine the risk of biopsy.

In a 2013 study published in Endoscopy, the researchers examined outcomes in 256 pancreatic cancer patients treated at the Mayo Clinic in Jacksonville. The team found no difference in cancer recurrence between 208 patients who had ultrasound-guided fine needle aspiration (EUS-FNA) and the 48 patients who did not have a biopsy.

In the current study, the researchers examined 11 years (1998-2009) of Medicare data on patients with non-metastatic pancreatic cancer who underwent surgery. The team examined overall survival and pancreatic cancer-specific survival in 498 patients who had EUS-FNA and in 1536 patients who did not have a biopsy.

During a mean follow-up time of 21 months, 285 patients (57%) in the EUS-FNA group and 1167 patients (76%) in the non-EUS-FNA group died. Pancreatic cancer was identified as the cause of death for 251 patients (50%) in the EUS-FNA group and 980 patients (64%) in the non-EUS-FNA group.

The median overall survival in the EUS-FNA group was 22 months, compared to 15 months in the non-EUS-FNA group. Multivariate analysis showed that receipt of EUS-FNA had a borderline significant association with improved overall survival (hazard ratio=0.84, P=0.03).

The median cancer-specific survival was 24 months in the EUS-FNA group and 18 months in the non-EUS-FNA group. Multivariate analysis revealed no significant difference between the two groups (hazard ratio=0.87, P=0.12).

“[Biopsies provide] very valuable information that allow us to tailor treatment,” Dr Wallace noted. “In some cases, we can offer chemotherapy and radiation before surgery for a better outcome, and, in other cases, we can avoid surgery and other therapy altogether.”

Micrograph showing MM

The US Food and Drug Administration (FDA) has granted selinexor (KPT-330) orphan drug designation to treat multiple myeloma (MM).

Selinexor already has orphan designation from the FDA to treat acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL).

The drug has also received orphan designation from the European Medicines Agency (EMA) to treat MM, AML, DLBCL, and chronic lymphocytic leukemia/small lymphocytic lymphoma, including Richter’s transformation.

“Orphan drug designation by the FDA for multiple myeloma is another significant milestone in the selinexor development program,” said Sharon Shacham, PhD, President and Chief Scientific Officer of Karyopharm Therapeutics, Inc., the company developing selinexor.

In the US, orphan designation qualifies a company for certain benefits, including an accelerated approval process, 7 years of market exclusivity following the drug’s approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

About selinexor

Selinexor (KPT-330) is a first-in-class, oral, selective inhibitor of nuclear export compound. The drug functions by inhibiting the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.

Selinexor combos in MM

In a poster presented at the 2014 ASH Annual Meeting (4773), researchers reported results observed with selinexor plus dexamethasone in preclinical models and in patients with heavily pretreated, refractory MM.

The study included 9 evaluable patients who received selinexor at 45 mg/m² twice weekly and dexamethasone at 20 mg twice weekly. The combination prompted an overall response rate of 67%, with one stringent complete response (11%) and 5 partial responses (56%), as well as a clinical benefit rate of 89%.

The combination demonstrated a reduction in nausea grades and very little weight loss compared with selinexor alone. The most common grade 1/2 adverse events were nausea, fatigue, anorexia, and vomiting.

The combination was also associated with an increase in time on study relative to selinexor alone. Sixty-six percent of patients remained on study for at least 16 weeks, including one patient for 28 weeks and one for 43 weeks as of December 1, 2014.

During the dose-evaluation part of the study, the 60 mg/m² selinexor dose was deemed intolerable in this heavily pretreated patient population. So 45 mg/m² is the recommended future study dose.

In another poster presented at the 2014 ASH Annual Meeting (3443), researchers described the activity of selinexor in combination with carfilzomib. This preclinical study revealed a novel, intracellular, membrane-embedded mechanism of caspase activation.

The results suggested a model of synergy wherein the selinexor-carfilzomib combination promotes caspase activation, likely by induced proximity, cleavage of other caspases, and subsequent apoptosis as well as autophagy.

Micrograph showing MM

The US Food and Drug Administration (FDA) has granted selinexor (KPT-330) orphan drug designation to treat multiple myeloma (MM).

Selinexor already has orphan designation from the FDA to treat acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL).

The drug has also received orphan designation from the European Medicines Agency (EMA) to treat MM, AML, DLBCL, and chronic lymphocytic leukemia/small lymphocytic lymphoma, including Richter’s transformation.

“Orphan drug designation by the FDA for multiple myeloma is another significant milestone in the selinexor development program,” said Sharon Shacham, PhD, President and Chief Scientific Officer of Karyopharm Therapeutics, Inc., the company developing selinexor.

In the US, orphan designation qualifies a company for certain benefits, including an accelerated approval process, 7 years of market exclusivity following the drug’s approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

About selinexor

Selinexor (KPT-330) is a first-in-class, oral, selective inhibitor of nuclear export compound. The drug functions by inhibiting the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.

Selinexor combos in MM

In a poster presented at the 2014 ASH Annual Meeting (4773), researchers reported results observed with selinexor plus dexamethasone in preclinical models and in patients with heavily pretreated, refractory MM.

The study included 9 evaluable patients who received selinexor at 45 mg/m² twice weekly and dexamethasone at 20 mg twice weekly. The combination prompted an overall response rate of 67%, with one stringent complete response (11%) and 5 partial responses (56%), as well as a clinical benefit rate of 89%.

The combination demonstrated a reduction in nausea grades and very little weight loss compared with selinexor alone. The most common grade 1/2 adverse events were nausea, fatigue, anorexia, and vomiting.

The combination was also associated with an increase in time on study relative to selinexor alone. Sixty-six percent of patients remained on study for at least 16 weeks, including one patient for 28 weeks and one for 43 weeks as of December 1, 2014.

During the dose-evaluation part of the study, the 60 mg/m² selinexor dose was deemed intolerable in this heavily pretreated patient population. So 45 mg/m² is the recommended future study dose.

In another poster presented at the 2014 ASH Annual Meeting (3443), researchers described the activity of selinexor in combination with carfilzomib. This preclinical study revealed a novel, intracellular, membrane-embedded mechanism of caspase activation.

The results suggested a model of synergy wherein the selinexor-carfilzomib combination promotes caspase activation, likely by induced proximity, cleavage of other caspases, and subsequent apoptosis as well as autophagy.

Micrograph showing MM

The US Food and Drug Administration (FDA) has granted selinexor (KPT-330) orphan drug designation to treat multiple myeloma (MM).

Selinexor already has orphan designation from the FDA to treat acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL).

The drug has also received orphan designation from the European Medicines Agency (EMA) to treat MM, AML, DLBCL, and chronic lymphocytic leukemia/small lymphocytic lymphoma, including Richter’s transformation.

“Orphan drug designation by the FDA for multiple myeloma is another significant milestone in the selinexor development program,” said Sharon Shacham, PhD, President and Chief Scientific Officer of Karyopharm Therapeutics, Inc., the company developing selinexor.

In the US, orphan designation qualifies a company for certain benefits, including an accelerated approval process, 7 years of market exclusivity following the drug’s approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

About selinexor

Selinexor (KPT-330) is a first-in-class, oral, selective inhibitor of nuclear export compound. The drug functions by inhibiting the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.

Selinexor combos in MM

In a poster presented at the 2014 ASH Annual Meeting (4773), researchers reported results observed with selinexor plus dexamethasone in preclinical models and in patients with heavily pretreated, refractory MM.

The study included 9 evaluable patients who received selinexor at 45 mg/m² twice weekly and dexamethasone at 20 mg twice weekly. The combination prompted an overall response rate of 67%, with one stringent complete response (11%) and 5 partial responses (56%), as well as a clinical benefit rate of 89%.

The combination demonstrated a reduction in nausea grades and very little weight loss compared with selinexor alone. The most common grade 1/2 adverse events were nausea, fatigue, anorexia, and vomiting.

The combination was also associated with an increase in time on study relative to selinexor alone. Sixty-six percent of patients remained on study for at least 16 weeks, including one patient for 28 weeks and one for 43 weeks as of December 1, 2014.

During the dose-evaluation part of the study, the 60 mg/m² selinexor dose was deemed intolerable in this heavily pretreated patient population. So 45 mg/m² is the recommended future study dose.

In another poster presented at the 2014 ASH Annual Meeting (3443), researchers described the activity of selinexor in combination with carfilzomib. This preclinical study revealed a novel, intracellular, membrane-embedded mechanism of caspase activation.

The results suggested a model of synergy wherein the selinexor-carfilzomib combination promotes caspase activation, likely by induced proximity, cleavage of other caspases, and subsequent apoptosis as well as autophagy.

Monoclonal antibodies

Credit: Linda Bartlett

SAN FRANCISCO—Combination therapy involving a novel monoclonal antibody (mAb) produces encouraging activity in relapsed or refractory multiple myeloma (MM), according to researchers.

The team conducted a phase 1b trial testing the IgG1 mAb SAR650984 in combination with lenalidomide and dexamethasone (SAR-len-dex).

The treatment produced an overall response rate (ORR) of 58% and a higher ORR among patients who received the highest dose of SAR.

Furthermore, the combination had a “very manageable safety profile,” according to study investigator Thomas Martin, MD, of the University of California at San Francisco.

“The safety findings are really consistent with those of the individual drugs,” he said.

Dr Martin presented these findings at the 2014 ASH Annual Meeting as abstract 83.* The trial was  sponsored by Sanofi (the company developing SAR), but investigators also received research funding from Karyopharm, Bristol Myers Squibb, Millennium, and Celgene.

Dr Martin explained that SAR is a humanized IgG1 mAb that binds selectively to a unique epitope on the human CD38 receptor, and it has 4 potential mechanisms of action: antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, direct apoptosis without crosslinking, and inhibition of CD38 enzyme activity.

He said there is “ample evidence” to suggest that SAR-len-dex would be active in MM. First, both lenalidomide and SAR have demonstrated single-agent activity in MM. Second, lenalidomide can increase IL-2 production, which leads to enhanced antibody-dependent cellular cytotoxicity. And finally, SAR and lenalidomide showed additive effects in a mouse model of MM.

With that in mind, Dr Martin and his colleagues decided to test SAR-len-dex in patients with relapsed or refractory MM.

The team enrolled 31 patients and administered SAR at 3 different dose levels. Patients received 3 mg/kg (n=4), 5 mg/kg (n=3), or 10 mg/kg (n=24) every 2 weeks. They received lenalidomide at 25 mg on days 1-21 per 28-day cycle and dexamethasone at 40 mg once a week on days 1, 8, 15, and 22.

The patients’ median age was 59 (range, 45-74), the median time since diagnosis was 4 years (range, 1-12), the median number of prior treatment regimens was 7 (range, 2-14), and the median number of prior lines of therapy was 4 (range, 1-11).

“The median time from the last lenalidomide-containing regimen was 9 months,” Dr Martin noted. “Ninety-four percent of the patients had prior lenalidomide, and 74% of these patients were lenalidomide refractory.”

Of the 29% of patients who had received prior pomalidomide, all were refractory to it. The same was true of the 48% of patients who received carfilzomib. And of the 94% of patients who received prior bortezomib, 52% were refractory to it.

Adverse events

The maximum-tolerated dose of SAR was not reached. Treatment-emergent adverse events occurring in 30% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, diarrhea, fatigue, insomnia, muscle spasms, nausea, pneumonia, pyrexia, and upper respiratory tract infections.

Grade 3/4 events occurring in 5% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, fatigue, insomnia, and pneumonia.

“All of these events are commonly associated with the backbone treatment of lenalidomide and dexamethasone, and no unexpected or untoward adverse events were seen,” Dr Martin noted.

The most common SAR-associated adverse events were infusion reactions. About 35% of patients experienced an infusion reaction in cycle 1, and 10% did so in cycle 2.

Most reactions were grade 1 and 2 and did not lead to treatment discontinuation. Two patients did discontinue treatment due to grade 3 infusion reactions, but both events were ultimately resolved.

Response and survival

The ORR was 58% (n=18), and the clinical benefit rate was 65% (n=20). Two patients had a stringent complete response, 7 had a very good partial response, 9 had a partial response, 2 had a minimal response, 6 had stable disease, 4 progressed, and 1 was not evaluable.

Responses were seen at all dose levels, but the best responses occurred in patients who received the highest dose of SAR. Among patients who received the highest dose, the ORR was 68%, and the clinical benefit rate was 65%.

The ORR was 50% in patients who were refractory to prior treatment with an immunomodulatory drug, 40% in patients who were refractory to carfilzomib, and 33% in patients who were refractory to pomalidomide.

At 9 months of follow-up, the median progression-free survival was 6.2 months. The median progression-free survival was not reached for patients who had received 1 to 2 prior lines of therapy, and it was 5.8 months for patients who had received 3 or more prior lines of therapy.

“SAR in combination with lenalidomide/dexamethasone showed encouraging activity in this heavily pretreated population,” Dr Martin said in closing, adding that the combination compares favorably to other treatments tested in patients who received the same number of prior lines of therapy.

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

Monoclonal antibodies

Credit: Linda Bartlett

SAN FRANCISCO—Combination therapy involving a novel monoclonal antibody (mAb) produces encouraging activity in relapsed or refractory multiple myeloma (MM), according to researchers.

The team conducted a phase 1b trial testing the IgG1 mAb SAR650984 in combination with lenalidomide and dexamethasone (SAR-len-dex).

The treatment produced an overall response rate (ORR) of 58% and a higher ORR among patients who received the highest dose of SAR.

Furthermore, the combination had a “very manageable safety profile,” according to study investigator Thomas Martin, MD, of the University of California at San Francisco.

“The safety findings are really consistent with those of the individual drugs,” he said.

Dr Martin presented these findings at the 2014 ASH Annual Meeting as abstract 83.* The trial was  sponsored by Sanofi (the company developing SAR), but investigators also received research funding from Karyopharm, Bristol Myers Squibb, Millennium, and Celgene.

Dr Martin explained that SAR is a humanized IgG1 mAb that binds selectively to a unique epitope on the human CD38 receptor, and it has 4 potential mechanisms of action: antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, direct apoptosis without crosslinking, and inhibition of CD38 enzyme activity.

He said there is “ample evidence” to suggest that SAR-len-dex would be active in MM. First, both lenalidomide and SAR have demonstrated single-agent activity in MM. Second, lenalidomide can increase IL-2 production, which leads to enhanced antibody-dependent cellular cytotoxicity. And finally, SAR and lenalidomide showed additive effects in a mouse model of MM.

With that in mind, Dr Martin and his colleagues decided to test SAR-len-dex in patients with relapsed or refractory MM.

The team enrolled 31 patients and administered SAR at 3 different dose levels. Patients received 3 mg/kg (n=4), 5 mg/kg (n=3), or 10 mg/kg (n=24) every 2 weeks. They received lenalidomide at 25 mg on days 1-21 per 28-day cycle and dexamethasone at 40 mg once a week on days 1, 8, 15, and 22.

The patients’ median age was 59 (range, 45-74), the median time since diagnosis was 4 years (range, 1-12), the median number of prior treatment regimens was 7 (range, 2-14), and the median number of prior lines of therapy was 4 (range, 1-11).

“The median time from the last lenalidomide-containing regimen was 9 months,” Dr Martin noted. “Ninety-four percent of the patients had prior lenalidomide, and 74% of these patients were lenalidomide refractory.”

Of the 29% of patients who had received prior pomalidomide, all were refractory to it. The same was true of the 48% of patients who received carfilzomib. And of the 94% of patients who received prior bortezomib, 52% were refractory to it.

Adverse events

The maximum-tolerated dose of SAR was not reached. Treatment-emergent adverse events occurring in 30% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, diarrhea, fatigue, insomnia, muscle spasms, nausea, pneumonia, pyrexia, and upper respiratory tract infections.

Grade 3/4 events occurring in 5% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, fatigue, insomnia, and pneumonia.

“All of these events are commonly associated with the backbone treatment of lenalidomide and dexamethasone, and no unexpected or untoward adverse events were seen,” Dr Martin noted.

The most common SAR-associated adverse events were infusion reactions. About 35% of patients experienced an infusion reaction in cycle 1, and 10% did so in cycle 2.

Most reactions were grade 1 and 2 and did not lead to treatment discontinuation. Two patients did discontinue treatment due to grade 3 infusion reactions, but both events were ultimately resolved.

Response and survival

The ORR was 58% (n=18), and the clinical benefit rate was 65% (n=20). Two patients had a stringent complete response, 7 had a very good partial response, 9 had a partial response, 2 had a minimal response, 6 had stable disease, 4 progressed, and 1 was not evaluable.

Responses were seen at all dose levels, but the best responses occurred in patients who received the highest dose of SAR. Among patients who received the highest dose, the ORR was 68%, and the clinical benefit rate was 65%.

The ORR was 50% in patients who were refractory to prior treatment with an immunomodulatory drug, 40% in patients who were refractory to carfilzomib, and 33% in patients who were refractory to pomalidomide.

At 9 months of follow-up, the median progression-free survival was 6.2 months. The median progression-free survival was not reached for patients who had received 1 to 2 prior lines of therapy, and it was 5.8 months for patients who had received 3 or more prior lines of therapy.

“SAR in combination with lenalidomide/dexamethasone showed encouraging activity in this heavily pretreated population,” Dr Martin said in closing, adding that the combination compares favorably to other treatments tested in patients who received the same number of prior lines of therapy.

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

Monoclonal antibodies

Credit: Linda Bartlett

SAN FRANCISCO—Combination therapy involving a novel monoclonal antibody (mAb) produces encouraging activity in relapsed or refractory multiple myeloma (MM), according to researchers.

The team conducted a phase 1b trial testing the IgG1 mAb SAR650984 in combination with lenalidomide and dexamethasone (SAR-len-dex).

The treatment produced an overall response rate (ORR) of 58% and a higher ORR among patients who received the highest dose of SAR.

Furthermore, the combination had a “very manageable safety profile,” according to study investigator Thomas Martin, MD, of the University of California at San Francisco.

“The safety findings are really consistent with those of the individual drugs,” he said.

Dr Martin presented these findings at the 2014 ASH Annual Meeting as abstract 83.* The trial was  sponsored by Sanofi (the company developing SAR), but investigators also received research funding from Karyopharm, Bristol Myers Squibb, Millennium, and Celgene.

Dr Martin explained that SAR is a humanized IgG1 mAb that binds selectively to a unique epitope on the human CD38 receptor, and it has 4 potential mechanisms of action: antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, direct apoptosis without crosslinking, and inhibition of CD38 enzyme activity.

He said there is “ample evidence” to suggest that SAR-len-dex would be active in MM. First, both lenalidomide and SAR have demonstrated single-agent activity in MM. Second, lenalidomide can increase IL-2 production, which leads to enhanced antibody-dependent cellular cytotoxicity. And finally, SAR and lenalidomide showed additive effects in a mouse model of MM.

With that in mind, Dr Martin and his colleagues decided to test SAR-len-dex in patients with relapsed or refractory MM.

The team enrolled 31 patients and administered SAR at 3 different dose levels. Patients received 3 mg/kg (n=4), 5 mg/kg (n=3), or 10 mg/kg (n=24) every 2 weeks. They received lenalidomide at 25 mg on days 1-21 per 28-day cycle and dexamethasone at 40 mg once a week on days 1, 8, 15, and 22.

The patients’ median age was 59 (range, 45-74), the median time since diagnosis was 4 years (range, 1-12), the median number of prior treatment regimens was 7 (range, 2-14), and the median number of prior lines of therapy was 4 (range, 1-11).

“The median time from the last lenalidomide-containing regimen was 9 months,” Dr Martin noted. “Ninety-four percent of the patients had prior lenalidomide, and 74% of these patients were lenalidomide refractory.”

Of the 29% of patients who had received prior pomalidomide, all were refractory to it. The same was true of the 48% of patients who received carfilzomib. And of the 94% of patients who received prior bortezomib, 52% were refractory to it.

Adverse events

The maximum-tolerated dose of SAR was not reached. Treatment-emergent adverse events occurring in 30% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, diarrhea, fatigue, insomnia, muscle spasms, nausea, pneumonia, pyrexia, and upper respiratory tract infections.

Grade 3/4 events occurring in 5% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, fatigue, insomnia, and pneumonia.

“All of these events are commonly associated with the backbone treatment of lenalidomide and dexamethasone, and no unexpected or untoward adverse events were seen,” Dr Martin noted.

The most common SAR-associated adverse events were infusion reactions. About 35% of patients experienced an infusion reaction in cycle 1, and 10% did so in cycle 2.

Most reactions were grade 1 and 2 and did not lead to treatment discontinuation. Two patients did discontinue treatment due to grade 3 infusion reactions, but both events were ultimately resolved.

Response and survival

The ORR was 58% (n=18), and the clinical benefit rate was 65% (n=20). Two patients had a stringent complete response, 7 had a very good partial response, 9 had a partial response, 2 had a minimal response, 6 had stable disease, 4 progressed, and 1 was not evaluable.

Responses were seen at all dose levels, but the best responses occurred in patients who received the highest dose of SAR. Among patients who received the highest dose, the ORR was 68%, and the clinical benefit rate was 65%.

The ORR was 50% in patients who were refractory to prior treatment with an immunomodulatory drug, 40% in patients who were refractory to carfilzomib, and 33% in patients who were refractory to pomalidomide.

At 9 months of follow-up, the median progression-free survival was 6.2 months. The median progression-free survival was not reached for patients who had received 1 to 2 prior lines of therapy, and it was 5.8 months for patients who had received 3 or more prior lines of therapy.

“SAR in combination with lenalidomide/dexamethasone showed encouraging activity in this heavily pretreated population,” Dr Martin said in closing, adding that the combination compares favorably to other treatments tested in patients who received the same number of prior lines of therapy.

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

Micrograph showing MM

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is recommending approval of continuous oral treatment with lenalidomide (Revlimid) in adults with previously untreated multiple myeloma (MM) who are ineligible for hematopoietic stem cell transplant (HSCT).

The European Commission, which generally follows the CHMP’s recommendations, is expected to make its final decision in about 2 months.

Lenalidomide is not currently approved to treat newly diagnosed MM in any country.

The drug is approved in the European Union (EU) for use in combination with dexamethasone to treat adults with MM who have received at least one 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.

The CHMP’s recommendation to extend the use of lenalidomide to HSCT-ineligible patients with newly diagnosed MM 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 HSCT.

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.

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.

Micrograph showing MM

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is recommending approval of continuous oral treatment with lenalidomide (Revlimid) in adults with previously untreated multiple myeloma (MM) who are ineligible for hematopoietic stem cell transplant (HSCT).

The European Commission, which generally follows the CHMP’s recommendations, is expected to make its final decision in about 2 months.

Lenalidomide is not currently approved to treat newly diagnosed MM in any country.

The drug is approved in the European Union (EU) for use in combination with dexamethasone to treat adults with MM who have received at least one 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.

The CHMP’s recommendation to extend the use of lenalidomide to HSCT-ineligible patients with newly diagnosed MM 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 HSCT.

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.

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.

Micrograph showing MM

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is recommending approval of continuous oral treatment with lenalidomide (Revlimid) in adults with previously untreated multiple myeloma (MM) who are ineligible for hematopoietic stem cell transplant (HSCT).

The European Commission, which generally follows the CHMP’s recommendations, is expected to make its final decision in about 2 months.

Lenalidomide is not currently approved to treat newly diagnosed MM in any country.

The drug is approved in the European Union (EU) for use in combination with dexamethasone to treat adults with MM who have received at least one 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.

The CHMP’s recommendation to extend the use of lenalidomide to HSCT-ineligible patients with newly diagnosed MM 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 HSCT.

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.

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.

Donald Metcalf, MD

Photo courtesy of The Walter

and Eliza Hall Institute

of Medical Research

Donald Metcalf, MD, an Australian researcher who has been called “the father of hematopoietic cytokines,” has died at the age of 85.

Dr Metcalf’s studies of blood production led to his speculation that there must be a biological mechanism—one or more hormones—that control white blood cell production.

These substances, which he termed colony-stimulating factors (CSFs), were the focus of more than 50 years of research.

Over this time, Dr Metcalf led researchers to characterize and purify 4 separate CSFs—granulocyte CSF (G-CSF), granulocyte-macrophage CSF (GM-CSF), macrophage CSF (M-CSF), and multi-CSF (now called interleukin-3).

Dr Metcalf recognized that CSFs had a potential role in clinical medicine, and his team was among the first in the world to discover the genes for CSFs.

Dr Metcalf was a central figure in the international clinical trials of CSFs in the 1980s, assessing whether CSFs could boost immune cell numbers in cancer patients whose immune system was weakened as a side effect of chemotherapy. On the basis of these studies, G-CSF (Neupogen) was approved for clinical use in 1991.

Now, an estimated 20 million people have been treated with CSFs. As well as boosting the immune system in patients who receive chemotherapy or have other immune deficiencies, CSFs are thought to have revolutionized hematopoietic stem cell transplantation.

A man with many achievements

Dr Metcalf was born in 1929 and started school at the age of 3, by which time he was already reading. He entered university at the age of 16, ultimately obtaining bachelor’s and medical degrees from the University of Sydney.

After an internship at the Royal Prince Alfred Hospital in Sydney, Dr Metcalf joined the staff of the Walter and Eliza Hall Institute of Medical Research (WEHI) in Melbourne in 1954. He was supported by Cancer Council Victoria’s Carden Fellowship, an award he held until his retirement in 2014. (Dr Metcalf officially retired in 1996 but continued to do research until 2014.)

Dr Metcalf spent his early years at WEHI studying vaccinia virus. In 1965, he began studying blood cell formation and, by association, leukemia. In 1966, he became deputy director of WEHI and the head of its Cancer Research Unit.

Dr Metcalf took several sabbaticals from WEHI, serving as a visiting scientist at Harvard Medical School in Boston, Massachusetts; the Roswell Park Memorial Institute in Buffalo, New York; the Swiss Institute for Experimental Cancer Research in Lausanne, Switzerland; the Radiobiological Institute in Rijswijk, The Netherlands; and the University of Cambridge in the UK.

Among Dr Metcalf’s many honors and awards are the Companion of the Order of Australia (1993), the Albert Lasker Award for Clinical Medical Research (1993), the Gairdner Foundation International Award (1994), the Royal Medal of the Royal Society (1995), the Victoria Prize (2000), and the Prime Minister’s Prize for Science (2001).

Dr Metcalf is survived by his wife Jo; daughters Kate, Johanna, Penelope, and Mary-Ann; grandchildren James, Martin, Patrick, Elizabeth, Rose, and Robert; and their extended families.

Donald Metcalf, MD

Photo courtesy of The Walter

and Eliza Hall Institute

of Medical Research

Donald Metcalf, MD, an Australian researcher who has been called “the father of hematopoietic cytokines,” has died at the age of 85.

Dr Metcalf’s studies of blood production led to his speculation that there must be a biological mechanism—one or more hormones—that control white blood cell production.

These substances, which he termed colony-stimulating factors (CSFs), were the focus of more than 50 years of research.

Over this time, Dr Metcalf led researchers to characterize and purify 4 separate CSFs—granulocyte CSF (G-CSF), granulocyte-macrophage CSF (GM-CSF), macrophage CSF (M-CSF), and multi-CSF (now called interleukin-3).

Dr Metcalf recognized that CSFs had a potential role in clinical medicine, and his team was among the first in the world to discover the genes for CSFs.

Dr Metcalf was a central figure in the international clinical trials of CSFs in the 1980s, assessing whether CSFs could boost immune cell numbers in cancer patients whose immune system was weakened as a side effect of chemotherapy. On the basis of these studies, G-CSF (Neupogen) was approved for clinical use in 1991.

Now, an estimated 20 million people have been treated with CSFs. As well as boosting the immune system in patients who receive chemotherapy or have other immune deficiencies, CSFs are thought to have revolutionized hematopoietic stem cell transplantation.

A man with many achievements

Dr Metcalf was born in 1929 and started school at the age of 3, by which time he was already reading. He entered university at the age of 16, ultimately obtaining bachelor’s and medical degrees from the University of Sydney.

After an internship at the Royal Prince Alfred Hospital in Sydney, Dr Metcalf joined the staff of the Walter and Eliza Hall Institute of Medical Research (WEHI) in Melbourne in 1954. He was supported by Cancer Council Victoria’s Carden Fellowship, an award he held until his retirement in 2014. (Dr Metcalf officially retired in 1996 but continued to do research until 2014.)

Dr Metcalf spent his early years at WEHI studying vaccinia virus. In 1965, he began studying blood cell formation and, by association, leukemia. In 1966, he became deputy director of WEHI and the head of its Cancer Research Unit.

Dr Metcalf took several sabbaticals from WEHI, serving as a visiting scientist at Harvard Medical School in Boston, Massachusetts; the Roswell Park Memorial Institute in Buffalo, New York; the Swiss Institute for Experimental Cancer Research in Lausanne, Switzerland; the Radiobiological Institute in Rijswijk, The Netherlands; and the University of Cambridge in the UK.

Among Dr Metcalf’s many honors and awards are the Companion of the Order of Australia (1993), the Albert Lasker Award for Clinical Medical Research (1993), the Gairdner Foundation International Award (1994), the Royal Medal of the Royal Society (1995), the Victoria Prize (2000), and the Prime Minister’s Prize for Science (2001).

Dr Metcalf is survived by his wife Jo; daughters Kate, Johanna, Penelope, and Mary-Ann; grandchildren James, Martin, Patrick, Elizabeth, Rose, and Robert; and their extended families.

Donald Metcalf, MD

Photo courtesy of The Walter

and Eliza Hall Institute

of Medical Research

Donald Metcalf, MD, an Australian researcher who has been called “the father of hematopoietic cytokines,” has died at the age of 85.

Dr Metcalf’s studies of blood production led to his speculation that there must be a biological mechanism—one or more hormones—that control white blood cell production.

These substances, which he termed colony-stimulating factors (CSFs), were the focus of more than 50 years of research.

Over this time, Dr Metcalf led researchers to characterize and purify 4 separate CSFs—granulocyte CSF (G-CSF), granulocyte-macrophage CSF (GM-CSF), macrophage CSF (M-CSF), and multi-CSF (now called interleukin-3).

Dr Metcalf recognized that CSFs had a potential role in clinical medicine, and his team was among the first in the world to discover the genes for CSFs.

Dr Metcalf was a central figure in the international clinical trials of CSFs in the 1980s, assessing whether CSFs could boost immune cell numbers in cancer patients whose immune system was weakened as a side effect of chemotherapy. On the basis of these studies, G-CSF (Neupogen) was approved for clinical use in 1991.

Now, an estimated 20 million people have been treated with CSFs. As well as boosting the immune system in patients who receive chemotherapy or have other immune deficiencies, CSFs are thought to have revolutionized hematopoietic stem cell transplantation.

A man with many achievements

Dr Metcalf was born in 1929 and started school at the age of 3, by which time he was already reading. He entered university at the age of 16, ultimately obtaining bachelor’s and medical degrees from the University of Sydney.

After an internship at the Royal Prince Alfred Hospital in Sydney, Dr Metcalf joined the staff of the Walter and Eliza Hall Institute of Medical Research (WEHI) in Melbourne in 1954. He was supported by Cancer Council Victoria’s Carden Fellowship, an award he held until his retirement in 2014. (Dr Metcalf officially retired in 1996 but continued to do research until 2014.)

Dr Metcalf spent his early years at WEHI studying vaccinia virus. In 1965, he began studying blood cell formation and, by association, leukemia. In 1966, he became deputy director of WEHI and the head of its Cancer Research Unit.

Dr Metcalf took several sabbaticals from WEHI, serving as a visiting scientist at Harvard Medical School in Boston, Massachusetts; the Roswell Park Memorial Institute in Buffalo, New York; the Swiss Institute for Experimental Cancer Research in Lausanne, Switzerland; the Radiobiological Institute in Rijswijk, The Netherlands; and the University of Cambridge in the UK.

Among Dr Metcalf’s many honors and awards are the Companion of the Order of Australia (1993), the Albert Lasker Award for Clinical Medical Research (1993), the Gairdner Foundation International Award (1994), the Royal Medal of the Royal Society (1995), the Victoria Prize (2000), and the Prime Minister’s Prize for Science (2001).

Dr Metcalf is survived by his wife Jo; daughters Kate, Johanna, Penelope, and Mary-Ann; grandchildren James, Martin, Patrick, Elizabeth, Rose, and Robert; and their extended families.