Professor MD Anderson Cancer Center Houston, United States
Introduction: High-Risk Smoldering Multiple Myeloma (HRSMM) patients (pts) have a median time to progression to symptomatic multiple myeloma of < 2 years. Phase 3 randomized trials of lenalidomide (LEN) and LEN-dexamethasone have shown a progression-free survival benefit in such patients. We here report the results of a planned interim analysis from a phase II trial evaluating the combination of isatuximab (ISA) and LEN (ISA-LEN) in pts with HRSMM (NCT04270409).
Methods: HRSMM was defined as per PETHEMA risk stratification (immunoparesis and ≥95% aberrant bone marrow plasma cells as measured by multiparametric flow cytometry). Patients were treated with ISA 20 mg/kg IV on days 1, 8, 15, and 22 of cycle 1, days 1 and 15 of cycles 2-6, and day 1 of cycles 7-30, with LEN 25 mg PO on days 1-21 every 28 days of cycles 1-6. The primary endpoint was overall response rate (ORR) after 6 months of ISA-LEN (Manasanch et al. ASCO 2023). Secondary endpoints were progression-free survival (PFS), defined as time from enrollment to development of symptomatic multiple myeloma (SLiM CRAB criteria), ORR at 18 and 30 cycles, and overall survival (OS). We here report efficacy and safety outcomes after 18 treatment cycles.
Results: Between September 2020 and October 2022, 36 pts were accrued, of whom 33 were response evaluable after 18 cycles. ORR was 94% [stringent complete response 2 (6%), complete response 1 (3%), very good partial response 11 (33%), partial response 17 (52%)], and response depth improved in 12 patients (36.4%) between cycles 6 and 18. At data cut-off (March 2024), 2-year PFS was 97.1% (CI: 91.8%-100%). Median PFS has not been reached, and no patients have died. The most frequent (≥20%) hematologic grade ≤2 treatment-related adverse events (TRAEs) were leukocytopenia (69%), lymphopenia (58%), anemia (44%), thrombocytopenia (39%), and neutropenia (36%), while common non-hematologic TRAEs were fatigue (58%), diarrhea (53%), constipation (39%), nausea (28%), and peripheral sensory neuropathy (22%). The most frequent (³5%) hematologic Grade 3 TRAEs were: neutropenia (42%), leukocytopenia (14%), lymphopenia (14%), and thrombocytopenia (6%); grade 3 non-hematologic AEs included fatigue and rash (6% each). Only 1 patient had a grade 4 TRAE (neutropenia). No grade 5 TRAEs occurred on study, and no patients discontinued therapy due to AEs
Conclusions: ISA-LEN is a well-tolerated therapy for smoldering myeloma, with an ORR of 94% after 18 treatment cycles. Compared with the natural history of PETHEMA HRSMM patients (Perez-Persona et al. Blood 2007), treatment with ISA-LEN delayed progression to symptomatic myeloma. The results of this study support the ongoing phase 3 ITHACA trial evaluating ISA +/- LEN-DEX which has the potential to change the standard of care in HRSMM.