Melflufen for R/R MM: Yay or nay?

In patients with relapsed/refractory multiple myeloma (R/R MM), a combination of melflufen and dexamethasone proved better than an approved doublet standard-of-care (SoC) comprising pomalidomide-dexamethasone in terms of progression-free survival (PFS), the phase III OCEAN trial has shown. However, the overall survival (OS) outcome with the melflufen-containing regimen appeared to digress from the PFS result, potentially casting doubt on its benefit for this condition.

“As triplet and quadruplet therapies move into earlier lines of therapy, patients with R/R MM might develop disease that is refractory to multiple SoC drug classes earlier, necessitating additional treatments with novel mechanisms of action,” said the researchers.

“[Our findings show] that melflufen, with its novel mechanism of action, plus dexamethasone, can improve PFS for patients with lenalidomide-refractory R/R MM who have received 2–4 previous* lines of therapy,” said the researchers.

A total of 495 participants (median age 68 years, 56 percent male) were randomized 1:1 to receive 28-day cycles of oral dexamethasone 40 mg** with either IV melflufen 40 mg (over 30 minutes on day 1 of each cycle) or oral pomalidomide 4 mg (daily on days 1–21 of each cycle). Dexamethasone was given on days 1, 8, 15, and 22 of each cycle. [Lancet Haematol 2022;9:e98-e110]

Compared with the pomalidomide arm, the melflufen arm had significantly longer PFS (median 6.8 vs 4.9 months; hazard ratio [HR], 0.79; p_log-rank=0.032) and numerically higher overall response rate*** (ORR; 33 percent vs 27 percent; p=0.16).

The incidence of grade 3/4 treatment-related treatment-emergent adverse events (TEAEs) was higher in the melflufen vs the pomalidomide arm, the most common being haematologic AEs (61 percent vs 9 percent [thrombocytopenia], 54 percent vs 39 percent [neutropenia], and 38 percent vs 10 percent [anaemia]).

“[Nonetheless, these were] was consistent with previous reports in which haematological TEAEs were the most common TEAEs … [Moreover, these] were generally manageable with dose modifications and supportive care,” said the researchers. Most melflufen recipients carried on with therapy despite frequent dose delays and reductions, and few AEs led to treatment withdrawal.

The drawback: OS

However, albeit immature and nonsignificant, the OS with melflufen-dexamethasone vs pomalidomide-dexamethasone was shorter (median 19.8 vs 25.0 months; HR, 1.10, p_log-rank=0.47), compelling the FDA to issue a safety alert in July 2021, the researchers noted.

Owing to the OS data, the FDA recommended suspending enrolment in OCEAN and other ongoing trials on melflufen, and “encouraged healthcare professionals to review patients’ progress on melflufen and discuss the risks of continued administration with each patient in the context of other treatments,” they said.

“An unplanned post hoc analysis suggested that this unexpected finding was ostensibly driven by the cohort that had previously undergone autologous HSCT^#,” noted Drs Prashant Kapoor and Wilson Gonsalves from the Mayo Clinic, Rochester, Minnesota, US, in a commentary. OS was considerably shorter with melflufen than pomalidomide in this subset (median 16.7 vs 31.0 months; HR, 1.61, p_log-rank=0.017), but not among those who were autologous HSCT-naïve (median 21.6 vs 16.5 months; HR, 0.78; p_log-rank=0.18). [Lancet Haematol 2022;9:e82-e84]

“The investigators speculated that the poor OS in the melflufen arm, among those with previous exposure to high-dose melphalan (ie, autologous HSCT subgroup), probably resulted from resistance to high-dose alkylator therapy and an already compromised marrow reserve at study entry, making melflufen, with its attendant severe haematological toxicities, less tolerable,” explained Kapoor and Gonsalves.

Grounds for guarded optimism

Kapoor and Gonsalves also commented that the “2-month PFS improvement over a control group that does not reflect the current SoC, casts doubt on clinical relevance as noted with previous studies.” Furthermore, ORR was “unimpressive”, and with two-thirds of melflufen recipients requiring growth factor support, “melflufen-induced haematological toxicities are likely to impede the prospects of successful partnership with other myeloma-directed therapies.”

“Nonetheless, by generating intriguing data in the transplantation-naïve population, OCEAN provides grounds for guarded optimism. These findings warrant confirmation in a well-designed [randomized trial], and highlight the arduous process of drug development,” said Kapoor and Gonsalves.