Withdrawal of melflufen in combination with dexamethasone for patients with RRMM in the U.S.

Update: The results of the OCEAN trial were published in the journal Lancet Oncology on January 12, 2022.¹ These results were previously discussed in the article below. 

On October 22, 2021, melphalan flufenamide, also known as melflufen, was withdrawn in the U.S. for relapsed or refractory multiple myeloma (R/R MM).²  The decision was based on the latest results from the phase III OCEAN study (NCT03151811), which demonstrated a worse overall survival in the ‘intention to treat’ population, with a hazard ratio of 1.104.³ 

 The withdrawal came to force after interactions and dialogue with the U.S. Food and Drug Administration (FDA), which concluded that the OCEAN trial does not meet the required criteria of a confirmatory study.

Prior to this, on February 2021, the FDA had granted accelerated approval to melflufen plus dexamethasone for adult patients with R/R MM who were refractory to one proteasome inhibitor, one immunomodulatory agent, one CD38-directed monoclonal antibody, and had been previously treated with at least four lines of therapy. This approval was based on the phase II HORIZON trial (NCT02963493) in heavily pretreated patients with R/R MM. Later that year, in July 2021, the FDA called for a partial hold on all clinical studies investigating melflufen due to the increased risk of death observed in prespecified patient subgroups.

Notably, melflufen’s European Medicines Agency (EMA) application for conditional marketing authorization in the European Union and the Committee for Medicinal Products for Human Use (CHMP) opinion remain pending.

About the OCEAN trial⁴ 

The following results were presented during the 18th International Myeloma Workshop (Tables 1 and 2). The OCEAN trial met its primary endpoint (superior progression-free survival versus pomalidomide plus dexamethasone), showing a higher effect in older subgroups and patients who did not undergo a previous autologous stem cell transplantation.

In total, 495 patients were randomized to receive melflufen plus dexamethasone or pomalidomide plus dexamethasone; the median age was 68 years (range, 39–91 years), median prior lines of therapy were three, and >99% of patients were refractory to lenalidomide.

Table 1. Key outcomes of the OCEAN trial*

ASCT, autologous stem cell transplantation; CI, confidence interval; dex, dexamethasone; HR, hazard ratio; NA, not applicable. *Data from Schjesvold, et al.4
Outcome	Melflufen + dex arm (n = 246)	Pomalidomide + dex arm (n = 249)	HR	95% CI	p value
Median progression free survival, months	6.8	4.9	0.79	0.64–0.98	0.0311
Prior ASCT (n = 245)	4.4	5.2	1.06	0.79–1.43	0.69
No prior ASCT (n = 250)	9.3	4.6	0.59	0.44–0.79	<0.001
Overall survival, months	19.8	25.0	1.10	0.85–1.44	0.47
Prior ASCT (n = 245)	16.7	31.1	1.61	1.09–2.40	0.0170
No prior ASCT (n = 250)	21.6	16.5	0.78	0.55–1.12	0.1766
Objective response rate, %	33	27	NA	NA	NA
Complete response, %	3	1	NA	NA	NA
Very good partial response, %	9	7	NA	NA	NA
Partial response, %	20	18	NA	NA	NA

Table 2. Safety overview (all values are in %)*

Dex, dexamethasone; TEAE, treatment-emergent adverse event. *Data from Schjesvold, et al.4  †Grouped term.
	Melflufen + dex arm (n = 228)	Pomalidomide + dex arm (n = 246)
Grade 3/4 TEAE	90	77
Serious TEAE	42	46
Thrombocytopenia†	76	13
Occurring with Grade 3/4 hemorrhage†	1	0
Neutropenia†	64	49
Occurring with Grade 3/4 infections	3	7
Anemia†	43	18
Infection†	13	22
Infective pneumonia	5	12
TEAE leading to dose reductions	47	15
TEAE leading to permanent discontinuations	26	22
Deaths	46	43
Deaths ≤30 days after last dose	10	13

Further analyses on time from transplantation, the impact of age, previous maintenance therapy, and subsequent therapies are guaranteed to understand the overall survival results and the differences seen in patient subgroups in the experimental arm and the control arm.

Watch below Pieter Sonneveld, Erasmus MC, explaining why the initial efficacy observed with melflufen plus dexamethasone has not translated into improved overall survival in the OCEAN trial.

DISCLAIMER: This interview was conducted prior to the withdrawal of melflufen in the U.S.; therefore, the limitations on patient eligibility discussed are no longer in effect.