Isatuximab subcutaneous in relapsed/refractory multiple myeloma: Exposure-response and serum m-protein dynamics analyses from phase 3 iraklia Study and the phase 1b Study

Introduction: The first Phase (Ph) 3 study in multiple myeloma (MM) using an on-body injector (OBI), IRAKLIA (NCT05405166), is a randomized, global, open-label, non-inferiority (NI) study investigating isatuximab (Isa) subcutaneous (SC) vs intravenous (IV) +pomalidomide and dexamethasone (Pd) in relapsed/refractory MM (RRMM). NI was met for both co-primary endpoints: overall response rate (ORR) and steady state trough level (Ctrough; Cycle [C] 6 Day 1 predose). Here, we evaluate relationships between Isa exposure and efficacy (ORR) and safety outcomes as well as serum M-protein (sMP) dynamics with IsaSC vs IsaIV +Pd in RRMM patients (pts) from IRAKLIA and in a Ph1b study (NCT04045795) that demonstrated the safety and efficacy of IsaSC via injection pump or OBI +Pd in RRMM. Methods: The exposure-efficacy (ORR) analysis was performed with IRAKLIA data (n=261 IsaSC; n=261 IsaIV) and the exposure-safety (adverse events [AEs] of interest) analysis with pooled IRAKLIA and Ph1b data (n=305 IsaSC; n=273 IsaIV). Exposure-response (E-R) analyses were conducted by administration route. A validated population pharmacokinetic (PK) model (POH1117) predicted individual exposure metrics. IsaSC was given via injection pump/OBI at 1400/1000mg once weekly (QW) for 4 weeks (wks) then every 2 wks (Q2W) in Ph1b study and via OBI at 1400mg QW/Q2W in IRAKLIA. IsaIV was given at 10mg/kg QW/Q2W. Logistic regression models were used to evaluate relationships between Isa exposure and ORR and AEs of interest. A sMP dynamics analysis using a tumor growth inhibition model was conducted with IRAKLIA data (n=177 IsaSC OBI; n=190 IsaIV). A simulation assessed SC vs IV regimens in IsaSC pts. Results: For IsaSC and IV, exposure-efficacy analyses identified Isa exposure, predose Ctrough at 4 wks (CT4W), as the best ORR predictor (P<0.0001). The probability of responding to treatment (tx) increased with log-linear increase in CT4W for IsaSC and IV. Besides CT4W, the final model included 5 covariates for IsaSC and 1 for IsaIV. At the same CT4W, higher ORR was predicted in pts with higher body weight (BW), <75 years, <3 prior lines of therapy, not refractory to immunomodulatory drugs (IMiDs), and without plasmacytoma for IsaSC, and pts without plasmacytoma for IsaIV. Model-predicted ORRs for IsaSC vs IV were 76.5% vs 81.8% at CT4W >median and 66.9% vs 63.2% at CT4W ≤median. Notably, low BW pts (≤50kg) responded less to Isa, despite most pts having CT4W >median. This may be attributed to disease characteristics, as most pts had high-risk cytogenetics, lower albumin levels (<35g/L), and higher % of bone marrow plasma cells, and all were refractory to IMiDs or proteasome inhibitors. A sMP dynamics analysis showed a similar sMP response with IsaSC OBI vs IV, but simulations in IsaSC pts suggested a slightly lower sMP increase after 18 months with IsaSC OBI vs IV. Simulations also predicted a slower sMP regrowth with IsaSC OBI vs IV in pts ≤50kg and similar sMP dynamics between arms in pts ≥100kg. Time to progression (TTP) profiles based on sMP were similar regardless of dose in pts ≤50 or ≥100kg. Moreover, in E-R analyses for IsaSC and IV, the lowest exposure quartile (Q1) included mostly pts who did not receive all 4 weekly Isa doses in C1. A higher Isa and/or P dose modification rate, mainly due to infection, neutropenia, and/or thrombocytopenia was reported in these pts and was likely to be associated with more aggressive baseline (BL) MM characteristics. Exposure-safety analyses showed no relationship between Isa exposure and AEs of interest (Grade ≥3 infections and infestations, neutropenia, thrombocytopenia, and lymphopenia; Grade 4 neutropenia; neutropenic complications; and pneumonia) for IsaSC and IV. Conclusions: E-R analyses confirmed CT4W as the best efficacy predictor, and higher Isa exposure was associated with higher ORR for IsaSC and IV +Pd. Q1 pts had more aggressive MM characteristics, reducing tx response and increasing AE development risk; with BL MM characteristics and high dose modification rates (mainly to manage AEs) likely confounding Q1 of the E-R curve. The completion of 4 weekly doses before switching to Q2W regimen would benefit pts receiving Isa. No relationship between Isa exposure and safety outcomes of interest was observed. IsaSC OBI would provide at least a comparable sMP decrease and similar TTP vs IsaIV. These results support the flat dose of 1400mg IsaSC +Pd providing adequate exposure without dose adjustment for tx of RRMM.