Multiple Myeloma

Photo by Graham Colm

The US Food and Drug Administration (FDA) has allowed marketing of the ClearLLab Reagent Panel, a combination of conjugated antibody cocktails designed to aid the detection of hematopoietic neoplasia.

This includes chronic and acute leukemias, non-Hodgkin lymphoma, myeloma, myelodysplastic syndromes, and myeloproliferative neoplasms.

The ClearLLab reagents are intended for in vitro diagnostic use to identify various cell populations by immunophenotyping on an FC 500 flow cytometer.

The reagents are directed against B, T, and myeloid lineage antigens and intended to identify relevant leukocyte surface molecules.

ClearLLab provides 2 T-cell tubes, 2 B-cell tubes, and a myeloid tube, each consisting of pre-mixed 4- to 5-color cocktails. Together, this totals 18 markers as directly conjugated antibodies.

The reagents can be used with peripheral whole blood, bone marrow, and lymph node specimens.

The results obtained via testing with the ClearLLab reagents should be interpreted along with additional clinical and laboratory findings, according to Beckman Coulter, Inc., the company that will be marketing the reagents.

The FDA reviewed data for the ClearLLab reagents through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already legally marketed device.

The FDA’s clearance of the ClearLLab reagents was supported by a study designed to demonstrate the reagents’ performance, which was conducted on 279 samples at 4 independent clinical sites.

Results with the ClearLLab reagents were compared to results with alternative detection methods used at the sites.

The ClearLLab results aligned with the study sites’ final diagnosis 93.4% of the time and correctly detected abnormalities 84.2% of the time.

Along with its clearance of the ClearLLab reagents, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the reagents’ accuracy, reliability, and clinical relevance.

These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for the ClearLLab reagents and similar tools.

The special controls also describe the least burdensome regulatory pathway for future developers of similar diagnostic tests.

Photo by Graham Colm

The US Food and Drug Administration (FDA) has allowed marketing of the ClearLLab Reagent Panel, a combination of conjugated antibody cocktails designed to aid the detection of hematopoietic neoplasia.

This includes chronic and acute leukemias, non-Hodgkin lymphoma, myeloma, myelodysplastic syndromes, and myeloproliferative neoplasms.

The ClearLLab reagents are intended for in vitro diagnostic use to identify various cell populations by immunophenotyping on an FC 500 flow cytometer.

The reagents are directed against B, T, and myeloid lineage antigens and intended to identify relevant leukocyte surface molecules.

ClearLLab provides 2 T-cell tubes, 2 B-cell tubes, and a myeloid tube, each consisting of pre-mixed 4- to 5-color cocktails. Together, this totals 18 markers as directly conjugated antibodies.

The reagents can be used with peripheral whole blood, bone marrow, and lymph node specimens.

The results obtained via testing with the ClearLLab reagents should be interpreted along with additional clinical and laboratory findings, according to Beckman Coulter, Inc., the company that will be marketing the reagents.

The FDA reviewed data for the ClearLLab reagents through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already legally marketed device.

The FDA’s clearance of the ClearLLab reagents was supported by a study designed to demonstrate the reagents’ performance, which was conducted on 279 samples at 4 independent clinical sites.

Results with the ClearLLab reagents were compared to results with alternative detection methods used at the sites.

The ClearLLab results aligned with the study sites’ final diagnosis 93.4% of the time and correctly detected abnormalities 84.2% of the time.

Along with its clearance of the ClearLLab reagents, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the reagents’ accuracy, reliability, and clinical relevance.

These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for the ClearLLab reagents and similar tools.

The special controls also describe the least burdensome regulatory pathway for future developers of similar diagnostic tests.

Photo by Graham Colm

The US Food and Drug Administration (FDA) has allowed marketing of the ClearLLab Reagent Panel, a combination of conjugated antibody cocktails designed to aid the detection of hematopoietic neoplasia.

This includes chronic and acute leukemias, non-Hodgkin lymphoma, myeloma, myelodysplastic syndromes, and myeloproliferative neoplasms.

The ClearLLab reagents are intended for in vitro diagnostic use to identify various cell populations by immunophenotyping on an FC 500 flow cytometer.

The reagents are directed against B, T, and myeloid lineage antigens and intended to identify relevant leukocyte surface molecules.

ClearLLab provides 2 T-cell tubes, 2 B-cell tubes, and a myeloid tube, each consisting of pre-mixed 4- to 5-color cocktails. Together, this totals 18 markers as directly conjugated antibodies.

The reagents can be used with peripheral whole blood, bone marrow, and lymph node specimens.

The results obtained via testing with the ClearLLab reagents should be interpreted along with additional clinical and laboratory findings, according to Beckman Coulter, Inc., the company that will be marketing the reagents.

The FDA reviewed data for the ClearLLab reagents through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already legally marketed device.

The FDA’s clearance of the ClearLLab reagents was supported by a study designed to demonstrate the reagents’ performance, which was conducted on 279 samples at 4 independent clinical sites.

Results with the ClearLLab reagents were compared to results with alternative detection methods used at the sites.

The ClearLLab results aligned with the study sites’ final diagnosis 93.4% of the time and correctly detected abnormalities 84.2% of the time.

Along with its clearance of the ClearLLab reagents, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the reagents’ accuracy, reliability, and clinical relevance.

These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for the ClearLLab reagents and similar tools.

The special controls also describe the least burdensome regulatory pathway for future developers of similar diagnostic tests.

Photo by Bill Branson

WASHINGTON, DC—In a head-to-head study comparing a single-dose oral antiemetic to a 3-day oral regimen, the single dose has shown itself to be non-inferior to the multi-day regimen in preventing chemotherapy-induced nausea and vomiting (CINV).

The investigators evaluated netupitant/palonosetron (NEPA) against aprepitant/granisetron (APR/GRAN) in patients on highly emetogenic chemotherapy.

They found the data suggest “that NEPA, in a single dose, had equivalent efficacy to a 3-day oral aprepitant/granisetron regimen,” according to the lead investigator and abstract presenter.

Li Zhang, MD, of Sun Yat-sen University Cancer Center in Guangzhou, China, presented the data at the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) Congress (abstract PS049, pp S55 – S56).

NEPA is a combination of the selective NK₁RA netupitant (300 mg) and the clinically and pharmacologically active 5-HT₃RA, palonosetron (0.5 mg) for the prevention of CINV.

Oral palonosetron prevents nausea and vomiting during the acute phase of treatment.

Netupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy.

It is formulated into a single oral capsule.

Study design

The study was a phase 3 randomized, double-blind, double-dummy study conducted in 828 chemotherapy-naïve Asian patients receiving cisplatin-based highly emetogenic chemotherapy (HEC) agents.

Patients received a single oral dose of NEPA on day 1 or a 3-day oral APR/GRAN regimen (days 1-3).

All patients received oral dexamethasone on days 1-4.

The primary efficacy endpoint was complete response (CR), defined as no emesis or rescue medication needed during the overall (0-120 hour) phase.

The investigators defined non-inferiority to be the lower limit of the two-sided 95% confidence interval greater than the non-inferiority margin set at  ̶ 10%.

Secondary endpoints included no emesis, no rescue medication, and no significant nausea (NSN), defined as <25 mm on 100 mm visual analog scale (VAS).

Results

The baseline demographics were comparable between the NEPA (n=413) and APR/GRAN (n=416) arms: 71% of the patients were male, a mean age of 55 years, and a little more than half were ECOG performance status 1.

The most common cancer types were lung and head and neck cancer.

Patients had received a median cisplatin dose of 73 and 72 mg/m² in the NEPA and APR/GRAN arms, respectively.

Within the first 24 hours (acute phase), NEPA was non-inferior to APR/GRAN. NEPA had a CR rate of 84.5% and APR/GRAN had a CR rate of 87.0%. The risk difference between the 2 agents was -2.5% (range, -7.2%, 2.3%).

In the delayed phase (25-120 hours), NEPA had a CR rate of 77.9% and APR/GRAN, 74.3%. The risk difference was 3.7% (range, -2.1%, 9.5%).

Overall, for both phases, the CR rate was 73.8% for NEPA and 72.4% for APR/GRAN. The risk difference was 1.5% (range, -4.5%, 7.5%).

Dr Zhang pointed out that although the overall CR rates were similar, the daily rates of patients experiencing CINV remained in the range of 13% - 15% for patients in the APR/GRAN arm.

However, daily rates of CINV for patients receiving NEPA declined from 16% to 8% over the 5 days. The investigators believe this suggests a benefit for delayed CINV.

Regarding secondary endpoints, significantly more patients receiving NEPA did not require rescue medication in the delayed phase and overall than patients in the APR/GRAN arm.

Treatment-emergent adverse events (TEAEs) were comparable between the arms—58.1% in the NEPA arm and 57.5% in the APR/GRAN arm, as were serious TEAS, at 4.5% and 4.6% for NEPA and APR/GRAN, respectively. And the no emesis and no significant nausea rates favored NEPA.

 

The most common treatment-emergent adverse events occurring in 2% or more of the patients in both arms were constipation and hiccups.

Two serious treatment-related adverse events occurred in each arm, 1 leading to discontinuation in the NEPA arm.

The investigators concluded that NEPA, as a convenient capsule administered once per cycle, is at least as effective as the 3-day regimen of APR/GRAN in patients receiving HEC.

NEPA (Akynzeo®) is approved by the US Food and Drug Administration and marketed globally by Helsinn, Lugano, Switzerland, the sponsor of the trial.

For the full US prescribing information, see the package insert.

Photo by Bill Branson

WASHINGTON, DC—In a head-to-head study comparing a single-dose oral antiemetic to a 3-day oral regimen, the single dose has shown itself to be non-inferior to the multi-day regimen in preventing chemotherapy-induced nausea and vomiting (CINV).

The investigators evaluated netupitant/palonosetron (NEPA) against aprepitant/granisetron (APR/GRAN) in patients on highly emetogenic chemotherapy.

They found the data suggest “that NEPA, in a single dose, had equivalent efficacy to a 3-day oral aprepitant/granisetron regimen,” according to the lead investigator and abstract presenter.

Li Zhang, MD, of Sun Yat-sen University Cancer Center in Guangzhou, China, presented the data at the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) Congress (abstract PS049, pp S55 – S56).

NEPA is a combination of the selective NK₁RA netupitant (300 mg) and the clinically and pharmacologically active 5-HT₃RA, palonosetron (0.5 mg) for the prevention of CINV.

Oral palonosetron prevents nausea and vomiting during the acute phase of treatment.

Netupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy.

It is formulated into a single oral capsule.

Study design

The study was a phase 3 randomized, double-blind, double-dummy study conducted in 828 chemotherapy-naïve Asian patients receiving cisplatin-based highly emetogenic chemotherapy (HEC) agents.

Patients received a single oral dose of NEPA on day 1 or a 3-day oral APR/GRAN regimen (days 1-3).

All patients received oral dexamethasone on days 1-4.

The primary efficacy endpoint was complete response (CR), defined as no emesis or rescue medication needed during the overall (0-120 hour) phase.

The investigators defined non-inferiority to be the lower limit of the two-sided 95% confidence interval greater than the non-inferiority margin set at  ̶ 10%.

Secondary endpoints included no emesis, no rescue medication, and no significant nausea (NSN), defined as <25 mm on 100 mm visual analog scale (VAS).

Results

The baseline demographics were comparable between the NEPA (n=413) and APR/GRAN (n=416) arms: 71% of the patients were male, a mean age of 55 years, and a little more than half were ECOG performance status 1.

The most common cancer types were lung and head and neck cancer.

Patients had received a median cisplatin dose of 73 and 72 mg/m² in the NEPA and APR/GRAN arms, respectively.

Within the first 24 hours (acute phase), NEPA was non-inferior to APR/GRAN. NEPA had a CR rate of 84.5% and APR/GRAN had a CR rate of 87.0%. The risk difference between the 2 agents was -2.5% (range, -7.2%, 2.3%).

In the delayed phase (25-120 hours), NEPA had a CR rate of 77.9% and APR/GRAN, 74.3%. The risk difference was 3.7% (range, -2.1%, 9.5%).

Overall, for both phases, the CR rate was 73.8% for NEPA and 72.4% for APR/GRAN. The risk difference was 1.5% (range, -4.5%, 7.5%).

Dr Zhang pointed out that although the overall CR rates were similar, the daily rates of patients experiencing CINV remained in the range of 13% - 15% for patients in the APR/GRAN arm.

However, daily rates of CINV for patients receiving NEPA declined from 16% to 8% over the 5 days. The investigators believe this suggests a benefit for delayed CINV.

Regarding secondary endpoints, significantly more patients receiving NEPA did not require rescue medication in the delayed phase and overall than patients in the APR/GRAN arm.

Treatment-emergent adverse events (TEAEs) were comparable between the arms—58.1% in the NEPA arm and 57.5% in the APR/GRAN arm, as were serious TEAS, at 4.5% and 4.6% for NEPA and APR/GRAN, respectively. And the no emesis and no significant nausea rates favored NEPA.

 

The most common treatment-emergent adverse events occurring in 2% or more of the patients in both arms were constipation and hiccups.

Two serious treatment-related adverse events occurred in each arm, 1 leading to discontinuation in the NEPA arm.

The investigators concluded that NEPA, as a convenient capsule administered once per cycle, is at least as effective as the 3-day regimen of APR/GRAN in patients receiving HEC.

NEPA (Akynzeo®) is approved by the US Food and Drug Administration and marketed globally by Helsinn, Lugano, Switzerland, the sponsor of the trial.

For the full US prescribing information, see the package insert.

Photo by Bill Branson

WASHINGTON, DC—In a head-to-head study comparing a single-dose oral antiemetic to a 3-day oral regimen, the single dose has shown itself to be non-inferior to the multi-day regimen in preventing chemotherapy-induced nausea and vomiting (CINV).

The investigators evaluated netupitant/palonosetron (NEPA) against aprepitant/granisetron (APR/GRAN) in patients on highly emetogenic chemotherapy.

They found the data suggest “that NEPA, in a single dose, had equivalent efficacy to a 3-day oral aprepitant/granisetron regimen,” according to the lead investigator and abstract presenter.

Li Zhang, MD, of Sun Yat-sen University Cancer Center in Guangzhou, China, presented the data at the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) Congress (abstract PS049, pp S55 – S56).

NEPA is a combination of the selective NK₁RA netupitant (300 mg) and the clinically and pharmacologically active 5-HT₃RA, palonosetron (0.5 mg) for the prevention of CINV.

Oral palonosetron prevents nausea and vomiting during the acute phase of treatment.

Netupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy.

It is formulated into a single oral capsule.

Study design

The study was a phase 3 randomized, double-blind, double-dummy study conducted in 828 chemotherapy-naïve Asian patients receiving cisplatin-based highly emetogenic chemotherapy (HEC) agents.

Patients received a single oral dose of NEPA on day 1 or a 3-day oral APR/GRAN regimen (days 1-3).

All patients received oral dexamethasone on days 1-4.

The primary efficacy endpoint was complete response (CR), defined as no emesis or rescue medication needed during the overall (0-120 hour) phase.

The investigators defined non-inferiority to be the lower limit of the two-sided 95% confidence interval greater than the non-inferiority margin set at  ̶ 10%.

Secondary endpoints included no emesis, no rescue medication, and no significant nausea (NSN), defined as <25 mm on 100 mm visual analog scale (VAS).

Results

The baseline demographics were comparable between the NEPA (n=413) and APR/GRAN (n=416) arms: 71% of the patients were male, a mean age of 55 years, and a little more than half were ECOG performance status 1.

The most common cancer types were lung and head and neck cancer.

Patients had received a median cisplatin dose of 73 and 72 mg/m² in the NEPA and APR/GRAN arms, respectively.

Within the first 24 hours (acute phase), NEPA was non-inferior to APR/GRAN. NEPA had a CR rate of 84.5% and APR/GRAN had a CR rate of 87.0%. The risk difference between the 2 agents was -2.5% (range, -7.2%, 2.3%).

In the delayed phase (25-120 hours), NEPA had a CR rate of 77.9% and APR/GRAN, 74.3%. The risk difference was 3.7% (range, -2.1%, 9.5%).

Overall, for both phases, the CR rate was 73.8% for NEPA and 72.4% for APR/GRAN. The risk difference was 1.5% (range, -4.5%, 7.5%).

Dr Zhang pointed out that although the overall CR rates were similar, the daily rates of patients experiencing CINV remained in the range of 13% - 15% for patients in the APR/GRAN arm.

However, daily rates of CINV for patients receiving NEPA declined from 16% to 8% over the 5 days. The investigators believe this suggests a benefit for delayed CINV.

Regarding secondary endpoints, significantly more patients receiving NEPA did not require rescue medication in the delayed phase and overall than patients in the APR/GRAN arm.

Treatment-emergent adverse events (TEAEs) were comparable between the arms—58.1% in the NEPA arm and 57.5% in the APR/GRAN arm, as were serious TEAS, at 4.5% and 4.6% for NEPA and APR/GRAN, respectively. And the no emesis and no significant nausea rates favored NEPA.

 

The most common treatment-emergent adverse events occurring in 2% or more of the patients in both arms were constipation and hiccups.

Two serious treatment-related adverse events occurred in each arm, 1 leading to discontinuation in the NEPA arm.

The investigators concluded that NEPA, as a convenient capsule administered once per cycle, is at least as effective as the 3-day regimen of APR/GRAN in patients receiving HEC.

NEPA (Akynzeo®) is approved by the US Food and Drug Administration and marketed globally by Helsinn, Lugano, Switzerland, the sponsor of the trial.

For the full US prescribing information, see the package insert.

Photo courtesy of Janssen

The US Food and Drug Administration (FDA) has approved daratumumab (Darzalex®) in combination with pomalidomide (POM) and dexamethasone (dex) for the treatment of multiple myeloma (MM) in patients who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor (PI).

The FDA previously approved daratumumab in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with MM who had at least 1 prior therapy.

Daratumumab is also approved by the FDA as monotherapy in MM patients who had at least 3 prior lines of therapy, including a PI and an immunomodulatory (IMiD) agent, or who are double refractory to a PI and an IMiD.

The latest indication is based on the results of the phase 1b MMY1001 EQUULEUS study, which demonstrated that daratumumab produced an overall response (OR) rate of 59% in combination with pomalidomide and dexamethasone, and a very good partial response (VGPR) in 28% of patients.

EQUULEUS study

The daratumumab-POM-Dex arm of the phase 1 open-label EQUULEUS study included 103 MM patients who had received prior treatment with a PI and an immunomodulatory agent.

Patients were a median age of 64 years, and 8% were older than 75.

They had received a median of 4 prior lines of therapy, and 74% had received prior autologous stem cell transplant.

Most (89%) were refractory to lenalidomide and 71% were refractory to bortezomib. Almost two thirds (64%) were refractory to bortezomib and lenalidomide.

Patients were treated with 16 mg/kg of daratumumab in combination with POM and Dex, and 6% achieved a complete response (CR) and 8% achieved a stringent CR.

The median time to response was 1 month (range, 0.9 to 2.8), and the median duration of response was 13.6 months (range, 0.9+ to 14.6+ months).

The most frequent adverse events (AEs) reported in more than 20% of patients were infusion reactions, fatigue, and upper respiratory tract infections (50% each), cough (43%), diarrhea (38%), dyspnea (33%), nausea (30%), muscle spasms (26%), pyrexia (25%), and vomiting (21%).

The overall incidence of serious adverse reactions was 49%.

Grade 3/4 serious AEs reported in 5% of patients or more included pneumonia (7%).

The most common treatment-emergent hematologic laboratory abnormalities included lymphopenia (94%), neutropenia (95%), thrombocytopenia (75%), and anemia (57%).

And the most common grade 3/4 treatment-emergent hematology laboratory abnormalities were neutropenia (82%), lymphopenia (71%), anemia (30%), and thrombocytopenia (20%).

Daratumumab is being developed by Janssen Biotech, Inc., under an exclusive worldwide license to develop, manufacture, and commercialize daratumumab from Genmab.

See the package insert for full prescribing information. 

Photo courtesy of Janssen

The US Food and Drug Administration (FDA) has approved daratumumab (Darzalex®) in combination with pomalidomide (POM) and dexamethasone (dex) for the treatment of multiple myeloma (MM) in patients who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor (PI).

The FDA previously approved daratumumab in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with MM who had at least 1 prior therapy.

Daratumumab is also approved by the FDA as monotherapy in MM patients who had at least 3 prior lines of therapy, including a PI and an immunomodulatory (IMiD) agent, or who are double refractory to a PI and an IMiD.

The latest indication is based on the results of the phase 1b MMY1001 EQUULEUS study, which demonstrated that daratumumab produced an overall response (OR) rate of 59% in combination with pomalidomide and dexamethasone, and a very good partial response (VGPR) in 28% of patients.

EQUULEUS study

The daratumumab-POM-Dex arm of the phase 1 open-label EQUULEUS study included 103 MM patients who had received prior treatment with a PI and an immunomodulatory agent.

Patients were a median age of 64 years, and 8% were older than 75.

They had received a median of 4 prior lines of therapy, and 74% had received prior autologous stem cell transplant.

Most (89%) were refractory to lenalidomide and 71% were refractory to bortezomib. Almost two thirds (64%) were refractory to bortezomib and lenalidomide.

Patients were treated with 16 mg/kg of daratumumab in combination with POM and Dex, and 6% achieved a complete response (CR) and 8% achieved a stringent CR.

The median time to response was 1 month (range, 0.9 to 2.8), and the median duration of response was 13.6 months (range, 0.9+ to 14.6+ months).

The most frequent adverse events (AEs) reported in more than 20% of patients were infusion reactions, fatigue, and upper respiratory tract infections (50% each), cough (43%), diarrhea (38%), dyspnea (33%), nausea (30%), muscle spasms (26%), pyrexia (25%), and vomiting (21%).

The overall incidence of serious adverse reactions was 49%.

Grade 3/4 serious AEs reported in 5% of patients or more included pneumonia (7%).

The most common treatment-emergent hematologic laboratory abnormalities included lymphopenia (94%), neutropenia (95%), thrombocytopenia (75%), and anemia (57%).

And the most common grade 3/4 treatment-emergent hematology laboratory abnormalities were neutropenia (82%), lymphopenia (71%), anemia (30%), and thrombocytopenia (20%).

Daratumumab is being developed by Janssen Biotech, Inc., under an exclusive worldwide license to develop, manufacture, and commercialize daratumumab from Genmab.

See the package insert for full prescribing information. 

Photo courtesy of Janssen

The US Food and Drug Administration (FDA) has approved daratumumab (Darzalex®) in combination with pomalidomide (POM) and dexamethasone (dex) for the treatment of multiple myeloma (MM) in patients who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor (PI).

The FDA previously approved daratumumab in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with MM who had at least 1 prior therapy.

Daratumumab is also approved by the FDA as monotherapy in MM patients who had at least 3 prior lines of therapy, including a PI and an immunomodulatory (IMiD) agent, or who are double refractory to a PI and an IMiD.

The latest indication is based on the results of the phase 1b MMY1001 EQUULEUS study, which demonstrated that daratumumab produced an overall response (OR) rate of 59% in combination with pomalidomide and dexamethasone, and a very good partial response (VGPR) in 28% of patients.

EQUULEUS study

The daratumumab-POM-Dex arm of the phase 1 open-label EQUULEUS study included 103 MM patients who had received prior treatment with a PI and an immunomodulatory agent.

Patients were a median age of 64 years, and 8% were older than 75.

They had received a median of 4 prior lines of therapy, and 74% had received prior autologous stem cell transplant.

Most (89%) were refractory to lenalidomide and 71% were refractory to bortezomib. Almost two thirds (64%) were refractory to bortezomib and lenalidomide.

Patients were treated with 16 mg/kg of daratumumab in combination with POM and Dex, and 6% achieved a complete response (CR) and 8% achieved a stringent CR.

The median time to response was 1 month (range, 0.9 to 2.8), and the median duration of response was 13.6 months (range, 0.9+ to 14.6+ months).

The most frequent adverse events (AEs) reported in more than 20% of patients were infusion reactions, fatigue, and upper respiratory tract infections (50% each), cough (43%), diarrhea (38%), dyspnea (33%), nausea (30%), muscle spasms (26%), pyrexia (25%), and vomiting (21%).

The overall incidence of serious adverse reactions was 49%.

Grade 3/4 serious AEs reported in 5% of patients or more included pneumonia (7%).

The most common treatment-emergent hematologic laboratory abnormalities included lymphopenia (94%), neutropenia (95%), thrombocytopenia (75%), and anemia (57%).

And the most common grade 3/4 treatment-emergent hematology laboratory abnormalities were neutropenia (82%), lymphopenia (71%), anemia (30%), and thrombocytopenia (20%).

Daratumumab is being developed by Janssen Biotech, Inc., under an exclusive worldwide license to develop, manufacture, and commercialize daratumumab from Genmab.

See the package insert for full prescribing information. 

Photo © ASCO/Scott Morgan 2017

CHICAGO—The largest international multiple myeloma (MM) trial ever conducted, according to the trial sponsor, met its primary endpoint, demonstrating that denosumab is non-inferior to zoledronic acid (ZA) in delaying the time to first on-study skeletal-related event (SRE) in patients with MM.

In addition to bone-specific benefits, denosumab-treated patients had significantly fewer renal adverse events and possible prolongation of progression-free survival.

Denosumab “may in fact be a new standard of care for multiple myeloma-related bone disease,” according to one of the investigators.

“The other important thing to note,” Noopur S. Raje, MD, said during her presentation at the ASCO 2017 Annual Meeting, “is denosumab can be administered despite renal function in patients with myeloma.” It does not need to be dose-adjusted, unlike bisphosphonates.

Dr Raje, of the Massachusetts General Hospital Cancer Center in Boston, Massachusetts, presented the study results as abstract 8005.

Study design

The international, phase 3, randomized, double-blind study is evaluating the safety of denosumab compared with ZA in newly diagnosed MM patients.

Investigators enrolled 1718 patients from 259 sites and 29 countries.

They randomized 859 patients to receive denosumab 120 mg subcutaneously every 4 weeks plus intravenous placebo every 4 weeks, and 859 patients to the standard ZA dose of 4 mg intravenously plus subcutaneous placebo every 4 weeks.

Patients were stratified by whether they were on novel-based anti-myeloma therapy, whether they planned to have an autologous peripheral blood stem cell (PBSC) transplant, disease stage, and previous SRE.

“We were looking for 676 on-study SREs, and if we saw a benefit, patients would be offered open-label denosumab for up to 2 years after this,” Dr Raje said.

“Patients had to have radiographic evidence of bone disease, and this is different from some of the other bone disease studies that you’ve seen in the recent past,” she added.

In addition to documented evidence of MM, patients had to be 18 years or older, be ECOG status of 2 or better, have adequate organ function, and plan to receive or be receiving primary frontline anti-myeloma therapy.

Patients were excluded if they had nonsecretory MM, more than 30 days of previous treatment with anti-myeloma therapy prior to screening, prior use of denosumab, use of oral bisphosphonates with a cumulative dose of more than 1 year, more than 1 previous dose of intravenous bisphosphonate, or prior history or current evidence of osteonecrosis/osteomyelitis of the jaw.

The primary endpoint was time to first on-study SRE, “and the idea here was to look for non-inferiority,” Dr Raje explained.

Secondary endpoints included time to the first on-study SRE (superiority), time to the first-and-subsequent on-study SRE (superiority), and overall survival.

Investigators also included the exploratory objective of progression-free survival (PFS).

Patient demographics

Patients were well balanced across the 2 arms, Dr Raje noted, and the breakdown of myeloma disease stage at diagnosis was comparable between the ZA and denosumab arms.

About 32% of patients were stage I, 37% stage II, and 29% stage III. Stage was not available for 49 patients.

A little more than half (54%) were male, mean age was 63 years, and 82% were white.

Two thirds had prior SRE history, and 54% of patients intended to undergo autologous PBSC transplant.

Enrollment began May 2012 and continued through the end of March 2016. The primary analysis cutoff was July 19, 2016.

Results

The primary endpoint for non-inferiority for time to first on-study SRE was met by denosumab (HR=0.98, 95%CI: 0.85, 1.14; P=0.01).

 

“When we looked at the secondary endpoints for superiority, we were not able to confirm superiority in this analysis, either for time to first SRE or time to first-and subsequent SRE on this study,” Dr Raje said.

The investigators also did not observe a survival difference between denosumab and ZA, with a hazard ratio (HR) (95% CI) of 0.90 (0.70, 1.16), P=0.41.

“Importantly, we had an exploratory endpoint where we looked at progression-free survival in this newly diagnosed patient population,” she added, “and we saw an interestingly increased or prolonged progression-free survival in patients getting denosumab.”

“And that survival difference was more than 10 months between denosumab and zoledronic acid, favoring the denosumab arm,” she affirmed. The HR was 0.82, 95% CI: 0.68, 0.99, P=0.036 (descriptive).

Safety

“[I]f you look at all treatment-emergent adverse events between denosumab and zoledronic acid, we really could not find a big difference in either of these 2 groups of patients,” Dr Raje said.

“We saw that in general both denosumab and zoledronic acid were extremely well tolerated between the 2 groups of patients.”

The investigators “drilled down” on certain toxicity issues of interest and examined events such as atypical stress fractures, hypersensitivity reactions, musculoskeletal pain, infections and infestations, new primary malignancies, and acute phase reactions.

They observed no atypical femur fractures on the study, nor did they see any big differences with respect to hypersensitivity or acute phase reactions.

The investigators examined closely any renal issues because dosing of ZA specifically is impacted by renal function.

The data showed that treatment-emergent adverse event (TEAE) renal toxicity was significantly higher in the ZA group compared to the denosumab group, 17% and 10%, respectively (P<0.001).

“When you look at patients who had a creatinine clearance less than 60 mL per minute,” Dr Raje emphasized, “we saw an almost doubling of renal toxicity in the zoledronic acid arm (26.4%) compared to the denosumab arm (12.9%).”

Patients with a creatinine level greater than 2 mg/dL had a significant increase in creatinine in the ZA arm (P=0.010), which was also significantly increased if their creatinine clearance was less than 60 mL/minute (P=0.054).

“There was a doubling of creatinine from baseline, more so in the zoledronic acid arm compared to the patients with denosumab,” Dr Raje said. “And this was again more pronounced if you had a creatinine clearance of less than 60.”

Hypocalcemia was “not surprisingly” more common in the denosumab arm than the ZA arm (P=0.009) for all patients, and osteonecrosis of the jaw was equal in both arms (P=0.147), although numerically slightly higher with denosumab treatment.

Dr Raje summarized that there was no difference in overall survival at the time of this analysis, “but I will say that the follow-up for a newly diagnosed patient population is fairly short right now.”

“Progression-free survival, which we saw [cut] off 10.7 months, was actually quite striking when denosumab was compared to zoledronic acid, and this was statistically highly significant.”

“The bone-specific benefits in combination with significantly fewer renal adverse events and possible prolongation of PFS with denosumab therapy we do think is very promising,” she said, “and may in fact be a new standard of care for multiple myeloma-related bone disease.”

The study was funded by Amgen Inc.

Denosumab (XGEVA^®) is indicated by the US Food and Drug Administration for the prevention of fractures and other SREs in patients with bone metastases from solid tumors. It is currently not indicated for the prevention of SREs in patients with MM. 

Photo © ASCO/Scott Morgan 2017

CHICAGO—The largest international multiple myeloma (MM) trial ever conducted, according to the trial sponsor, met its primary endpoint, demonstrating that denosumab is non-inferior to zoledronic acid (ZA) in delaying the time to first on-study skeletal-related event (SRE) in patients with MM.

In addition to bone-specific benefits, denosumab-treated patients had significantly fewer renal adverse events and possible prolongation of progression-free survival.

Denosumab “may in fact be a new standard of care for multiple myeloma-related bone disease,” according to one of the investigators.

“The other important thing to note,” Noopur S. Raje, MD, said during her presentation at the ASCO 2017 Annual Meeting, “is denosumab can be administered despite renal function in patients with myeloma.” It does not need to be dose-adjusted, unlike bisphosphonates.

Dr Raje, of the Massachusetts General Hospital Cancer Center in Boston, Massachusetts, presented the study results as abstract 8005.

Study design

The international, phase 3, randomized, double-blind study is evaluating the safety of denosumab compared with ZA in newly diagnosed MM patients.

Investigators enrolled 1718 patients from 259 sites and 29 countries.

They randomized 859 patients to receive denosumab 120 mg subcutaneously every 4 weeks plus intravenous placebo every 4 weeks, and 859 patients to the standard ZA dose of 4 mg intravenously plus subcutaneous placebo every 4 weeks.

Patients were stratified by whether they were on novel-based anti-myeloma therapy, whether they planned to have an autologous peripheral blood stem cell (PBSC) transplant, disease stage, and previous SRE.

“We were looking for 676 on-study SREs, and if we saw a benefit, patients would be offered open-label denosumab for up to 2 years after this,” Dr Raje said.

“Patients had to have radiographic evidence of bone disease, and this is different from some of the other bone disease studies that you’ve seen in the recent past,” she added.

In addition to documented evidence of MM, patients had to be 18 years or older, be ECOG status of 2 or better, have adequate organ function, and plan to receive or be receiving primary frontline anti-myeloma therapy.

Patients were excluded if they had nonsecretory MM, more than 30 days of previous treatment with anti-myeloma therapy prior to screening, prior use of denosumab, use of oral bisphosphonates with a cumulative dose of more than 1 year, more than 1 previous dose of intravenous bisphosphonate, or prior history or current evidence of osteonecrosis/osteomyelitis of the jaw.

The primary endpoint was time to first on-study SRE, “and the idea here was to look for non-inferiority,” Dr Raje explained.

Secondary endpoints included time to the first on-study SRE (superiority), time to the first-and-subsequent on-study SRE (superiority), and overall survival.

Investigators also included the exploratory objective of progression-free survival (PFS).

Patient demographics

Patients were well balanced across the 2 arms, Dr Raje noted, and the breakdown of myeloma disease stage at diagnosis was comparable between the ZA and denosumab arms.

About 32% of patients were stage I, 37% stage II, and 29% stage III. Stage was not available for 49 patients.

A little more than half (54%) were male, mean age was 63 years, and 82% were white.

Two thirds had prior SRE history, and 54% of patients intended to undergo autologous PBSC transplant.

Enrollment began May 2012 and continued through the end of March 2016. The primary analysis cutoff was July 19, 2016.

Results

The primary endpoint for non-inferiority for time to first on-study SRE was met by denosumab (HR=0.98, 95%CI: 0.85, 1.14; P=0.01).

 

“When we looked at the secondary endpoints for superiority, we were not able to confirm superiority in this analysis, either for time to first SRE or time to first-and subsequent SRE on this study,” Dr Raje said.

The investigators also did not observe a survival difference between denosumab and ZA, with a hazard ratio (HR) (95% CI) of 0.90 (0.70, 1.16), P=0.41.

“Importantly, we had an exploratory endpoint where we looked at progression-free survival in this newly diagnosed patient population,” she added, “and we saw an interestingly increased or prolonged progression-free survival in patients getting denosumab.”

“And that survival difference was more than 10 months between denosumab and zoledronic acid, favoring the denosumab arm,” she affirmed. The HR was 0.82, 95% CI: 0.68, 0.99, P=0.036 (descriptive).

Safety

“[I]f you look at all treatment-emergent adverse events between denosumab and zoledronic acid, we really could not find a big difference in either of these 2 groups of patients,” Dr Raje said.

“We saw that in general both denosumab and zoledronic acid were extremely well tolerated between the 2 groups of patients.”

The investigators “drilled down” on certain toxicity issues of interest and examined events such as atypical stress fractures, hypersensitivity reactions, musculoskeletal pain, infections and infestations, new primary malignancies, and acute phase reactions.

They observed no atypical femur fractures on the study, nor did they see any big differences with respect to hypersensitivity or acute phase reactions.

The investigators examined closely any renal issues because dosing of ZA specifically is impacted by renal function.

The data showed that treatment-emergent adverse event (TEAE) renal toxicity was significantly higher in the ZA group compared to the denosumab group, 17% and 10%, respectively (P<0.001).

“When you look at patients who had a creatinine clearance less than 60 mL per minute,” Dr Raje emphasized, “we saw an almost doubling of renal toxicity in the zoledronic acid arm (26.4%) compared to the denosumab arm (12.9%).”

Patients with a creatinine level greater than 2 mg/dL had a significant increase in creatinine in the ZA arm (P=0.010), which was also significantly increased if their creatinine clearance was less than 60 mL/minute (P=0.054).

“There was a doubling of creatinine from baseline, more so in the zoledronic acid arm compared to the patients with denosumab,” Dr Raje said. “And this was again more pronounced if you had a creatinine clearance of less than 60.”

Hypocalcemia was “not surprisingly” more common in the denosumab arm than the ZA arm (P=0.009) for all patients, and osteonecrosis of the jaw was equal in both arms (P=0.147), although numerically slightly higher with denosumab treatment.

Dr Raje summarized that there was no difference in overall survival at the time of this analysis, “but I will say that the follow-up for a newly diagnosed patient population is fairly short right now.”

“Progression-free survival, which we saw [cut] off 10.7 months, was actually quite striking when denosumab was compared to zoledronic acid, and this was statistically highly significant.”

“The bone-specific benefits in combination with significantly fewer renal adverse events and possible prolongation of PFS with denosumab therapy we do think is very promising,” she said, “and may in fact be a new standard of care for multiple myeloma-related bone disease.”

The study was funded by Amgen Inc.

Denosumab (XGEVA^®) is indicated by the US Food and Drug Administration for the prevention of fractures and other SREs in patients with bone metastases from solid tumors. It is currently not indicated for the prevention of SREs in patients with MM. 

Photo © ASCO/Scott Morgan 2017

CHICAGO—The largest international multiple myeloma (MM) trial ever conducted, according to the trial sponsor, met its primary endpoint, demonstrating that denosumab is non-inferior to zoledronic acid (ZA) in delaying the time to first on-study skeletal-related event (SRE) in patients with MM.

In addition to bone-specific benefits, denosumab-treated patients had significantly fewer renal adverse events and possible prolongation of progression-free survival.

Denosumab “may in fact be a new standard of care for multiple myeloma-related bone disease,” according to one of the investigators.

“The other important thing to note,” Noopur S. Raje, MD, said during her presentation at the ASCO 2017 Annual Meeting, “is denosumab can be administered despite renal function in patients with myeloma.” It does not need to be dose-adjusted, unlike bisphosphonates.

Dr Raje, of the Massachusetts General Hospital Cancer Center in Boston, Massachusetts, presented the study results as abstract 8005.

Study design

The international, phase 3, randomized, double-blind study is evaluating the safety of denosumab compared with ZA in newly diagnosed MM patients.

Investigators enrolled 1718 patients from 259 sites and 29 countries.

They randomized 859 patients to receive denosumab 120 mg subcutaneously every 4 weeks plus intravenous placebo every 4 weeks, and 859 patients to the standard ZA dose of 4 mg intravenously plus subcutaneous placebo every 4 weeks.

Patients were stratified by whether they were on novel-based anti-myeloma therapy, whether they planned to have an autologous peripheral blood stem cell (PBSC) transplant, disease stage, and previous SRE.

“We were looking for 676 on-study SREs, and if we saw a benefit, patients would be offered open-label denosumab for up to 2 years after this,” Dr Raje said.

“Patients had to have radiographic evidence of bone disease, and this is different from some of the other bone disease studies that you’ve seen in the recent past,” she added.

In addition to documented evidence of MM, patients had to be 18 years or older, be ECOG status of 2 or better, have adequate organ function, and plan to receive or be receiving primary frontline anti-myeloma therapy.

Patients were excluded if they had nonsecretory MM, more than 30 days of previous treatment with anti-myeloma therapy prior to screening, prior use of denosumab, use of oral bisphosphonates with a cumulative dose of more than 1 year, more than 1 previous dose of intravenous bisphosphonate, or prior history or current evidence of osteonecrosis/osteomyelitis of the jaw.

The primary endpoint was time to first on-study SRE, “and the idea here was to look for non-inferiority,” Dr Raje explained.

Secondary endpoints included time to the first on-study SRE (superiority), time to the first-and-subsequent on-study SRE (superiority), and overall survival.

Investigators also included the exploratory objective of progression-free survival (PFS).

Patient demographics

Patients were well balanced across the 2 arms, Dr Raje noted, and the breakdown of myeloma disease stage at diagnosis was comparable between the ZA and denosumab arms.

About 32% of patients were stage I, 37% stage II, and 29% stage III. Stage was not available for 49 patients.

A little more than half (54%) were male, mean age was 63 years, and 82% were white.

Two thirds had prior SRE history, and 54% of patients intended to undergo autologous PBSC transplant.

Enrollment began May 2012 and continued through the end of March 2016. The primary analysis cutoff was July 19, 2016.

Results

The primary endpoint for non-inferiority for time to first on-study SRE was met by denosumab (HR=0.98, 95%CI: 0.85, 1.14; P=0.01).

 

“When we looked at the secondary endpoints for superiority, we were not able to confirm superiority in this analysis, either for time to first SRE or time to first-and subsequent SRE on this study,” Dr Raje said.

The investigators also did not observe a survival difference between denosumab and ZA, with a hazard ratio (HR) (95% CI) of 0.90 (0.70, 1.16), P=0.41.

“Importantly, we had an exploratory endpoint where we looked at progression-free survival in this newly diagnosed patient population,” she added, “and we saw an interestingly increased or prolonged progression-free survival in patients getting denosumab.”

“And that survival difference was more than 10 months between denosumab and zoledronic acid, favoring the denosumab arm,” she affirmed. The HR was 0.82, 95% CI: 0.68, 0.99, P=0.036 (descriptive).

Safety

“[I]f you look at all treatment-emergent adverse events between denosumab and zoledronic acid, we really could not find a big difference in either of these 2 groups of patients,” Dr Raje said.

“We saw that in general both denosumab and zoledronic acid were extremely well tolerated between the 2 groups of patients.”

The investigators “drilled down” on certain toxicity issues of interest and examined events such as atypical stress fractures, hypersensitivity reactions, musculoskeletal pain, infections and infestations, new primary malignancies, and acute phase reactions.

They observed no atypical femur fractures on the study, nor did they see any big differences with respect to hypersensitivity or acute phase reactions.

The investigators examined closely any renal issues because dosing of ZA specifically is impacted by renal function.

The data showed that treatment-emergent adverse event (TEAE) renal toxicity was significantly higher in the ZA group compared to the denosumab group, 17% and 10%, respectively (P<0.001).

“When you look at patients who had a creatinine clearance less than 60 mL per minute,” Dr Raje emphasized, “we saw an almost doubling of renal toxicity in the zoledronic acid arm (26.4%) compared to the denosumab arm (12.9%).”

Patients with a creatinine level greater than 2 mg/dL had a significant increase in creatinine in the ZA arm (P=0.010), which was also significantly increased if their creatinine clearance was less than 60 mL/minute (P=0.054).

“There was a doubling of creatinine from baseline, more so in the zoledronic acid arm compared to the patients with denosumab,” Dr Raje said. “And this was again more pronounced if you had a creatinine clearance of less than 60.”

Hypocalcemia was “not surprisingly” more common in the denosumab arm than the ZA arm (P=0.009) for all patients, and osteonecrosis of the jaw was equal in both arms (P=0.147), although numerically slightly higher with denosumab treatment.

Dr Raje summarized that there was no difference in overall survival at the time of this analysis, “but I will say that the follow-up for a newly diagnosed patient population is fairly short right now.”

“Progression-free survival, which we saw [cut] off 10.7 months, was actually quite striking when denosumab was compared to zoledronic acid, and this was statistically highly significant.”

“The bone-specific benefits in combination with significantly fewer renal adverse events and possible prolongation of PFS with denosumab therapy we do think is very promising,” she said, “and may in fact be a new standard of care for multiple myeloma-related bone disease.”

The study was funded by Amgen Inc.

Denosumab (XGEVA^®) is indicated by the US Food and Drug Administration for the prevention of fractures and other SREs in patients with bone metastases from solid tumors. It is currently not indicated for the prevention of SREs in patients with MM. 

 

Bortezomib treatment using liposome nanocarriers leads to decreased cell viability and greater apoptosis in vitro, compared with treatment with free bortezomib, according to a study in the Journal of Pharmaceutical Sciences and Pharmacology.

Liposomes are lipid sacs with a watery compartment, which can be used to encapsulate and deliver a therapeutic cargo. The delivery method has been found to have improved efficacy with lesser side effects.

Dennis Barten/Wikimedia Commons/CC-ASA 3.0

Medha D. Joshi, PhD, and researchers at the Midwestern University Chicago College of Pharmacy loaded bortezomib – a proteasome-inhibitor approved for treatment of multiple myeloma and mantle cell lymphoma – into two types of liposomes, either ceramide and cationic.

Ceramide liposomes are an attractive drug-delivery vehicle, the researchers said, because of their cell-permeability and because they’ve been found, on their own, to mediate apoptosis. Researchers said they believed this was the first time results have been reported on combining ceramide liposomes with an anticancer drug such as bortezomib. Cationic liposomes were picked because they’re known to destabilize cell membranes, helping with intracellular delivery of the drug.

Free bortezomib and bortezomib loaded into liposomes were tested for efficacy on mouse preosteoclast calvaria MC3T3 cells, mouse macrophage-like RAW 264.7 cells, and human osteosarcoma U2OS cells.

On the RAW 264.7 cells, researchers found a significant difference in cell viability between free bortezomib and ceramide liposomes after 24 hours (P less than .01) and 48 hours (P less than .05) and between free bortezomib and cationic liposomes at 24 hours (P less than .01). They also reported a significant difference with cationic liposomes on MC3T3 cells and U2OS cells at 48 hours (both P less than .01).

One nanomolar (nM) of ceramide-loaded bortezomib induced significantly more apoptosis than did 1 nM of free bortezomib (P less than .01), and 10 nM of ceramide-loaded bortezomib brought about more cell death and apoptosis than did 10 nM of free bortezomib (P less than .05). These effects were likely the result of increased expression of proteins involved in apoptosis.

Liposomes might be able to boost the efficacy of bortezomib, according to the researchers, who are now studying the localization of these liposomes with confocal microscopes to better understand the mechanism of action.

“Such improvements,” they wrote, “offer the potential to reduce side effects known to occur with this chemotherapy, such as peripheral neuropathy, as well as to target Bort-resistant cancers.”

 

Bortezomib treatment using liposome nanocarriers leads to decreased cell viability and greater apoptosis in vitro, compared with treatment with free bortezomib, according to a study in the Journal of Pharmaceutical Sciences and Pharmacology.

Liposomes are lipid sacs with a watery compartment, which can be used to encapsulate and deliver a therapeutic cargo. The delivery method has been found to have improved efficacy with lesser side effects.

Dennis Barten/Wikimedia Commons/CC-ASA 3.0

Medha D. Joshi, PhD, and researchers at the Midwestern University Chicago College of Pharmacy loaded bortezomib – a proteasome-inhibitor approved for treatment of multiple myeloma and mantle cell lymphoma – into two types of liposomes, either ceramide and cationic.

Ceramide liposomes are an attractive drug-delivery vehicle, the researchers said, because of their cell-permeability and because they’ve been found, on their own, to mediate apoptosis. Researchers said they believed this was the first time results have been reported on combining ceramide liposomes with an anticancer drug such as bortezomib. Cationic liposomes were picked because they’re known to destabilize cell membranes, helping with intracellular delivery of the drug.

Free bortezomib and bortezomib loaded into liposomes were tested for efficacy on mouse preosteoclast calvaria MC3T3 cells, mouse macrophage-like RAW 264.7 cells, and human osteosarcoma U2OS cells.

On the RAW 264.7 cells, researchers found a significant difference in cell viability between free bortezomib and ceramide liposomes after 24 hours (P less than .01) and 48 hours (P less than .05) and between free bortezomib and cationic liposomes at 24 hours (P less than .01). They also reported a significant difference with cationic liposomes on MC3T3 cells and U2OS cells at 48 hours (both P less than .01).

One nanomolar (nM) of ceramide-loaded bortezomib induced significantly more apoptosis than did 1 nM of free bortezomib (P less than .01), and 10 nM of ceramide-loaded bortezomib brought about more cell death and apoptosis than did 10 nM of free bortezomib (P less than .05). These effects were likely the result of increased expression of proteins involved in apoptosis.

Liposomes might be able to boost the efficacy of bortezomib, according to the researchers, who are now studying the localization of these liposomes with confocal microscopes to better understand the mechanism of action.

“Such improvements,” they wrote, “offer the potential to reduce side effects known to occur with this chemotherapy, such as peripheral neuropathy, as well as to target Bort-resistant cancers.”

 

Bortezomib treatment using liposome nanocarriers leads to decreased cell viability and greater apoptosis in vitro, compared with treatment with free bortezomib, according to a study in the Journal of Pharmaceutical Sciences and Pharmacology.

Liposomes are lipid sacs with a watery compartment, which can be used to encapsulate and deliver a therapeutic cargo. The delivery method has been found to have improved efficacy with lesser side effects.

Dennis Barten/Wikimedia Commons/CC-ASA 3.0

Medha D. Joshi, PhD, and researchers at the Midwestern University Chicago College of Pharmacy loaded bortezomib – a proteasome-inhibitor approved for treatment of multiple myeloma and mantle cell lymphoma – into two types of liposomes, either ceramide and cationic.

Ceramide liposomes are an attractive drug-delivery vehicle, the researchers said, because of their cell-permeability and because they’ve been found, on their own, to mediate apoptosis. Researchers said they believed this was the first time results have been reported on combining ceramide liposomes with an anticancer drug such as bortezomib. Cationic liposomes were picked because they’re known to destabilize cell membranes, helping with intracellular delivery of the drug.

Free bortezomib and bortezomib loaded into liposomes were tested for efficacy on mouse preosteoclast calvaria MC3T3 cells, mouse macrophage-like RAW 264.7 cells, and human osteosarcoma U2OS cells.

On the RAW 264.7 cells, researchers found a significant difference in cell viability between free bortezomib and ceramide liposomes after 24 hours (P less than .01) and 48 hours (P less than .05) and between free bortezomib and cationic liposomes at 24 hours (P less than .01). They also reported a significant difference with cationic liposomes on MC3T3 cells and U2OS cells at 48 hours (both P less than .01).

One nanomolar (nM) of ceramide-loaded bortezomib induced significantly more apoptosis than did 1 nM of free bortezomib (P less than .01), and 10 nM of ceramide-loaded bortezomib brought about more cell death and apoptosis than did 10 nM of free bortezomib (P less than .05). These effects were likely the result of increased expression of proteins involved in apoptosis.

Liposomes might be able to boost the efficacy of bortezomib, according to the researchers, who are now studying the localization of these liposomes with confocal microscopes to better understand the mechanism of action.

“Such improvements,” they wrote, “offer the potential to reduce side effects known to occur with this chemotherapy, such as peripheral neuropathy, as well as to target Bort-resistant cancers.”

Photo courtesy of Merck

Merck announced that it is pausing enrollment onto 2 phase 3 trials of pembrolizumab (Keytruda®) in combination with other agents to treat multiple myeloma (MM).

An external Data Monitoring Committee recommended the trial be interrupted “to allow for additional information be collected to better understand more reports of death” in the pembrolizumab groups in the KEYNOTE-183 and KEYNOTE-185 trials.

Patients currently enrolled on the trials can continue to receive treatment. Other pembrolizumab trials are continuing without changes.

Merck in its statement did not disclose the number of deaths nor provide any other details on the deaths.

Pembrolizumab is a humanized monoclonal antibody that blocks interaction between the programmed cell death protein 1 (PD-1) and its receptor ligands, PD-L1 and PD-L2.

The US Food & Drug Administration approved pembrolizumab to treat unresectable or metastatic melanoma after ipilimumab treatment.

Pembrolizumab has also been approved to treat non-small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, urothelial carcinoma, and microsatellite instability-high solid tumors.

KEYNOTE-183 (NCT02576977), which has an estimated enrollment of 300 patients, is comparing the combination of pembrolizumab, pomalidomide, and low-dose dexamethasone to pomalidomide and low-dose dexamethasone alone in patients with relapsed or refractory MM who have undergone at least 2 lines of prior therapy.

KEYNOTE-185 (NCT02579863), which has an estimated enrollment of 640 patients, is comparing the combination of pembrolizumab, lenalidomide, and low-dose dexamethasone to lenalidomide and low-dose desamethasone alone in patients with newly diagnosed and treatment-native MM who are ineligible for autologous stem cell transplant.

The comparator agents pomalidomide (Pomalyst®) and lenalidomide (Revlimid®) are products of Celgene Corporation. 

Photo courtesy of Merck

Merck announced that it is pausing enrollment onto 2 phase 3 trials of pembrolizumab (Keytruda®) in combination with other agents to treat multiple myeloma (MM).

An external Data Monitoring Committee recommended the trial be interrupted “to allow for additional information be collected to better understand more reports of death” in the pembrolizumab groups in the KEYNOTE-183 and KEYNOTE-185 trials.

Patients currently enrolled on the trials can continue to receive treatment. Other pembrolizumab trials are continuing without changes.

Merck in its statement did not disclose the number of deaths nor provide any other details on the deaths.

Pembrolizumab is a humanized monoclonal antibody that blocks interaction between the programmed cell death protein 1 (PD-1) and its receptor ligands, PD-L1 and PD-L2.

The US Food & Drug Administration approved pembrolizumab to treat unresectable or metastatic melanoma after ipilimumab treatment.

Pembrolizumab has also been approved to treat non-small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, urothelial carcinoma, and microsatellite instability-high solid tumors.

KEYNOTE-183 (NCT02576977), which has an estimated enrollment of 300 patients, is comparing the combination of pembrolizumab, pomalidomide, and low-dose dexamethasone to pomalidomide and low-dose dexamethasone alone in patients with relapsed or refractory MM who have undergone at least 2 lines of prior therapy.

KEYNOTE-185 (NCT02579863), which has an estimated enrollment of 640 patients, is comparing the combination of pembrolizumab, lenalidomide, and low-dose dexamethasone to lenalidomide and low-dose desamethasone alone in patients with newly diagnosed and treatment-native MM who are ineligible for autologous stem cell transplant.

The comparator agents pomalidomide (Pomalyst®) and lenalidomide (Revlimid®) are products of Celgene Corporation. 

Photo courtesy of Merck

Merck announced that it is pausing enrollment onto 2 phase 3 trials of pembrolizumab (Keytruda®) in combination with other agents to treat multiple myeloma (MM).

An external Data Monitoring Committee recommended the trial be interrupted “to allow for additional information be collected to better understand more reports of death” in the pembrolizumab groups in the KEYNOTE-183 and KEYNOTE-185 trials.

Patients currently enrolled on the trials can continue to receive treatment. Other pembrolizumab trials are continuing without changes.

Merck in its statement did not disclose the number of deaths nor provide any other details on the deaths.

Pembrolizumab is a humanized monoclonal antibody that blocks interaction between the programmed cell death protein 1 (PD-1) and its receptor ligands, PD-L1 and PD-L2.

The US Food & Drug Administration approved pembrolizumab to treat unresectable or metastatic melanoma after ipilimumab treatment.

Pembrolizumab has also been approved to treat non-small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, urothelial carcinoma, and microsatellite instability-high solid tumors.

KEYNOTE-183 (NCT02576977), which has an estimated enrollment of 300 patients, is comparing the combination of pembrolizumab, pomalidomide, and low-dose dexamethasone to pomalidomide and low-dose dexamethasone alone in patients with relapsed or refractory MM who have undergone at least 2 lines of prior therapy.

KEYNOTE-185 (NCT02579863), which has an estimated enrollment of 640 patients, is comparing the combination of pembrolizumab, lenalidomide, and low-dose dexamethasone to lenalidomide and low-dose desamethasone alone in patients with newly diagnosed and treatment-native MM who are ineligible for autologous stem cell transplant.

The comparator agents pomalidomide (Pomalyst®) and lenalidomide (Revlimid®) are products of Celgene Corporation. 

Photo © ASCO/Scott Morgan 2017

CHICAGO—Results of an open-label phase 1b study of daratumumab combined with carfilzomib, lenalidomide, and dexamethasone (KRd) in newly diagnosed multiple myeloma (MM) patients have shown the combination to be highly effective, with an overall response rate of 100%.

Ninety-one percent of patients achieved a very good partial response (VGPR) or better, and 43% achieved a complete response (CR) or better.

Investigators had hypothesized that rather than using autologous stem cell transplant (ASCT) to improve results of treatment with KRd, the combination could alternatively be improved by incorporating daratumumab into a KRd regimen.

Andrzej Jakubowiak, MD, of the University of Chicago Medical Center in Illinois, presented the findings of the MMY1001 study at the 2017 ASCO Annual Meeting (abstract 8000*).

“I think what was one of the more important developments in myeloma last year,” Dr Jakubowiak said, “was data from randomized studies showing that adding daratumumab to either lenalidomide and dexamethasone in the POLLUX study or bortezomib and dexamethasone, a proteasome inhibitor, in the CASTOR study, improves responses, depth of response, and . . .  dramatically improved progression-free survival.”

“[W]e have now the rationale to potentially combine daratumumab with both an IMiD and proteasome inhibitor,” he explained, “which led to the development of this phase 1b study in which we combined daratumumab with KRd and evaluated tolerability and efficacy.”

Study design

Twenty-two transplant-eligible or -ineligible newly diagnosed MM patients were enrolled on the study.

Treatment duration was planned to be 13 cycles or less and patients had the option to move to transplant after 4 cycles.

They could have no clinically significant cardiac disease and echocardiogram was required prior to transplant.

The dosing schedule was the established dosing schema for daratumumab and KRd with 2 notable differences in the 28-day cycles.

First, the daratumumab dose was a split dose. So patients received 8 mg/kg on days 1-2 of cycle 1, 16 mg/kg a week on cycle 2, 16 mg/kg every 2 weeks on cycles 3 – 6, and every 4^th week thereafter.

The second difference was carfilzomib dosing was a weekly regimen with escalation from 20 mg/m² on day 1, cycle 1 to 70 mg/m² on day 8 of cycle 1.

Lenalidomide (25 mg on days 1-21 of each cycle) and dexamethasone (40 mg/week) were the standard regimens for these drugs.

The primary endpoint was safety and tolerability. The secondary endpoint was overall response rate (ORR), duration of response, time to response, and infusion-related reactions (IRR).

The study also had an exploratory endpoint of progression-free survival (PFS).

Baseline characteristics

Patients were a median age of 59.5 years (range 34 – 74). About two thirds were younger than 65 and one third were between 65 and 75.

A little over half were male and most (86%) were white.

A little more than half (55%) had an ECOG score of 0, 41% were ECOG 1, and 5% were ECOG 2.

Patient disposition

As of the cutoff date of March 24, 8 of the 22 patients enrolled (36%) discontinued treatment: 1 due to an adverse event (AE), 1 due to progressive disease, and 6 patients (27%) proceeded to ASCT.

Dr Jakubowiak pointed out that response was censored at this point for patients who proceeded to transplant.

The median follow-up was 10.8 months (range, 4.0 – 12.5) and the median number of treatment cycles was 11.5 (range, 1.0 – 13.0).

“What is of interest to many of us,” Dr Jakubowiak said, “is that patients were escalated to the planned dose of 70 mg/m² by cycle 2 except for 3 patients.”

 

Of the 3, 1 discontinued before day 1 of the second cycle due to toxicity, 1 had a dose reduction to 56 mg/m² at day of the second cycle, and 1 escalated to 70 mg/m² at day 8 of cycle 3.

Ultimately, all patients who remained on study were able to escalate to 70 mg/m².

Safety

The hematologic treatment-emergent adverse events (TEAE) generally followed what has been observed in similar studies before, Dr Jakubowiak noted.

Hematologic TEAEs of all grades occurring in 30% or more of patients were lymphopenia (68%), thrombocytopenia (55%), anemia (46%), leukopenia (41%), and neutropenia (32%).

The most common non-hematologic TEAEs of all grades occurring in 30% of patients or more were diarrhea (73%), upper respiratory infection (59%) cough, constipation, and fatigue (50% each), dyspnea and insomnia (46%), nausea, rash, and back pain (41%), muscle spasm (36%), and vomiting, pain in extremity, hyperglycemia, and increased ALT (32%).

The most common grade 3/4 TEAEs were infrequent and many events had none of grade 3/4 severity.

The safety profile is consistent with what was previously reported for daratumumab or KRd, Dr Jakubowiak affirmed.

Serious TEAEs

Serious TEAEs occurred in 10 patients (46%), with many occurring in just 1 patient. Pulmonary embolism (PE) was the most frequent, occurring in 3 patients.

All patients were required to be on aspirin prophylaxis and 1 of the patients who had a PE discontinued therapy.

The number of patients with a serious TEAE reasonably related to an individual study drug were 3 (14%) for daratumumab, 5 (23%) for carfilzomib, 5 (23%) for lenalidomide, and 2 (9%) for dexamethasone.

The TEAEs of interest—tachycardia, congestive heart failure, and hypertension—occurred in a single patient each.

Overall, serious TEAEs were consistent with previous reports from KRd studies.

Echocardiogram assessment

Investigators conducted 30 systemic evaluations on the impact of this regimen on heart function.  The investigators observed no change from baseline through the duration of treatment in patients’ left ventricular ejection fractions.

One patient developed congestive heart failure, possibly related to daratumumab or carfilzomib. This patient resumed treatment with a reduced carfilzomib dose, elected ASCT on study day 113, and ended treatment with a VGPR.

“In all,” Dr Jakubowiak said, “we feel that there is no apparent signal of adverse impact of the addition of daratumumab on cardiac function.”

Infusion times and reactions

Overall, IRRs occurred in 27% of the patients, “which appears lower than with previous daratumumab studies,” Dr Jakubowiak noted. And IRRs occurred more frequently during the first infusion than subsequent infusions.

The split-dose infusion time was very similar to that of second and subsequent cycles.

There were limited events related to infusions. All were grade 1 or 2 and most occurred in only a single patient.

Response rate

The median number of treatment cycles administered was 11.5 (range, 2.0 – 13.0). The best response was 100% PR or better, 91% achieved VGPR or better, 42% CR or better, and 29% a stringent CR.

The depth of response improved with duration of treatment. For example, the sCR rate increased from 5% after 4 cycles to 29% at the end of treatment.

PFS was an exploratory endpoint. One patient progressed at 10.8 months and the 12-month PFS rate was 94% with all patients alive.

Stem cell harvest and ASCT

“For many of us,” Dr Jakubowiak commented, “it’s also of interest how this regimen will impact stem cell harvest.”

Nineteen of 22 patients were deemed to be transplant eligible, and the median number of CD34+ cells collected from them was 10.4 x 10⁶ cells/kg.

 

Patients had a median of 5 treatment cycles prior to stem cell harvest, and 14 (74%) had a VGPR or better prior to harvest.

The investigators believe stem cell yield was consistent with previous KRd studies.

Dr Jakubowiak commented that the deepening of response over time “is a phenomenon we think is important. . . . In all, the data from this small phase 1b study provide support for further evaluation of this regimen in newly diagnosed myeloma."

The study was funded by Janssen Research and Development, LLC. 

*Data presented during the meeting differ from the abstract.

Photo © ASCO/Scott Morgan 2017

CHICAGO—Results of an open-label phase 1b study of daratumumab combined with carfilzomib, lenalidomide, and dexamethasone (KRd) in newly diagnosed multiple myeloma (MM) patients have shown the combination to be highly effective, with an overall response rate of 100%.

Ninety-one percent of patients achieved a very good partial response (VGPR) or better, and 43% achieved a complete response (CR) or better.

Investigators had hypothesized that rather than using autologous stem cell transplant (ASCT) to improve results of treatment with KRd, the combination could alternatively be improved by incorporating daratumumab into a KRd regimen.

Andrzej Jakubowiak, MD, of the University of Chicago Medical Center in Illinois, presented the findings of the MMY1001 study at the 2017 ASCO Annual Meeting (abstract 8000*).

“I think what was one of the more important developments in myeloma last year,” Dr Jakubowiak said, “was data from randomized studies showing that adding daratumumab to either lenalidomide and dexamethasone in the POLLUX study or bortezomib and dexamethasone, a proteasome inhibitor, in the CASTOR study, improves responses, depth of response, and . . .  dramatically improved progression-free survival.”

“[W]e have now the rationale to potentially combine daratumumab with both an IMiD and proteasome inhibitor,” he explained, “which led to the development of this phase 1b study in which we combined daratumumab with KRd and evaluated tolerability and efficacy.”

Study design

Twenty-two transplant-eligible or -ineligible newly diagnosed MM patients were enrolled on the study.

Treatment duration was planned to be 13 cycles or less and patients had the option to move to transplant after 4 cycles.

They could have no clinically significant cardiac disease and echocardiogram was required prior to transplant.

The dosing schedule was the established dosing schema for daratumumab and KRd with 2 notable differences in the 28-day cycles.

First, the daratumumab dose was a split dose. So patients received 8 mg/kg on days 1-2 of cycle 1, 16 mg/kg a week on cycle 2, 16 mg/kg every 2 weeks on cycles 3 – 6, and every 4^th week thereafter.

The second difference was carfilzomib dosing was a weekly regimen with escalation from 20 mg/m² on day 1, cycle 1 to 70 mg/m² on day 8 of cycle 1.

Lenalidomide (25 mg on days 1-21 of each cycle) and dexamethasone (40 mg/week) were the standard regimens for these drugs.

The primary endpoint was safety and tolerability. The secondary endpoint was overall response rate (ORR), duration of response, time to response, and infusion-related reactions (IRR).

The study also had an exploratory endpoint of progression-free survival (PFS).

Baseline characteristics

Patients were a median age of 59.5 years (range 34 – 74). About two thirds were younger than 65 and one third were between 65 and 75.

A little over half were male and most (86%) were white.

A little more than half (55%) had an ECOG score of 0, 41% were ECOG 1, and 5% were ECOG 2.

Patient disposition

As of the cutoff date of March 24, 8 of the 22 patients enrolled (36%) discontinued treatment: 1 due to an adverse event (AE), 1 due to progressive disease, and 6 patients (27%) proceeded to ASCT.

Dr Jakubowiak pointed out that response was censored at this point for patients who proceeded to transplant.

The median follow-up was 10.8 months (range, 4.0 – 12.5) and the median number of treatment cycles was 11.5 (range, 1.0 – 13.0).

“What is of interest to many of us,” Dr Jakubowiak said, “is that patients were escalated to the planned dose of 70 mg/m² by cycle 2 except for 3 patients.”

 

Of the 3, 1 discontinued before day 1 of the second cycle due to toxicity, 1 had a dose reduction to 56 mg/m² at day of the second cycle, and 1 escalated to 70 mg/m² at day 8 of cycle 3.

Ultimately, all patients who remained on study were able to escalate to 70 mg/m².

Safety

The hematologic treatment-emergent adverse events (TEAE) generally followed what has been observed in similar studies before, Dr Jakubowiak noted.

Hematologic TEAEs of all grades occurring in 30% or more of patients were lymphopenia (68%), thrombocytopenia (55%), anemia (46%), leukopenia (41%), and neutropenia (32%).

The most common non-hematologic TEAEs of all grades occurring in 30% of patients or more were diarrhea (73%), upper respiratory infection (59%) cough, constipation, and fatigue (50% each), dyspnea and insomnia (46%), nausea, rash, and back pain (41%), muscle spasm (36%), and vomiting, pain in extremity, hyperglycemia, and increased ALT (32%).

The most common grade 3/4 TEAEs were infrequent and many events had none of grade 3/4 severity.

The safety profile is consistent with what was previously reported for daratumumab or KRd, Dr Jakubowiak affirmed.

Serious TEAEs

Serious TEAEs occurred in 10 patients (46%), with many occurring in just 1 patient. Pulmonary embolism (PE) was the most frequent, occurring in 3 patients.

All patients were required to be on aspirin prophylaxis and 1 of the patients who had a PE discontinued therapy.

The number of patients with a serious TEAE reasonably related to an individual study drug were 3 (14%) for daratumumab, 5 (23%) for carfilzomib, 5 (23%) for lenalidomide, and 2 (9%) for dexamethasone.

The TEAEs of interest—tachycardia, congestive heart failure, and hypertension—occurred in a single patient each.

Overall, serious TEAEs were consistent with previous reports from KRd studies.

Echocardiogram assessment

Investigators conducted 30 systemic evaluations on the impact of this regimen on heart function.  The investigators observed no change from baseline through the duration of treatment in patients’ left ventricular ejection fractions.

One patient developed congestive heart failure, possibly related to daratumumab or carfilzomib. This patient resumed treatment with a reduced carfilzomib dose, elected ASCT on study day 113, and ended treatment with a VGPR.

“In all,” Dr Jakubowiak said, “we feel that there is no apparent signal of adverse impact of the addition of daratumumab on cardiac function.”

Infusion times and reactions

Overall, IRRs occurred in 27% of the patients, “which appears lower than with previous daratumumab studies,” Dr Jakubowiak noted. And IRRs occurred more frequently during the first infusion than subsequent infusions.

The split-dose infusion time was very similar to that of second and subsequent cycles.

There were limited events related to infusions. All were grade 1 or 2 and most occurred in only a single patient.

Response rate

The median number of treatment cycles administered was 11.5 (range, 2.0 – 13.0). The best response was 100% PR or better, 91% achieved VGPR or better, 42% CR or better, and 29% a stringent CR.

The depth of response improved with duration of treatment. For example, the sCR rate increased from 5% after 4 cycles to 29% at the end of treatment.

PFS was an exploratory endpoint. One patient progressed at 10.8 months and the 12-month PFS rate was 94% with all patients alive.

Stem cell harvest and ASCT

“For many of us,” Dr Jakubowiak commented, “it’s also of interest how this regimen will impact stem cell harvest.”

Nineteen of 22 patients were deemed to be transplant eligible, and the median number of CD34+ cells collected from them was 10.4 x 10⁶ cells/kg.

 

Patients had a median of 5 treatment cycles prior to stem cell harvest, and 14 (74%) had a VGPR or better prior to harvest.

The investigators believe stem cell yield was consistent with previous KRd studies.

Dr Jakubowiak commented that the deepening of response over time “is a phenomenon we think is important. . . . In all, the data from this small phase 1b study provide support for further evaluation of this regimen in newly diagnosed myeloma."

The study was funded by Janssen Research and Development, LLC. 

*Data presented during the meeting differ from the abstract.

Photo © ASCO/Scott Morgan 2017

CHICAGO—Results of an open-label phase 1b study of daratumumab combined with carfilzomib, lenalidomide, and dexamethasone (KRd) in newly diagnosed multiple myeloma (MM) patients have shown the combination to be highly effective, with an overall response rate of 100%.

Ninety-one percent of patients achieved a very good partial response (VGPR) or better, and 43% achieved a complete response (CR) or better.

Investigators had hypothesized that rather than using autologous stem cell transplant (ASCT) to improve results of treatment with KRd, the combination could alternatively be improved by incorporating daratumumab into a KRd regimen.

Andrzej Jakubowiak, MD, of the University of Chicago Medical Center in Illinois, presented the findings of the MMY1001 study at the 2017 ASCO Annual Meeting (abstract 8000*).

“I think what was one of the more important developments in myeloma last year,” Dr Jakubowiak said, “was data from randomized studies showing that adding daratumumab to either lenalidomide and dexamethasone in the POLLUX study or bortezomib and dexamethasone, a proteasome inhibitor, in the CASTOR study, improves responses, depth of response, and . . .  dramatically improved progression-free survival.”

“[W]e have now the rationale to potentially combine daratumumab with both an IMiD and proteasome inhibitor,” he explained, “which led to the development of this phase 1b study in which we combined daratumumab with KRd and evaluated tolerability and efficacy.”

Study design

Twenty-two transplant-eligible or -ineligible newly diagnosed MM patients were enrolled on the study.

Treatment duration was planned to be 13 cycles or less and patients had the option to move to transplant after 4 cycles.

They could have no clinically significant cardiac disease and echocardiogram was required prior to transplant.

The dosing schedule was the established dosing schema for daratumumab and KRd with 2 notable differences in the 28-day cycles.

First, the daratumumab dose was a split dose. So patients received 8 mg/kg on days 1-2 of cycle 1, 16 mg/kg a week on cycle 2, 16 mg/kg every 2 weeks on cycles 3 – 6, and every 4^th week thereafter.

The second difference was carfilzomib dosing was a weekly regimen with escalation from 20 mg/m² on day 1, cycle 1 to 70 mg/m² on day 8 of cycle 1.

Lenalidomide (25 mg on days 1-21 of each cycle) and dexamethasone (40 mg/week) were the standard regimens for these drugs.

The primary endpoint was safety and tolerability. The secondary endpoint was overall response rate (ORR), duration of response, time to response, and infusion-related reactions (IRR).

The study also had an exploratory endpoint of progression-free survival (PFS).

Baseline characteristics

Patients were a median age of 59.5 years (range 34 – 74). About two thirds were younger than 65 and one third were between 65 and 75.

A little over half were male and most (86%) were white.

A little more than half (55%) had an ECOG score of 0, 41% were ECOG 1, and 5% were ECOG 2.

Patient disposition

As of the cutoff date of March 24, 8 of the 22 patients enrolled (36%) discontinued treatment: 1 due to an adverse event (AE), 1 due to progressive disease, and 6 patients (27%) proceeded to ASCT.

Dr Jakubowiak pointed out that response was censored at this point for patients who proceeded to transplant.

The median follow-up was 10.8 months (range, 4.0 – 12.5) and the median number of treatment cycles was 11.5 (range, 1.0 – 13.0).

“What is of interest to many of us,” Dr Jakubowiak said, “is that patients were escalated to the planned dose of 70 mg/m² by cycle 2 except for 3 patients.”

 

Of the 3, 1 discontinued before day 1 of the second cycle due to toxicity, 1 had a dose reduction to 56 mg/m² at day of the second cycle, and 1 escalated to 70 mg/m² at day 8 of cycle 3.

Ultimately, all patients who remained on study were able to escalate to 70 mg/m².

Safety

The hematologic treatment-emergent adverse events (TEAE) generally followed what has been observed in similar studies before, Dr Jakubowiak noted.

Hematologic TEAEs of all grades occurring in 30% or more of patients were lymphopenia (68%), thrombocytopenia (55%), anemia (46%), leukopenia (41%), and neutropenia (32%).

The most common non-hematologic TEAEs of all grades occurring in 30% of patients or more were diarrhea (73%), upper respiratory infection (59%) cough, constipation, and fatigue (50% each), dyspnea and insomnia (46%), nausea, rash, and back pain (41%), muscle spasm (36%), and vomiting, pain in extremity, hyperglycemia, and increased ALT (32%).

The most common grade 3/4 TEAEs were infrequent and many events had none of grade 3/4 severity.

The safety profile is consistent with what was previously reported for daratumumab or KRd, Dr Jakubowiak affirmed.

Serious TEAEs

Serious TEAEs occurred in 10 patients (46%), with many occurring in just 1 patient. Pulmonary embolism (PE) was the most frequent, occurring in 3 patients.

All patients were required to be on aspirin prophylaxis and 1 of the patients who had a PE discontinued therapy.

The number of patients with a serious TEAE reasonably related to an individual study drug were 3 (14%) for daratumumab, 5 (23%) for carfilzomib, 5 (23%) for lenalidomide, and 2 (9%) for dexamethasone.

The TEAEs of interest—tachycardia, congestive heart failure, and hypertension—occurred in a single patient each.

Overall, serious TEAEs were consistent with previous reports from KRd studies.

Echocardiogram assessment

Investigators conducted 30 systemic evaluations on the impact of this regimen on heart function.  The investigators observed no change from baseline through the duration of treatment in patients’ left ventricular ejection fractions.

One patient developed congestive heart failure, possibly related to daratumumab or carfilzomib. This patient resumed treatment with a reduced carfilzomib dose, elected ASCT on study day 113, and ended treatment with a VGPR.

“In all,” Dr Jakubowiak said, “we feel that there is no apparent signal of adverse impact of the addition of daratumumab on cardiac function.”

Infusion times and reactions

Overall, IRRs occurred in 27% of the patients, “which appears lower than with previous daratumumab studies,” Dr Jakubowiak noted. And IRRs occurred more frequently during the first infusion than subsequent infusions.

The split-dose infusion time was very similar to that of second and subsequent cycles.

There were limited events related to infusions. All were grade 1 or 2 and most occurred in only a single patient.

Response rate

The median number of treatment cycles administered was 11.5 (range, 2.0 – 13.0). The best response was 100% PR or better, 91% achieved VGPR or better, 42% CR or better, and 29% a stringent CR.

The depth of response improved with duration of treatment. For example, the sCR rate increased from 5% after 4 cycles to 29% at the end of treatment.

PFS was an exploratory endpoint. One patient progressed at 10.8 months and the 12-month PFS rate was 94% with all patients alive.

Stem cell harvest and ASCT

“For many of us,” Dr Jakubowiak commented, “it’s also of interest how this regimen will impact stem cell harvest.”

Nineteen of 22 patients were deemed to be transplant eligible, and the median number of CD34+ cells collected from them was 10.4 x 10⁶ cells/kg.

 

Patients had a median of 5 treatment cycles prior to stem cell harvest, and 14 (74%) had a VGPR or better prior to harvest.

The investigators believe stem cell yield was consistent with previous KRd studies.

Dr Jakubowiak commented that the deepening of response over time “is a phenomenon we think is important. . . . In all, the data from this small phase 1b study provide support for further evaluation of this regimen in newly diagnosed myeloma."

The study was funded by Janssen Research and Development, LLC. 

*Data presented during the meeting differ from the abstract.

 

CHICAGO – CARs just keep getting better: In an early clinical trial, a chimeric antigen receptor (CAR) T-cell construct targeting B-cell maturation protein induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.

“In our current trials we have observed revolutionary, quick, and durable remissions in patients with multiple myeloma,” said Wanhong Zhao, MD, of the Second Affiliated Hospital of Xi’an (China) Jiaotong University.

He presented early results from a single-arm trial of the CAR T cell, labeled LCAR-B38M, in 35 patients at a briefing at the American Society of Clinical Oncology (ASCO) annual meeting.

“I think what you’re seeing here is the expansion of immunotherapy to cancers that really are refractory to chemotherapy and how immunotherapy is now providing hope to a lot of patients with cancers that were not really responding to our standard chemotherapies,” commented ASCO expert Michael S. Sabel, MD, of the University of Michigan, Ann Arbor. “What I also think is really fascinating about this and similar forms of research is that you are now seeing the merger of immunotherapy with personalized medicine.”

Current CAR T-cell technologies targeting CD19 or a similar antigen have shown efficacy against acute lymphoblastic leukemia and some forms of lymphoma, but it has been difficult to identify a suitable target in multiple myeloma.

B-cell maturation antigen (BCMA) was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.

Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA.

In the study by Dr. Zhao and his colleagues, 19 patients had been followed for more than 4 months before the data cutoff in January 2017. Four months is the minimum established by the International Myeloma Working Group for efficacy assessment.

Of the 19 patients, 14 had achieved a stringent complete response (sCR), 4 had very good partial responses, and 1 had a partial response, for an objective response rate of 100%.

No patients who achieved an sCR have had relapses, and all five patients who have been in follow-up for more than a year have maintained their sCRs and are free of minimal residual disease, Dr. Zhao reported.

One patient with a very good partial response had disease progression, with recurrence of an extramedullary lesion that had previously disappeared.

The most common adverse event was cytokine release syndrome, which occurred in 85% of patients, but the condition was transient and manageable in a majority, Dr. Zhao said.

Two patients developed grade 3 cytokine release syndrome and were treated with tocilizumab (Actemra).

The investigators plan to enroll a total of 100 patients from participating hospitals in China and are planning a U.S. trial for launch in early 2018.

The investigators hope to look at BCMA CAR-T cell therapy in the frontline for patients with newly diagnosed multiple myeloma.

The study was funded by Legend Biotech. Coauthor Fran (Xiaohu) Fan, MD, PhD, is employed by the company. Dr. Zhao did not report disclosures. Dr. Sabel had no disclosures relevant to the study.

 

CHICAGO – CARs just keep getting better: In an early clinical trial, a chimeric antigen receptor (CAR) T-cell construct targeting B-cell maturation protein induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.

“In our current trials we have observed revolutionary, quick, and durable remissions in patients with multiple myeloma,” said Wanhong Zhao, MD, of the Second Affiliated Hospital of Xi’an (China) Jiaotong University.

He presented early results from a single-arm trial of the CAR T cell, labeled LCAR-B38M, in 35 patients at a briefing at the American Society of Clinical Oncology (ASCO) annual meeting.

“I think what you’re seeing here is the expansion of immunotherapy to cancers that really are refractory to chemotherapy and how immunotherapy is now providing hope to a lot of patients with cancers that were not really responding to our standard chemotherapies,” commented ASCO expert Michael S. Sabel, MD, of the University of Michigan, Ann Arbor. “What I also think is really fascinating about this and similar forms of research is that you are now seeing the merger of immunotherapy with personalized medicine.”

Current CAR T-cell technologies targeting CD19 or a similar antigen have shown efficacy against acute lymphoblastic leukemia and some forms of lymphoma, but it has been difficult to identify a suitable target in multiple myeloma.

B-cell maturation antigen (BCMA) was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.

Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA.

In the study by Dr. Zhao and his colleagues, 19 patients had been followed for more than 4 months before the data cutoff in January 2017. Four months is the minimum established by the International Myeloma Working Group for efficacy assessment.

Of the 19 patients, 14 had achieved a stringent complete response (sCR), 4 had very good partial responses, and 1 had a partial response, for an objective response rate of 100%.

No patients who achieved an sCR have had relapses, and all five patients who have been in follow-up for more than a year have maintained their sCRs and are free of minimal residual disease, Dr. Zhao reported.

One patient with a very good partial response had disease progression, with recurrence of an extramedullary lesion that had previously disappeared.

The most common adverse event was cytokine release syndrome, which occurred in 85% of patients, but the condition was transient and manageable in a majority, Dr. Zhao said.

Two patients developed grade 3 cytokine release syndrome and were treated with tocilizumab (Actemra).

The investigators plan to enroll a total of 100 patients from participating hospitals in China and are planning a U.S. trial for launch in early 2018.

The investigators hope to look at BCMA CAR-T cell therapy in the frontline for patients with newly diagnosed multiple myeloma.

The study was funded by Legend Biotech. Coauthor Fran (Xiaohu) Fan, MD, PhD, is employed by the company. Dr. Zhao did not report disclosures. Dr. Sabel had no disclosures relevant to the study.

 

CHICAGO – CARs just keep getting better: In an early clinical trial, a chimeric antigen receptor (CAR) T-cell construct targeting B-cell maturation protein induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.

“In our current trials we have observed revolutionary, quick, and durable remissions in patients with multiple myeloma,” said Wanhong Zhao, MD, of the Second Affiliated Hospital of Xi’an (China) Jiaotong University.

He presented early results from a single-arm trial of the CAR T cell, labeled LCAR-B38M, in 35 patients at a briefing at the American Society of Clinical Oncology (ASCO) annual meeting.

“I think what you’re seeing here is the expansion of immunotherapy to cancers that really are refractory to chemotherapy and how immunotherapy is now providing hope to a lot of patients with cancers that were not really responding to our standard chemotherapies,” commented ASCO expert Michael S. Sabel, MD, of the University of Michigan, Ann Arbor. “What I also think is really fascinating about this and similar forms of research is that you are now seeing the merger of immunotherapy with personalized medicine.”

Current CAR T-cell technologies targeting CD19 or a similar antigen have shown efficacy against acute lymphoblastic leukemia and some forms of lymphoma, but it has been difficult to identify a suitable target in multiple myeloma.

B-cell maturation antigen (BCMA) was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.

Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA.

In the study by Dr. Zhao and his colleagues, 19 patients had been followed for more than 4 months before the data cutoff in January 2017. Four months is the minimum established by the International Myeloma Working Group for efficacy assessment.

Of the 19 patients, 14 had achieved a stringent complete response (sCR), 4 had very good partial responses, and 1 had a partial response, for an objective response rate of 100%.

No patients who achieved an sCR have had relapses, and all five patients who have been in follow-up for more than a year have maintained their sCRs and are free of minimal residual disease, Dr. Zhao reported.

One patient with a very good partial response had disease progression, with recurrence of an extramedullary lesion that had previously disappeared.

The most common adverse event was cytokine release syndrome, which occurred in 85% of patients, but the condition was transient and manageable in a majority, Dr. Zhao said.

Two patients developed grade 3 cytokine release syndrome and were treated with tocilizumab (Actemra).

The investigators plan to enroll a total of 100 patients from participating hospitals in China and are planning a U.S. trial for launch in early 2018.

The investigators hope to look at BCMA CAR-T cell therapy in the frontline for patients with newly diagnosed multiple myeloma.

The study was funded by Legend Biotech. Coauthor Fran (Xiaohu) Fan, MD, PhD, is employed by the company. Dr. Zhao did not report disclosures. Dr. Sabel had no disclosures relevant to the study.

Photo © ASCO/David Eulitt 2017

CHICAGO—A new type of chimeric antigen receptor (CAR) T cell, one that is specific for the B-cell maturation antigen (BCMA), has produced durable remissions in patients with multiple myeloma (MM), according to research reported at the 2017 ASCO Annual Meeting (abstract LBA3001).

BCMA is a cell surface antigen universally expressed on malignant plasma cells. It plays a role in the progression of MM and is turning out to be a highly selective antigen to target in novel treatments for MM.

This trial of LCAR-B38M is one of the first clinical trials of CAR T cells to target BCMA.

“[W]hat makes our CAR T different from other CAR T all over the world is we are truly a bispecific CAR T modality,” Frank (Xiaohu) Fan, MD, PhD, explained in a media briefing, “especially our antigen-binding units compared to single domain antibodies.” Dr Fan is CSO of  Nanjing Legend Biotech in China, the developer of LCAR-B38M.

“We believe targeting BCMA alone should be enough to get a good efficacy,” he said.

To date the objective response rate is 100%.

The investigators treated 35 relapsed/refractory MM patients thus far with LCAR-B38M. Patients received the modified CAR T cells in 3 doses, on days 0, 2, and 6.

The investigators reported on 19 patients who they followed for more than 4 months, a criterion established by the International Myeloma Working Group for full efficacy evaluation.

Efficacy

Of the 19 patients, 14 (74%) achieved a stringent complete response (sCR), 4 (21%) a very good partial response (VGPR), and 1 (5%) a PR.

One patient who achieved a VGPR relapsed due to an extramedullary lesion.

Investigators observed no evidence of relapse among patients who achieved sCR.

Five patients have been followed for more than a year and all have maintained sCR.

Safety

Safety is a major issue with CAR T-cell therapies, with a frequent and major adverse event being cytokine release syndrome (CRS).

Of the 35 patients treated, 6 experienced no CRS, 17 had grade 1, 10 had grade 2, and 2 had grade 3 CRS. No patient experienced grade 4 CRS or any grade 5 event.

Because LCAR-B38M demonstrates “outstanding” efficacy with a “great” safety profile, the investigators believe this technology raises the hope of cure for MM patients.

A clinical trial of LCAR-B38M is planned in the United States.

Photo © ASCO/David Eulitt 2017

CHICAGO—A new type of chimeric antigen receptor (CAR) T cell, one that is specific for the B-cell maturation antigen (BCMA), has produced durable remissions in patients with multiple myeloma (MM), according to research reported at the 2017 ASCO Annual Meeting (abstract LBA3001).

BCMA is a cell surface antigen universally expressed on malignant plasma cells. It plays a role in the progression of MM and is turning out to be a highly selective antigen to target in novel treatments for MM.

This trial of LCAR-B38M is one of the first clinical trials of CAR T cells to target BCMA.

“[W]hat makes our CAR T different from other CAR T all over the world is we are truly a bispecific CAR T modality,” Frank (Xiaohu) Fan, MD, PhD, explained in a media briefing, “especially our antigen-binding units compared to single domain antibodies.” Dr Fan is CSO of  Nanjing Legend Biotech in China, the developer of LCAR-B38M.

“We believe targeting BCMA alone should be enough to get a good efficacy,” he said.

To date the objective response rate is 100%.

The investigators treated 35 relapsed/refractory MM patients thus far with LCAR-B38M. Patients received the modified CAR T cells in 3 doses, on days 0, 2, and 6.

The investigators reported on 19 patients who they followed for more than 4 months, a criterion established by the International Myeloma Working Group for full efficacy evaluation.

Efficacy

Of the 19 patients, 14 (74%) achieved a stringent complete response (sCR), 4 (21%) a very good partial response (VGPR), and 1 (5%) a PR.

One patient who achieved a VGPR relapsed due to an extramedullary lesion.

Investigators observed no evidence of relapse among patients who achieved sCR.

Five patients have been followed for more than a year and all have maintained sCR.

Safety

Safety is a major issue with CAR T-cell therapies, with a frequent and major adverse event being cytokine release syndrome (CRS).

Of the 35 patients treated, 6 experienced no CRS, 17 had grade 1, 10 had grade 2, and 2 had grade 3 CRS. No patient experienced grade 4 CRS or any grade 5 event.

Because LCAR-B38M demonstrates “outstanding” efficacy with a “great” safety profile, the investigators believe this technology raises the hope of cure for MM patients.

A clinical trial of LCAR-B38M is planned in the United States.

Photo © ASCO/David Eulitt 2017

CHICAGO—A new type of chimeric antigen receptor (CAR) T cell, one that is specific for the B-cell maturation antigen (BCMA), has produced durable remissions in patients with multiple myeloma (MM), according to research reported at the 2017 ASCO Annual Meeting (abstract LBA3001).

BCMA is a cell surface antigen universally expressed on malignant plasma cells. It plays a role in the progression of MM and is turning out to be a highly selective antigen to target in novel treatments for MM.

This trial of LCAR-B38M is one of the first clinical trials of CAR T cells to target BCMA.

“[W]hat makes our CAR T different from other CAR T all over the world is we are truly a bispecific CAR T modality,” Frank (Xiaohu) Fan, MD, PhD, explained in a media briefing, “especially our antigen-binding units compared to single domain antibodies.” Dr Fan is CSO of  Nanjing Legend Biotech in China, the developer of LCAR-B38M.

“We believe targeting BCMA alone should be enough to get a good efficacy,” he said.

To date the objective response rate is 100%.

The investigators treated 35 relapsed/refractory MM patients thus far with LCAR-B38M. Patients received the modified CAR T cells in 3 doses, on days 0, 2, and 6.

The investigators reported on 19 patients who they followed for more than 4 months, a criterion established by the International Myeloma Working Group for full efficacy evaluation.

Efficacy

Of the 19 patients, 14 (74%) achieved a stringent complete response (sCR), 4 (21%) a very good partial response (VGPR), and 1 (5%) a PR.

One patient who achieved a VGPR relapsed due to an extramedullary lesion.

Investigators observed no evidence of relapse among patients who achieved sCR.

Five patients have been followed for more than a year and all have maintained sCR.

Safety

Safety is a major issue with CAR T-cell therapies, with a frequent and major adverse event being cytokine release syndrome (CRS).

Of the 35 patients treated, 6 experienced no CRS, 17 had grade 1, 10 had grade 2, and 2 had grade 3 CRS. No patient experienced grade 4 CRS or any grade 5 event.

Because LCAR-B38M demonstrates “outstanding” efficacy with a “great” safety profile, the investigators believe this technology raises the hope of cure for MM patients.

A clinical trial of LCAR-B38M is planned in the United States.

multiple myeloma

A team of researchers has confirmed that minimal residual disease (MRD) negativity is superior to complete response (CR) as a prognostic marker for progression-free survival (PFS) and overall survival (OS) in patients with multiple myeloma (MM).

MRD-positive patients who achieved CR had a similar survival to MRD-positive patients who achieved near CR (nCR) or partial response (PR). And this held true despite different induction regimens, disease stages, patient ages, cytogenetic groups, and whether the patients were transplant eligible or ineligible.

The team conducted the pooled analysis on behalf of the GEM (Grupo Español de Mieloma)/PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) Cooperative Study Group.

They analyzed data from a large pool of 609 patients newly diagnosed with MM enrolled in 3 clinical trials—GEM 2000 (n=256), GEM2005MENOS65 (n=226), and GEM2010MAS65 (n=127). All patients had MRD assessments 9 months after study enrollment. The median follow-up was 71 months.

Juan-Jose Lahuerta, MD, PhD, of Hospital 12 de Octubre in Madrid, Spain, and colleagues reported the results in the Journal of Clinical Oncology.

Of the 609 patients, 286 (47%) achieved CR and had a significantly longer PFS (median, 49 months) than those who achieved nCR (median, 37 months), PR (median, 34 months) or less than PR (median, 11 months).

Patients who achieved CR also had a significantly longer OS (median, 128 months) than those who achieved PR (median, 75 months) or less than PR (median, 28 months), but not nCR (median, 77 months).

But patients who achieved CR and were still MRD-positive had a similar PFS (median, 27 months) to those patients who achieved nCR and PR and were MRD-positive (median 27 and 29 months, respectively). Median OS for MRD-positive patients in CR was a median 59 months, compared to 64 and 65 months, respectively, for MRD-positive patients in nCR and PR.

The team found that only MRD negativity significantly prolonged PFS and OS. Patients who were MRD-negative, even without achieving a CR, had a median PFS of 63 months (P<0.001) and the median OS not reached (P<0.001).

According to their paper, the investigators consider MRD negativity to be “one of the most relevant clinical end points and an aim of MM treatment of transplant-eligible and elderly patients who can tolerate intensive therapies.”

The team also investigated whether MRD negativity could be used as a meaningful clinical endpoint. They compared outcomes between patients who achieved CR according to MRD status before and after high-dose therapy and autologous stem cell transplant (ASCT).

Patients who were MRD-positive before transplant but MRD-negative afterwards had similar PFS and OS compared to patients who were MRD-negative before and after transplant. Patients who remained MRD-positive after transplant had inferior PFS and OS.

The team believes these results “support the adoption of MRD testing in routine practice to help discriminate between patients with clinically meaningful (MRD-negative) and misleading (MRD- positive) CRs.”

They noted, however, that a limitation of the study was the use of 2 different flow cytometries (8- and 4-color) with different sensitivities (10^-5 and 10^-4, respectively).

They also cautioned that these results should not be used to tailor treatments. Rather, new clinical trials that incorporate MRD assessments at additional time points need to be conducted.

multiple myeloma

A team of researchers has confirmed that minimal residual disease (MRD) negativity is superior to complete response (CR) as a prognostic marker for progression-free survival (PFS) and overall survival (OS) in patients with multiple myeloma (MM).

MRD-positive patients who achieved CR had a similar survival to MRD-positive patients who achieved near CR (nCR) or partial response (PR). And this held true despite different induction regimens, disease stages, patient ages, cytogenetic groups, and whether the patients were transplant eligible or ineligible.

The team conducted the pooled analysis on behalf of the GEM (Grupo Español de Mieloma)/PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) Cooperative Study Group.

They analyzed data from a large pool of 609 patients newly diagnosed with MM enrolled in 3 clinical trials—GEM 2000 (n=256), GEM2005MENOS65 (n=226), and GEM2010MAS65 (n=127). All patients had MRD assessments 9 months after study enrollment. The median follow-up was 71 months.

Juan-Jose Lahuerta, MD, PhD, of Hospital 12 de Octubre in Madrid, Spain, and colleagues reported the results in the Journal of Clinical Oncology.

Of the 609 patients, 286 (47%) achieved CR and had a significantly longer PFS (median, 49 months) than those who achieved nCR (median, 37 months), PR (median, 34 months) or less than PR (median, 11 months).

Patients who achieved CR also had a significantly longer OS (median, 128 months) than those who achieved PR (median, 75 months) or less than PR (median, 28 months), but not nCR (median, 77 months).

But patients who achieved CR and were still MRD-positive had a similar PFS (median, 27 months) to those patients who achieved nCR and PR and were MRD-positive (median 27 and 29 months, respectively). Median OS for MRD-positive patients in CR was a median 59 months, compared to 64 and 65 months, respectively, for MRD-positive patients in nCR and PR.

The team found that only MRD negativity significantly prolonged PFS and OS. Patients who were MRD-negative, even without achieving a CR, had a median PFS of 63 months (P<0.001) and the median OS not reached (P<0.001).

According to their paper, the investigators consider MRD negativity to be “one of the most relevant clinical end points and an aim of MM treatment of transplant-eligible and elderly patients who can tolerate intensive therapies.”

The team also investigated whether MRD negativity could be used as a meaningful clinical endpoint. They compared outcomes between patients who achieved CR according to MRD status before and after high-dose therapy and autologous stem cell transplant (ASCT).

Patients who were MRD-positive before transplant but MRD-negative afterwards had similar PFS and OS compared to patients who were MRD-negative before and after transplant. Patients who remained MRD-positive after transplant had inferior PFS and OS.

The team believes these results “support the adoption of MRD testing in routine practice to help discriminate between patients with clinically meaningful (MRD-negative) and misleading (MRD- positive) CRs.”

They noted, however, that a limitation of the study was the use of 2 different flow cytometries (8- and 4-color) with different sensitivities (10^-5 and 10^-4, respectively).

They also cautioned that these results should not be used to tailor treatments. Rather, new clinical trials that incorporate MRD assessments at additional time points need to be conducted.

multiple myeloma

A team of researchers has confirmed that minimal residual disease (MRD) negativity is superior to complete response (CR) as a prognostic marker for progression-free survival (PFS) and overall survival (OS) in patients with multiple myeloma (MM).

MRD-positive patients who achieved CR had a similar survival to MRD-positive patients who achieved near CR (nCR) or partial response (PR). And this held true despite different induction regimens, disease stages, patient ages, cytogenetic groups, and whether the patients were transplant eligible or ineligible.

The team conducted the pooled analysis on behalf of the GEM (Grupo Español de Mieloma)/PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) Cooperative Study Group.

They analyzed data from a large pool of 609 patients newly diagnosed with MM enrolled in 3 clinical trials—GEM 2000 (n=256), GEM2005MENOS65 (n=226), and GEM2010MAS65 (n=127). All patients had MRD assessments 9 months after study enrollment. The median follow-up was 71 months.

Juan-Jose Lahuerta, MD, PhD, of Hospital 12 de Octubre in Madrid, Spain, and colleagues reported the results in the Journal of Clinical Oncology.

Of the 609 patients, 286 (47%) achieved CR and had a significantly longer PFS (median, 49 months) than those who achieved nCR (median, 37 months), PR (median, 34 months) or less than PR (median, 11 months).

Patients who achieved CR also had a significantly longer OS (median, 128 months) than those who achieved PR (median, 75 months) or less than PR (median, 28 months), but not nCR (median, 77 months).

But patients who achieved CR and were still MRD-positive had a similar PFS (median, 27 months) to those patients who achieved nCR and PR and were MRD-positive (median 27 and 29 months, respectively). Median OS for MRD-positive patients in CR was a median 59 months, compared to 64 and 65 months, respectively, for MRD-positive patients in nCR and PR.

The team found that only MRD negativity significantly prolonged PFS and OS. Patients who were MRD-negative, even without achieving a CR, had a median PFS of 63 months (P<0.001) and the median OS not reached (P<0.001).

According to their paper, the investigators consider MRD negativity to be “one of the most relevant clinical end points and an aim of MM treatment of transplant-eligible and elderly patients who can tolerate intensive therapies.”

The team also investigated whether MRD negativity could be used as a meaningful clinical endpoint. They compared outcomes between patients who achieved CR according to MRD status before and after high-dose therapy and autologous stem cell transplant (ASCT).

Patients who were MRD-positive before transplant but MRD-negative afterwards had similar PFS and OS compared to patients who were MRD-negative before and after transplant. Patients who remained MRD-positive after transplant had inferior PFS and OS.

The team believes these results “support the adoption of MRD testing in routine practice to help discriminate between patients with clinically meaningful (MRD-negative) and misleading (MRD- positive) CRs.”

They noted, however, that a limitation of the study was the use of 2 different flow cytometries (8- and 4-color) with different sensitivities (10^-5 and 10^-4, respectively).

They also cautioned that these results should not be used to tailor treatments. Rather, new clinical trials that incorporate MRD assessments at additional time points need to be conducted.