Hematologic Malignancies—Plasma Cell Dyscrasia
Phase III (IMROZ) study design: Isatuximab plus bortezomib (V), lenalidomide (R), and dexamethasone (d) vs VRd in transplant-ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM).
Background: Pts with transplant-ineligible NDMM require therapies which prolong survival and improve quality of life. The combination of VRd significantly improves progression-free (PFS) and overall survival compared with Rd in NDMM, and has an acceptable safety profile. Combining VRd with a monoclonal antibody (mAb) may further improve efficacy. Isatuximab (ISA) is an anti-CD38 mAb that demonstrates antitumor and immunomodulatory activities with strong potentiation when combined with V and R in MM xenograft models. Here we describe a Phase III, randomized, open-label, multicenter study (NCT03319667; IMROZ), evaluating clinical benefit of ISA plus VRd vs VRd in pts with transplant-ineligible NDMM. Methods: Approximately 440 adult pts with symptomatic MM (International Myeloma Working Group [IMWG] criteria) will be randomly assigned, according to Revised International Staging System criteria (I or II vs III vs unknown) and age ( < 70 vs ≥70 years), in a 3:2 ratio to ISA (10 mg/kg on Days 1, 8, 15, 22, 29 in Cycle 1; every 2 weeks [Q2W] thereafter), plus V (1.3 mg/m2 on Days 1, 4, 8, 11, 22, 25, 29, 32), R (25 mg on Days 1–14, Days 22–35), and d (20 mg on Days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, 33), or VRd alone for 4 6-week cycles (induction phase). After Cycle 4, pts will receive Rd with or without ISA in 4-week cycles (R on Days 1–21; d weekly; ISA Q2W) until disease progression, unacceptable adverse events (AEs), or pt decision to discontinue (continuous phase). ISA will be reduced to monthly dosing from Cycle 18. Pts who progress on Rd can cross-over to ISA plus Rd. Primary endpoint is PFS (IMWG criteria) assessed by a blinded independent review committee, and analyzed with a 1-sided stratified log-rank test. Key secondary endpoints include rate of very good partial response or better, minimal residual disease negativity rate, and complete response rate. Safety evaluations include AEs, laboratory parameters, vital signs, and physical examination. The IMROZ study is currently enrolling pts; recruitment is planned in approximately 100 countries worldwide, including Japan and China. Study funding: Sanofi. Clinical trial information: NCT03319667.