Isatuximab monotherapy in relapsed/refractory multiple myeloma: A Japanese, multicenter, phase 1/2, safety and efficacy study

Abstract

Isatuximab, an anti‐CD38 monoclonal antibody, targets cells that strongly express CD38 including malignant plasma cells. This open‐label, single‐arm, multicenter, phase 1/2 trial investigated the tolerability/safety and efficacy of isatuximab monotherapy in Japanese patients with heavily pretreated, relapsed/refractory multiple myeloma (RRMM). In Phase 1, patients were sequentially assigned to receive isatuximab once weekly (QW) in cycle 1 (4 weeks) and every 2 weeks (Q2W) in subsequent cycles. Cohort 1 (n = 3) received 10 mg/kg QW/Q2W; cohort 2 (n = 5) received 20 mg/kg QW/Q2W. No dose‐limiting toxicities occurred; the recommended dose for the single‐arm phase 2 study (n = 28) was 20 mg/kg QW/Q2W. The overall safety profile was consistent with the current knowledge of isatuximab. The most common adverse events were infusion reactions (42.9%; 12/28); all were grade 1/2 and generally occurred during the first infusion. The overall response rate with 20 mg/kg QW/Q2W isatuximab was 36.4% (12/33); patients with high‐risk cytogenetic abnormalities had comparable results. In phase 2, the median progression‐free survival was 4.7 (95% confidence interval, 3.75 to not reached) months. Median overall survival was not reached. Isatuximab monotherapy was well tolerated and effective in patients with heavily pretreated RRMM including high‐risk cytogenetic patients. This trial is registered at ClinicalTrials.gov as NCT02812706.

PK/PD modeling analysis for dosing regimen selection of isatuximab as single agent and in combination therapy in patients with multiple myeloma

“…The 20-mg/kg dosing regimen was assessed in the phase I/II ISLAND study in Japanese patients with RRMM, whose results demonstrated a 36.4% ORR (12/33 patients). 29 For Isa-Rd, model predictions confirmed, similar to the monotherapy study, that regimens initiated with weekly dosing for cycle 1 (QW4-Q2W) induced a greater reduction in M-protein levels compared with Q2W dosing. However, simulations revealed that increasing the isatuximab dose from 10 to 20 mg/kg does not significantly affect M-protein reduction (Figure 2).…”

“…The 20-mg/kg dosing regimen was assessed in the phase I/II ISLAND study in Japanese patients with RRMM, whose results demonstrated a 36.4% ORR (12/33 patients). 29 F I G U R E 1 Model predictions of M-protein profiles under different isatuximab dose regimens. Q2W, administration every 2 weeks; QW4-Q2W, weekly administration for 4 weeks followed by every 2 weeks thereafter | 11…”

“…Consequently, model predictions along with clinical findings and E‐R analysis 21 selected isatuximab 20 mg/kg QW4–Q2W as monotherapy for patients with RRMM. The 20‐mg/kg dosing regimen was assessed in the phase I/II ISLAND study in Japanese patients with RRMM, whose results demonstrated a 36.4% ORR (12/33 patients) 29 …”

“…The 20‐mg/kg dosing regimen was assessed in the phase I/II ISLAND study in Japanese patients with RRMM, whose results demonstrated a 36.4% ORR (12/33 patients). 29 …”

Contribution of the Tumor Microenvironment to Metabolic Changes Triggering Resistance of Multiple Myeloma to Proteasome Inhibitors

“…Current clinical practice uses monoclonal anti-CD38 antibodies, such as Daratumumab ( 309 , 310 ) or Isatuximab ( 311 , 312 ), in combination with a PI and IMiDs as standard upfront therapy ( 313 ). Given the fact that PI-induced mitochondrial trafficking between BMSCs and MM PCs is a CD38-dependent process ( 75 ), this provides a solid biological rational for combining PIs in triplet/quadruplet therapies as per current practice.…”