Multiple Myeloma

MMprofiler™

Photo courtesy of SkylineDx

The MMprofiler™, a test used to risk-stratify patients with multiple myeloma (MM), has received the CE-IVD mark.

The CE-IVD mark indicates that an in vitro device complies with the European In Vitro Diagnostics Directive and may be legally commercialized and distributed in the European Union.

The MMprofiler classifies patients into high- or standard-risk groups based on the activity of 92 genes considered to be related to MM.

In a 2012 Leukemia paper, researchers described a gene-expression signature, now known as SKY92, that maps the activity of the 92 genes. MM patients who were defined as high-risk by the SKY92 gene signature (called “the EMC92 gene signature” in the paper) had inferior overall survival.

Subsequent studies, including one recently published in Blood, have shown that patients whose plasma cells are SKY92-positive have, on average, 4-times shorter survival and relapse more quickly after treatment than patients whose cells are SKY92-negative.

The intention of the MMprofiler is to classify MM patients according to the SKY92 gene signature and help healthcare professionals select appropriate treatment on the basis of existing guidelines. Healthcare professionals may also decide to monitor patients differently according to their risk group.

The MMprofiler is a product of SkylineDx. The test is run on the company’s proprietary Profiler™ platform, which makes centralized data analysis possible for labs that have the necessary equipment.

To run the MMprofiler test, labs must install a software module on their Affymetrix DX2 Gene scanning equipment and establish a secured gateway connection with the Profiler platform. Then, the lab can process a patient sample and generate the raw genetic data.

The patient’s bone marrow sample is purified, processed, applied to a biochip, and analyzed in the scanner. This is how the MMprofiler determines the active properties of the various genes in the plasma cells of each patient.

The data is then processed via the software system, which reveals the genetic subtype of the plasma cells. Knowing the SKY92 genetic subtype can help healthcare professionals distinguish between high-risk and standard-risk patients.

For more information on the test, visit www.mmprofiler.com.

MMprofiler™

Photo courtesy of SkylineDx

The MMprofiler™, a test used to risk-stratify patients with multiple myeloma (MM), has received the CE-IVD mark.

The CE-IVD mark indicates that an in vitro device complies with the European In Vitro Diagnostics Directive and may be legally commercialized and distributed in the European Union.

The MMprofiler classifies patients into high- or standard-risk groups based on the activity of 92 genes considered to be related to MM.

In a 2012 Leukemia paper, researchers described a gene-expression signature, now known as SKY92, that maps the activity of the 92 genes. MM patients who were defined as high-risk by the SKY92 gene signature (called “the EMC92 gene signature” in the paper) had inferior overall survival.

Subsequent studies, including one recently published in Blood, have shown that patients whose plasma cells are SKY92-positive have, on average, 4-times shorter survival and relapse more quickly after treatment than patients whose cells are SKY92-negative.

The intention of the MMprofiler is to classify MM patients according to the SKY92 gene signature and help healthcare professionals select appropriate treatment on the basis of existing guidelines. Healthcare professionals may also decide to monitor patients differently according to their risk group.

The MMprofiler is a product of SkylineDx. The test is run on the company’s proprietary Profiler™ platform, which makes centralized data analysis possible for labs that have the necessary equipment.

To run the MMprofiler test, labs must install a software module on their Affymetrix DX2 Gene scanning equipment and establish a secured gateway connection with the Profiler platform. Then, the lab can process a patient sample and generate the raw genetic data.

The patient’s bone marrow sample is purified, processed, applied to a biochip, and analyzed in the scanner. This is how the MMprofiler determines the active properties of the various genes in the plasma cells of each patient.

The data is then processed via the software system, which reveals the genetic subtype of the plasma cells. Knowing the SKY92 genetic subtype can help healthcare professionals distinguish between high-risk and standard-risk patients.

For more information on the test, visit www.mmprofiler.com.

MMprofiler™

Photo courtesy of SkylineDx

The MMprofiler™, a test used to risk-stratify patients with multiple myeloma (MM), has received the CE-IVD mark.

The CE-IVD mark indicates that an in vitro device complies with the European In Vitro Diagnostics Directive and may be legally commercialized and distributed in the European Union.

The MMprofiler classifies patients into high- or standard-risk groups based on the activity of 92 genes considered to be related to MM.

In a 2012 Leukemia paper, researchers described a gene-expression signature, now known as SKY92, that maps the activity of the 92 genes. MM patients who were defined as high-risk by the SKY92 gene signature (called “the EMC92 gene signature” in the paper) had inferior overall survival.

Subsequent studies, including one recently published in Blood, have shown that patients whose plasma cells are SKY92-positive have, on average, 4-times shorter survival and relapse more quickly after treatment than patients whose cells are SKY92-negative.

The intention of the MMprofiler is to classify MM patients according to the SKY92 gene signature and help healthcare professionals select appropriate treatment on the basis of existing guidelines. Healthcare professionals may also decide to monitor patients differently according to their risk group.

The MMprofiler is a product of SkylineDx. The test is run on the company’s proprietary Profiler™ platform, which makes centralized data analysis possible for labs that have the necessary equipment.

To run the MMprofiler test, labs must install a software module on their Affymetrix DX2 Gene scanning equipment and establish a secured gateway connection with the Profiler platform. Then, the lab can process a patient sample and generate the raw genetic data.

The patient’s bone marrow sample is purified, processed, applied to a biochip, and analyzed in the scanner. This is how the MMprofiler determines the active properties of the various genes in the plasma cells of each patient.

The data is then processed via the software system, which reveals the genetic subtype of the plasma cells. Knowing the SKY92 genetic subtype can help healthcare professionals distinguish between high-risk and standard-risk patients.

For more information on the test, visit www.mmprofiler.com.

Preparing a patient

for radiation therapy

Photo by Rhoda Baer

A new template can help standardize plans for long-term care of cancer survivors who have undergone radiation therapy (RT), according to the American Society for Radiation Oncology (ASTRO).

An ASTRO advisory committee created the template to coordinate post-treatment care for cancer survivors among primary care providers (PCPs) and oncology

specialists (radiation, medical, and surgical), as well as patients themselves.

Details on the template appear in Practical Radiation Oncology.

“Factors such as earlier detection of cancer, increasingly effective treatment options, and an aging population lead to a growing number of cancer survivors and, ultimately, a need to educate and empower these individuals for their ongoing care,” said ASTRO chair Bruce D. Minsky, MD.

“The ASTRO template is designed to foster better coordination of post-treatment care for cancer survivors, including greater clarity in the dialogue between radiation oncologists and PCPs for issues such as less common side effects that may appear well after treatment is complete.”

Many radiation oncologists may already provide their patients with post-treatment materials such as diagnosis and treatment summaries, contacts for ancillary services such as financial or nutritional counselling, and information on potential late treatment effects.

But the ASTRO template coordinates these components in a central, plain-language document.

It also enables practices to meet new accreditation requirements set by the American College of Surgeons Commission on Cancer (CoC).

In response to a 2006 recommendation from the Institutes of Medicine that cancer patients be provided with a survivorship care plan (SCP) following treatment, CoC issued a mandate that cancer programs provide SCPs for all curative cancer patients by 2019 to maintain accreditation.

ASTRO’s template includes both elements required by the CoC in SCPs—namely, a summary of past treatment and directions for future care.

The treatment summary outlines the survivor’s diagnosis and stage information; treatment details such as the site, dosage, and schedule of RT; and contact information for providers who delivered the treatment.

The plan for follow-up care covers anticipated toxicities from RT, expected course of recovery from treatment-related toxicities, possible functional and/or social limitations, recommendations for preventative measures and behaviors, cancer information resources, and referrals to supportive care providers.

“This 2-page template facilitates consistency in SCPs across the discipline and also reduces the time and effort required by providers to complete each individual plan,” said Ronald Chen, MD, of the University of North Carolina at Chapel Hill.

“The field of radiation oncology has a long tradition of creating treatment summaries for each patient, even before the Institute of Medicine recommended survivorship care plans in 2006. This radiation-oncology-specific template will serve a dual purpose as both a traditional radiation oncology treatment summary and a plan for survivorship care that meets CoC requirements, thus reducing the burden on radiation oncologists from having to create 2 documents for each patient.”

Preparing a patient

for radiation therapy

Photo by Rhoda Baer

A new template can help standardize plans for long-term care of cancer survivors who have undergone radiation therapy (RT), according to the American Society for Radiation Oncology (ASTRO).

An ASTRO advisory committee created the template to coordinate post-treatment care for cancer survivors among primary care providers (PCPs) and oncology

specialists (radiation, medical, and surgical), as well as patients themselves.

Details on the template appear in Practical Radiation Oncology.

“Factors such as earlier detection of cancer, increasingly effective treatment options, and an aging population lead to a growing number of cancer survivors and, ultimately, a need to educate and empower these individuals for their ongoing care,” said ASTRO chair Bruce D. Minsky, MD.

“The ASTRO template is designed to foster better coordination of post-treatment care for cancer survivors, including greater clarity in the dialogue between radiation oncologists and PCPs for issues such as less common side effects that may appear well after treatment is complete.”

Many radiation oncologists may already provide their patients with post-treatment materials such as diagnosis and treatment summaries, contacts for ancillary services such as financial or nutritional counselling, and information on potential late treatment effects.

But the ASTRO template coordinates these components in a central, plain-language document.

It also enables practices to meet new accreditation requirements set by the American College of Surgeons Commission on Cancer (CoC).

In response to a 2006 recommendation from the Institutes of Medicine that cancer patients be provided with a survivorship care plan (SCP) following treatment, CoC issued a mandate that cancer programs provide SCPs for all curative cancer patients by 2019 to maintain accreditation.

ASTRO’s template includes both elements required by the CoC in SCPs—namely, a summary of past treatment and directions for future care.

The treatment summary outlines the survivor’s diagnosis and stage information; treatment details such as the site, dosage, and schedule of RT; and contact information for providers who delivered the treatment.

The plan for follow-up care covers anticipated toxicities from RT, expected course of recovery from treatment-related toxicities, possible functional and/or social limitations, recommendations for preventative measures and behaviors, cancer information resources, and referrals to supportive care providers.

“This 2-page template facilitates consistency in SCPs across the discipline and also reduces the time and effort required by providers to complete each individual plan,” said Ronald Chen, MD, of the University of North Carolina at Chapel Hill.

“The field of radiation oncology has a long tradition of creating treatment summaries for each patient, even before the Institute of Medicine recommended survivorship care plans in 2006. This radiation-oncology-specific template will serve a dual purpose as both a traditional radiation oncology treatment summary and a plan for survivorship care that meets CoC requirements, thus reducing the burden on radiation oncologists from having to create 2 documents for each patient.”

Preparing a patient

for radiation therapy

Photo by Rhoda Baer

A new template can help standardize plans for long-term care of cancer survivors who have undergone radiation therapy (RT), according to the American Society for Radiation Oncology (ASTRO).

An ASTRO advisory committee created the template to coordinate post-treatment care for cancer survivors among primary care providers (PCPs) and oncology

specialists (radiation, medical, and surgical), as well as patients themselves.

Details on the template appear in Practical Radiation Oncology.

“Factors such as earlier detection of cancer, increasingly effective treatment options, and an aging population lead to a growing number of cancer survivors and, ultimately, a need to educate and empower these individuals for their ongoing care,” said ASTRO chair Bruce D. Minsky, MD.

“The ASTRO template is designed to foster better coordination of post-treatment care for cancer survivors, including greater clarity in the dialogue between radiation oncologists and PCPs for issues such as less common side effects that may appear well after treatment is complete.”

Many radiation oncologists may already provide their patients with post-treatment materials such as diagnosis and treatment summaries, contacts for ancillary services such as financial or nutritional counselling, and information on potential late treatment effects.

But the ASTRO template coordinates these components in a central, plain-language document.

It also enables practices to meet new accreditation requirements set by the American College of Surgeons Commission on Cancer (CoC).

In response to a 2006 recommendation from the Institutes of Medicine that cancer patients be provided with a survivorship care plan (SCP) following treatment, CoC issued a mandate that cancer programs provide SCPs for all curative cancer patients by 2019 to maintain accreditation.

ASTRO’s template includes both elements required by the CoC in SCPs—namely, a summary of past treatment and directions for future care.

The treatment summary outlines the survivor’s diagnosis and stage information; treatment details such as the site, dosage, and schedule of RT; and contact information for providers who delivered the treatment.

The plan for follow-up care covers anticipated toxicities from RT, expected course of recovery from treatment-related toxicities, possible functional and/or social limitations, recommendations for preventative measures and behaviors, cancer information resources, and referrals to supportive care providers.

“This 2-page template facilitates consistency in SCPs across the discipline and also reduces the time and effort required by providers to complete each individual plan,” said Ronald Chen, MD, of the University of North Carolina at Chapel Hill.

“The field of radiation oncology has a long tradition of creating treatment summaries for each patient, even before the Institute of Medicine recommended survivorship care plans in 2006. This radiation-oncology-specific template will serve a dual purpose as both a traditional radiation oncology treatment summary and a plan for survivorship care that meets CoC requirements, thus reducing the burden on radiation oncologists from having to create 2 documents for each patient.”

Multiple myeloma

The US Food and Drug Administration (FDA) has approved ixazomib (Ninlaro), the first oral proteasome inhibitor, for use in combination with lenalidomide and dexamethasone to treat multiple myeloma (MM) patients who have received at least 1 prior therapy.

The FDA previously granted ixazomib priority review and orphan designation.

The regulatory submission for ixazomib was primarily based on results from the first interim analysis of the phase 3 TOURMALINE-MM1 trial.

In this trial, patients with relapsed and/or refractory MM who received ixazomib plus lenalidomide and dexamethasone had superior progression-free survival when compared to patients who received placebo plus lenalidomide and dexamethasone.

Results from TOURMALINE-MM1 are scheduled to be presented at the 2015 ASH Annual Meeting (abstract 727) in December.

Ixazomib is currently under investigation in 3 other phase 3 trials of MM patients:

• TOURMALINE-MM2, investigating ixazomib vs placebo, both in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM
• TOURMALINE-MM3, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM following induction therapy and autologous stem cell transplant
• TOURMALINE-MM4, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM who have not undergone autologous stem cell transplant.

Ixazomib is marketed by Takeda Pharmaceuticals.

Multiple myeloma

The US Food and Drug Administration (FDA) has approved ixazomib (Ninlaro), the first oral proteasome inhibitor, for use in combination with lenalidomide and dexamethasone to treat multiple myeloma (MM) patients who have received at least 1 prior therapy.

The FDA previously granted ixazomib priority review and orphan designation.

The regulatory submission for ixazomib was primarily based on results from the first interim analysis of the phase 3 TOURMALINE-MM1 trial.

In this trial, patients with relapsed and/or refractory MM who received ixazomib plus lenalidomide and dexamethasone had superior progression-free survival when compared to patients who received placebo plus lenalidomide and dexamethasone.

Results from TOURMALINE-MM1 are scheduled to be presented at the 2015 ASH Annual Meeting (abstract 727) in December.

Ixazomib is currently under investigation in 3 other phase 3 trials of MM patients:

• TOURMALINE-MM2, investigating ixazomib vs placebo, both in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM
• TOURMALINE-MM3, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM following induction therapy and autologous stem cell transplant
• TOURMALINE-MM4, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM who have not undergone autologous stem cell transplant.

Ixazomib is marketed by Takeda Pharmaceuticals.

Multiple myeloma

The US Food and Drug Administration (FDA) has approved ixazomib (Ninlaro), the first oral proteasome inhibitor, for use in combination with lenalidomide and dexamethasone to treat multiple myeloma (MM) patients who have received at least 1 prior therapy.

The FDA previously granted ixazomib priority review and orphan designation.

The regulatory submission for ixazomib was primarily based on results from the first interim analysis of the phase 3 TOURMALINE-MM1 trial.

In this trial, patients with relapsed and/or refractory MM who received ixazomib plus lenalidomide and dexamethasone had superior progression-free survival when compared to patients who received placebo plus lenalidomide and dexamethasone.

Results from TOURMALINE-MM1 are scheduled to be presented at the 2015 ASH Annual Meeting (abstract 727) in December.

Ixazomib is currently under investigation in 3 other phase 3 trials of MM patients:

• TOURMALINE-MM2, investigating ixazomib vs placebo, both in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM
• TOURMALINE-MM3, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM following induction therapy and autologous stem cell transplant
• TOURMALINE-MM4, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM who have not undergone autologous stem cell transplant.

Ixazomib is marketed by Takeda Pharmaceuticals.

Carfilzomib (Kyprolis)

Photo courtesy of Amgen

The European Commission (EC) has granted marketing authorization for carfilzomib (Kyprolis) to be used in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.

Carfilzomib is the first irreversible proteasome inhibitor approved in the European Union (EU) as part of combination treatment for patients with relapsed MM.

Carfilzomib was granted orphan designation in the EU in 2008. The drug also received accelerated assessment, which shortened the review period from 210 days to 150 days.

Carfilzomib is a product of Onyx Pharmaceuticals, Inc., a subsidiary of Amgen that holds development and commercialization rights to the drug globally, excluding Japan.

ASPIRE trial

The EC approved carfilzomib based on data from the phase 3 ASPIRE trial, which were presented at ASH 2014 and published in NEJM.

The trial enrolled 792 patients with relapsed or refractory MM who had received 1 to 3 prior lines of therapy. The patients were randomized (1:1) to receive carfilzomib plus lenalidomide and dexamethasone (KRd) or just lenalidomide and dexamethasone (Rd) for 18 cycles.

Lenalidomide and dexamethasone were continued thereafter until disease progression. There was no planned cross-over from the control arm to treatment with carfilzomib.

The study’s primary endpoint was progression-free survival. The median progression-free survival was significantly longer in the KRd arm than the Rd arm—26.3 months and 17.6 months, respectively (hazard ratio=0.69, P=0.0001).

At the time of analysis, the difference in overall survival did not reach the prespecified boundary for statistical significance.

The overall response rate was 87% in the KRd arm and 67% in the Rd arm. The median duration of response was 28.6 months and 21.2 months, respectively.

The rates of death due to adverse events (AEs) within 30 days of the last dose were similar between the treatment arms.

The most common causes of death not due to progressive disease occurring in patients in the KRd arm and the Rd arm, respectively, were cardiac disorders (3% vs 2%), infection (2% vs 3%), renal events (0% vs less than 1%), and other AEs (2% vs 3%).

Serious AEs were reported in 60% of patients in the KRd arm and 54% in the Rd arm. The most common serious AEs reported in the KRd arm and the Rd arm, respectively, were pneumonia (14% vs 11%), respiratory tract infection (4% vs 2%), pyrexia (4% vs 2%), and pulmonary embolism (3% vs 2%).

Global development

In the US, carfilzomib is approved for use in combination with lenalidomide and dexamethasone to treat MM patients who have received 1 to 3 prior lines of therapy.

Carfilzomib also has accelerated approval in the US as a single agent to treat MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of the completion of last therapy.

Amgen plans to submit data from the phase 3 ENDEAVOR trial for potential authorization of carfilzomib in combination with dexamethasone in the EU.

This data serves as the basis of the supplemental new drug application of carfilzomib in combination with dexamethasone for patients with relapsed MM, which has been accepted for priority review in the US.

In addition to the US and EU, carfilzomib is approved for use in Argentina, Israel, Kuwait, Mexico, Thailand, and Colombia. Additional regulatory applications for the drug have been submitted to health authorities worldwide.

Carfilzomib (Kyprolis)

Photo courtesy of Amgen

The European Commission (EC) has granted marketing authorization for carfilzomib (Kyprolis) to be used in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.

Carfilzomib is the first irreversible proteasome inhibitor approved in the European Union (EU) as part of combination treatment for patients with relapsed MM.

Carfilzomib was granted orphan designation in the EU in 2008. The drug also received accelerated assessment, which shortened the review period from 210 days to 150 days.

Carfilzomib is a product of Onyx Pharmaceuticals, Inc., a subsidiary of Amgen that holds development and commercialization rights to the drug globally, excluding Japan.

ASPIRE trial

The EC approved carfilzomib based on data from the phase 3 ASPIRE trial, which were presented at ASH 2014 and published in NEJM.

The trial enrolled 792 patients with relapsed or refractory MM who had received 1 to 3 prior lines of therapy. The patients were randomized (1:1) to receive carfilzomib plus lenalidomide and dexamethasone (KRd) or just lenalidomide and dexamethasone (Rd) for 18 cycles.

Lenalidomide and dexamethasone were continued thereafter until disease progression. There was no planned cross-over from the control arm to treatment with carfilzomib.

The study’s primary endpoint was progression-free survival. The median progression-free survival was significantly longer in the KRd arm than the Rd arm—26.3 months and 17.6 months, respectively (hazard ratio=0.69, P=0.0001).

At the time of analysis, the difference in overall survival did not reach the prespecified boundary for statistical significance.

The overall response rate was 87% in the KRd arm and 67% in the Rd arm. The median duration of response was 28.6 months and 21.2 months, respectively.

The rates of death due to adverse events (AEs) within 30 days of the last dose were similar between the treatment arms.

The most common causes of death not due to progressive disease occurring in patients in the KRd arm and the Rd arm, respectively, were cardiac disorders (3% vs 2%), infection (2% vs 3%), renal events (0% vs less than 1%), and other AEs (2% vs 3%).

Serious AEs were reported in 60% of patients in the KRd arm and 54% in the Rd arm. The most common serious AEs reported in the KRd arm and the Rd arm, respectively, were pneumonia (14% vs 11%), respiratory tract infection (4% vs 2%), pyrexia (4% vs 2%), and pulmonary embolism (3% vs 2%).

Global development

In the US, carfilzomib is approved for use in combination with lenalidomide and dexamethasone to treat MM patients who have received 1 to 3 prior lines of therapy.

Carfilzomib also has accelerated approval in the US as a single agent to treat MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of the completion of last therapy.

Amgen plans to submit data from the phase 3 ENDEAVOR trial for potential authorization of carfilzomib in combination with dexamethasone in the EU.

This data serves as the basis of the supplemental new drug application of carfilzomib in combination with dexamethasone for patients with relapsed MM, which has been accepted for priority review in the US.

In addition to the US and EU, carfilzomib is approved for use in Argentina, Israel, Kuwait, Mexico, Thailand, and Colombia. Additional regulatory applications for the drug have been submitted to health authorities worldwide.

Carfilzomib (Kyprolis)

Photo courtesy of Amgen

The European Commission (EC) has granted marketing authorization for carfilzomib (Kyprolis) to be used in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.

Carfilzomib is the first irreversible proteasome inhibitor approved in the European Union (EU) as part of combination treatment for patients with relapsed MM.

Carfilzomib was granted orphan designation in the EU in 2008. The drug also received accelerated assessment, which shortened the review period from 210 days to 150 days.

Carfilzomib is a product of Onyx Pharmaceuticals, Inc., a subsidiary of Amgen that holds development and commercialization rights to the drug globally, excluding Japan.

ASPIRE trial

The EC approved carfilzomib based on data from the phase 3 ASPIRE trial, which were presented at ASH 2014 and published in NEJM.

The trial enrolled 792 patients with relapsed or refractory MM who had received 1 to 3 prior lines of therapy. The patients were randomized (1:1) to receive carfilzomib plus lenalidomide and dexamethasone (KRd) or just lenalidomide and dexamethasone (Rd) for 18 cycles.

Lenalidomide and dexamethasone were continued thereafter until disease progression. There was no planned cross-over from the control arm to treatment with carfilzomib.

The study’s primary endpoint was progression-free survival. The median progression-free survival was significantly longer in the KRd arm than the Rd arm—26.3 months and 17.6 months, respectively (hazard ratio=0.69, P=0.0001).

At the time of analysis, the difference in overall survival did not reach the prespecified boundary for statistical significance.

The overall response rate was 87% in the KRd arm and 67% in the Rd arm. The median duration of response was 28.6 months and 21.2 months, respectively.

The rates of death due to adverse events (AEs) within 30 days of the last dose were similar between the treatment arms.

The most common causes of death not due to progressive disease occurring in patients in the KRd arm and the Rd arm, respectively, were cardiac disorders (3% vs 2%), infection (2% vs 3%), renal events (0% vs less than 1%), and other AEs (2% vs 3%).

Serious AEs were reported in 60% of patients in the KRd arm and 54% in the Rd arm. The most common serious AEs reported in the KRd arm and the Rd arm, respectively, were pneumonia (14% vs 11%), respiratory tract infection (4% vs 2%), pyrexia (4% vs 2%), and pulmonary embolism (3% vs 2%).

Global development

In the US, carfilzomib is approved for use in combination with lenalidomide and dexamethasone to treat MM patients who have received 1 to 3 prior lines of therapy.

Carfilzomib also has accelerated approval in the US as a single agent to treat MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of the completion of last therapy.

Amgen plans to submit data from the phase 3 ENDEAVOR trial for potential authorization of carfilzomib in combination with dexamethasone in the EU.

This data serves as the basis of the supplemental new drug application of carfilzomib in combination with dexamethasone for patients with relapsed MM, which has been accepted for priority review in the US.

In addition to the US and EU, carfilzomib is approved for use in Argentina, Israel, Kuwait, Mexico, Thailand, and Colombia. Additional regulatory applications for the drug have been submitted to health authorities worldwide.

Bone marrow aspirate

showing multiple myeloma

Researchers have created a 3-dimensional model that can be used to screen drugs designed to treat multiple myeloma (MM).

The team developed 3D tissue-engineered bone marrow (3DTEBM) cultures that could, ideally, help physicians determine which drug or combination therapy might be most effective for a particular MM patient.

The cultures also provide guidance regarding dosage.

The researchers described this work in Biomaterials.

“Even before the patient completes all of the MRIs, CT scans, and other imaging procedures following diagnosis, we can have a recommendation for which drug and dosage to prescribe,” said study author Kareem Azab, PhD, of Washington University School of Medicine in St Louis, Missouri. “The test results come in 3 to 4 days.”

Dr Azab and his colleagues developed their 3DTEBM cultures using bone marrow samples from MM patients. The team took small samples of a patient’s cells and remodeled them in the lab.

This tumor microenvironment includes the cancer cells and neighboring blood vessels, immune cells, and other components whose interaction can help or inhibit the tumor cells’ growth. Drugs are tested on the remodeled patient cells to determine which treatment is likely to be most effective.

Dr Azab’s method gauges the sensitivity of a patient’s cells to different drugs at any time in the course of the disease.

Therefore, as a patient’s disease becomes more resistant to particular drugs, continued drug screening could suggest when to change therapies. This could save valuable time, Dr Azab said.

“Now, we have a drug test that closely replicates what’s going on with a patient at any given moment,” he noted. “We think this method has a better chance of working than existing options.”

The 3DTEBM cultures are currently being tested in a clinical trial of MM patients.

To further the technology, Dr Azab and his colleagues have launched a company, Cellatrix, in coordination with Washington University’s Office of Technology Management and BioGenerator, a nonprofit organization that helps launch bioscience companies.

Cellatrix is scheduled to begin testing potential therapies on behalf of pharmaceutical companies soon. Dr Azab’s team is also studying how well the screening method works for patients with leukemia or lymphoma.

Bone marrow aspirate

showing multiple myeloma

Researchers have created a 3-dimensional model that can be used to screen drugs designed to treat multiple myeloma (MM).

The team developed 3D tissue-engineered bone marrow (3DTEBM) cultures that could, ideally, help physicians determine which drug or combination therapy might be most effective for a particular MM patient.

The cultures also provide guidance regarding dosage.

The researchers described this work in Biomaterials.

“Even before the patient completes all of the MRIs, CT scans, and other imaging procedures following diagnosis, we can have a recommendation for which drug and dosage to prescribe,” said study author Kareem Azab, PhD, of Washington University School of Medicine in St Louis, Missouri. “The test results come in 3 to 4 days.”

Dr Azab and his colleagues developed their 3DTEBM cultures using bone marrow samples from MM patients. The team took small samples of a patient’s cells and remodeled them in the lab.

This tumor microenvironment includes the cancer cells and neighboring blood vessels, immune cells, and other components whose interaction can help or inhibit the tumor cells’ growth. Drugs are tested on the remodeled patient cells to determine which treatment is likely to be most effective.

Dr Azab’s method gauges the sensitivity of a patient’s cells to different drugs at any time in the course of the disease.

Therefore, as a patient’s disease becomes more resistant to particular drugs, continued drug screening could suggest when to change therapies. This could save valuable time, Dr Azab said.

“Now, we have a drug test that closely replicates what’s going on with a patient at any given moment,” he noted. “We think this method has a better chance of working than existing options.”

The 3DTEBM cultures are currently being tested in a clinical trial of MM patients.

To further the technology, Dr Azab and his colleagues have launched a company, Cellatrix, in coordination with Washington University’s Office of Technology Management and BioGenerator, a nonprofit organization that helps launch bioscience companies.

Cellatrix is scheduled to begin testing potential therapies on behalf of pharmaceutical companies soon. Dr Azab’s team is also studying how well the screening method works for patients with leukemia or lymphoma.

Bone marrow aspirate

showing multiple myeloma

Researchers have created a 3-dimensional model that can be used to screen drugs designed to treat multiple myeloma (MM).

The team developed 3D tissue-engineered bone marrow (3DTEBM) cultures that could, ideally, help physicians determine which drug or combination therapy might be most effective for a particular MM patient.

The cultures also provide guidance regarding dosage.

The researchers described this work in Biomaterials.

“Even before the patient completes all of the MRIs, CT scans, and other imaging procedures following diagnosis, we can have a recommendation for which drug and dosage to prescribe,” said study author Kareem Azab, PhD, of Washington University School of Medicine in St Louis, Missouri. “The test results come in 3 to 4 days.”

Dr Azab and his colleagues developed their 3DTEBM cultures using bone marrow samples from MM patients. The team took small samples of a patient’s cells and remodeled them in the lab.

This tumor microenvironment includes the cancer cells and neighboring blood vessels, immune cells, and other components whose interaction can help or inhibit the tumor cells’ growth. Drugs are tested on the remodeled patient cells to determine which treatment is likely to be most effective.

Dr Azab’s method gauges the sensitivity of a patient’s cells to different drugs at any time in the course of the disease.

Therefore, as a patient’s disease becomes more resistant to particular drugs, continued drug screening could suggest when to change therapies. This could save valuable time, Dr Azab said.

“Now, we have a drug test that closely replicates what’s going on with a patient at any given moment,” he noted. “We think this method has a better chance of working than existing options.”

The 3DTEBM cultures are currently being tested in a clinical trial of MM patients.

To further the technology, Dr Azab and his colleagues have launched a company, Cellatrix, in coordination with Washington University’s Office of Technology Management and BioGenerator, a nonprofit organization that helps launch bioscience companies.

Cellatrix is scheduled to begin testing potential therapies on behalf of pharmaceutical companies soon. Dr Azab’s team is also studying how well the screening method works for patients with leukemia or lymphoma.

Proliferating HSCs

Image by John Perry

Previous studies have shown that hematopoietic stresses—such as myelofibrosis, anemia, and myeloablation—can induce extramedullary hematopoiesis (EMH), in which hematopoietic stem cells (HSCs) are mobilized to sites outside the bone marrow.

The splenic red pulp is known to be a prominent site of EMH in both mice and humans, but not much is known about the EMH niche.

Now, investigators say they have characterized this niche.

They detailed their findings in Nature.

The team used mouse models to examine the expression patterns of 2 known niche cell factors, SCF and CXCL12.

They discovered that the hematopoietic microenvironment in the spleen is found near sinusoidal blood vessels and is created by endothelial cells and perivascular stromal cells, just like the microenvironment in the bone marrow.

“Under emergency conditions, the endothelial cells and perivascular stromal cells that reside in the spleen are induced to proliferate so they can sustain all the new blood-forming stem cells that migrate into the spleen,” explained study author Sean Morrison, PhD, of the University of Texas Southwestern Medical Center, Dallas.

“We determined that this process in the spleen is physiologically important for responding to hematopoietic stress. Without it, the mice we studied could not maintain normal blood cell counts during pregnancy or quickly regenerate blood cell counts after bleeding or chemotherapy.”

The investigators believe these findings could aid the development of therapeutic interventions to enhance blood formation following chemotherapy or HSC transplant and thus accelerate the recovery of blood cell counts.

Proliferating HSCs

Image by John Perry

Previous studies have shown that hematopoietic stresses—such as myelofibrosis, anemia, and myeloablation—can induce extramedullary hematopoiesis (EMH), in which hematopoietic stem cells (HSCs) are mobilized to sites outside the bone marrow.

The splenic red pulp is known to be a prominent site of EMH in both mice and humans, but not much is known about the EMH niche.

Now, investigators say they have characterized this niche.

They detailed their findings in Nature.

The team used mouse models to examine the expression patterns of 2 known niche cell factors, SCF and CXCL12.

They discovered that the hematopoietic microenvironment in the spleen is found near sinusoidal blood vessels and is created by endothelial cells and perivascular stromal cells, just like the microenvironment in the bone marrow.

“Under emergency conditions, the endothelial cells and perivascular stromal cells that reside in the spleen are induced to proliferate so they can sustain all the new blood-forming stem cells that migrate into the spleen,” explained study author Sean Morrison, PhD, of the University of Texas Southwestern Medical Center, Dallas.

“We determined that this process in the spleen is physiologically important for responding to hematopoietic stress. Without it, the mice we studied could not maintain normal blood cell counts during pregnancy or quickly regenerate blood cell counts after bleeding or chemotherapy.”

The investigators believe these findings could aid the development of therapeutic interventions to enhance blood formation following chemotherapy or HSC transplant and thus accelerate the recovery of blood cell counts.

Proliferating HSCs

Image by John Perry

Previous studies have shown that hematopoietic stresses—such as myelofibrosis, anemia, and myeloablation—can induce extramedullary hematopoiesis (EMH), in which hematopoietic stem cells (HSCs) are mobilized to sites outside the bone marrow.

The splenic red pulp is known to be a prominent site of EMH in both mice and humans, but not much is known about the EMH niche.

Now, investigators say they have characterized this niche.

They detailed their findings in Nature.

The team used mouse models to examine the expression patterns of 2 known niche cell factors, SCF and CXCL12.

They discovered that the hematopoietic microenvironment in the spleen is found near sinusoidal blood vessels and is created by endothelial cells and perivascular stromal cells, just like the microenvironment in the bone marrow.

“Under emergency conditions, the endothelial cells and perivascular stromal cells that reside in the spleen are induced to proliferate so they can sustain all the new blood-forming stem cells that migrate into the spleen,” explained study author Sean Morrison, PhD, of the University of Texas Southwestern Medical Center, Dallas.

“We determined that this process in the spleen is physiologically important for responding to hematopoietic stress. Without it, the mice we studied could not maintain normal blood cell counts during pregnancy or quickly regenerate blood cell counts after bleeding or chemotherapy.”

The investigators believe these findings could aid the development of therapeutic interventions to enhance blood formation following chemotherapy or HSC transplant and thus accelerate the recovery of blood cell counts.

 

 

Hodgkin lymphoma

 

A small-molecule inhibitor has shown modest anticancer activity in a phase 1 trial of patients with relapsed/refractory lymphoma or multiple myeloma (MM), according to an investigator involved in the study.

A majority of patients who recieved the drug, pevonedistat, achieved stable disease, and a few patients with lymphoma experienced partial responses.

Investigators said pevonedistat could be given safely, although 100% of patients experienced adverse events (AEs), and a majority experienced grade 3 or higher AEs.

“The most important findings from our study are that pevonedistat hits its target in cancer cells in patients, can be given safely, and has modest activity in heavily pretreated patients with relapsed/refractory lymphoma, suggesting that we are on the right path,” said Jatin J. Shah, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Shah and his colleagues reported these findings in Clinical Cancer Research. The trial was sponsored by Millennium Pharmaceuticals, Inc., the company developing pevonedistat.

Pevonedistat is a first-in-class, investigational, small-molecule inhibitor of the NEDD8-activating enzyme.

“This enzyme is part of the ubiquitin-proteasome system, which is the target of a number of FDA-approved anticancer therapeutics, including bortezomib . . . ,” Dr Shah explained. “Pevonedistat also alters the ability of cancer cells to repair damaged DNA.”

Patient and treatment characteristics

Dr Shah and his colleagues enrolled 44 patients on this trial. Seventeen patients had relapsed/refractory MM, and 27 had relapsed/refractory lymphoma.

The types of lymphoma were diffuse large B-cell lymphoma (n=10), follicular lymphoma (n=5), Hodgkin lymphoma (n=5), small lymphocytic lymphoma/chronic lymphocytic leukemia (n=2), mantle cell lymphoma (n=1), lymphoplasmacytic lymphoma (n=1), peripheral T-cell lymphoma (n=1), splenic marginal zone B-cell lymphoma (n=1), and “other” (n=1).

Twenty-seven patients received escalating doses of pevonedistat on schedule A, which was days 1, 2, 8, and 9 of a 21-day cycle, and 17 patients received escalating doses of the drug on schedule B, which was days 1, 4, 8, and 11 of a 21-day cycle.

Safety

The maximum tolerated doses were 110 mg/m² and 196 mg/m² on schedule A and B, respectively. The dose-limiting toxicities were febrile neutropenia, transaminase elevations, and muscle cramps on schedule A, and thrombocytopenia on schedule B.

On schedule A, 100% of patients experienced AEs, and 59% had AEs of grade 3 or higher. The grade 3 or higher AEs were anemia (19%), thrombocytopenia (4%), neutropenia (7%), fatigue (7%), ALT increase (4%), AST increase (7%), diarrhea (4%), pain (4%), dyspnea (4%), hypercalcemia (7%), hypophosphatemia (11%), hyperkalemia (4%), muscle spasms (4%), abdominal discomfort (4%), and pneumonia (4%).

On schedule B, 100% of patients experienced AEs, and 71% had grade 3 or higher AEs. The grade 3 or higher AEs were anemia (6%), thrombocytopenia (6%), neutropenia (12%), fatigue (6%), ALT increase (6%), pyrexia (6%), pain (6%), dyspnea (6%), hypophosphatemia (6%), muscle spasms (6%), upper respiratory tract infection (6%), dehydration (6%), hyperbilirubinemia (6%), and pneumonia (12%).

Efficacy

Three patients had a partial response to treatment, including 1 patient with relapsed nodular sclerosis Hodgkin lymphoma, 1 with relapsed diffuse large B-cell lymphoma, and 1 with relapsed peripheral T-cell lymphoma.

Another 30 patients, 17 with lymphoma and 13 with MM, had stable disease.

“Although pevonedistat had modest activity as a single-agent treatment, we expect greater activity when it is given in combination with standard therapy,” Dr Shah said.

“The pharmacodynamics data showed that pevonedistat hit its target in cancer cells in patients at low doses. This is important because it may mean that we do not need to escalate the dose in future trials to increase anticancer activity. This has the potential to increase the risk-benefit ratio of pevonedistat.”

Dr Shah said a limitation of this study is that it included a small number of patients, all of whom were very heavily pretreated, which may limit assessment of how active pevonedistat could be.

 

 

Hodgkin lymphoma

 

A small-molecule inhibitor has shown modest anticancer activity in a phase 1 trial of patients with relapsed/refractory lymphoma or multiple myeloma (MM), according to an investigator involved in the study.

A majority of patients who recieved the drug, pevonedistat, achieved stable disease, and a few patients with lymphoma experienced partial responses.

Investigators said pevonedistat could be given safely, although 100% of patients experienced adverse events (AEs), and a majority experienced grade 3 or higher AEs.

“The most important findings from our study are that pevonedistat hits its target in cancer cells in patients, can be given safely, and has modest activity in heavily pretreated patients with relapsed/refractory lymphoma, suggesting that we are on the right path,” said Jatin J. Shah, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Shah and his colleagues reported these findings in Clinical Cancer Research. The trial was sponsored by Millennium Pharmaceuticals, Inc., the company developing pevonedistat.

Pevonedistat is a first-in-class, investigational, small-molecule inhibitor of the NEDD8-activating enzyme.

“This enzyme is part of the ubiquitin-proteasome system, which is the target of a number of FDA-approved anticancer therapeutics, including bortezomib . . . ,” Dr Shah explained. “Pevonedistat also alters the ability of cancer cells to repair damaged DNA.”

Patient and treatment characteristics

Dr Shah and his colleagues enrolled 44 patients on this trial. Seventeen patients had relapsed/refractory MM, and 27 had relapsed/refractory lymphoma.

The types of lymphoma were diffuse large B-cell lymphoma (n=10), follicular lymphoma (n=5), Hodgkin lymphoma (n=5), small lymphocytic lymphoma/chronic lymphocytic leukemia (n=2), mantle cell lymphoma (n=1), lymphoplasmacytic lymphoma (n=1), peripheral T-cell lymphoma (n=1), splenic marginal zone B-cell lymphoma (n=1), and “other” (n=1).

Twenty-seven patients received escalating doses of pevonedistat on schedule A, which was days 1, 2, 8, and 9 of a 21-day cycle, and 17 patients received escalating doses of the drug on schedule B, which was days 1, 4, 8, and 11 of a 21-day cycle.

Safety

The maximum tolerated doses were 110 mg/m² and 196 mg/m² on schedule A and B, respectively. The dose-limiting toxicities were febrile neutropenia, transaminase elevations, and muscle cramps on schedule A, and thrombocytopenia on schedule B.

On schedule A, 100% of patients experienced AEs, and 59% had AEs of grade 3 or higher. The grade 3 or higher AEs were anemia (19%), thrombocytopenia (4%), neutropenia (7%), fatigue (7%), ALT increase (4%), AST increase (7%), diarrhea (4%), pain (4%), dyspnea (4%), hypercalcemia (7%), hypophosphatemia (11%), hyperkalemia (4%), muscle spasms (4%), abdominal discomfort (4%), and pneumonia (4%).

On schedule B, 100% of patients experienced AEs, and 71% had grade 3 or higher AEs. The grade 3 or higher AEs were anemia (6%), thrombocytopenia (6%), neutropenia (12%), fatigue (6%), ALT increase (6%), pyrexia (6%), pain (6%), dyspnea (6%), hypophosphatemia (6%), muscle spasms (6%), upper respiratory tract infection (6%), dehydration (6%), hyperbilirubinemia (6%), and pneumonia (12%).

Efficacy

Three patients had a partial response to treatment, including 1 patient with relapsed nodular sclerosis Hodgkin lymphoma, 1 with relapsed diffuse large B-cell lymphoma, and 1 with relapsed peripheral T-cell lymphoma.

Another 30 patients, 17 with lymphoma and 13 with MM, had stable disease.

“Although pevonedistat had modest activity as a single-agent treatment, we expect greater activity when it is given in combination with standard therapy,” Dr Shah said.

“The pharmacodynamics data showed that pevonedistat hit its target in cancer cells in patients at low doses. This is important because it may mean that we do not need to escalate the dose in future trials to increase anticancer activity. This has the potential to increase the risk-benefit ratio of pevonedistat.”

Dr Shah said a limitation of this study is that it included a small number of patients, all of whom were very heavily pretreated, which may limit assessment of how active pevonedistat could be.

 

 

Hodgkin lymphoma

 

A small-molecule inhibitor has shown modest anticancer activity in a phase 1 trial of patients with relapsed/refractory lymphoma or multiple myeloma (MM), according to an investigator involved in the study.

A majority of patients who recieved the drug, pevonedistat, achieved stable disease, and a few patients with lymphoma experienced partial responses.

Investigators said pevonedistat could be given safely, although 100% of patients experienced adverse events (AEs), and a majority experienced grade 3 or higher AEs.

“The most important findings from our study are that pevonedistat hits its target in cancer cells in patients, can be given safely, and has modest activity in heavily pretreated patients with relapsed/refractory lymphoma, suggesting that we are on the right path,” said Jatin J. Shah, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Shah and his colleagues reported these findings in Clinical Cancer Research. The trial was sponsored by Millennium Pharmaceuticals, Inc., the company developing pevonedistat.

Pevonedistat is a first-in-class, investigational, small-molecule inhibitor of the NEDD8-activating enzyme.

“This enzyme is part of the ubiquitin-proteasome system, which is the target of a number of FDA-approved anticancer therapeutics, including bortezomib . . . ,” Dr Shah explained. “Pevonedistat also alters the ability of cancer cells to repair damaged DNA.”

Patient and treatment characteristics

Dr Shah and his colleagues enrolled 44 patients on this trial. Seventeen patients had relapsed/refractory MM, and 27 had relapsed/refractory lymphoma.

The types of lymphoma were diffuse large B-cell lymphoma (n=10), follicular lymphoma (n=5), Hodgkin lymphoma (n=5), small lymphocytic lymphoma/chronic lymphocytic leukemia (n=2), mantle cell lymphoma (n=1), lymphoplasmacytic lymphoma (n=1), peripheral T-cell lymphoma (n=1), splenic marginal zone B-cell lymphoma (n=1), and “other” (n=1).

Twenty-seven patients received escalating doses of pevonedistat on schedule A, which was days 1, 2, 8, and 9 of a 21-day cycle, and 17 patients received escalating doses of the drug on schedule B, which was days 1, 4, 8, and 11 of a 21-day cycle.

Safety

The maximum tolerated doses were 110 mg/m² and 196 mg/m² on schedule A and B, respectively. The dose-limiting toxicities were febrile neutropenia, transaminase elevations, and muscle cramps on schedule A, and thrombocytopenia on schedule B.

On schedule A, 100% of patients experienced AEs, and 59% had AEs of grade 3 or higher. The grade 3 or higher AEs were anemia (19%), thrombocytopenia (4%), neutropenia (7%), fatigue (7%), ALT increase (4%), AST increase (7%), diarrhea (4%), pain (4%), dyspnea (4%), hypercalcemia (7%), hypophosphatemia (11%), hyperkalemia (4%), muscle spasms (4%), abdominal discomfort (4%), and pneumonia (4%).

On schedule B, 100% of patients experienced AEs, and 71% had grade 3 or higher AEs. The grade 3 or higher AEs were anemia (6%), thrombocytopenia (6%), neutropenia (12%), fatigue (6%), ALT increase (6%), pyrexia (6%), pain (6%), dyspnea (6%), hypophosphatemia (6%), muscle spasms (6%), upper respiratory tract infection (6%), dehydration (6%), hyperbilirubinemia (6%), and pneumonia (12%).

Efficacy

Three patients had a partial response to treatment, including 1 patient with relapsed nodular sclerosis Hodgkin lymphoma, 1 with relapsed diffuse large B-cell lymphoma, and 1 with relapsed peripheral T-cell lymphoma.

Another 30 patients, 17 with lymphoma and 13 with MM, had stable disease.

“Although pevonedistat had modest activity as a single-agent treatment, we expect greater activity when it is given in combination with standard therapy,” Dr Shah said.

“The pharmacodynamics data showed that pevonedistat hit its target in cancer cells in patients at low doses. This is important because it may mean that we do not need to escalate the dose in future trials to increase anticancer activity. This has the potential to increase the risk-benefit ratio of pevonedistat.”

Dr Shah said a limitation of this study is that it included a small number of patients, all of whom were very heavily pretreated, which may limit assessment of how active pevonedistat could be.