Isatuximab Plus Pomalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma and Soft-Tissue Plasmacytomas: Icaria-MM Subgroup Analysis

Background: Pomalidomide (P) plus dexamethasone (d) is approved for the treatment of relapsed/refractory multiple myeloma (RRMM). Isatuximab (Isa) is a monoclonal antibody that binds to a specific epitope on the human CD38 receptor and triggers a cascade of events, leading to the death of CD38-expressing tumor cells. Isa, in combination with Pd, is approved in the United States, the European Union, Canada, Australia, Switzerland, and Japan for the treatment of adult patients with RRMM who have received at least two prior therapies including lenalidomide and a proteasome inhibitor. The Phase 3 ICARIA-MM trial (NCT02990338) demonstrated the benefit of combining Isa with Pd (Isa-Pd) versus Pd in RRMM. The presence of soft-tissue plasmacytomas is associated with poor prognosis, even in the era of novel agents, and newer therapies are urgently needed.

Aim: To assess the efficacy and safety of treatment with Isa-Pd compared with Pd in patients with RRMM and pre-existing plasmacytomas.

Methods: RRMM patients (n=307) were randomized to two study arms: Isa-Pd (n=154) or Pd (n=153). Isa was administered intravenously at 10 mg/kg weekly for 4 weeks, and every other week thereafter. If soft-tissue plasmacytomas were present at study entry, a computed tomography (CT) scan or magnetic resonance imaging (MRI) was carried out at baseline and repeated every 12 ± 1 weeks, and when clinically indicated. Imaging results were submitted to central radiology review as part of the independent review committee assessment. The primary objective was to assess the impact of Isa-Pd on the progression-free survival (PFS) compared with Pd. Safety information including treatment-emergent adverse events (TEAEs) was assessed according to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 4.03.

Results: At study entry, soft-tissue plasmacytomas were present in 24 (7.8%) patients (14 [9.1%] in the Isa-Pd and 10 [6.5%] patients in the Pd arm). Baseline characteristics of patients with plasmacytomas included: median (range) age, 61 (36, 82) years in the Isa-Pd arm vs. 64 (42, 71) years in the Pd arm; median (range) number of prior regimens before study entry, 3.5 (2, 13) in the Isa-Pd arm vs. 5.5 (2, 6) in the Pd arm; International Staging System, Stage I 50.0%, Stage II, 21.4% and Stage III, 28.6% in the Isa-Pd arm vs Stage I 10.0%, Stage II, 50.0% and Stage III, 40.0% in the Pd arm; high-risk cytogenetics, 21.4% in the Isa-Pd vs. 10% in the Pd arm. PFS was improved by adding Isa to Pd: hazard ratio: 0.22, 95% confidence intervals (CI): 0.07, 0.69. Median PFS was 4.57 (95% CI: 2.40, not calculable [NC]) months in the Isa-Pd arm vs. 1.56 (95% CI: 0.95, 4.47) months in the Pd arm. The probability of PFS at 12 months was 0.31 (95% CI: 0.10, 0.56) in the Isa-Pd arm vs. 0.00 (95% CI: NC, NC) in the Pd arm. The overall response rate (ORR) also improved with 50% (7/14) and 10% (1/10) responders in the Isa-Pd and Pd arms, respectively. Very good partial response (VGPR) occurred in 21.4% (3/14) of patients in the Isa-Pd arm and 10% (1/10) of patients in the Pd arm. Two patients with VGPR in the Isa-Pd arm who presented with plasmacytomas at baseline showed complete remission at cycle 3 (Fig. 1A-B) and significant reduction at cycle 4 (Fig. 1C-D) of the extramedullary lesions, respectively, vs 0 in the Pd arm. Grade ≥3 TEAE occurred in 12/14 (85.7%) patients in Isa-Pd arm and 7/10 (70.0%) patients in the Pd arm. Infusion reactions (IRs) of any Grade occurred in 42.9% of Isa-Pd patients, but there were no Grade ≥3 IRs.

Conclusions: In patients with RRMM and plasmacytomas, Isa-Pd treatment significantly prolonged PFS and improved ORR compared with Pd alone, with a manageable safety profile. The trend in efficacy and safety of plasmacytoma patients treated with Isa-Pd are consistent with the ICARIA-MM overall population and other study subgroups.