Melflufen Approved in EU, Withdrawn in U.S. for Multiple Myeloma

The regulatory path for melphalan flufenamide, referred to as Melflufen, as treatment for relapsed and refractory multiple myeloma, has been both challenging and full of twists and turns. While receiving full approval from the European Medicines Agency (EMA), this product was formally withdrawn by the U.S. FDA. In order to discuss this complex regulatory situation, Oncology Times conducted interviews with Paul G. Richardson, MD, Clinical Program Leader and Director of Clinical Research at the Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute; Yvonne Efebera, MD, MPH, Program and Medical Director of the Blood and Marrow Transplant and Cellular Therapy at Ohio Health; C. Anthony Blau, MD, Founder and CEO of All4Cure; and Heinz Ludwig, MD, at the Wilhelminen Cancer Research Institute in Wilhelminenspital, Vienna, Austria. Richardson noted, “As I understood it, the decision for withdrawal of Melflufen by the FDA was largely based upon the hazard ratio for overall survival being marginally higher for the experimental Melflufen-dexamethasone combination vs. the active comparator combination of pomalidomide plus dexamethasone used in the confirmatory Phase III OCEAN study.” To this, Ludwig added, “The accelerated approval process itself accepts a degree of uncertainty. If the threshold for surrogate endpoint validation is too high, it could discourage innovation and especially in cases where direct overall survival benefits are hard to measure within a trial's timeframe.” Background Melflufen is a peptide-drug conjugate consisting of a lipophilic peptide segment, which allows targeted entry into a malignant plasma cell and a potent alkylating agent, the melphalan warhead, leading to highly selective targeted cytotoxicity against tumor cells while sparing normal tissue through the leveraging of aminopeptidases, which are markedly overexpressed in myeloma. In December 2019, positive results were reported from the multicenter HORIZON trial (NCT02963493) at the American Society of Hematology Annual Meeting, and later published in the Journal of Clinical Oncology in 2020 (doi.org/10.1200/JCO.20.02259). Notably, a significant majority of the participants in that trial, which included 155 patients, had multiple myeloma that was triple-class refractory, which is resistant to an anti-CD38 antibody, immunomodulators, and proteasome inhibitors, as well as other poor prognosis features, including extramedullary disease. Based on these and subsequent results from HORIZON, in February of 2021, the U.S. FDA granted accelerated approval to Melflufen combined with dexamethasone for patients with relapsed/refractory multiple myeloma who had at least four prior lines of therapy, including one each of the three classes listed previously. Later that year, the FDA issued a partial clinical hold on trials including Melflufen based on preliminary survival data obtained in the phase III OCEAN trial (NCT03151811), noted above. Withdrawal of Melflufen by the FDA was subsequently initiated in October 2021. In August 2022, the EMA granted full approval to the Melflufen-dexamethasone combination for the treatment of multiple myeloma in patients with worsening disease since their last therapy, who had received at least three previous therapies, including the three major therapeutic classes. Formally, the FDA issued a final decision regarding the withdrawal of Melflufen from the U.S. market in February 2024. In that decision, the regulatory agency cited the overall survival data, which showed a hazard ratio of 1.104, favoring the comparator arm of patients treated with pomalidomide and dexamethasone. Regarding this, Richardson noted, “This was an earlier survival analysis, which included patient subpopulations, which were less than ideal candidates for this particular therapy. Importantly, with longer follow-up and more mature data for all the patients, the hazard ratio improved to 1.09, with no safety signal seen.” Autopsy Subsequent to Melflufen's withdrawal, in December 2024, regulators from the Center for Drug Evaluation and Research and the Oncology Center of Excellence departments of the FDA published a perspective article in The New England Journal of Medicine, highlighting their decision regarding the withdrawal of Melflufen (doi.org/10.1056/NEJMp2412068). In this article, the authors cited the results from the confirmatory Phase III OCEAN trial, which, although meeting its primary endpoint of having superior progression-free survival, had overall survival marginally favoring the comparator pomalidomide-dexamethasone group. In response to this article, Richardson and other clinicians drafted a reply. “The perspectives article from the FDA we felt needed more context, and so Drs. Marivi Mateos, Pieter Sonneveld, and I, as principal investigators of key studies in relapsed and refractory myeloma of melflufen and dexamethasone-based therapy, including HORIZON, OCEAN, and LIGHTHOUSE, submitted a letter to The New England Journal of Medicine where we outlined the clinical benefit seen with Melflufen and the positive findings of the EMA leading to its full approval in Europe,” Richardson said. “Unfortunately for editorial policy reasons on perspective articles, this was not able to be published. Nonetheless, the facts remain, and hopefully, going forward, there can be a more constructive approach, not least with next generation peptide-drug conjugates, and to ultimately benefit our patients.” One particular area of contention was with regard to subgroup analysis. “Analysis of the trial data showed that there was a clear survival advantage for the Melflufen-dexamethasone combination in patients who had not received stem-cell transplant or were more than 3 years past that procedure,” Richardson stated. “Post-hoc analysis of the overall survival data from OCEAN in patients who had never received or were more than 36 months past stem cell transplant showed a hazard ratio of 0.88, favoring Melflufen-dexamethasone over the pomalidomide-dexamethasone combination; in contrast, in those patients who were less than 36 months from stem cell transplant, the hazard ratio for survival was 1.60, favoring pomalidomide-dexamethasone,” Richardson added. In the paper, the FDA stated that the trial lacked the power to draw meaningful conclusions from subgroup analyses and thus considered those findings “exploratory.” Regarding this handling of subgroup analyses, Ludwig noted, “The supporting company argued for interactions between variables in the survival results, which the FDA rejected, meaning that the FDA unfortunately excluded important biological information from their decision-making process.” Oncology Drugs Advisory Committee The Oncology Drugs Advisory Committee (ODAC) convened for Melflufen consisted of 16 experts in different areas of oncology, including one expert in myeloma and one patient advocate, for a total of 15 members and the head of the committee. This group, as its name suggests, serves in an advisory capacity to the U.S. FDA, offering recommendations on marketed and investigational treatments for solid and hematologic malignancies. Richardson participated as a presenter during the ODAC and called for Melflufen in September 2023, as did Efebera, who graciously granted an interview to lend her perspective on the FDA's decision regarding Melflufen. “As someone who participated in the ODAC, I was surprised by the withdrawal of this therapy, but there was also disappointment for my patients who were being treated with Melflufen,” Efebera said. “In the OCEAN trial, the combination of Melflufen and dexamethasone met its primary endpoint and showed superior progression-free survival (PFS) compared to the pomalidomide-dexamethasone combination (median PFS 6.8 vs. 4.9 months, P=0.0319),” Efebera noted (The Lancet Haematology 2022; doi.org/10.1016/S2352-3026(21)00381-1). “The withdrawal was especially puzzling given the regulatory decision made by the EMA's issuance of a full approval for this drug in 2022.” Lending further insight into her statements, Efebera said, “The clinical trials for Melflufen included patients who were frequently excluded from other studies because of the difficult clinical characteristics of their disease, such as having extramedullary disease.” “There may even be certain populations for whom the use of Melflufen may be highly advantageous,” Efebera noted. “From our studies, we identified that patients who had not received stem cell transplant or who were more than 3 years past their last transplant fared well with this therapy. These studies also showed that older patients (age ≥65) were better candidates for this therapy. The side effect profile is fairly mild and easily manageable, and with this, when coupled with the once-monthly single half-hour infusion dosing, one can understand why some patients actually prefer Melflufen for treating their advanced multiple myeloma.” Compassionate Use of Melflufen One person who has a unique perspective on multiple myeloma therapy is C. Anthony Blau, MD, who not only had an extensive academic career of more than 25 years as a hematologist but is also a patient, who was diagnosed with multiple myeloma in 2015. This unique combination played a role in Blau's founding of All4Cure, a collaborative online platform for patients, clinicians, and researchers that equips oncologists with the means to deliver expert-level treatment using its clinical pathway and by leveraging the experiences of thousands of similar patients. “All4Cure's initial focus is on multiple myeloma, a disease for which many different treatment options are available, but which remains incurable,” Blau explained. “We will eventually extend our platform to patients with other types of cancer, after establishing proof of principle in myeloma, where we are making excellent progress. The need for compassionate care use therapies became more pressing after the FDA's withdrawal of Melflufen in the U.S.” When asked about the current state of compassionate care use Melflufen in the U.S., Blau said, “As of right now, there is basically no more access for Melflufen, even for compassionate care use in the U.S. This is unfortunate because several patients with relapsed refractory myeloma enrolled in All4Cure benefitted from Melflufen. Currently, multiple myeloma is still an incurable disease, with patients normally undergoing several courses of treatment with different classes of therapies before frequently and sadly succumbing to their disease.” When asked if there were patients he felt could theoretically be reasonable candidates for Melflufen if it were available, Blau replied, “Based on subgroup analyses done in the OCEAN trial, Melflufen might be of benefit to patients who had not received or who were more than 3 years past stem cell transplant. Plus, given its manageable toxicity profile, it might be a reasonable therapy for those who cannot handle more vigorous treatments, such as those who are older or have other underlying comorbidities.” When queried about why there may be an effect for patients receiving a recent stem cell transplant, Blau answered, “It is not surprising that patients receiving stem cell transplants less than 3 years before Melflufen treatment might not be the ideal candidates for this therapy when one considers the fact that these patients receive high-dose melphalan-based myeloablation therapy prior to stem cell transplant. Any malignant cells surviving that myeloablation may well have some resistance to Melflufen, which is a lipophilic prodrug of melphalan,” he further added. “This could, in itself, provide a strong pathobiological rationale for this sub-group not being able to benefit as much as others.” Dana-Farber Retrospective Analysis In further support for the rational use of Melflufen, clinicians from Dana-Farber recently published results from a retrospective analysis of 12 patients treated with Melflufen and dexamethasone per label while it was available in the U.S., reflecting a real-world experience (European Journal of Haematology 2025; doi.org/10.1111/ejh.14398). Richardson noted, “Our observations from this analysis were remarkably consistent with those obtained in the clinical studies of Melflufen. The patients included were heavily pretreated, receiving a median 5.5 prior therapies. As in other Melflufen studies, there were a number of patients with extramedullary disease and/or high-risk cytogenetic features.” Importantly, a response rate of 55% was observed, including several complete responses and very good partial responses. No alopecia, mucositis, or secondary cancers were observed, and treatment was well tolerated. Only a small number of patients experienced disease progression. Richardson observed, “One-third of the patients were withdrawn from receiving treatment because of the drug withdrawal and not because of toxicity or progression. Unfortunately, this was not the only treatment study bought to a close because of Melflufen's withdrawal.” Specifically, the Phase III LIGHTHOUSE (NCT04649060) and Phase I/II ANCHOR (NCT04649060) studies, which were evaluating different combination therapies including Melflufen, were also halted (Haematologica 2024; doi.org/10.3324/haematol.2023.283509; Haematologica 2024; doi.org/10.3324/haematol.2023.283490). The pivotal OCEAN study had already been completed and a prior Phase I/II study of Melflufen/dexamethasone (O-12-M1), with almost 70 heavily pre-treated patients with advanced myeloma enrolled, had also been completed and achieved mature follow-up, with an encouraging median overall survival seen of approximately 22 months (The Lancet Haematology 2020; doi.org/10.1016/S2352-3026(20)30044-2). Conclusion “One earlier and very good example where the FDA waited for maturation of additional data for full approval was the proteasome inhibitor carfilzomib,” Richardson noted. “In that case, by waiting for the Phase III data to evolve, despite the failure of the initial Phase III FOCUS study, a strong confirmatory signal was then observed in the ASPIRE trial, thus allowing the full approval of this drug and subsequent significant benefit for our patients since.” Richardson added, “Despite the challenges seen with Melflufen, there is reason to be optimistic in my view, as shown by the success of the antibody-drug conjugate Belantamab Mafodotin in relapsed and refractory myeloma. In that case, a confirmatory progression-free survival signal was not seen initially in the Phase III DREAMM-8 trial (NCT04484623), and the drug was withdrawn for patients with relapsed/refractory multiple myeloma, but subsequent Phase III studies, specifically DREAMM 7 and DREAMM 8, were allowed to continue and have reported a highly significant degree of progression-free and overall survival benefit, opening the door to full approval.” Regarding the challenges of developing novel therapeutics, Ludwig noted, “The high bar set for confirmatory trials in accelerated approval cases may unintentionally stifle innovation, particularly for drugs targeting refractory conditions with limited therapeutic options.” When asked if there were any analogs of Melflufen that were currently under development, Richardson replied, “Importantly, there are next-generation peptide-drug conjugates in the development pipeline, including OPD5 and OPDC3, which show promise as more active and potentially highly efficacious approaches to delivering targeted therapy, with less toxicity. In fact, in April of this year, the FDA lifted the clinical hold that had been placed on OPD5. As a result of this action, the sponsor can begin planning for trials to evaluate this new analog,” he concluded. Richard Simoneaux is a contributing writer.