(PA-527) Population Pharmacokinetic Model-Based Melphalan Dosing with Siltuximab Interleukin-6 Blockade in Older Multiple Myeloma Patients Undergoing AHCT: Phase II Run-In Results

Introduction: High-dose melphalan followed by autologous hematopoietic cell transplantation (AHCT) is a standard consolidation strategy in multiple myeloma (MM), but dose-related toxicities limit its tolerability, particularly in older adults. Based on our 2 prior pilot studies, we hypothesized that population pharmacokinetic (pop PK) model-based melphalan dosing coupled with interleukin-6 (IL-6) blockade using siltuximab, would optimize anti-myeloma efficacy while minimizing transplant-related symptom burden.

Methods: We conducted a single-center phase II 15-patient run-in trial (NCT06679829) to evaluate the feasibility of targeting a goal cumulative melphalan area under the curve (AUC) of 13 ± 1.5 mg*h/L using our pop PK model (Shah et al Clin Pharmacokinet. 2022). Patients aged ≥60 years with newly diagnosed MM undergoing AHCT received 70 mg/m² melphalan on day -2, followed by individualized pop PK model-based dosing on day -1 (InsightRX, Inc.). Siltuximab (11 mg/kg IV) was administered on days -7 and +14. Primary endpoints for the run-in included safety and feasibility of achieving the AUC target in ≥10 of 15 patients. Secondary endpoints included MM response rates, minimal residual disease (MRD) by next-generation flow and engraftment kinetics.

Results: To date, 14 of the 15 patients have been treated (median age 68 [61–73], 50% male, 71% standard-risk cytogenetics). All patients received quadruplet therapy as induction for MM, with a median of 1 prior line of treatment (range 1-2). Pre-AHCT disease status was complete response (CR) without measurable residual disease (MRD-) (n=1), very good partial response (VGPR) (n=9), partial response (PR) (n=3) and stable disease (SD) (n=1). Median melphalan AUC was 12.9 mg*h/L (range 11.3–14.4), with 13 of 14 (93%) patients achieving the target AUC. Nine patients have had day +100 restaging with 4 achieving a CR (2 MRD-negative) and 3 achieving a VGPR. No relapses or deaths have occurred. Median time to neutrophil engraftment was 12 days (range 9-16). Engraftment syndrome occurred in 2 patients. CTCAE grade 3 toxicities included neutropenic fever (n=5) and mucositis (n=3), with no observed grade 4-5 toxicities.

Conclusions: In this first prospective study of its kind, we demonstrate the safety and feasibility of using individualized pop PK model-based melphalan dosing to achieve a target AUC, along with IL-6 blockade to decrease symptom burden in older adults with MM undergoing AHCT. The upcoming randomized phase II portion of the study will evaluate efficacy and patient-reported outcomes compared to standard BSA-based dosing.