Updated Efficacy and Safety of Melflufen in Patients with Relapsed/ Refractory Multiple Myeloma Refractory to Daratumumab and/or Pomalidomide: HORIZON (OP-106)

Purpose of the Study: Despite advances in therapy, MM remains incurable. Patients with late-stage relapsed/refractory multiple myeloma (RRMM) refractory to pomalidomide and/or daratumumab have limited effective treatment options. Melflufen is a lipophilic peptide- conjugated alkylator that rapidly delivers a highly cytotoxic payload into myeloma cells through peptidase activity. In a previous data cut for the phase 2 HORIZON study, melflufen + dexamethasone showed encouraging efficacy in patients with RRMM exposed to IMiDs and proteasome inhibitors (PIs) and refractory to daratumumab and/or pomalidomide (overall response rate [ORR], 33%; clinical benefit rate [CBR], 39%) and was well tolerated (Richardson, et al. ASH 2018; Oral 600). This is an updated analysis of HORIZON.

Summarized Description of the Project: Patients with RRMM must have received 2 prior lines and have been exposed to IMiDs and PIs and refractory to pomalidomide and/or daratumumab. Patients receive 40 mg melflufen intravenously on day 1 of each 28-day cycle + 40 mg dexamethasone (20 mg for patients 75 years) weekly until progressive disease (PD) or unacceptable toxicity. The primary end- point is ORR (partial response [PR]) by investigator assessment per International Myeloma Working Group criteria. Secondary endpoints include safety, CBR (minimal response), progression-free survival (PFS), overall survival (OS), and duration of response (DOR).

Results: As of 6 February 2019, 95 patients were treated. Median age was 63 years (35-86); median time since diagnosis was 6.3 years (0.7-24.6); 39% of patients were International Staging System stage 3; 61% (n=66) had high-risk cytogenetics at study entry. Median prior lines was 5 (2-13). All patients were pomalidomide or daratumumab refractory and had received prior PIs and IMiDs; 91%, 73%, and 63% were refractory to pomalidomide, daratumumab, or both, respectively; 87%, 97%, and 86% were refractory to PI, IMiDs, or both, respec- tively.  Sixty-five  percent  were  double  +  anti-CD38  +  last-line refractory (triple-class + last-line); 82% had received prior alkylator therapy (57% alkylator refractory), and 69% had 1 prior autologous transplant. A median of 3 cycles (1-17) of melflufen were administered.

ORR in evaluable patients (n=90) was 30%; 1 patient achieved stringent complete response, 11% very good partial response, and 18% PR. CBR was 40%. Median PFS for all patients treated (N=95) was 4.0 months (95% CI, 3.3- 4.7), median OS was 10 months (95% CI, 8.1-not reached [NR]), and median DOR (n=27) was 4.8 months (95% CI, 3.6-NR).

Treatment was ongoing in 22% of patients and discontinued in 57% due to PD, 14% due to adverse events (AEs), and 7% for other reasons. Treatment-related grade 3/4 AEs were reported in 68 patients (72%), most commonly (>20%) neutropenia (55%), thrombocytopenia (52%), and anemia (26%). Most common treatment-related non- hematologic grade 3/4 AE was pneumonia (3%). AEs aside from infections/infestations and blood/lymphatic system were infrequent, with grade 3/4 treatment-related AEs in 9 patients (9%). Sixteen patients (17%) experienced treatment-related serious AEs. No treatment- related deaths were reported.

Conclusion: Melflufen continues to show promising activity in patients with late-stage RRMM refractory to daratumumab and/or pomalidomide and was generally well tolerated, with infrequent non- hematologic AEs and low discontinuation rates due to AEs.