Treatment with the investigational anti-CD38 monoclonal antibody isatuximab (in combination with lenalidomide and dexamethasone) led to an overall response rate (ORR) of 51 percent in a phase Ib study of patients with relapsed/refractory multiple myeloma (MM). The results, published in Blood, suggest that “potent, synergistic pro-immune activity can be achieved by the addition of an [immunomodulatory therapy] to anti-CD38 therapy across the spectrum of patients with relapsed/refractory MM … especially in patients who have limited treatment options,” wrote Thomas Martin, MD, from the Division of Hematology/Oncology at the University of California, San Francisco, and co-authors.
Adult patients with relapsed/refractory MM were eligible if they had adequate blood counts, measurable disease, and an abnormal serum free light chain ratio (<0.26 or >1.65) or biopsy-proven plasmacytoma. Patients were excluded if they had received an autologous hematopoietic cell transplantation (AHCT) within 12 weeks, or had baseline neuropathy grade ≥3 or painful neuropathy grade ≥2.
Between February 2013 and August 2015, investigators enrolled 57 patients (median age = 61 years; range = 42-76 years; 35% of patients were >65 years) from five U.S. centers. The median time from MM diagnosis to study enrollment was 4.3 years (range not provided). Patients had received a median of seven prior lines of anti-MM therapy (range = 2-15 therapies). Most had previously received proteasome inhibitors and immunomodulatory drugs (93%; n=53), as well as pomalidomide or carfilzomib (68%; n=39). Almost all patients (95%; n=54) had received a prior AHCT.
During the dose-escalation phase, 24 patients received isatuximab intravenously in two schedules:
- 3 mg/kg (n=4), 5 mg/kg (n=3), and 10 mg/kg (n=6) every other week (Q2W)
- 10 mg/kg (n=3) or 20 mg/kg (n=8) weekly for 4 weeks, then every other week thereafter (QW/Q2W)
Thirty-three patients were treated in the dose-expansion phase: isatuximab 10 mg/kg Q2W (n=18) or isatuximab 10 (n=9) or 20 (n=6) mg QW/Q2W.
In both phases, patients also received lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg weekly in each 28-day cycle.
“Once the maximum tolerated dose (MTD; primary objective) was reached or the highest planned dose was achieved safely, expansion cohorts were to be enrolled for both schedules,” the authors explained. However, after a median dosing duration of 36.4 weeks, the MTD was not determined. One dose-limiting toxicity occurred (grade 3 pneumonia) at the isatuximab 20 mg/kg dose, and was resolved after treatment discontinuation.
Patients received a median of nine cycles of isatuximab treatment (range = 1-37 cycles).
Fifteen patients remained on treatment at data cutoff (May 26, 2016); forty-two patients discontinued treatment, most often because of disease progression (n=29) or adverse events (AEs; n=9).
Most patients (88%; n=50) experienced at least one grade 3/4 AE, and more than half (56%; n=32) experienced a serious AE. The most common AE associated with isatuximab was infusion-related reactions (IRRs; 56%; n=32), most of which (84%) were grade 1/2 and predominantly occurred during the first infusion (88%; n=28). The researchers adjusted the isatuximab infusion rate to 175 mg/hour after observing that IRRs were more common with the 250 mg/hour initial isatuximab infusion rate.
Other common AEs were diarrhea (53%), fatigue (49%), upper respiratory tract infection (40%), and nausea (35%).
Five deaths occurred during treatment (≤30 days after last dose), two because of AEs unrelated to the drugs (bacterial sepsis and intraoperative hemorrhage) and three related to disease progression. “No important drug-related AEs were observed beyond those anticipated based on previous studies of lenalidomide and dexamethasone alone,” the authors wrote.
After a median 9 months of follow-up (range not provided), the ORR for patients who received at least one dose of isatuximab was 51 percent, including two patients with stringent complete response, 17 with very good partial response (PR), and 10 with PR. Another eight patients achieved minimal response, for a “clinical benefit rate (CBR) for the all-treated population [of] 65 percent,” the authors wrote. The ORR among the 52 patients who completed at least one treatment cycle was 56 percent (n=29), and the CBR was 71 percent.
Results were similar among the dosing groups, with ORRs of:
- 63% for isatuximab 10 mg/kg Q2W
- 50% for isatuximab 10 mg/kg QW/Q2W
- 50% for isatuximab 20 mg/kg QW/Q2W
Among the 42 patients who were lenalidomide refractory, the ORR was 52 percent and the CBR was 67 percent.
Among those who completed at least one treatment cycle, the median duration of response (defined as a PR or better) was 10.9 months (range = 1.4-31.4 months). Durations were similar among dosing groups but appeared to be longest in the 10 mg/kg QW group (13.01 months), compared with 10.28 months and 8.54 months in the 10 mg/kg QW/Q2W and 20 mg/kg QW/Q2W groups, respectively (ranges not provided).
The median progression-free survival (PFS) was 8.5 months (95% CI 4.73-16.59). PFS was longer for those in the 10 mg/kg QW/Q2W dosing group (9.7 months), compared with the
10 mg/kg QW dosing schedule (5.7 months), though the p value was not reported. The median PFS was not reached at the 20 mg/kg QW/Q2W dose.
“The efficacy data are particularly encouraging because of the heavily pretreated nature of this population,” the authors wrote.
Based on the results, researchers selected isatuximab 10 mg/kg QW/Q2W for further investigation. The authors are also testing this dose in a phase III trial of isatuximab plus pomalidomide and dexamethasone in patients with relapsed/refractory MM.
The study is limited by its small patient population and lack of a comparator arm.
Drs. Martin, Baz, and Benson report research funding from Sanofi.
Martin T, Baz R, Benson DM, et al. A phase 1b study of isatuximab plus lenalidomide and dexamethasone for relapsed/refractory multiple myeloma. Blood. 2017 May 8. [Epub ahead of print]