Interim results from a phase 2 trial indicate that the combination of isatuximab (Sarclisa; Sanofi) and lenalidomide (Revlimid; Bristol Myers Squibb) (ISA-LEN) is showing significant efficacy and tolerability in patients with high-risk smoldering multiple myeloma (HRSMM). The data, presented at the 21st International Myeloma Society (IMS) Annual Meeting, suggest the potential for this combination to improve outcomes for patients at high risk of progressing to symptomatic multiple myeloma (MM).
Typically, patients with HRSMM progress to symptomatic MM within two years. Prior phase 3 trials have demonstrated that lenalidomide-based therapies can improve progression-free survival (PFS) in this population.
The phase 2 trial (NCT04270409) evaluated ISA-LEN in patients with HRSMM. The primary endpoint was overall response rate (ORR) after 6 months of ISA-LEN therapy, with secondary endpoints including PFS, ORR at cycles 18 and 30, and overall survival (OS). The reported results are from the 18-cycle point.
Efficacy and Outcomes
Thirty-six patients were enrolled in the trial between September 2020 and October 2022, with 33 exhibiting an evaluable response after 18 cycles. The ORR was 94%. Notably, the depth of response improved in 12 patients (36.4%) between cycles 6 and 18. At the data cut-off in March 2022, the 2-year PFS was 97.1% (CI: 91.8%-100%). The median PFS has not yet been reached, and no patient deaths were reported.
Safety Profile
The most frequent hematologic grade ≤ 2 treatment-related adverse events (TRAEs) included leukocytopenia (69%), lymphopenia (58%), anemia (44%), thrombocytopenia (39%), and neutropenia (36%). Common non-hematologic TRAEs included nausea, fatigue, and diarrhea.
Implications and Future Directions
Isatuximab has received FDA approval in combination with bortezomib, lenalidomide, and dexamethasone for newly diagnosed MM patients ineligible for autologous stem cell transplantation. These interim results add to the growing body of research on these therapies, including the ongoing phase 3 ITHACA trial, which is evaluating isatuximab with or without lenalidomide and dexamethasone. The investigators believe the ITHACA trial could change the standard of care in HRSMM and potentially become an FDA-approved treatment option for multiple myeloma patients.
