Population Pharmacokinetics and Exposure-Response Analyses for Belantamab Mafodotin in Combination with Standard of Care in Transplant-Ineligible Newly Diagnosed Multiple Myeloma from Dreamm-9
Authors: Carreño Fernando , Kaisermann Morrys C , Egger Jacqueline L , Ferron-Brady Geraldine 
Published: December 2024

Introduction: Belantamab mafodotin (belamaf), a B-cell maturation antigen (BCMA)-binding antibody-drug conjugate (ADC), has been shown to enhance anti-myeloma activity in combination therapies for relapsed/refractory multiple myeloma (RRMM; Dimopoulos et al. NEJM, 2024; Hungria et al. NEJM, 2024). DREAMM-9 (NCT04091126) is an ongoing randomized Phase 1 dose optimization study evaluating belamaf in addition to standard of care (bortezomib, lenalidomide, and dexamethasone; VRd) over a range of doses (1.0‒1.9 mg/kg) and schedules with fixed or step-down (S/D) dosing in autologous stem cell transplant (ASCT)-ineligible patients (pts) with newly diagnosed MM. We report the characterization of population pharmacokinetics (PK) and exposure-response (E-R) relationships for efficacy and select safety endpoints to inform clinical dosing regimen selection.

Methods : Pts were ≥18 years, ineligible for ASCT, with no prior systemic therapy for MM. The study comprises 8 cohorts (n=10‒18) with differing belamaf dose (mg/kg)/schedules and follow-up: 1.9 Q3W for Cycles 1‒8 and then Q4W for Cycles 9+ (Q3/4W; 1.9 Q3/4W), 1.9 Q6/8W, 1.4 Q3/4W, 1.4 Q6/8W, 1.9 S/D to 1.4 Q9/12W, 1.0 Q3/4W, 1.4 S/D to 1.0 Q9/12W, and 1.0 Q12W. All cohorts received standard VRd for Cycles 1‒8 (21-day cycle), followed by Rd for Cycles 9+ (28-day cycle). Individual ADC and the free payload cys-mcMMAF concentration time profiles were evaluated using a qualified population PK model and MAXEVALS option set to zero in NONMEM. Individual predicted PK parameters were used to derive Cycle 1 PK exposure measures using the actual administered dose and baseline characteristics. E-R analyses were used to assess relationship between clinical efficacy (e.g. probability of complete response or better [CR+] and time to response) or safety endpoints (e.g. probability of Grade [Gr] 2+ or Gr3+ corneal event [using keratopathy and visual acuity scale] and Gr3+ thrombocytopenia) and ADC (belamaf) or free payload (cys-mcMMAF) Cycle 1 PK exposure measures. Impact of key disease factors were also evaluated. Logistic regression models were used to assess probability of efficacy or safety endpoints occurring, while Cox proportional hazard models were used to assess time-to-event endpoints. Univariate covariate search followed by a stepwise covariate selection procedure were used to identify significant covariates.

Results: With consideration of baseline characteristics, the PK of belamaf and cys-mcMMAF in DREAMM-9 pts (n=105) were well described by the population PK models developed with data from pts with RRMM, showing similar PK across lines of therapy and treatment. Belamaf PK were impacted by disease-related clinical factors (e.g. baseline sBCMA, IgG and albumin). Belamaf clearance (CL) was reduced over time, associated with reduced disease burden. In DREAMM-9, CL was reduced by 49%, resulting in an average elimination half-life increase from 12 to 20 days. Time to 50% change in CL was 60 days, with time to 95% change approximately 24 weeks. Cycle 1 exposure to belamaf increased with higher doses with large interpatient variability within cohorts and large overlap among the dosing cohorts. E-R efficacy analyses showed a positive trend, within each schedule type, between Cycle 1 belamaf exposure and probability of achieving response of CR+. In addition, 1.9 to 1.4 and 1.4 to 1.0 S/D Q9/12W and 1.0 Q12W dosing schedules were significantly associated with reduced probability of achieving a response of CR+ (p=0.002) and with longer time to response (p&lt;0.001) independent of Cycle 1 belamaf exposure. E-R ocular safety analyses showed that probability of Gr2+ or Gr3+ corneal event was significantly associated with schedules but not Cycle 1 belamaf exposure. Step-down Q9/12W and 1.0 Q12W schedules were significantly associated with lower probability of Gr2+ corneal events. The probability of Gr2+ ocular adverse event of special interest (CTCAE), Gr3+ thrombocytopenia and probability of dose modifications were not significantly associated with schedule or Cycle 1 belamaf PK exposure.

Conclusion: Overall, belamaf PK is consistent across lines of therapy and E-R analyses suggest that higher early belamaf exposure may improve the probability for a deeper response, and longer dosing intervals reduced the probability of ocular events.