Background: In analyses conducted by the Spanish Myeloma Group, Mayo Clinic and International Myeloma Working Group, patients with HRSMM have a median time to progression to symptomatic disease of <2 years. Randomized trials of lenalidomide (LEN) +/- dexamethasone vs. observation (E3A06, QuiReDex), carfilzomib-lenalidomide-dexamethasone (KRd) with transplant, consolidation, and maintenance (GEM-CESAR), and anti-CD38 monoclonal antibodies alone (CENTAURUS) or with KRd (ASCENT), have all shown efficacy in terms of response and progression free survival (PFS) in such patients; some have also reported improved overall survival (OS). In this multi-center phase II trial, we evaluated the efficacy and safety of combining isatuximab and LEN (ISA-LEN) in HRSMM patients (NCT04270409). 

Methods: Patients were treated on 28-day cycles with ISA 20 mg/kg IV on days 1, 8, 15, and 22 of cycle (C) 1, days 1 and 15 of C2-6, and day 1 of C7-30, together with LEN 25 mg PO on days 1-21 of cycles 1-6; methylprednisolone 100mg iv was given prior to each ISA infusion. The primary endpoint was overall response rate (ORR) after C6 (Manasanch et al. ASCO 2023). Secondary endpoints were progression-free survival (PFS), defined as time from enrollment to development of symptomatic multiple myeloma, ORR after completion of 18 and 30 cycles, and OS. HRSMM was defined per Programa Español de Tratamientos en Hematología (PETHEMA) risk stratification (immunoparesis and ≥95% aberrant bone marrow plasma cells as measured by multiparametric flow cytometry). We here report final efficacy and safety outcomes at completion of 30 cycles.

Results: Between 9/2020 and 10/2022, 36 patients were enrolled. The median age was 67 years, 57% were women, and 12% were of Black or Hispanic ancestry. One patient was belatedly determined to be ineligible by high-risk bone marrow flow cytometry criteria. All others had HRSMM by PETHEMA criteria. Prior to completing C30, 4 patients came off-study: 2 had progressive disease after C6 and C29 respectively, 1 (in partial response (PR)) withdrew consent after completing C14, and 1 (in complete response (CR)) was diagnosed with pancreatic adenocarcinoma after C21.

At completion of 6 cycles (n = 35), ORR was 86% % [23% very good partial response (VGPR), 63% PR]. This improved to 94% by the end of 18 cycles (n = 34; 9% CR, 35% VGPR, 50% PR) with improved depth of response in 12 of 34 patients (34%) between cycles 6 and 18.

Among patients (n= 31) completing all 30 cycles, the ORR was 97% [10% stringent CR, 3% CR, 35% VGPR, 48% PR]. Response quality improved in 5 of 31 patients (16%) between cycles 18 and 30.

With a median follow up of 37.8 months, the 4-year PFS was 94.3% (CI: 86.9%-100%). Median PFS has not been reached, and no patients have died. Best ORR at any time on study (n = 35) was 94% [stringent CR 11%, CR 6%, VGPR 29% and PR 49%].

Data from all 36 patients were included in the safety analysis. The most frequent (≥20%) hematologic grade ≤2 treatment-related adverse events (TRAEs) were leukocytopenia (69%), lymphopenia (58%), anemia (56%), thrombocytopenia (39%), and neutropenia (36%), while common non-hematologic TRAEs were fatigue (58%), diarrhea (53%), constipation (39%), maculo-papular rash (31%), nausea (28%), and peripheral sensory neuropathy (22%). The most frequent (³5%) hematologic Grade 3 TRAEs were: neutropenia (42%), leukopenia (14%), lymphopenia (14%), and thrombocytopenia (6%); non-hematologic grade 3 TRAEs were maculopapular rash (8%) and fatigue (6%). Only 1 patient had a grade 4 TRAE (neutropenia). No grade 5 TRAEs occurred on study. As above, 1 patient discontinued therapy due to a new diagnosis of pancreatic adenocarcinoma.

Conclusions: ISA-LEN is a well-tolerated therapy for high risk smoldering multiple myeloma, with a 4-year PFS of 94.3%. The final results of this phase 2 trial compare favorably with the natural history of PETHEMA HRSMM patients (Perez-Persona et al. Blood 2007), while limiting both steroid and LEN use. They support the ongoing phase 3 ITHACA trial which is evaluating ISA ± LEN-DEX and has the potential to change the standard of care in HRSMM.

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2025
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