Isatuximab in Combination with Pomalidomide and Dexamethasone in RRMM Patients with One Prior Line of Lenalidomide-Containing Therapy: A Phase 2 Study of the Greek Myeloma Study Group

Introduction Despite the rapidly evolving treatment landscape of multiple myeloma (MM), nearly all patients (pts) eventually relapse. Combining a monoclonal antibody (mAb) with a proteasome inhibitor (PI) or an immunomodulatory drug (IMiD), along with low-dose dexamethasone (Dex) has led to significant clinical improvements in pts with relapsed/refractory MM (RRMM). On that basis, current guidelines recommend such triplet regimens at relapse. Isatuximab (Isa), a novel anti-CD38 mAb, has been approved in combination with pomalidomide (Pom) and low-dose Dex for the treatment of RRMM pts who have received ≥2 prior therapies including lenalidomide and a PI, and have progressed on the last therapy, based on the positive results of the phase 3 ICARIA-MM study. Herein, we report preliminary results from the EAE115 study, which investigates the efficacy and safety of IsaPomDex in an earlier setting, specifically in MM pts experiencing their first relapse after treatment with a lenalidomide-containing regimen. Methods EAE115 (NCT05298683) is an investigator-initiated, phase 2, prospective, open-label, multicenter study currently underway in Greece, aiming to enroll 108 adult RRMM pts who have received only one prior line of treatment containing lenalidomide and a PI. Patients must also have sufficient bone marrow and liver function and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 2 or less. Pts who have received previous anti-CD38 mAb therapy, Pom or stem cell transplantation within 12 weeks prior to treatment initiation are excluded. Pts initially receive six 28-day cycles of Isa 10 mg/kg IV (once weekly [QW] in cycle 1, then every two weeks [QW2]) plus Pom 4 mg/day PO (days 1-21) and Dex 40 mg (or 20 mg if ≥75 years) PO/IV (QW). Thereafter, pts achieving at least very good partial response (VGPR) are randomized 1:1 to receive Isa QW2 or QW4 plus PomDex, while pts achieving <VGPR continue treatment with Isa QW2 plus PomDex. The study primary endpoint is the 6-month overall response rate (ORR; defined as partial response [PR] or better) to IsaPomDex. Results As of 31 May 2024 (data cut-off), 39 patients had received ≥1 dose of IsaPomDex and thus are included in this analysis. Of these, 24 (61.5%) pts were still under treatment and 15 (38.5%) had discontinued due to progressive disease (8 pts; 20.5%), death (4 pts; 10.3%), consent withdrawal (2 pts; 5.1%) or physician's decision (1 pt; 2.6%). The median age at baseline was 72.0 years (range 60.0-87.0), with 24 (61.5%) pts being male. Thirty-seven (94.9%) pts had ECOG PS ≤1, 19 (48.7%) pts had stage I and 17 (43.6%) stage II disease as per the revised International Staging System (R-IIS), 8 (20.5%) had high-risk cytogenetics, 19 (48.7%) had lytic bone lesions and 3 (7.7%) had soft-tissue plasmacytomas. Twenty-seven (69.2%) pts had achieved ≥VGPR in the previous line, while 8 (20.5%) had undergone autologous stem cell transplantation (ASCT). At a median follow-up of 7.4 months (range 0.7-19.0), pts have reached a median of 7 cycles of IsaPomDex (range 1-20), with 23 (59.0%) pts having completed ≥6 cycles. Among 34 response-evaluable pts, the ORR was 73.5% with 29.4% achieving ≥VGPR. The median time to first response was 1.0 month (range 0.9-13.8). Thirty-three (84.6%) pts experienced ≥1 treatment-emergent AE (TEAE) and 14 (35.9%) ≥1 serious TEAE. Grade ≥3 TEAEs occurred in 25 (64.1%) pts, with neutropenia being the most common (18 pts; 46.2%). Conclusion In this preliminary analysis, IsaPomDex demonstrated promising clinical activity, with rapid responses in pts at first relapse following treatment with a lenalidomide-containing regimen. The safety of IsaPomDex was consistent with the known safety profile of this combination. As study enrollment is still ongoing, further data and longer follow-up are expected to better characterize the safety and efficacy of the combination in this patient population.