Phase I/II Study Shows Promise for Melflufen in Multiple Myeloma

Researchers indicated that these results show the feasibility of this regimen and support the development of additional studies of melflufen in multiple myeloma, both in combination with dexamethasone as well as in triplet regimens.

According to a phase I/II study published in The Lancet Haematology, melflufen is active in patients with relapsed and refractory multiple myeloma (MM) and tolerable in most patients.1

Researchers indicated that these results show the feasibility of this regimen and support the development of additional studies of melflufen in multiple myeloma, both in combination with dexamethasone (Ozurdex) as well as in triplet regimens with additional classes of drugs.

“We are excited to share with the scientific community these findings from our phase I/II study of our peptide-drug conjugate, melflufen. The results published today served as the foundation of our broad clinical development program,” Klaas Bakker, MD chief medical officer at Oncopeptides, said in a press release.2 “We recognize the significant unmet needs of patients with relapsed and refractory MM who currently have few available treatment options and are in desperate need of well-tolerated treatments with the potential to overcome cancer resistance patterns.”

In the O-12-M1 phase I/II study, eligible patients had relapsed and refractory MM, had received 2 or more previous lines of therapy (including lenalidomide [Revlimid] and bortezomib [Velcade]), were refractory to their last line of therapy, and had an Eastern Cooperative Oncology Group performance status of 2 or less. Patients were enrolled between July 4, 2013 and December 31, 2016. 

In phase I of the study, patients received an intravenous infusion of melflufen at 15 mg, 25 mg, 40 mg, or 55 mg for 30 minutes on day 1 in 21-day cycles plus 40 mg of oral dexamethasone weekly and did not receive melflufen as a single agent. Phase II patients were treated with the maximum tolerated dose identified in phase I as a single agent, as well as in combination with dexamethasone.

The phase I primary objective was to determine the maximum tolerated dose. The phase II primary objective was to evaluate overall response rate and clinical benefit rate. 

Overall, 23 patients were enrolled in phase I and 58 patients in phase II, including 6 patients from phase I treated at the maximum tolerated dose. In phase II, 45 patients were given a combination of melflufen plus dexamethasone and 13 were given melflufen as a single agent. 

In phase I, the established maximum tolerated dose was 40 mg of melflufen in combination with dexamethasone. In the first 3 dose cohorts, no dose-limiting toxicities were observed. However, the highest dose cohort tested exceeded the maximum tolerated dose because 4 of the 6 patients experienced grade 4 neutropenia, with grade 4 thrombocytopenia also occurring in 3 patients. 

Patients treated with the combination therapy in phase II achieved an overall response rate of 31% (14 of 45 patients; 95% CI, 18-47) and a clinical benefit rate of 49% (22 of 45; 34-64) in the all-treated population, and 41% (14 of 34; 25-59) and 65% (22 of 34; 47-80) in the efficacy-evaluable population. In the single-agent cohort, the overall response rate was 8% (1 of 13 patients; 0.2-36.0) and the clinical benefit rate was 23% (3 of 13; 5-54).

Of the 45 patients given the combination during phase II, the most common grade 3–4 adverse events were clinically manageable thrombocytopenia (28 [62%] patients) and neutropenia (26 [58%]), and non-hematological toxicity was infrequent. Moreover, 24 serious adverse events were reported in 17 (38%) of 45 patients, most commonly pneumonia (5 [11%]).

The most common grade 3–4 adverse events that were observed in the phase 2 single-agent cohort of 13 patients were neutropenia (9 [69%]) and thrombocytopenia (8 [62%]). Nine patients experienced serious adverse events in the single-agent cohort, most commonly thrombocytopenia (2 [15%]).

Additionally, there were 3 deaths from adverse events within 30 days of treatment that were potentially related to treatment, including 1 in the 25 mg cohort in phase I (due to bacteremia) and 2 in the phase II combination cohort (1 due to neutropenic sepsis and 1 due to Escherichia coli sepsis), each in the setting of progressive disease.

Though the study has already been completed, survival follow-up remains ongoing.


1. Richardson PG, Bringhen S, Voorhees P, et al. Melfulfen plus dexamethasone in relapsed and refractory multiple myeloma (O-12-M1): a multicenter, international, open-label, phase 1-2 study. The Lancet Haematology. doi:10.1016/S2352-3026(20)30044-2.

2. The Lancet Haematology Publishes Results From Oncopeptides’ Multicenter, International Phase 1/2 Study (O-12-M1) [news release]. Stockholm. Published March 23, 2020. Accessed March 25, 2020.