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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 4th 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—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 4th 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—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 4th 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.