A phase 1b study of isatuximab plus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma

Abstract

K E Y P O I N T Sl Isatuximab combined with pomalidomide/ dexamethasone has a manageable safety profile with promising clinical activity.l Isatuximab 10 mg/kg (4 weekly doses followed by dosing every 2 weeks thereafter) has been selected for future combination studies.This phase 1b dose-escalation study evaluated isatuximab plus pomalidomide/dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). Patients who had received ‡2 prior MM therapies, including lenalidomide and a proteasome inhibitor (PI), were enrolled and received isatuximab at 5, 10, or 20 mg/kg (weekly for 4 weeks, followed by every 2 weeks), pomalidomide 4 mg (days 1-21), and dexamethasone 40 mg (weekly) in 28-day cycles until progression/intolerable toxicity. The primary objective was to determine the safety and recommended dose of isatuximab with this combination. Secondary objectives included evaluation of pharmacokinetics, immunogenicity, and efficacy. Forty-five patients received isatuximab (5 [n 5 8], 10 [n 5 31], or 20 [n 5 6] mg/kg). Patients received a median of 3 (range, 1-10) prior lines; most were refractory to their last regimen (91%), with 82% lenalidomide-refractory and 84% PI-refractory. Median treatment duration was 9.6 months; 19 patients (42%) remain on treatment. Most common adverse events included fatigue (62%), and upper respiratory tract infection (42%), infusion reactions (42%), and dyspnea (40%). The most common grade ‡3 treatment-emergent adverse event was pneumonia, which occurred in 8 patients (17.8%). Hematologic laboratory abnormalities were common (lymphopenia, leukopenia, anemia, 98% each; neutropenia, 93%; and thrombocytopenia, 84%). Overall response rate was 62%; median duration of response was 18.7 months; median progression-free survival was 17.6 months. These results demonstrate potential meaningful clinical activity and a manageable safety profile of isatuximab plus pomalidomide/dexamethasone in heavily pretreated patients with RRMM. The 10 mg/kg weekly/every 2 weeks isatuximab dose was selected for future studies.

The role of ubiquitination in tumorigenesis and targeted drug discovery

“…467 In regard to relapsed MM, recommended therapies usually involve PIs and immunomodulatory drugs (IMiDs; e.g., lenalidomide, pomalidomide) in doublet or triplet combinations with corticosteroids or other systemic therapies including the anti-CD38 monoclonal antibody daratumumab and the immunoglobulin G1 (IgG1) monoclonal antibody isatuximab for the CD38 receptor. [468][469][470] For patients with MCL and diffuse large B-cell lymphoma, combination treatment of PIs and chemotherapies or histone deacetylase inhibitors also yields benefits, 471,472 which may also overcome the impact of gain-of-function p53 mutations in solid tumors. 473 In the clinic, with regard to bortezomibresistant tumors, the combination treatments of bortezomib with chemotherapy drugs such as doxorubicin, plerixafor and daratumumab have shown improved clinical outcomes, suggesting that conventional chemotherapy could increase the sensitivity of bortezomib to malignancies.…”

CD38 Expression by Myeloma Cells and Its Role in the Context of Bone Marrow Microenvironment: Modulation by Therapeutic Agents

“…A phase Ib trial reported an ORR of 56% with a median PFS of 8.5 months, with no safety concerns [61]. The phase Ib trial of isatuximab in combination with pomalidomide showed even more promising results, with an ORR of 62% and a median PFS of 17.6 months in patients heavily pretreated [62]. The phase III randomized trial is currently ongoing.…”

Monoclonal antibodies in relapsed/refractory myeloma: updated evidence from clinical trials, real-life studies, and meta-analyses

“…Another phase 1b dose-escalation study (NCT02283775) evaluated isatuximab plus pomalidomide and dexamethasone (Isa-Pd) in 45 patients with RRMM who had received a median of 3 (range 1-10) prior lines. Most patients were refractory to their last regimen (91%), with 82% lenalidomide-refractory and 84% PI-refractory [63]. Patients were subdivided to receive isatuximab at 5, 10 or 20 mg/kg QW for 4 weeks, then Q2W until progression or intolerable toxicity.…”