Multiple Myeloma

Photo by Bill Branson

Cancer drug costs in the US increase substantially after launch, regardless of competition, according to a study published in the Journal of Clinical Oncology.*

Researchers studied 24 cancer drugs approved over the last 20 years and found a mean cumulative cost increase of about 37%, or 19% when adjusted for inflation.

Among drugs approved to treat hematologic malignancies, the greatest inflation-adjusted price increases were for arsenic trioxide (57%), nelarabine (55%), and rituximab (49%).

The lowest inflation-adjusted price increases were for ofatumumab (8%), clofarabine (8%), and liposomal vincristine (18%).

For this study, Daniel A. Goldstein, MD, of Emory University in Atlanta, Georgia, and his colleagues measured the monthly price trajectories of 24 cancer drugs approved by the US Food and Drug Administration. This included 10 drugs approved to treat hematologic malignancies between 1997 and 2011.

To account for discounts and rebates, the researchers used the average sales prices published by the Centers for Medicare and Medicaid Services and adjusted to general and health-related inflation rates. For each drug, the researchers calculated the cumulative and annual drug cost changes.

Results

The mean follow-up was 8 years. The mean cumulative cost increase for all 24 drugs was +36.5% (95% CI, 24.7% to 48.3%).

The general inflation-adjusted increase was +19.1% (95% CI, 11.0% to 27.2%), and the health-related inflation-adjusted increase was +8.4% (95% CI, 1.4% to 15.4%).

Only 1 of the 24 drugs studied had a price decrease over time. That drug is ziv-aflibercept, which was approved to treat metastatic colorectal cancer in 2012.

Ziv-aflibercept was launched with an annual price exceeding $110,000. After public outcry, the drug’s manufacturer, Sanofi, cut the price in half. By the end of the study’s follow-up period in 2017, the cost of ziv-aflibercept had decreased 13% (inflation-adjusted decrease of 15%, health-related inflation-adjusted decrease of 20%).

Cost changes for the drugs approved to treat hematologic malignancies are listed in the following table.

Abbreviations: ALL, acute lymphoblastic leukemia; APL, acute promyelocytic leukemia; CLL, chronic lymphocytic leukemia; MCL, mantle cell lymphoma; MM, multiple myeloma; NHL, non-Hodgkin lymphoma; SD, standard deviation.

The researchers noted that there was a steady increase in drug costs over the study period, regardless of whether a drug was granted a new supplemental indication, the drug had a new off-label indication, or a competitor drug was approved.

The only variable that was significantly associated with price change was the amount of time that had elapsed from a drug’s launch.

This association was significant in models in which the researchers used prices adjusted to inflation (P=0.002) and health-related inflation (P=0.023). However, it was not significant when the researchers used the actual drug price (P=0.085).

*Data in the abstract differ from data in the body of the JCO paper. This article includes data from the body of the JCO paper.

Photo by Bill Branson

Cancer drug costs in the US increase substantially after launch, regardless of competition, according to a study published in the Journal of Clinical Oncology.*

Researchers studied 24 cancer drugs approved over the last 20 years and found a mean cumulative cost increase of about 37%, or 19% when adjusted for inflation.

Among drugs approved to treat hematologic malignancies, the greatest inflation-adjusted price increases were for arsenic trioxide (57%), nelarabine (55%), and rituximab (49%).

The lowest inflation-adjusted price increases were for ofatumumab (8%), clofarabine (8%), and liposomal vincristine (18%).

For this study, Daniel A. Goldstein, MD, of Emory University in Atlanta, Georgia, and his colleagues measured the monthly price trajectories of 24 cancer drugs approved by the US Food and Drug Administration. This included 10 drugs approved to treat hematologic malignancies between 1997 and 2011.

To account for discounts and rebates, the researchers used the average sales prices published by the Centers for Medicare and Medicaid Services and adjusted to general and health-related inflation rates. For each drug, the researchers calculated the cumulative and annual drug cost changes.

Results

The mean follow-up was 8 years. The mean cumulative cost increase for all 24 drugs was +36.5% (95% CI, 24.7% to 48.3%).

The general inflation-adjusted increase was +19.1% (95% CI, 11.0% to 27.2%), and the health-related inflation-adjusted increase was +8.4% (95% CI, 1.4% to 15.4%).

Only 1 of the 24 drugs studied had a price decrease over time. That drug is ziv-aflibercept, which was approved to treat metastatic colorectal cancer in 2012.

Ziv-aflibercept was launched with an annual price exceeding $110,000. After public outcry, the drug’s manufacturer, Sanofi, cut the price in half. By the end of the study’s follow-up period in 2017, the cost of ziv-aflibercept had decreased 13% (inflation-adjusted decrease of 15%, health-related inflation-adjusted decrease of 20%).

Cost changes for the drugs approved to treat hematologic malignancies are listed in the following table.

Abbreviations: ALL, acute lymphoblastic leukemia; APL, acute promyelocytic leukemia; CLL, chronic lymphocytic leukemia; MCL, mantle cell lymphoma; MM, multiple myeloma; NHL, non-Hodgkin lymphoma; SD, standard deviation.

The researchers noted that there was a steady increase in drug costs over the study period, regardless of whether a drug was granted a new supplemental indication, the drug had a new off-label indication, or a competitor drug was approved.

The only variable that was significantly associated with price change was the amount of time that had elapsed from a drug’s launch.

This association was significant in models in which the researchers used prices adjusted to inflation (P=0.002) and health-related inflation (P=0.023). However, it was not significant when the researchers used the actual drug price (P=0.085).

*Data in the abstract differ from data in the body of the JCO paper. This article includes data from the body of the JCO paper.

Photo by Bill Branson

Cancer drug costs in the US increase substantially after launch, regardless of competition, according to a study published in the Journal of Clinical Oncology.*

Researchers studied 24 cancer drugs approved over the last 20 years and found a mean cumulative cost increase of about 37%, or 19% when adjusted for inflation.

Among drugs approved to treat hematologic malignancies, the greatest inflation-adjusted price increases were for arsenic trioxide (57%), nelarabine (55%), and rituximab (49%).

The lowest inflation-adjusted price increases were for ofatumumab (8%), clofarabine (8%), and liposomal vincristine (18%).

For this study, Daniel A. Goldstein, MD, of Emory University in Atlanta, Georgia, and his colleagues measured the monthly price trajectories of 24 cancer drugs approved by the US Food and Drug Administration. This included 10 drugs approved to treat hematologic malignancies between 1997 and 2011.

To account for discounts and rebates, the researchers used the average sales prices published by the Centers for Medicare and Medicaid Services and adjusted to general and health-related inflation rates. For each drug, the researchers calculated the cumulative and annual drug cost changes.

Results

The mean follow-up was 8 years. The mean cumulative cost increase for all 24 drugs was +36.5% (95% CI, 24.7% to 48.3%).

The general inflation-adjusted increase was +19.1% (95% CI, 11.0% to 27.2%), and the health-related inflation-adjusted increase was +8.4% (95% CI, 1.4% to 15.4%).

Only 1 of the 24 drugs studied had a price decrease over time. That drug is ziv-aflibercept, which was approved to treat metastatic colorectal cancer in 2012.

Ziv-aflibercept was launched with an annual price exceeding $110,000. After public outcry, the drug’s manufacturer, Sanofi, cut the price in half. By the end of the study’s follow-up period in 2017, the cost of ziv-aflibercept had decreased 13% (inflation-adjusted decrease of 15%, health-related inflation-adjusted decrease of 20%).

Cost changes for the drugs approved to treat hematologic malignancies are listed in the following table.

Abbreviations: ALL, acute lymphoblastic leukemia; APL, acute promyelocytic leukemia; CLL, chronic lymphocytic leukemia; MCL, mantle cell lymphoma; MM, multiple myeloma; NHL, non-Hodgkin lymphoma; SD, standard deviation.

The researchers noted that there was a steady increase in drug costs over the study period, regardless of whether a drug was granted a new supplemental indication, the drug had a new off-label indication, or a competitor drug was approved.

The only variable that was significantly associated with price change was the amount of time that had elapsed from a drug’s launch.

This association was significant in models in which the researchers used prices adjusted to inflation (P=0.002) and health-related inflation (P=0.023). However, it was not significant when the researchers used the actual drug price (P=0.085).

*Data in the abstract differ from data in the body of the JCO paper. This article includes data from the body of the JCO paper.

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to GSK2857916, an anti-B-cell maturation antigen (BCMA) monoclonal antibody conjugated to the cytotoxic agent monomethyl auristatin-F via a non-cleavable linker.

The designation is for GSK2857916 as monotherapy for patients with multiple myeloma (MM) who have failed at least 3 prior lines of therapy, including an anti-CD38 antibody, and who are refractory to a proteasome inhibitor and an immunomodulatory agent.

The designation is based on results from a phase 1, dose-escalation and expansion study in patients with relapsed/refractory MM, irrespective of BCMA expression (NCT02064387).

Data from this ongoing trial are scheduled to be presented December 11 in an oral presentation at the 59th Annual Meeting of the American Society of Hematology (ASH) in Atlanta, Georgia.

GSK2857916 has also received orphan drug designation from the FDA and the European Medicines Agency (EMA) as well as PRIME designation from the EMA.

About breakthrough designation

The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions. The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

Orphan and PRIME designations

The FDA grants orphan designation to therapies intended to treat conditions that affect fewer than 200,000 people in the US. The designation qualifies a drug’s sponsor for various development incentives of the Orphan Drug Act, including tax credits for qualified clinical testing and 7 years of market exclusivity.

In Europe, sponsors who obtain orphan designation for a potential new medicine benefit from a range of incentives, including protocol assistance, access to the centralized procedure, 10 years of market exclusivity, and fee reductions.

The EMA grants PRIME designation to enhance support for the development of medicines that target an unmet medical need. The designation is based on enhanced interaction between sponsor companies and the EMA to optimize development plans and speed up evaluation so these medicines can reach patients earlier.

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to GSK2857916, an anti-B-cell maturation antigen (BCMA) monoclonal antibody conjugated to the cytotoxic agent monomethyl auristatin-F via a non-cleavable linker.

The designation is for GSK2857916 as monotherapy for patients with multiple myeloma (MM) who have failed at least 3 prior lines of therapy, including an anti-CD38 antibody, and who are refractory to a proteasome inhibitor and an immunomodulatory agent.

The designation is based on results from a phase 1, dose-escalation and expansion study in patients with relapsed/refractory MM, irrespective of BCMA expression (NCT02064387).

Data from this ongoing trial are scheduled to be presented December 11 in an oral presentation at the 59th Annual Meeting of the American Society of Hematology (ASH) in Atlanta, Georgia.

GSK2857916 has also received orphan drug designation from the FDA and the European Medicines Agency (EMA) as well as PRIME designation from the EMA.

About breakthrough designation

The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions. The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

Orphan and PRIME designations

The FDA grants orphan designation to therapies intended to treat conditions that affect fewer than 200,000 people in the US. The designation qualifies a drug’s sponsor for various development incentives of the Orphan Drug Act, including tax credits for qualified clinical testing and 7 years of market exclusivity.

In Europe, sponsors who obtain orphan designation for a potential new medicine benefit from a range of incentives, including protocol assistance, access to the centralized procedure, 10 years of market exclusivity, and fee reductions.

The EMA grants PRIME designation to enhance support for the development of medicines that target an unmet medical need. The designation is based on enhanced interaction between sponsor companies and the EMA to optimize development plans and speed up evaluation so these medicines can reach patients earlier.

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to GSK2857916, an anti-B-cell maturation antigen (BCMA) monoclonal antibody conjugated to the cytotoxic agent monomethyl auristatin-F via a non-cleavable linker.

The designation is for GSK2857916 as monotherapy for patients with multiple myeloma (MM) who have failed at least 3 prior lines of therapy, including an anti-CD38 antibody, and who are refractory to a proteasome inhibitor and an immunomodulatory agent.

The designation is based on results from a phase 1, dose-escalation and expansion study in patients with relapsed/refractory MM, irrespective of BCMA expression (NCT02064387).

Data from this ongoing trial are scheduled to be presented December 11 in an oral presentation at the 59th Annual Meeting of the American Society of Hematology (ASH) in Atlanta, Georgia.

GSK2857916 has also received orphan drug designation from the FDA and the European Medicines Agency (EMA) as well as PRIME designation from the EMA.

About breakthrough designation

The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions. The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

Orphan and PRIME designations

The FDA grants orphan designation to therapies intended to treat conditions that affect fewer than 200,000 people in the US. The designation qualifies a drug’s sponsor for various development incentives of the Orphan Drug Act, including tax credits for qualified clinical testing and 7 years of market exclusivity.

In Europe, sponsors who obtain orphan designation for a potential new medicine benefit from a range of incentives, including protocol assistance, access to the centralized procedure, 10 years of market exclusivity, and fee reductions.

The EMA grants PRIME designation to enhance support for the development of medicines that target an unmet medical need. The designation is based on enhanced interaction between sponsor companies and the EMA to optimize development plans and speed up evaluation so these medicines can reach patients earlier.

Photo courtesy of NIH

SAN DIEGO—A new study suggests patients with advanced cancer may prefer doctors who do not use a computer while communicating with them.

Most of the 120 patients studied said they preferred face-to-face consultations in which a doctor used a notepad rather than a computer.

Doctors who did not use a computer were perceived as more compassionate, communicative, and professional.

These findings were presented at the 2017 Palliative and Supportive Care in Oncology Symposium (abstract 26*).

“To our knowledge, this is the only study that compares exam room interactions between people with advanced cancer and their physicians, with or without a computer present,” said study investigator Ali Haider, MD, of the University of Texas MD Anderson Cancer Center in Houston.

For this study, Dr Haider and his colleagues enrolled 120 patients with localized, recurrent, or metastatic disease. The patients’ median ECOG performance status was 2.

All patients were English speakers, they had a median age of 58 (range, 44-66), and 55% were female. Sixty-seven percent of patients were white, 18% were Hispanic, 13% were African American, and 2% were “other.” Forty-one percent of patients had completed college.

According to the Edmonton Symptom Assessment System, patients’ median pain score was 5 (range, 2-7), and their median fatigue score was 4 (range, 3-7). According to the Hospital Anxiety and Depression Scale, patients’ median anxiety score was 6 (range, 4-8), and their median depression score was 6 (range, 4-9).

The intervention

The investigators randomly assigned patients to watch different videos showing doctor-patient interactions with and without computer use. The team had filmed 4 short videos that featured actors playing the parts of doctor and patient.

All study participants were blinded to the hypothesis of the study. The actors were carefully scripted and used the same gestures, expressions, and other nonverbal communication in each video to minimize bias.

Video 1 involved Doctor A in a face-to-face consultation with just a notepad in hand, and Video 2 involved Doctor A in a consultation using a computer.

Video 3 involved Doctor B in a face-to-face consultation with just a notepad in hand, and Video 4 involved Doctor B in a consultation using a computer.

Doctors A and B looked similar, which was intended to minimize bias.

After viewing their first video, patients completed a validated questionnaire rating the doctor’s communication skills, professionalism, and compassion.

Subsequently, each group was assigned to a video topic (face-to-face or computer) they had not viewed previously featuring the doctor they had not viewed in the first video.

A follow-up questionnaire was given after this round of viewing, and the patients were also asked to rate their overall physician preference.

Results

After the first round of viewing, the patients gave better ratings to doctors (A or B) in the face-to-face videos than in the computer videos. Face-to-face doctors were rated significantly higher for compassion (P=0.0003), communication skills (P=0.0012), and professionalism (P=0.0001).

After patients had watched both videos, doctors in the face-to-face videos still had better scores for compassion, communication, and professionalism (P<0.001 for all).

Most patients (72%) said they preferred the face-to-face consultation, while 8% said they preferred the computer consultation, and 20% said they had no preference.

Dr Haider said a possible explanation for these findings is that patients with serious chronic illnesses might value undivided attention from their physicians, and patients might perceive providers using computers as more distracted or multitasking during visits.

“We know that having a good rapport with patients can be extremely beneficial for their health,” Dr Haider said. “Patients with advanced disease need the cues that come with direct interaction to help them along with their care.”

However, Dr Haider also noted that additional research is needed to confirm these results. And he said perceptions might be different in a younger population with higher computer literacy.

*Data in the abstract differ from the presentation.

Photo courtesy of NIH

SAN DIEGO—A new study suggests patients with advanced cancer may prefer doctors who do not use a computer while communicating with them.

Most of the 120 patients studied said they preferred face-to-face consultations in which a doctor used a notepad rather than a computer.

Doctors who did not use a computer were perceived as more compassionate, communicative, and professional.

These findings were presented at the 2017 Palliative and Supportive Care in Oncology Symposium (abstract 26*).

“To our knowledge, this is the only study that compares exam room interactions between people with advanced cancer and their physicians, with or without a computer present,” said study investigator Ali Haider, MD, of the University of Texas MD Anderson Cancer Center in Houston.

For this study, Dr Haider and his colleagues enrolled 120 patients with localized, recurrent, or metastatic disease. The patients’ median ECOG performance status was 2.

All patients were English speakers, they had a median age of 58 (range, 44-66), and 55% were female. Sixty-seven percent of patients were white, 18% were Hispanic, 13% were African American, and 2% were “other.” Forty-one percent of patients had completed college.

According to the Edmonton Symptom Assessment System, patients’ median pain score was 5 (range, 2-7), and their median fatigue score was 4 (range, 3-7). According to the Hospital Anxiety and Depression Scale, patients’ median anxiety score was 6 (range, 4-8), and their median depression score was 6 (range, 4-9).

The intervention

The investigators randomly assigned patients to watch different videos showing doctor-patient interactions with and without computer use. The team had filmed 4 short videos that featured actors playing the parts of doctor and patient.

All study participants were blinded to the hypothesis of the study. The actors were carefully scripted and used the same gestures, expressions, and other nonverbal communication in each video to minimize bias.

Video 1 involved Doctor A in a face-to-face consultation with just a notepad in hand, and Video 2 involved Doctor A in a consultation using a computer.

Video 3 involved Doctor B in a face-to-face consultation with just a notepad in hand, and Video 4 involved Doctor B in a consultation using a computer.

Doctors A and B looked similar, which was intended to minimize bias.

After viewing their first video, patients completed a validated questionnaire rating the doctor’s communication skills, professionalism, and compassion.

Subsequently, each group was assigned to a video topic (face-to-face or computer) they had not viewed previously featuring the doctor they had not viewed in the first video.

A follow-up questionnaire was given after this round of viewing, and the patients were also asked to rate their overall physician preference.

Results

After the first round of viewing, the patients gave better ratings to doctors (A or B) in the face-to-face videos than in the computer videos. Face-to-face doctors were rated significantly higher for compassion (P=0.0003), communication skills (P=0.0012), and professionalism (P=0.0001).

After patients had watched both videos, doctors in the face-to-face videos still had better scores for compassion, communication, and professionalism (P<0.001 for all).

Most patients (72%) said they preferred the face-to-face consultation, while 8% said they preferred the computer consultation, and 20% said they had no preference.

Dr Haider said a possible explanation for these findings is that patients with serious chronic illnesses might value undivided attention from their physicians, and patients might perceive providers using computers as more distracted or multitasking during visits.

“We know that having a good rapport with patients can be extremely beneficial for their health,” Dr Haider said. “Patients with advanced disease need the cues that come with direct interaction to help them along with their care.”

However, Dr Haider also noted that additional research is needed to confirm these results. And he said perceptions might be different in a younger population with higher computer literacy.

*Data in the abstract differ from the presentation.

Photo courtesy of NIH

SAN DIEGO—A new study suggests patients with advanced cancer may prefer doctors who do not use a computer while communicating with them.

Most of the 120 patients studied said they preferred face-to-face consultations in which a doctor used a notepad rather than a computer.

Doctors who did not use a computer were perceived as more compassionate, communicative, and professional.

These findings were presented at the 2017 Palliative and Supportive Care in Oncology Symposium (abstract 26*).

“To our knowledge, this is the only study that compares exam room interactions between people with advanced cancer and their physicians, with or without a computer present,” said study investigator Ali Haider, MD, of the University of Texas MD Anderson Cancer Center in Houston.

For this study, Dr Haider and his colleagues enrolled 120 patients with localized, recurrent, or metastatic disease. The patients’ median ECOG performance status was 2.

All patients were English speakers, they had a median age of 58 (range, 44-66), and 55% were female. Sixty-seven percent of patients were white, 18% were Hispanic, 13% were African American, and 2% were “other.” Forty-one percent of patients had completed college.

According to the Edmonton Symptom Assessment System, patients’ median pain score was 5 (range, 2-7), and their median fatigue score was 4 (range, 3-7). According to the Hospital Anxiety and Depression Scale, patients’ median anxiety score was 6 (range, 4-8), and their median depression score was 6 (range, 4-9).

The intervention

The investigators randomly assigned patients to watch different videos showing doctor-patient interactions with and without computer use. The team had filmed 4 short videos that featured actors playing the parts of doctor and patient.

All study participants were blinded to the hypothesis of the study. The actors were carefully scripted and used the same gestures, expressions, and other nonverbal communication in each video to minimize bias.

Video 1 involved Doctor A in a face-to-face consultation with just a notepad in hand, and Video 2 involved Doctor A in a consultation using a computer.

Video 3 involved Doctor B in a face-to-face consultation with just a notepad in hand, and Video 4 involved Doctor B in a consultation using a computer.

Doctors A and B looked similar, which was intended to minimize bias.

After viewing their first video, patients completed a validated questionnaire rating the doctor’s communication skills, professionalism, and compassion.

Subsequently, each group was assigned to a video topic (face-to-face or computer) they had not viewed previously featuring the doctor they had not viewed in the first video.

A follow-up questionnaire was given after this round of viewing, and the patients were also asked to rate their overall physician preference.

Results

After the first round of viewing, the patients gave better ratings to doctors (A or B) in the face-to-face videos than in the computer videos. Face-to-face doctors were rated significantly higher for compassion (P=0.0003), communication skills (P=0.0012), and professionalism (P=0.0001).

After patients had watched both videos, doctors in the face-to-face videos still had better scores for compassion, communication, and professionalism (P<0.001 for all).

Most patients (72%) said they preferred the face-to-face consultation, while 8% said they preferred the computer consultation, and 20% said they had no preference.

Dr Haider said a possible explanation for these findings is that patients with serious chronic illnesses might value undivided attention from their physicians, and patients might perceive providers using computers as more distracted or multitasking during visits.

“We know that having a good rapport with patients can be extremely beneficial for their health,” Dr Haider said. “Patients with advanced disease need the cues that come with direct interaction to help them along with their care.”

However, Dr Haider also noted that additional research is needed to confirm these results. And he said perceptions might be different in a younger population with higher computer literacy.

*Data in the abstract differ from the presentation.

Bone marrow aspirate showing plasma cells of multiple myeloma

NEW YORK, NY—The B-cell maturation antigen (BCMA) is emerging as a promising target in multiple myeloma (MM), according to Adam D. Cohen, MD, of the University of Pennsylvania in Philadelphia.

BCMA is highly expressed on MM cells and, with its 2 ligands, is responsible for maintaining normal plasma cell homeostasis.

“And it’s really not expressed on any other normal tissues of the body,” Dr Cohen said.

“Importantly, BCMA is not just sitting on the cell surface as a target but actually promotes myeloma pathogenesis.”

Dr Cohen reviewed the progress being made using BCMA as a target in MM, paying particular attention to chimeric antigen receptor (CAR) T cells. He presented the update at Lymphoma & Myeloma 2017.

NCI BCMA-specific CARs

The first CAR to specifically target BCMA in MM was developed at the National Cancer Institute (NCI). It consisted of a murine single-chain variable fragment (scFv), CD3/CD28 signaling domains, and a gamma-retroviral vector.

Investigators conducted the first-in-human trial of this CAR T-cell therapy in 12 relapsed/refractory MM patients.

All patients received a lymphodepleting conditioning regimen of cyclophosphamide and fludarabine and a single infusion of 1 of 4 doses of the CAR T-cell therapy.

At higher dose levels, the BCMA-CAR produced objective responses “even in these highly refractory patients,” Dr Cohen said. “Some responses lasted 4 to 6 months.”

Patients who had the greatest degree of expansion of CAR T cells were the ones who had the best responses.

The BCMA-CAR is associated with the same toxicities as the CD19-directed CAR T-cell therapies now approved in acute lymphoblastic leukemia and non-Hodgkin lymphoma—cytokine release syndrome (CRS) and neurotoxicity.

The NCI study (NCT02215967) is ongoing.

Penn BCMA-specific CAR

A different BCMA CAR is being investigated at the University of Pennsylvania. It is a fully human CAR that consists of a human scFv, CD3/4-1BB costimulatory domains, and a lentiviral vector.

Investigators designed the first-in-human trial* (NCT02546167) with 3 different cohorts.

Patients in cohort 1 received 5 x 10⁸ CAR T cells without any lymphodepleting chemotherapy.

The remaining patients received cyclophosphamide, followed by 5 x 10⁷ CAR T cells in cohort 2 and 5 x 10⁸ CAR T cells in cohort 3.

Dr Cohen reviewed current data from cohort 1, which included 9 patients. They were a median age of 57 (range, 44-70), and 67% were male. They were heavily pretreated with a median of 9 prior lines of therapy (range, 4-11).

All had high-risk cytogenetics, 67% had deletion 17p or TP53 mutation, and they had a median of 80% bone marrow plasma cells (range, 15%-95%).

“Despite this,” Dr Cohen said, “we were able to generate, successfully, CAR T cells from all patients, although 1 patient did require a second apheresis and manufacturing attempt.”

Four of the 9 patients achieved very good partial responses, and an additional 2 patients had minimal responses.

One patient had a stringent CR (sCR) for close to 2 years without having any intervening therapy.

“[The sCR] shows the potential for this [therapy] to create a durable remission in a patient without any other therapy,” Dr Cohen said. “And this patient still has circulating CAR cells detectable.”

Most of the other patients did not have as durable a response. Responses lasted a median of 3 to 5 months before the patients relapsed.

Dr Cohen noted that the Penn data confirm the NCI experience showing proof of principle.

“You can target BCMA with these cells and get objective responses that can lead to a durable one in a subset of patients,” he added.

Dr Cohen is scheduled to report the preliminary data on the cyclophosphamide cohorts (cohorts 2 and 3) at ASH 2017. Those cohorts, he said, are showing a bit more persistence and increased frequency of responses.

Other BCMA-specific CAR trials

Another BCMA CAR, bb2121, consists of a human anti-BCMA scFv, a lentiviral vector, and a CD3/4-1BB costimulatory domain.

In the first-in-human trial of bb2121* (NCT02658929), all 21 patients received cyclophosphamide and fludarabine conditioning first.

There were “very impressive response rates in this study,” Dr Cohen said.

Once patients were dosed at the higher levels of 150 million cells or greater, every patient responded.

“Many responses are still durable,” he pointed out, “some approaching a year.”

LCAR-B38M is structurally different from the other BCMA-specific CARs. It has 2 binding sites for BCMA.

Thirty-five patients enrolled on the trial of LCAR-B38M (NCT03090659), and 19 were evaluable for response.

Patients had a median of 3 or 4 lines of prior therapy. All received cyclophosphamide alone as conditioning.

All 19 evaluable patients responded, and 14 (74%) achieved an sCR.

Dr Cohen noted the differences among the 4 trials: costimulatory domains varied, the Penn study did not require a pre-existing level of BCMA on the MM cells, other studies excluded patients who didn’t meet a certain threshold level of BCMA expression, median lines of prior therapy differed, and conditioning regimens differed as well.

All trials, however, presented data on fewer than 20 patients.

“And so I think it’s a little too early to compare head-to-head between all of these, but they all are really demonstrating promising results so far,” he observed.

Toxicities

“Unfortunately, there’s no free lunch with CAR T cells,” Dr Cohen stated, “and these extraordinary responses do come at the cost of several somewhat unique toxicities that can be serious.”

Toxicities have included:

• Tumor lysis syndrome, which is expected and manageable
• B-cell aplasia, which is not as much of an issue with BCMA as with CD19-directed CAR Ts, since most B cells don’t express BCMA
• Hypogammaglobulinemia, which can be mitigated with IVIG
• CRS, which can be alleviated with tocilizumab
• Neurotoxicity and encephalopathy, which do not occur as frequently as CRS.

“These, I think, are things we still obviously need to learn more about and try to mitigate before this [BCMA-directed CAR therapy] is expanded and brought earlier to patients,” Dr Cohen said.

“The other issues with CAR T cells are logistical. Limited access (the procedure is available at only a few centers); manufacturing can take 2 to 4 weeks, during which time it is difficult to maintain disease control; and the cost is significant.”

“We are really in the early days of CAR cells for myeloma, but, certainly, this appears very bright in terms of its future.” 

* Data from the presentation differ from the abstract.

Bone marrow aspirate showing plasma cells of multiple myeloma

NEW YORK, NY—The B-cell maturation antigen (BCMA) is emerging as a promising target in multiple myeloma (MM), according to Adam D. Cohen, MD, of the University of Pennsylvania in Philadelphia.

BCMA is highly expressed on MM cells and, with its 2 ligands, is responsible for maintaining normal plasma cell homeostasis.

“And it’s really not expressed on any other normal tissues of the body,” Dr Cohen said.

“Importantly, BCMA is not just sitting on the cell surface as a target but actually promotes myeloma pathogenesis.”

Dr Cohen reviewed the progress being made using BCMA as a target in MM, paying particular attention to chimeric antigen receptor (CAR) T cells. He presented the update at Lymphoma & Myeloma 2017.

NCI BCMA-specific CARs

The first CAR to specifically target BCMA in MM was developed at the National Cancer Institute (NCI). It consisted of a murine single-chain variable fragment (scFv), CD3/CD28 signaling domains, and a gamma-retroviral vector.

Investigators conducted the first-in-human trial of this CAR T-cell therapy in 12 relapsed/refractory MM patients.

All patients received a lymphodepleting conditioning regimen of cyclophosphamide and fludarabine and a single infusion of 1 of 4 doses of the CAR T-cell therapy.

At higher dose levels, the BCMA-CAR produced objective responses “even in these highly refractory patients,” Dr Cohen said. “Some responses lasted 4 to 6 months.”

Patients who had the greatest degree of expansion of CAR T cells were the ones who had the best responses.

The BCMA-CAR is associated with the same toxicities as the CD19-directed CAR T-cell therapies now approved in acute lymphoblastic leukemia and non-Hodgkin lymphoma—cytokine release syndrome (CRS) and neurotoxicity.

The NCI study (NCT02215967) is ongoing.

Penn BCMA-specific CAR

A different BCMA CAR is being investigated at the University of Pennsylvania. It is a fully human CAR that consists of a human scFv, CD3/4-1BB costimulatory domains, and a lentiviral vector.

Investigators designed the first-in-human trial* (NCT02546167) with 3 different cohorts.

Patients in cohort 1 received 5 x 10⁸ CAR T cells without any lymphodepleting chemotherapy.

The remaining patients received cyclophosphamide, followed by 5 x 10⁷ CAR T cells in cohort 2 and 5 x 10⁸ CAR T cells in cohort 3.

Dr Cohen reviewed current data from cohort 1, which included 9 patients. They were a median age of 57 (range, 44-70), and 67% were male. They were heavily pretreated with a median of 9 prior lines of therapy (range, 4-11).

All had high-risk cytogenetics, 67% had deletion 17p or TP53 mutation, and they had a median of 80% bone marrow plasma cells (range, 15%-95%).

“Despite this,” Dr Cohen said, “we were able to generate, successfully, CAR T cells from all patients, although 1 patient did require a second apheresis and manufacturing attempt.”

Four of the 9 patients achieved very good partial responses, and an additional 2 patients had minimal responses.

One patient had a stringent CR (sCR) for close to 2 years without having any intervening therapy.

“[The sCR] shows the potential for this [therapy] to create a durable remission in a patient without any other therapy,” Dr Cohen said. “And this patient still has circulating CAR cells detectable.”

Most of the other patients did not have as durable a response. Responses lasted a median of 3 to 5 months before the patients relapsed.

Dr Cohen noted that the Penn data confirm the NCI experience showing proof of principle.

“You can target BCMA with these cells and get objective responses that can lead to a durable one in a subset of patients,” he added.

Dr Cohen is scheduled to report the preliminary data on the cyclophosphamide cohorts (cohorts 2 and 3) at ASH 2017. Those cohorts, he said, are showing a bit more persistence and increased frequency of responses.

Other BCMA-specific CAR trials

Another BCMA CAR, bb2121, consists of a human anti-BCMA scFv, a lentiviral vector, and a CD3/4-1BB costimulatory domain.

In the first-in-human trial of bb2121* (NCT02658929), all 21 patients received cyclophosphamide and fludarabine conditioning first.

There were “very impressive response rates in this study,” Dr Cohen said.

Once patients were dosed at the higher levels of 150 million cells or greater, every patient responded.

“Many responses are still durable,” he pointed out, “some approaching a year.”

LCAR-B38M is structurally different from the other BCMA-specific CARs. It has 2 binding sites for BCMA.

Thirty-five patients enrolled on the trial of LCAR-B38M (NCT03090659), and 19 were evaluable for response.

Patients had a median of 3 or 4 lines of prior therapy. All received cyclophosphamide alone as conditioning.

All 19 evaluable patients responded, and 14 (74%) achieved an sCR.

Dr Cohen noted the differences among the 4 trials: costimulatory domains varied, the Penn study did not require a pre-existing level of BCMA on the MM cells, other studies excluded patients who didn’t meet a certain threshold level of BCMA expression, median lines of prior therapy differed, and conditioning regimens differed as well.

All trials, however, presented data on fewer than 20 patients.

“And so I think it’s a little too early to compare head-to-head between all of these, but they all are really demonstrating promising results so far,” he observed.

Toxicities

“Unfortunately, there’s no free lunch with CAR T cells,” Dr Cohen stated, “and these extraordinary responses do come at the cost of several somewhat unique toxicities that can be serious.”

Toxicities have included:

• Tumor lysis syndrome, which is expected and manageable
• B-cell aplasia, which is not as much of an issue with BCMA as with CD19-directed CAR Ts, since most B cells don’t express BCMA
• Hypogammaglobulinemia, which can be mitigated with IVIG
• CRS, which can be alleviated with tocilizumab
• Neurotoxicity and encephalopathy, which do not occur as frequently as CRS.

“These, I think, are things we still obviously need to learn more about and try to mitigate before this [BCMA-directed CAR therapy] is expanded and brought earlier to patients,” Dr Cohen said.

“The other issues with CAR T cells are logistical. Limited access (the procedure is available at only a few centers); manufacturing can take 2 to 4 weeks, during which time it is difficult to maintain disease control; and the cost is significant.”

“We are really in the early days of CAR cells for myeloma, but, certainly, this appears very bright in terms of its future.” 

* Data from the presentation differ from the abstract.

Bone marrow aspirate showing plasma cells of multiple myeloma

NEW YORK, NY—The B-cell maturation antigen (BCMA) is emerging as a promising target in multiple myeloma (MM), according to Adam D. Cohen, MD, of the University of Pennsylvania in Philadelphia.

BCMA is highly expressed on MM cells and, with its 2 ligands, is responsible for maintaining normal plasma cell homeostasis.

“And it’s really not expressed on any other normal tissues of the body,” Dr Cohen said.

“Importantly, BCMA is not just sitting on the cell surface as a target but actually promotes myeloma pathogenesis.”

Dr Cohen reviewed the progress being made using BCMA as a target in MM, paying particular attention to chimeric antigen receptor (CAR) T cells. He presented the update at Lymphoma & Myeloma 2017.

NCI BCMA-specific CARs

The first CAR to specifically target BCMA in MM was developed at the National Cancer Institute (NCI). It consisted of a murine single-chain variable fragment (scFv), CD3/CD28 signaling domains, and a gamma-retroviral vector.

Investigators conducted the first-in-human trial of this CAR T-cell therapy in 12 relapsed/refractory MM patients.

All patients received a lymphodepleting conditioning regimen of cyclophosphamide and fludarabine and a single infusion of 1 of 4 doses of the CAR T-cell therapy.

At higher dose levels, the BCMA-CAR produced objective responses “even in these highly refractory patients,” Dr Cohen said. “Some responses lasted 4 to 6 months.”

Patients who had the greatest degree of expansion of CAR T cells were the ones who had the best responses.

The BCMA-CAR is associated with the same toxicities as the CD19-directed CAR T-cell therapies now approved in acute lymphoblastic leukemia and non-Hodgkin lymphoma—cytokine release syndrome (CRS) and neurotoxicity.

The NCI study (NCT02215967) is ongoing.

Penn BCMA-specific CAR

A different BCMA CAR is being investigated at the University of Pennsylvania. It is a fully human CAR that consists of a human scFv, CD3/4-1BB costimulatory domains, and a lentiviral vector.

Investigators designed the first-in-human trial* (NCT02546167) with 3 different cohorts.

Patients in cohort 1 received 5 x 10⁸ CAR T cells without any lymphodepleting chemotherapy.

The remaining patients received cyclophosphamide, followed by 5 x 10⁷ CAR T cells in cohort 2 and 5 x 10⁸ CAR T cells in cohort 3.

Dr Cohen reviewed current data from cohort 1, which included 9 patients. They were a median age of 57 (range, 44-70), and 67% were male. They were heavily pretreated with a median of 9 prior lines of therapy (range, 4-11).

All had high-risk cytogenetics, 67% had deletion 17p or TP53 mutation, and they had a median of 80% bone marrow plasma cells (range, 15%-95%).

“Despite this,” Dr Cohen said, “we were able to generate, successfully, CAR T cells from all patients, although 1 patient did require a second apheresis and manufacturing attempt.”

Four of the 9 patients achieved very good partial responses, and an additional 2 patients had minimal responses.

One patient had a stringent CR (sCR) for close to 2 years without having any intervening therapy.

“[The sCR] shows the potential for this [therapy] to create a durable remission in a patient without any other therapy,” Dr Cohen said. “And this patient still has circulating CAR cells detectable.”

Most of the other patients did not have as durable a response. Responses lasted a median of 3 to 5 months before the patients relapsed.

Dr Cohen noted that the Penn data confirm the NCI experience showing proof of principle.

“You can target BCMA with these cells and get objective responses that can lead to a durable one in a subset of patients,” he added.

Dr Cohen is scheduled to report the preliminary data on the cyclophosphamide cohorts (cohorts 2 and 3) at ASH 2017. Those cohorts, he said, are showing a bit more persistence and increased frequency of responses.

Other BCMA-specific CAR trials

Another BCMA CAR, bb2121, consists of a human anti-BCMA scFv, a lentiviral vector, and a CD3/4-1BB costimulatory domain.

In the first-in-human trial of bb2121* (NCT02658929), all 21 patients received cyclophosphamide and fludarabine conditioning first.

There were “very impressive response rates in this study,” Dr Cohen said.

Once patients were dosed at the higher levels of 150 million cells or greater, every patient responded.

“Many responses are still durable,” he pointed out, “some approaching a year.”

LCAR-B38M is structurally different from the other BCMA-specific CARs. It has 2 binding sites for BCMA.

Thirty-five patients enrolled on the trial of LCAR-B38M (NCT03090659), and 19 were evaluable for response.

Patients had a median of 3 or 4 lines of prior therapy. All received cyclophosphamide alone as conditioning.

All 19 evaluable patients responded, and 14 (74%) achieved an sCR.

Dr Cohen noted the differences among the 4 trials: costimulatory domains varied, the Penn study did not require a pre-existing level of BCMA on the MM cells, other studies excluded patients who didn’t meet a certain threshold level of BCMA expression, median lines of prior therapy differed, and conditioning regimens differed as well.

All trials, however, presented data on fewer than 20 patients.

“And so I think it’s a little too early to compare head-to-head between all of these, but they all are really demonstrating promising results so far,” he observed.

Toxicities

“Unfortunately, there’s no free lunch with CAR T cells,” Dr Cohen stated, “and these extraordinary responses do come at the cost of several somewhat unique toxicities that can be serious.”

Toxicities have included:

• Tumor lysis syndrome, which is expected and manageable
• B-cell aplasia, which is not as much of an issue with BCMA as with CD19-directed CAR Ts, since most B cells don’t express BCMA
• Hypogammaglobulinemia, which can be mitigated with IVIG
• CRS, which can be alleviated with tocilizumab
• Neurotoxicity and encephalopathy, which do not occur as frequently as CRS.

“These, I think, are things we still obviously need to learn more about and try to mitigate before this [BCMA-directed CAR therapy] is expanded and brought earlier to patients,” Dr Cohen said.

“The other issues with CAR T cells are logistical. Limited access (the procedure is available at only a few centers); manufacturing can take 2 to 4 weeks, during which time it is difficult to maintain disease control; and the cost is significant.”

“We are really in the early days of CAR cells for myeloma, but, certainly, this appears very bright in terms of its future.” 

* Data from the presentation differ from the abstract.

Photo courtesy of Mayo Clinic

NEW YORK, NY—Despite the attraction of incorporating monoclonal antibodies (mAbs) into upfront therapy for multiple myeloma (MM), a speaker at Lymphoma & Myeloma 2017 suggested mAbs are “not quite ready” for this use.

MAbs, particularly daratumumab, have shown single-agent activity in refractory MM and have been feasibly added to proteasome inhibitors and immunomodulatory drugs.

MAbs may even have the potential to enhance induction and shorten the time to minimal residual disease negativity.

“So the tendency is to simply add them to frontline therapy,” said the speaker, Joseph Mikhael, MD, from Mayo Clinic Arizona in Scottsdale.

However, he noted that there is little long-term experience with these agents.

“I’m going to suggest to you that they’re not quite ready [for upfront use] but will likely be ready in the future,” Dr Mikhael said. “We’ve had such a revolution in myeloma the last decade that it’s just easy for us to say, ‘Oh, throw it in there, just like we did, frankly, with rituximab in the lymphoma days. We added it to CVP, we added it to CHOP, we added it to bendamustine. It didn’t matter what we added it to, it just upgraded the response.”

“And, sometimes, I think we have the same approach with daratumumab or elotuzumab or some of the other mAbs that we have. I think we just have to do so cautiously.”

At present, the combination of a proteasome inhibitor and an immunomodulatory drug are the standard of care upfront in transplant-eligible and -ineligible MM patients.

Daratumumab plus KRd

Dr Mikhael described the experience of daratumumab added to carfilzomib, lenalidomide, and dexamethasone (KRd) in patients with newly diagnosed MM in the MMY1001 study.

Twenty-two patients were enrolled on the study, 91% achieved a very good partial response (VGPR) or better, and 43% achieved a complete response (CR). The depth of response improved with the duration of treatment.

Eight patients (36%) discontinued treatment.

Dr Mikhael emphasized that the preliminary data included very small numbers.

“There is a little bit of a yellow flag that pops up here,” he added, “when I see that 36% discontinued treatment, even in small numbers.”

The safety profile was consistent with previous reports for daratumumab or KRd.

The most common hematologic grade 3-4 treatment-emergent adverse events (AEs) occurring in 30% or more of patients were lymphopenia (64%), thrombocytopenia (9%), anemia (9%), leukopenia (9%), and neutropenia (14%).

Diarrhea (14%), cough (5%), fatigue (5%), insomnia (5%), and increased ALT (9%) were the most common grade 3-4 nonhematologic treatment-emergent AEs occurring in 30% or more of patients.

The treatment had no adverse impact on stem cell collection.

Elotuzumab plus VRd

Turning to elotuzumab in combination with bortezomib, lenalidomide, and dexamethasone (VRd), Dr Mikhael reviewed the phase 2a study (NCT02375555) presented at ASCO 2017 (abstract 8002).

Forty-one patients were enrolled on the study.

The overall response rate after 4 cycles was 100%, with 24% achieving a CR, 47% achieving a VGPR, and 29% a partial response.

Fatigue (60%), neuropathy (55%), musculoskeletal/joint pain (55%), infection (50%), back/neck pain (48%), diarrhea (45%), edema (38%), constipation (38%), cough (35%), mood alteration (35%), rash (35%), and insomnia (30%) occurred in 30% or more of patients.

“So again, not shocking,” Dr Mikhael said, “there was fatigue, there was neuropathy, and there were infections in 50% of patients.”

Grade 4 or greater AEs included thrombocytopenia, hyperglycemia, sepsis, cardiac arrest, and respiratory failure.

“However, here, [we have] maybe not even a yellow flag but a red flag of caution that there were 2 patients who died,” Dr Mikhael noted.

One patient died on study due to respiratory failure and sepsis that arose during cycle 2.

The other patient died more than 30 days after discontinuing study therapy due to febrile neutropenia and hypotension related to sepsis, followed by renal failure.

“Again, in a study that has such small numbers, I don’t want to overstate the case . . ., we don’t want to overreact, but whenever there is death involved, obviously, we have to be particularly cautious,” Dr Mikhael said.

Put into the context of 3 other VRd studies, he noted, the response rate with elotuzumab and VRd is relatively similar but not as good as the phase 3 study of VRd, which was a much larger study of 350 patients.

The situation with daratumumab and KRd is similar to elotuzumab, Dr Mikhael pointed out.

The initial response rates are impressive, but, when compared to other studies, “71% VGPR is good, only after 4 cycles, but we know that, in other studies, after a few more cycles, it was significantly higher.”

Cost

Dr Mikhael also considered cost in his assessment of daratumumab and elotuzumab integrated into frontline regimens.

Adding elotuzumab to VRd would almost double the cost of 12 weeks of therapy. And adding daratumumab to KRd would increase the cost even more.

“These costs are real,” Dr Mikhael said, “and, ultimately, if it’s the best thing for our patients, that’s what we are going to do. But until we have that convincing evidence, I think it’s critical to keep that in perspective. I would suggest that VRd, in many respects, is the standard of care for most patients.”

In terms of adding a mAb upfront, he said, “I don’t think we’re there yet. Do I think, in time, we will be? Quite likely, but I don’t think we are there yet.” 

Photo courtesy of Mayo Clinic

NEW YORK, NY—Despite the attraction of incorporating monoclonal antibodies (mAbs) into upfront therapy for multiple myeloma (MM), a speaker at Lymphoma & Myeloma 2017 suggested mAbs are “not quite ready” for this use.

MAbs, particularly daratumumab, have shown single-agent activity in refractory MM and have been feasibly added to proteasome inhibitors and immunomodulatory drugs.

MAbs may even have the potential to enhance induction and shorten the time to minimal residual disease negativity.

“So the tendency is to simply add them to frontline therapy,” said the speaker, Joseph Mikhael, MD, from Mayo Clinic Arizona in Scottsdale.

However, he noted that there is little long-term experience with these agents.

“I’m going to suggest to you that they’re not quite ready [for upfront use] but will likely be ready in the future,” Dr Mikhael said. “We’ve had such a revolution in myeloma the last decade that it’s just easy for us to say, ‘Oh, throw it in there, just like we did, frankly, with rituximab in the lymphoma days. We added it to CVP, we added it to CHOP, we added it to bendamustine. It didn’t matter what we added it to, it just upgraded the response.”

“And, sometimes, I think we have the same approach with daratumumab or elotuzumab or some of the other mAbs that we have. I think we just have to do so cautiously.”

At present, the combination of a proteasome inhibitor and an immunomodulatory drug are the standard of care upfront in transplant-eligible and -ineligible MM patients.

Daratumumab plus KRd

Dr Mikhael described the experience of daratumumab added to carfilzomib, lenalidomide, and dexamethasone (KRd) in patients with newly diagnosed MM in the MMY1001 study.

Twenty-two patients were enrolled on the study, 91% achieved a very good partial response (VGPR) or better, and 43% achieved a complete response (CR). The depth of response improved with the duration of treatment.

Eight patients (36%) discontinued treatment.

Dr Mikhael emphasized that the preliminary data included very small numbers.

“There is a little bit of a yellow flag that pops up here,” he added, “when I see that 36% discontinued treatment, even in small numbers.”

The safety profile was consistent with previous reports for daratumumab or KRd.

The most common hematologic grade 3-4 treatment-emergent adverse events (AEs) occurring in 30% or more of patients were lymphopenia (64%), thrombocytopenia (9%), anemia (9%), leukopenia (9%), and neutropenia (14%).

Diarrhea (14%), cough (5%), fatigue (5%), insomnia (5%), and increased ALT (9%) were the most common grade 3-4 nonhematologic treatment-emergent AEs occurring in 30% or more of patients.

The treatment had no adverse impact on stem cell collection.

Elotuzumab plus VRd

Turning to elotuzumab in combination with bortezomib, lenalidomide, and dexamethasone (VRd), Dr Mikhael reviewed the phase 2a study (NCT02375555) presented at ASCO 2017 (abstract 8002).

Forty-one patients were enrolled on the study.

The overall response rate after 4 cycles was 100%, with 24% achieving a CR, 47% achieving a VGPR, and 29% a partial response.

Fatigue (60%), neuropathy (55%), musculoskeletal/joint pain (55%), infection (50%), back/neck pain (48%), diarrhea (45%), edema (38%), constipation (38%), cough (35%), mood alteration (35%), rash (35%), and insomnia (30%) occurred in 30% or more of patients.

“So again, not shocking,” Dr Mikhael said, “there was fatigue, there was neuropathy, and there were infections in 50% of patients.”

Grade 4 or greater AEs included thrombocytopenia, hyperglycemia, sepsis, cardiac arrest, and respiratory failure.

“However, here, [we have] maybe not even a yellow flag but a red flag of caution that there were 2 patients who died,” Dr Mikhael noted.

One patient died on study due to respiratory failure and sepsis that arose during cycle 2.

The other patient died more than 30 days after discontinuing study therapy due to febrile neutropenia and hypotension related to sepsis, followed by renal failure.

“Again, in a study that has such small numbers, I don’t want to overstate the case . . ., we don’t want to overreact, but whenever there is death involved, obviously, we have to be particularly cautious,” Dr Mikhael said.

Put into the context of 3 other VRd studies, he noted, the response rate with elotuzumab and VRd is relatively similar but not as good as the phase 3 study of VRd, which was a much larger study of 350 patients.

The situation with daratumumab and KRd is similar to elotuzumab, Dr Mikhael pointed out.

The initial response rates are impressive, but, when compared to other studies, “71% VGPR is good, only after 4 cycles, but we know that, in other studies, after a few more cycles, it was significantly higher.”

Cost

Dr Mikhael also considered cost in his assessment of daratumumab and elotuzumab integrated into frontline regimens.

Adding elotuzumab to VRd would almost double the cost of 12 weeks of therapy. And adding daratumumab to KRd would increase the cost even more.

“These costs are real,” Dr Mikhael said, “and, ultimately, if it’s the best thing for our patients, that’s what we are going to do. But until we have that convincing evidence, I think it’s critical to keep that in perspective. I would suggest that VRd, in many respects, is the standard of care for most patients.”

In terms of adding a mAb upfront, he said, “I don’t think we’re there yet. Do I think, in time, we will be? Quite likely, but I don’t think we are there yet.” 

Photo courtesy of Mayo Clinic

NEW YORK, NY—Despite the attraction of incorporating monoclonal antibodies (mAbs) into upfront therapy for multiple myeloma (MM), a speaker at Lymphoma & Myeloma 2017 suggested mAbs are “not quite ready” for this use.

MAbs, particularly daratumumab, have shown single-agent activity in refractory MM and have been feasibly added to proteasome inhibitors and immunomodulatory drugs.

MAbs may even have the potential to enhance induction and shorten the time to minimal residual disease negativity.

“So the tendency is to simply add them to frontline therapy,” said the speaker, Joseph Mikhael, MD, from Mayo Clinic Arizona in Scottsdale.

However, he noted that there is little long-term experience with these agents.

“I’m going to suggest to you that they’re not quite ready [for upfront use] but will likely be ready in the future,” Dr Mikhael said. “We’ve had such a revolution in myeloma the last decade that it’s just easy for us to say, ‘Oh, throw it in there, just like we did, frankly, with rituximab in the lymphoma days. We added it to CVP, we added it to CHOP, we added it to bendamustine. It didn’t matter what we added it to, it just upgraded the response.”

“And, sometimes, I think we have the same approach with daratumumab or elotuzumab or some of the other mAbs that we have. I think we just have to do so cautiously.”

At present, the combination of a proteasome inhibitor and an immunomodulatory drug are the standard of care upfront in transplant-eligible and -ineligible MM patients.

Daratumumab plus KRd

Dr Mikhael described the experience of daratumumab added to carfilzomib, lenalidomide, and dexamethasone (KRd) in patients with newly diagnosed MM in the MMY1001 study.

Twenty-two patients were enrolled on the study, 91% achieved a very good partial response (VGPR) or better, and 43% achieved a complete response (CR). The depth of response improved with the duration of treatment.

Eight patients (36%) discontinued treatment.

Dr Mikhael emphasized that the preliminary data included very small numbers.

“There is a little bit of a yellow flag that pops up here,” he added, “when I see that 36% discontinued treatment, even in small numbers.”

The safety profile was consistent with previous reports for daratumumab or KRd.

The most common hematologic grade 3-4 treatment-emergent adverse events (AEs) occurring in 30% or more of patients were lymphopenia (64%), thrombocytopenia (9%), anemia (9%), leukopenia (9%), and neutropenia (14%).

Diarrhea (14%), cough (5%), fatigue (5%), insomnia (5%), and increased ALT (9%) were the most common grade 3-4 nonhematologic treatment-emergent AEs occurring in 30% or more of patients.

The treatment had no adverse impact on stem cell collection.

Elotuzumab plus VRd

Turning to elotuzumab in combination with bortezomib, lenalidomide, and dexamethasone (VRd), Dr Mikhael reviewed the phase 2a study (NCT02375555) presented at ASCO 2017 (abstract 8002).

Forty-one patients were enrolled on the study.

The overall response rate after 4 cycles was 100%, with 24% achieving a CR, 47% achieving a VGPR, and 29% a partial response.

Fatigue (60%), neuropathy (55%), musculoskeletal/joint pain (55%), infection (50%), back/neck pain (48%), diarrhea (45%), edema (38%), constipation (38%), cough (35%), mood alteration (35%), rash (35%), and insomnia (30%) occurred in 30% or more of patients.

“So again, not shocking,” Dr Mikhael said, “there was fatigue, there was neuropathy, and there were infections in 50% of patients.”

Grade 4 or greater AEs included thrombocytopenia, hyperglycemia, sepsis, cardiac arrest, and respiratory failure.

“However, here, [we have] maybe not even a yellow flag but a red flag of caution that there were 2 patients who died,” Dr Mikhael noted.

One patient died on study due to respiratory failure and sepsis that arose during cycle 2.

The other patient died more than 30 days after discontinuing study therapy due to febrile neutropenia and hypotension related to sepsis, followed by renal failure.

“Again, in a study that has such small numbers, I don’t want to overstate the case . . ., we don’t want to overreact, but whenever there is death involved, obviously, we have to be particularly cautious,” Dr Mikhael said.

Put into the context of 3 other VRd studies, he noted, the response rate with elotuzumab and VRd is relatively similar but not as good as the phase 3 study of VRd, which was a much larger study of 350 patients.

The situation with daratumumab and KRd is similar to elotuzumab, Dr Mikhael pointed out.

The initial response rates are impressive, but, when compared to other studies, “71% VGPR is good, only after 4 cycles, but we know that, in other studies, after a few more cycles, it was significantly higher.”

Cost

Dr Mikhael also considered cost in his assessment of daratumumab and elotuzumab integrated into frontline regimens.

Adding elotuzumab to VRd would almost double the cost of 12 weeks of therapy. And adding daratumumab to KRd would increase the cost even more.

“These costs are real,” Dr Mikhael said, “and, ultimately, if it’s the best thing for our patients, that’s what we are going to do. But until we have that convincing evidence, I think it’s critical to keep that in perspective. I would suggest that VRd, in many respects, is the standard of care for most patients.”

In terms of adding a mAb upfront, he said, “I don’t think we’re there yet. Do I think, in time, we will be? Quite likely, but I don’t think we are there yet.” 

Bone fracture

NEW YORK, NY—Investigators have developed a model that suggests the clinical benefits of denosumab translate into economic value.

The investigators designed their model, X-GEM (Exgeva-Global Economic Model), using results from a large multiple myeloma (MM) trial that showed denosumab to be non-inferior to zoledronic acid (ZA) for skeletal-related events (SRE).

Noopur S. Raje, MD, of Massachusetts General Hospital Cancer Center in Boston, discussed this work at Lymphoma & Myeloma 2017.

The abstract was selected as the best clinical myeloma abstract of the meeting.

“I do think this is a very timely topic because people are not just concerned about the clinical outcomes in patients,” Dr Raje said. “[T]here’s a lot of buzz around the economic evaluation of what we do.”

Trial results

The phase 3 study (NCT01345019) on which X-GEM is based enrolled 1718 MM patients and randomized them to either denosumab or ZA.

The results, reported this year at ASCO, showed denosumab to be non-inferior to ZA in time to first on-study SRE, the primary endpoint.

Denosumab was also found to be non-inferior to ZA for the secondary endpoint of overall survival.

For the exploratory endpoint of progression-free survival (PFS), denosumab-treated patients experienced a significant benefit in terms of PFS. The median PFS was 46.09 months with denosumab and 35.38 months with ZA (difference, 10.71 months).

“Now, we’ve never really seen a survival difference or progression-free survival difference in patients, even in treatment studies, amounting to about 10.7 months,” Dr Raje said. “So this, we found, was quite remarkable in the study.”

Dr Raje also highlighted some safety features from the study. There was significantly less renal toxicity with denosumab than with ZA.

“And in patients who had a creatinine clearance of less than 60 [mL/min], there was almost a doubling of renal toxicity in patients getting zoledronic acid,” she said.

“[D]enosumab may, in fact, be the safer alternative, specifically, in our patients with multiple myeloma who we all know have this problem of renal toxicity throughout the course of their lifetime with myeloma.”

X-GEM

Investigators based X-GEM on the original model published by Stopeck et al. in 2012, which evaluated the cost-effectiveness of denosumab to prevent SREs compared with ZA in patients with solid tumors—prostate, breast, and lung cancer.

“[Stopeck’s] data did show that denosumab was, in fact, cost-effective when compared to zoledronic acid in respect to SREs,” Dr Raje noted.

The timeline for the economic analysis in MM patients spanned the time from diagnosis to death, and patients were evaluated for SREs every 4 weeks on study.

Investigators used 2 cost scenarios. The first was based on an average sales price for 28 days, which was $1928 for denosumab and $45 for ZA. The second was based on the wholesale acquisition cost, which was $2155 for denosumab and $922 for ZA.

“No surprise to anybody,” Dr Raje noted, “denosumab is a lot more expensive. But obviously, this does not tell the whole story. Built into the X-GEM model are a whole host of other factors.”

These include the costs of administration, adverse events, the number of SREs, treatment of an MM patient, and the quality-adjusted life year (QALY) gain with either denosumab or zoledronic acid.

“When you count up all these costs and calculate them based on the data set from the 1800 patients, we found that there was really a difference of zoledronic acid costing a little bit more than denosumab,” Dr Raje said.

From the payer perspective, when clinical outcomes were monetized, the net monetary benefit of denosumab compared with ZA was $5959.

And from a societal perspective, the model calculated the net monetary benefit for denosumab to be $10,259.

The societal perspective included SRE direct costs (hospital, outpatient, and emergency department visits, long-term care, hospice, physical therapy and devices, skilled nursing facility, and strong opioids), direct non-medical costs (driving for treatment, parking, and caregiver costs), and indirect costs (short-term disability and productivity loss).

The investigators concluded that denosumab is cost-effective below a willingness-to-pay threshold of $150,000/QALY regardless of ZA price, whether wholesale or average sales price.

“The bone-specific benefits and observed prolongation of progression-free survival in combination with the economic analysis provides denosumab as a valuable option for patients with multiple myeloma,” Dr Raje said. “In total, we still think it’s more cost-effective to use denosumab when compared to zoledronic acid in this patient population.”

At present, treatment options to prevent bone complications in MM patients are limited to bisphosphonates, including ZA. Denosumab is under review by the US Food and Drug Administration for an expanded indication to include MM.

Both the phase 3 and cost-effectiveness studies were funded by Amgen, Inc. Dr Raje and co-investigators of the study have either consulted for or are employed by Amgen, Inc.

Bone fracture

NEW YORK, NY—Investigators have developed a model that suggests the clinical benefits of denosumab translate into economic value.

The investigators designed their model, X-GEM (Exgeva-Global Economic Model), using results from a large multiple myeloma (MM) trial that showed denosumab to be non-inferior to zoledronic acid (ZA) for skeletal-related events (SRE).

Noopur S. Raje, MD, of Massachusetts General Hospital Cancer Center in Boston, discussed this work at Lymphoma & Myeloma 2017.

The abstract was selected as the best clinical myeloma abstract of the meeting.

“I do think this is a very timely topic because people are not just concerned about the clinical outcomes in patients,” Dr Raje said. “[T]here’s a lot of buzz around the economic evaluation of what we do.”

Trial results

The phase 3 study (NCT01345019) on which X-GEM is based enrolled 1718 MM patients and randomized them to either denosumab or ZA.

The results, reported this year at ASCO, showed denosumab to be non-inferior to ZA in time to first on-study SRE, the primary endpoint.

Denosumab was also found to be non-inferior to ZA for the secondary endpoint of overall survival.

For the exploratory endpoint of progression-free survival (PFS), denosumab-treated patients experienced a significant benefit in terms of PFS. The median PFS was 46.09 months with denosumab and 35.38 months with ZA (difference, 10.71 months).

“Now, we’ve never really seen a survival difference or progression-free survival difference in patients, even in treatment studies, amounting to about 10.7 months,” Dr Raje said. “So this, we found, was quite remarkable in the study.”

Dr Raje also highlighted some safety features from the study. There was significantly less renal toxicity with denosumab than with ZA.

“And in patients who had a creatinine clearance of less than 60 [mL/min], there was almost a doubling of renal toxicity in patients getting zoledronic acid,” she said.

“[D]enosumab may, in fact, be the safer alternative, specifically, in our patients with multiple myeloma who we all know have this problem of renal toxicity throughout the course of their lifetime with myeloma.”

X-GEM

Investigators based X-GEM on the original model published by Stopeck et al. in 2012, which evaluated the cost-effectiveness of denosumab to prevent SREs compared with ZA in patients with solid tumors—prostate, breast, and lung cancer.

“[Stopeck’s] data did show that denosumab was, in fact, cost-effective when compared to zoledronic acid in respect to SREs,” Dr Raje noted.

The timeline for the economic analysis in MM patients spanned the time from diagnosis to death, and patients were evaluated for SREs every 4 weeks on study.

Investigators used 2 cost scenarios. The first was based on an average sales price for 28 days, which was $1928 for denosumab and $45 for ZA. The second was based on the wholesale acquisition cost, which was $2155 for denosumab and $922 for ZA.

“No surprise to anybody,” Dr Raje noted, “denosumab is a lot more expensive. But obviously, this does not tell the whole story. Built into the X-GEM model are a whole host of other factors.”

These include the costs of administration, adverse events, the number of SREs, treatment of an MM patient, and the quality-adjusted life year (QALY) gain with either denosumab or zoledronic acid.

“When you count up all these costs and calculate them based on the data set from the 1800 patients, we found that there was really a difference of zoledronic acid costing a little bit more than denosumab,” Dr Raje said.

From the payer perspective, when clinical outcomes were monetized, the net monetary benefit of denosumab compared with ZA was $5959.

And from a societal perspective, the model calculated the net monetary benefit for denosumab to be $10,259.

The societal perspective included SRE direct costs (hospital, outpatient, and emergency department visits, long-term care, hospice, physical therapy and devices, skilled nursing facility, and strong opioids), direct non-medical costs (driving for treatment, parking, and caregiver costs), and indirect costs (short-term disability and productivity loss).

The investigators concluded that denosumab is cost-effective below a willingness-to-pay threshold of $150,000/QALY regardless of ZA price, whether wholesale or average sales price.

“The bone-specific benefits and observed prolongation of progression-free survival in combination with the economic analysis provides denosumab as a valuable option for patients with multiple myeloma,” Dr Raje said. “In total, we still think it’s more cost-effective to use denosumab when compared to zoledronic acid in this patient population.”

At present, treatment options to prevent bone complications in MM patients are limited to bisphosphonates, including ZA. Denosumab is under review by the US Food and Drug Administration for an expanded indication to include MM.

Both the phase 3 and cost-effectiveness studies were funded by Amgen, Inc. Dr Raje and co-investigators of the study have either consulted for or are employed by Amgen, Inc.

Bone fracture

NEW YORK, NY—Investigators have developed a model that suggests the clinical benefits of denosumab translate into economic value.

The investigators designed their model, X-GEM (Exgeva-Global Economic Model), using results from a large multiple myeloma (MM) trial that showed denosumab to be non-inferior to zoledronic acid (ZA) for skeletal-related events (SRE).

Noopur S. Raje, MD, of Massachusetts General Hospital Cancer Center in Boston, discussed this work at Lymphoma & Myeloma 2017.

The abstract was selected as the best clinical myeloma abstract of the meeting.

“I do think this is a very timely topic because people are not just concerned about the clinical outcomes in patients,” Dr Raje said. “[T]here’s a lot of buzz around the economic evaluation of what we do.”

Trial results

The phase 3 study (NCT01345019) on which X-GEM is based enrolled 1718 MM patients and randomized them to either denosumab or ZA.

The results, reported this year at ASCO, showed denosumab to be non-inferior to ZA in time to first on-study SRE, the primary endpoint.

Denosumab was also found to be non-inferior to ZA for the secondary endpoint of overall survival.

For the exploratory endpoint of progression-free survival (PFS), denosumab-treated patients experienced a significant benefit in terms of PFS. The median PFS was 46.09 months with denosumab and 35.38 months with ZA (difference, 10.71 months).

“Now, we’ve never really seen a survival difference or progression-free survival difference in patients, even in treatment studies, amounting to about 10.7 months,” Dr Raje said. “So this, we found, was quite remarkable in the study.”

Dr Raje also highlighted some safety features from the study. There was significantly less renal toxicity with denosumab than with ZA.

“And in patients who had a creatinine clearance of less than 60 [mL/min], there was almost a doubling of renal toxicity in patients getting zoledronic acid,” she said.

“[D]enosumab may, in fact, be the safer alternative, specifically, in our patients with multiple myeloma who we all know have this problem of renal toxicity throughout the course of their lifetime with myeloma.”

X-GEM

Investigators based X-GEM on the original model published by Stopeck et al. in 2012, which evaluated the cost-effectiveness of denosumab to prevent SREs compared with ZA in patients with solid tumors—prostate, breast, and lung cancer.

“[Stopeck’s] data did show that denosumab was, in fact, cost-effective when compared to zoledronic acid in respect to SREs,” Dr Raje noted.

The timeline for the economic analysis in MM patients spanned the time from diagnosis to death, and patients were evaluated for SREs every 4 weeks on study.

Investigators used 2 cost scenarios. The first was based on an average sales price for 28 days, which was $1928 for denosumab and $45 for ZA. The second was based on the wholesale acquisition cost, which was $2155 for denosumab and $922 for ZA.

“No surprise to anybody,” Dr Raje noted, “denosumab is a lot more expensive. But obviously, this does not tell the whole story. Built into the X-GEM model are a whole host of other factors.”

These include the costs of administration, adverse events, the number of SREs, treatment of an MM patient, and the quality-adjusted life year (QALY) gain with either denosumab or zoledronic acid.

“When you count up all these costs and calculate them based on the data set from the 1800 patients, we found that there was really a difference of zoledronic acid costing a little bit more than denosumab,” Dr Raje said.

From the payer perspective, when clinical outcomes were monetized, the net monetary benefit of denosumab compared with ZA was $5959.

And from a societal perspective, the model calculated the net monetary benefit for denosumab to be $10,259.

The societal perspective included SRE direct costs (hospital, outpatient, and emergency department visits, long-term care, hospice, physical therapy and devices, skilled nursing facility, and strong opioids), direct non-medical costs (driving for treatment, parking, and caregiver costs), and indirect costs (short-term disability and productivity loss).

The investigators concluded that denosumab is cost-effective below a willingness-to-pay threshold of $150,000/QALY regardless of ZA price, whether wholesale or average sales price.

“The bone-specific benefits and observed prolongation of progression-free survival in combination with the economic analysis provides denosumab as a valuable option for patients with multiple myeloma,” Dr Raje said. “In total, we still think it’s more cost-effective to use denosumab when compared to zoledronic acid in this patient population.”

At present, treatment options to prevent bone complications in MM patients are limited to bisphosphonates, including ZA. Denosumab is under review by the US Food and Drug Administration for an expanded indication to include MM.

Both the phase 3 and cost-effectiveness studies were funded by Amgen, Inc. Dr Raje and co-investigators of the study have either consulted for or are employed by Amgen, Inc.

Photo by Daniel Sone

Preclinical research suggests the protein BMI-1 may be a therapeutic target for multiple myeloma (MM).

Researchers found that BMI-1 inhibition, with a drug called PTC-209, induced apoptosis in MM cell lines and primary cells.

In addition, PTC-209’s anti-myeloma activity was enhanced by inhibitors targeting EZH2 and BET bromodomains.

The researchers reported these results in Oncotarget.

The team noted that previous studies have suggested epigenetic alterations are involved in the development of MM. They chose to focus the current study on BMI-1 because it’s part of a protein complex involved in epigenetic regulation and could therefore be a potential target for influencing MM development.

“We used the substance PTC-209, which we know inhibits BMI-1, and treated cultivated multiple myeloma cells,” said study author Mohammad Alzrigat, PhD, of Uppsala University in Uppsala, Sweden.

“We used both cell lines that are continuously kept as cultivated cells and cells that were purified from multiple myeloma patients, either newly diagnosed or at relapse. In all cases, we found that [PTC-209] decreased cell survival, which indicates that PTC-209 has an anti-myeloma effect.”

The researchers said PTC-209 demonstrated “potent anti-myeloma activity, reducing the viability of MM cell lines at concentrations ranging up to 1.6 μM over 48 hours of treatment.” INA-6 was the cell line that proved most responsive to PTC-209, and U266-1970 was the least responsive.

The team also found that a 10 μM concentration of PTC-209 reduced the viability of all primary MM cells. This anti-myeloma activity was independent of disease state (whether patients were newly diagnosed or had relapsed disease) and cytogenetic karyotype.

“Our study showed that PTC-209 most likely functions as an anti-myeloma agent by inhibiting the production of BMI-1,” said study author Helena Jernberg-Wiklund, PhD, also of Uppsala University.

“We also saw that when PTC-209 was combined with other substances that inhibit epigenetic alterations, the myeloma cells’ survival was reduced even further compared to when only PTC-209 was used.”

Specifically, the researchers observed synergistic and additive activity when PTC-209 was combined with the EZH2 inhibitor UNC1999 and the BET inhibitor JQ1.

“Our results have both increased our understanding of how epigenetic alterations affect cancer development and shown how inhibiting these mechanisms in combination could potentially be utilized for future treatment of multiple myeloma patients, especially at relapse,” Dr Jernberg-Wiklund said.

Photo by Daniel Sone

Preclinical research suggests the protein BMI-1 may be a therapeutic target for multiple myeloma (MM).

Researchers found that BMI-1 inhibition, with a drug called PTC-209, induced apoptosis in MM cell lines and primary cells.

In addition, PTC-209’s anti-myeloma activity was enhanced by inhibitors targeting EZH2 and BET bromodomains.

The researchers reported these results in Oncotarget.

The team noted that previous studies have suggested epigenetic alterations are involved in the development of MM. They chose to focus the current study on BMI-1 because it’s part of a protein complex involved in epigenetic regulation and could therefore be a potential target for influencing MM development.

“We used the substance PTC-209, which we know inhibits BMI-1, and treated cultivated multiple myeloma cells,” said study author Mohammad Alzrigat, PhD, of Uppsala University in Uppsala, Sweden.

“We used both cell lines that are continuously kept as cultivated cells and cells that were purified from multiple myeloma patients, either newly diagnosed or at relapse. In all cases, we found that [PTC-209] decreased cell survival, which indicates that PTC-209 has an anti-myeloma effect.”

The researchers said PTC-209 demonstrated “potent anti-myeloma activity, reducing the viability of MM cell lines at concentrations ranging up to 1.6 μM over 48 hours of treatment.” INA-6 was the cell line that proved most responsive to PTC-209, and U266-1970 was the least responsive.

The team also found that a 10 μM concentration of PTC-209 reduced the viability of all primary MM cells. This anti-myeloma activity was independent of disease state (whether patients were newly diagnosed or had relapsed disease) and cytogenetic karyotype.

“Our study showed that PTC-209 most likely functions as an anti-myeloma agent by inhibiting the production of BMI-1,” said study author Helena Jernberg-Wiklund, PhD, also of Uppsala University.

“We also saw that when PTC-209 was combined with other substances that inhibit epigenetic alterations, the myeloma cells’ survival was reduced even further compared to when only PTC-209 was used.”

Specifically, the researchers observed synergistic and additive activity when PTC-209 was combined with the EZH2 inhibitor UNC1999 and the BET inhibitor JQ1.

“Our results have both increased our understanding of how epigenetic alterations affect cancer development and shown how inhibiting these mechanisms in combination could potentially be utilized for future treatment of multiple myeloma patients, especially at relapse,” Dr Jernberg-Wiklund said.

Photo by Daniel Sone

Preclinical research suggests the protein BMI-1 may be a therapeutic target for multiple myeloma (MM).

Researchers found that BMI-1 inhibition, with a drug called PTC-209, induced apoptosis in MM cell lines and primary cells.

In addition, PTC-209’s anti-myeloma activity was enhanced by inhibitors targeting EZH2 and BET bromodomains.

The researchers reported these results in Oncotarget.

The team noted that previous studies have suggested epigenetic alterations are involved in the development of MM. They chose to focus the current study on BMI-1 because it’s part of a protein complex involved in epigenetic regulation and could therefore be a potential target for influencing MM development.

“We used the substance PTC-209, which we know inhibits BMI-1, and treated cultivated multiple myeloma cells,” said study author Mohammad Alzrigat, PhD, of Uppsala University in Uppsala, Sweden.

“We used both cell lines that are continuously kept as cultivated cells and cells that were purified from multiple myeloma patients, either newly diagnosed or at relapse. In all cases, we found that [PTC-209] decreased cell survival, which indicates that PTC-209 has an anti-myeloma effect.”

The researchers said PTC-209 demonstrated “potent anti-myeloma activity, reducing the viability of MM cell lines at concentrations ranging up to 1.6 μM over 48 hours of treatment.” INA-6 was the cell line that proved most responsive to PTC-209, and U266-1970 was the least responsive.

The team also found that a 10 μM concentration of PTC-209 reduced the viability of all primary MM cells. This anti-myeloma activity was independent of disease state (whether patients were newly diagnosed or had relapsed disease) and cytogenetic karyotype.

“Our study showed that PTC-209 most likely functions as an anti-myeloma agent by inhibiting the production of BMI-1,” said study author Helena Jernberg-Wiklund, PhD, also of Uppsala University.

“We also saw that when PTC-209 was combined with other substances that inhibit epigenetic alterations, the myeloma cells’ survival was reduced even further compared to when only PTC-209 was used.”

Specifically, the researchers observed synergistic and additive activity when PTC-209 was combined with the EZH2 inhibitor UNC1999 and the BET inhibitor JQ1.

“Our results have both increased our understanding of how epigenetic alterations affect cancer development and shown how inhibiting these mechanisms in combination could potentially be utilized for future treatment of multiple myeloma patients, especially at relapse,” Dr Jernberg-Wiklund said.

Photo from TESARO

The US Food and Drug Administration (FDA) has approved an intravenous (IV) formulation of rolapitant (VARUBI®) for the same indication as the oral formulation.

This means IV rolapitant is now FDA-approved for use in combination with other antiemetic agents to prevent delayed nausea and vomiting associated with initial and repeat courses of emetogenic chemotherapy in adults with cancer.

TESARO Inc., makers of rolapitant, said the US commercial launch of IV rolapitant is planned for November.

Rolapitant is a selective and competitive antagonist of human substance P/neurokinin 1 receptors, which play an important role in the delayed phase of chemotherapy-induced nausea and vomiting (CINV).

IV rolapitant features a ready-to-use, single-dose vial for administration. It does not require refrigerated storage or mixing.

The recommended dose of IV rolapitant is 166.5 mg, administered over 30 minutes. The drug is to be administered up to 2 hours before chemotherapy administration in combination with a 5-HT3 receptor antagonist and dexamethasone.

The full prescribing information for IV rolapitant is available at www.varubirx.com.

Bioequivalence trial

Results from a bioequivalence trial suggest the IV and oral formulations of rolapitant are comparable.

The study was conducted in healthy volunteers. Subjects were randomized to receive a single dose of IV rolapitant at 166.5 mg administered over 30 minutes (n=61) or oral rolapitant at 180 mg (n=62).

The primary endpoint was bioequivalence, and the 166.5 mg IV infusion of rolapitant met bioequivalence criteria.

Researchers said the safety profile of IV rolapitant was largely consistent with that of oral rolapitant, although infusion-site reactions were observed with the IV formulation. These included the sensation of warmth, abdominal pain, dizziness, and paresthesia.

These results were recently published in The Journal of Clinical Pharmacology.

Oral rolapitant trials

Two phase 3 trials showed that oral rolapitant, in combination with a 5-HT3 receptor antagonist and dexamethasone, was well tolerated and more effective than active control in preventing CINV after highly emetogenic chemotherapy.

Results from these trials (NCT01499849 and NCT01500213) were published in a single article in The Lancet Oncology.

A third phase 3 trial showed that oral rolapitant, in combination with a 5-HT3 receptor antagonist and dexamethasone, was well tolerated and more effective than active control in preventing CINV after moderately emetogenic chemotherapy.

Results from this trial (NCT01500226) were also published in The Lancet Oncology.

Photo from TESARO

The US Food and Drug Administration (FDA) has approved an intravenous (IV) formulation of rolapitant (VARUBI®) for the same indication as the oral formulation.

This means IV rolapitant is now FDA-approved for use in combination with other antiemetic agents to prevent delayed nausea and vomiting associated with initial and repeat courses of emetogenic chemotherapy in adults with cancer.

TESARO Inc., makers of rolapitant, said the US commercial launch of IV rolapitant is planned for November.

Rolapitant is a selective and competitive antagonist of human substance P/neurokinin 1 receptors, which play an important role in the delayed phase of chemotherapy-induced nausea and vomiting (CINV).

IV rolapitant features a ready-to-use, single-dose vial for administration. It does not require refrigerated storage or mixing.

The recommended dose of IV rolapitant is 166.5 mg, administered over 30 minutes. The drug is to be administered up to 2 hours before chemotherapy administration in combination with a 5-HT3 receptor antagonist and dexamethasone.

The full prescribing information for IV rolapitant is available at www.varubirx.com.

Bioequivalence trial

Results from a bioequivalence trial suggest the IV and oral formulations of rolapitant are comparable.

The study was conducted in healthy volunteers. Subjects were randomized to receive a single dose of IV rolapitant at 166.5 mg administered over 30 minutes (n=61) or oral rolapitant at 180 mg (n=62).

The primary endpoint was bioequivalence, and the 166.5 mg IV infusion of rolapitant met bioequivalence criteria.

Researchers said the safety profile of IV rolapitant was largely consistent with that of oral rolapitant, although infusion-site reactions were observed with the IV formulation. These included the sensation of warmth, abdominal pain, dizziness, and paresthesia.

These results were recently published in The Journal of Clinical Pharmacology.

Oral rolapitant trials

Two phase 3 trials showed that oral rolapitant, in combination with a 5-HT3 receptor antagonist and dexamethasone, was well tolerated and more effective than active control in preventing CINV after highly emetogenic chemotherapy.

Results from these trials (NCT01499849 and NCT01500213) were published in a single article in The Lancet Oncology.

A third phase 3 trial showed that oral rolapitant, in combination with a 5-HT3 receptor antagonist and dexamethasone, was well tolerated and more effective than active control in preventing CINV after moderately emetogenic chemotherapy.

Results from this trial (NCT01500226) were also published in The Lancet Oncology.

Photo from TESARO

The US Food and Drug Administration (FDA) has approved an intravenous (IV) formulation of rolapitant (VARUBI®) for the same indication as the oral formulation.

This means IV rolapitant is now FDA-approved for use in combination with other antiemetic agents to prevent delayed nausea and vomiting associated with initial and repeat courses of emetogenic chemotherapy in adults with cancer.

TESARO Inc., makers of rolapitant, said the US commercial launch of IV rolapitant is planned for November.

Rolapitant is a selective and competitive antagonist of human substance P/neurokinin 1 receptors, which play an important role in the delayed phase of chemotherapy-induced nausea and vomiting (CINV).

IV rolapitant features a ready-to-use, single-dose vial for administration. It does not require refrigerated storage or mixing.

The recommended dose of IV rolapitant is 166.5 mg, administered over 30 minutes. The drug is to be administered up to 2 hours before chemotherapy administration in combination with a 5-HT3 receptor antagonist and dexamethasone.

The full prescribing information for IV rolapitant is available at www.varubirx.com.

Bioequivalence trial

Results from a bioequivalence trial suggest the IV and oral formulations of rolapitant are comparable.

The study was conducted in healthy volunteers. Subjects were randomized to receive a single dose of IV rolapitant at 166.5 mg administered over 30 minutes (n=61) or oral rolapitant at 180 mg (n=62).

The primary endpoint was bioequivalence, and the 166.5 mg IV infusion of rolapitant met bioequivalence criteria.

Researchers said the safety profile of IV rolapitant was largely consistent with that of oral rolapitant, although infusion-site reactions were observed with the IV formulation. These included the sensation of warmth, abdominal pain, dizziness, and paresthesia.

These results were recently published in The Journal of Clinical Pharmacology.

Oral rolapitant trials

Two phase 3 trials showed that oral rolapitant, in combination with a 5-HT3 receptor antagonist and dexamethasone, was well tolerated and more effective than active control in preventing CINV after highly emetogenic chemotherapy.

Results from these trials (NCT01499849 and NCT01500213) were published in a single article in The Lancet Oncology.

A third phase 3 trial showed that oral rolapitant, in combination with a 5-HT3 receptor antagonist and dexamethasone, was well tolerated and more effective than active control in preventing CINV after moderately emetogenic chemotherapy.

Results from this trial (NCT01500226) were also published in The Lancet Oncology.

multiple myeloma

Preclinical research has revealed a potential method of overcoming resistance to proteasome inhibitors.

By studying a rare genetic disease known as NGLY1 deficiency, researchers have gained new understanding of resistance to proteasome inhibitors.

The team found that treatment with a NGLY1 inhibitor can enhance the activity of the proteasome inhibitor carfilzomib against multiple myeloma (MM) and T-cell acute lymphoblastic leukemia (T-ALL).

Carolyn Bertozzi, PhD, of Stanford University in California, and her colleagues reported these findings in ACS Central Science.

Previous studies have suggested that proteasome inhibitor resistance could be linked to a protein called Nrf1. When proteasome inhibitors swing into action, Nrf1 is spurred into overdrive to restore cancer cells’ normal activities and keep them alive.

Researchers theorized that, if they could block Nrf1, they might be able to overcome proteasome inhibitor resistance.

Through studying NGLY1 deficiency, Dr Bertozzi and her colleagues may have hit upon an approach to do just that.

The researchers were investigating how lacking NGLY1 causes a host of debilitating symptoms, and they found that NGLY1 is responsible for activating Nrf1.

Further testing revealed that inhibiting NGLY1 eliminated interference from Nrf1 and enhanced the cytotoxicity of carfilzomib in MM and T-ALL cell lines.

The researchers treated the MM cell lines U266 and H929 with the NGLY1 inhibitor, known as WRR139, and carfilzomib and observed a significant decrease in cell survival when compared to treatment with carfilzomib alone. The team observed the same results when testing the T-ALL Jurkat cell line.

The addition of WRR139 resulted in a 2.6-fold reduction in carfilzomib’s LD50 for U266, a 2.0-fold reduction for H929, and a 1.5-fold reduction for Jurkat cells.

The researchers said these findings hold promise for the development of combination therapies for hematologic malignancies.

multiple myeloma

Preclinical research has revealed a potential method of overcoming resistance to proteasome inhibitors.

By studying a rare genetic disease known as NGLY1 deficiency, researchers have gained new understanding of resistance to proteasome inhibitors.

The team found that treatment with a NGLY1 inhibitor can enhance the activity of the proteasome inhibitor carfilzomib against multiple myeloma (MM) and T-cell acute lymphoblastic leukemia (T-ALL).

Carolyn Bertozzi, PhD, of Stanford University in California, and her colleagues reported these findings in ACS Central Science.

Previous studies have suggested that proteasome inhibitor resistance could be linked to a protein called Nrf1. When proteasome inhibitors swing into action, Nrf1 is spurred into overdrive to restore cancer cells’ normal activities and keep them alive.

Researchers theorized that, if they could block Nrf1, they might be able to overcome proteasome inhibitor resistance.

Through studying NGLY1 deficiency, Dr Bertozzi and her colleagues may have hit upon an approach to do just that.

The researchers were investigating how lacking NGLY1 causes a host of debilitating symptoms, and they found that NGLY1 is responsible for activating Nrf1.

Further testing revealed that inhibiting NGLY1 eliminated interference from Nrf1 and enhanced the cytotoxicity of carfilzomib in MM and T-ALL cell lines.

The researchers treated the MM cell lines U266 and H929 with the NGLY1 inhibitor, known as WRR139, and carfilzomib and observed a significant decrease in cell survival when compared to treatment with carfilzomib alone. The team observed the same results when testing the T-ALL Jurkat cell line.

The addition of WRR139 resulted in a 2.6-fold reduction in carfilzomib’s LD50 for U266, a 2.0-fold reduction for H929, and a 1.5-fold reduction for Jurkat cells.

The researchers said these findings hold promise for the development of combination therapies for hematologic malignancies.

multiple myeloma

Preclinical research has revealed a potential method of overcoming resistance to proteasome inhibitors.

By studying a rare genetic disease known as NGLY1 deficiency, researchers have gained new understanding of resistance to proteasome inhibitors.

The team found that treatment with a NGLY1 inhibitor can enhance the activity of the proteasome inhibitor carfilzomib against multiple myeloma (MM) and T-cell acute lymphoblastic leukemia (T-ALL).

Carolyn Bertozzi, PhD, of Stanford University in California, and her colleagues reported these findings in ACS Central Science.

Previous studies have suggested that proteasome inhibitor resistance could be linked to a protein called Nrf1. When proteasome inhibitors swing into action, Nrf1 is spurred into overdrive to restore cancer cells’ normal activities and keep them alive.

Researchers theorized that, if they could block Nrf1, they might be able to overcome proteasome inhibitor resistance.

Through studying NGLY1 deficiency, Dr Bertozzi and her colleagues may have hit upon an approach to do just that.

The researchers were investigating how lacking NGLY1 causes a host of debilitating symptoms, and they found that NGLY1 is responsible for activating Nrf1.

Further testing revealed that inhibiting NGLY1 eliminated interference from Nrf1 and enhanced the cytotoxicity of carfilzomib in MM and T-ALL cell lines.

The researchers treated the MM cell lines U266 and H929 with the NGLY1 inhibitor, known as WRR139, and carfilzomib and observed a significant decrease in cell survival when compared to treatment with carfilzomib alone. The team observed the same results when testing the T-ALL Jurkat cell line.

The addition of WRR139 resulted in a 2.6-fold reduction in carfilzomib’s LD50 for U266, a 2.0-fold reduction for H929, and a 1.5-fold reduction for Jurkat cells.

The researchers said these findings hold promise for the development of combination therapies for hematologic malignancies.

Photo courtesy of Amgen

Top-line results from the phase 3 A.R.R.O.W. trial support a 70 mg/m² weekly dose of carfilzomib in combination with dexamethasone for patients with relapsed and refractory multiple myeloma (MM).

The data suggest a weekly dose of carfilzomib at 70 mg/m² is more effective than, and just as safe as, a twice-weekly dose of carfilzomib at 27 mg/m².

These results were recently announced by Amgen, makers of carfilzomib.

The A.R.R.O.W. trial included 478 patients with relapsed and refractory MM who had received 2 to 3 prior therapies, including bortezomib and an immunomodulatory drug.

Patients were randomized to receive once-weekly carfilzomib (20 mg/m² on day 1 of cycle 1; 70 mg/m² on days 8 and 15 of cycle 1; and 70 mg/m² on days 1, 8 and 15 of subsequent cycles) with dexamethasone (40 mg) or twice-weekly carfilzomib (20 mg/m² on days 1 and 2 of cycle 1; 27 mg/m² on days 8, 9, 15 and 16 of cycle 1; and 27 mg/m² on days 1, 2, 8, 9, 15 and 16 of subsequent cycles) with dexamethasone (40 mg).

The study’s primary endpoint is progression-free survival (PFS).

Patients treated with the once-weekly regimen had significantly better PFS than patients who received carfilzomib twice weekly. The median PFS was 11.2 months and 7.6 months, respectively (hazard ratio=0.69, 95% confidence interval, 0.54–0.88).

The overall safety profile of the once-weekly regimen was comparable to that of the twice-weekly regimen.

The most frequently reported treatment-emergent adverse events (occurring in at least 20% of patients) in either treatment arm were anemia, diarrhea, fatigue, hypertension, insomnia, and pyrexia.

Photo courtesy of Amgen

Top-line results from the phase 3 A.R.R.O.W. trial support a 70 mg/m² weekly dose of carfilzomib in combination with dexamethasone for patients with relapsed and refractory multiple myeloma (MM).

The data suggest a weekly dose of carfilzomib at 70 mg/m² is more effective than, and just as safe as, a twice-weekly dose of carfilzomib at 27 mg/m².

These results were recently announced by Amgen, makers of carfilzomib.

The A.R.R.O.W. trial included 478 patients with relapsed and refractory MM who had received 2 to 3 prior therapies, including bortezomib and an immunomodulatory drug.

Patients were randomized to receive once-weekly carfilzomib (20 mg/m² on day 1 of cycle 1; 70 mg/m² on days 8 and 15 of cycle 1; and 70 mg/m² on days 1, 8 and 15 of subsequent cycles) with dexamethasone (40 mg) or twice-weekly carfilzomib (20 mg/m² on days 1 and 2 of cycle 1; 27 mg/m² on days 8, 9, 15 and 16 of cycle 1; and 27 mg/m² on days 1, 2, 8, 9, 15 and 16 of subsequent cycles) with dexamethasone (40 mg).

The study’s primary endpoint is progression-free survival (PFS).

Patients treated with the once-weekly regimen had significantly better PFS than patients who received carfilzomib twice weekly. The median PFS was 11.2 months and 7.6 months, respectively (hazard ratio=0.69, 95% confidence interval, 0.54–0.88).

The overall safety profile of the once-weekly regimen was comparable to that of the twice-weekly regimen.

The most frequently reported treatment-emergent adverse events (occurring in at least 20% of patients) in either treatment arm were anemia, diarrhea, fatigue, hypertension, insomnia, and pyrexia.

Photo courtesy of Amgen

Top-line results from the phase 3 A.R.R.O.W. trial support a 70 mg/m² weekly dose of carfilzomib in combination with dexamethasone for patients with relapsed and refractory multiple myeloma (MM).

The data suggest a weekly dose of carfilzomib at 70 mg/m² is more effective than, and just as safe as, a twice-weekly dose of carfilzomib at 27 mg/m².

These results were recently announced by Amgen, makers of carfilzomib.

The A.R.R.O.W. trial included 478 patients with relapsed and refractory MM who had received 2 to 3 prior therapies, including bortezomib and an immunomodulatory drug.

Patients were randomized to receive once-weekly carfilzomib (20 mg/m² on day 1 of cycle 1; 70 mg/m² on days 8 and 15 of cycle 1; and 70 mg/m² on days 1, 8 and 15 of subsequent cycles) with dexamethasone (40 mg) or twice-weekly carfilzomib (20 mg/m² on days 1 and 2 of cycle 1; 27 mg/m² on days 8, 9, 15 and 16 of cycle 1; and 27 mg/m² on days 1, 2, 8, 9, 15 and 16 of subsequent cycles) with dexamethasone (40 mg).

The study’s primary endpoint is progression-free survival (PFS).

Patients treated with the once-weekly regimen had significantly better PFS than patients who received carfilzomib twice weekly. The median PFS was 11.2 months and 7.6 months, respectively (hazard ratio=0.69, 95% confidence interval, 0.54–0.88).

The overall safety profile of the once-weekly regimen was comparable to that of the twice-weekly regimen.

The most frequently reported treatment-emergent adverse events (occurring in at least 20% of patients) in either treatment arm were anemia, diarrhea, fatigue, hypertension, insomnia, and pyrexia.