Melflufen in RRMM with Extramedullary Disease: Phase 2 HORIZON Study

Outcomes for patients with relapsed or refractory multiple myeloma (RRMM) and extramedullary disease (EMD) remain very poor despite recent advances in therapy. The phase 2 HORIZON study is investigating melflufen, a novel aminopeptidase-activated conjugated alkylator, plus dexamethasone in patients with RRMM who are refractory to available therapies. This report describes outcomes in RRMM patients with EMD in HORIZON, the largest prospective clinical trial cohort of patients with EMD described to date. 

Patients in HORIZON must have received at least 2 prior lines, been exposed to an immunomodulatory drug (IMiD)- and proteasome inhibitor (PI)-based therapy and be refractory to pomalidomide and/or daratumumab. Patients received melflufen 40 mg intravenously on day 1 of each 28-day cycle and dexamethasone 40 mg weekly (20 mg for patients aged ≥75 years) until progressive disease or unacceptable toxicity.

The primary end point was overall response rate (ORR; ≥partial response per International Myeloma Working Group criteria). EMD assessment at screening was required for patients with known or suspected soft tissue and/or bone-related extramedullary plasmacytomas. 

At data cutoff (May 2019; median follow-up, 10.8 months), 121 patients have been treated. Most of these patients (96 of 121) were anti-CD38 refractory and 88% of these were at least penta-class refractory (resistant to 2 IMiDs, 2 PIs, and anti-CD38 therapy). Of the remaining 25 patients, 92% were at least quad-class refractory (ie, 2 IMiDs and 2 PIs).

Updated interim data (July 2019) demonstrated that 45 patients had EMD at screening, 57 patients had no known EMD, and 19 patients have data pending, with an EMD incidence of 44% (ie, 45 of 102 patients with available EMD data). Importantly, the incidence of EMD was associated with prior anti-CD38 therapy (P = .0016); 43 of 45 EMD patients reported in the anti-CD38 exposed group.

The ORR of melflufen for patients with EMD (n = 45) was 24% compared with an ORR of 30% in patients without EMD (n = 57). Median duration of response was 3.1 months for patients with EMD compared with 7.5 months in patients without EMD.  

Melflufen + dexamethasone demonstrated encouraging activity in advanced RRMM patients with EMD. Response rates appear higher than observed in prior studies. These results support continued investigation in ongoing and future clinical trials of melflufen-based combination therapy for this population with exquisite unmet medical need.

Abstract OAB-86: Richardson P, Mateos M-V, Rodríguez-Otero P, et al. Activity of Melflufen in RR MM Patients with Extramedullary Disease in the Phase 2 HORIZON Study (OP-106): Promising Results in a High-Risk Population