Isatuximab (Isa) plus lenalidomide (R), Bortezomib (V), and dexamethasone (d) (Isa-RVd) as induction therapy in transplant-eligible patients (pts) with newly diagnosed multiple myeloma (NDMM): Primary analysis of parallel phase 2 studies by the Dana-Farber Cancer Institute (DFCI) and Cancer Trials Ireland (CTI)

Abstract Background: RVd is a standard-of-care first-line regimen for pts with NDMM, regardless of eligibility for autologous stem cell transplant (ASCT), and the backbone of highly active quadruplet regimens with Isa and daratumumab. Isa is approved with RVd for pts with NDMM who are not eligible for ASCT based on the phase 3 IMROZ trial, and Isa-RVd is being studied as induction and consolidation therapy for transplant-eligible pts. We report two parallel phase 2 studies of Isa-RVd as a potentially ASCT-sparing first-line treatment approach for transplant-eligible pts with NDMM. Methods Pts aged 18–75 y (specific approval required if aged >70 y) with ECOG performance status 0–2 received two 42-day induction cycles of Isa-RVd – Isa 10 mg/kg IV (cycle 1: days 1, 8, 15, 22, 29; cycle 2: days 1, 15, 29), R 25 mg PO (days 1–14, 22–35), V 1.3 mg/m2 SC (days 1, 4, 8, 11, 22, 25, 29, 32), and d 20 mg IV/PO (days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, 33) – and stem cell mobilization at the investigator's discretion/per institutional standards. Pts with a partial response or better (≥PR) after two cycles could receive consolidation with melphalan 200 mg/m2 plus ASCT or two further cycles of Isa-RVd (Isa: days 1, 15, 29; V: days 1, 8, 22, 29; Rd as above). Pts were then to receive risk-stratified maintenance therapy with Isa-R(V) until disease progression. The primary endpoint was the rate of very good PR or better (≥VGPR) after two induction cycles. Secondary endpoints included rate of minimal residual disease (MRD)-negative response post induction and safety and tolerability of Isa-RVd. Results In the DFCI study, 49 pts were enrolled, and 42 received treatment (safety set; median age 59.0 y [range 33–72], 59.5% male) and had post-baseline efficacy evaluation (full analysis set; 11.9%/7.1% ISS/Revised-ISS stage III disease; 9.5% t(4;14), 14.3% t(11;14), 7.1% t(14;16), 14.3% del17p, and 2.3% t(14;20) in pts with available data; 1p and 1q abnormalities not assessed). In the CTI CTRIAL-IE 19-34 study, 51 pts were enrolled, 50 received treatment (safety set; median age 62.0 y [range 41–73], 74% male), and 49 had post-baseline efficacy evaluation (full analysis set; 16.3%/12.2% ISS/Revised-ISS stage III disease; 13.5% t(4;14), 17.6% t(11;14), 8.6% t(14;16), 4.8% del17p, and 10.0% and 46.3% 1p and 1q abnormalities, respectively, in pts with available data). At the end of induction cycle 2, the ≥VGPR rate was 61.9% (90% CI 48.0–74.4; n=26/42) in the DFCI study, including 2 stringent complete responses (sCRs) and 24 VGPRs, and 89.8% (90% CI 79.7–95.9; n=44/49) in the CTI study, including 1 sCR and 43 VGPRs. In the DFCI study, a further 14 (33.3%) pts had PRs (overall response rate [ORR, ≥PR] 95.2%) and 2 (4.8%) had minimal responses. In the CTI study, 4 (8.2%) pts had PRs (ORR 98.0%) and 1 (2.0%) had progressive disease. Among pts in the DFCI study, assessment of MRD status by end of cycle 2 is ongoing, while in the CTI study MRD-negative rate was 37.5% (90% CI 22.7–54.2; n=15/40). In the DFCI study safety set, 95% of pts had treatment-emergent adverse events (TEAEs) by the end of induction cycle 2 (33% grade 3/4; 95% any treatment-related TEAE). The most common TEAEs (any grade) were thrombocytopenia (69%), hypocalcemia (67%), limb edema (62%), neutropenia (60%), anemia (57%), and peripheral sensory neuropathy (PN, 57%). The most common grade 3/4 TEAEs were neutropenia (10%) and hypertension (7%). Six (14%) pts had COVID-19 (1 [2%] grade 3). No pts discontinued study treatment due to TEAEs. In the CTI study safety set, all pts had TEAEs during induction (50%/8% grade 3/4; 96% any treatment-related TEAE). TEAEs (any grade) occurring in ≥25% of pts were fatigue, PN (each 44%), constipation, peripheral edema (each 36%), and insomnia (26%). The most common grade 3/4 TEAEs were neutropenia (12%/4%), PN (8%/0%), and ALT increased (6%/0%). Five (10%) pts had COVID-19 (1 [2%] grade 3). Overall, 3 pts (6%) discontinued any study treatment due to TEAEs. Conclusions Both the DFCI and CTI studies met the success criterion for the primary endpoint, with ≥VGPR rates of ≥60% at the end of Isa-RVd cycle 2 and ORRs >95%. More than a third of evaluated pts in the CTI study were MRD-negative by this time point. Induction was generally well tolerated with no new or unexpected TEAEs and no COVID-19 mortality. Both studies are ongoing, with pts in the consolidation and maintenance phases, along with correlative proteomics and genetics analyses.