Richardson Discusses Implications of the FDA Withdrawal of Melflufen in Multiple Myeloma


Paul G. Richardson, MD, speaks on the FDA’s decision to withdraw the approval of melflufen plus dexamethasone in multiple myeloma.

Paul G. Richardson, MD

Paul G. Richardson, MD

On February 23, 2024, the FDA decided to withdraw the approval of melphalan flufenamide (melflufen; Pepaxto) plus dexamethasone for the treatment of patients with multiple myeloma. The decision came after the phase 3 OCEAN trial (NCT03151811) that was conducted as a condition of accelerated approval did not confirm the clinical benefit of melflufen and the available evidence did not demonstrate that the agent was safe and effective under its conditions of use.1 The FDA’s decision did not affect marketing authorization for the agent in the European Union, and Paul G. Richardson, MD, noted that more data are needed on melflufen in the US.

“It [is] very clear that re-engagement and more research is needed—that’s the way forward. That’s the way we’re going to address the questions that were raised and build up combination strategies, which was always where I personally felt the drug’s value lay," Richardson said. “I am very hopeful. The good news with melflufen is that there are research plans going forward, be it with melflufen or with next-generation peptide drug conjugates that are in development, which can provide patients with what we hoped melflufen would and [what it] certainly outside of the US currently does.”

In OCEAN, a statistically significant difference was not observed regarding progression-free survival (PFS) as patients who received melflufen plus dexamethasone (n = 246) experienced a median PFS of 6.9 months (95% CI, 5.1-8.5) compared with 4.9 months (95% CI, 4.2-5.9) for those treated with pomalidomide (Pomalyst) plus dexamethasone (n = 249; HR, 0.817; 95% CI, 0.659-1.012; P = .0644). The median overall survival was 19.7 months (95% CI, 15.1-25.6) vs 25.0 months (95% CI, 18.1-31.9), respectively (HR, 1.104; 95% CI, 0.846-1.441).2

In an interview with OncLive, Richardson discussed the design of melflufen and data on the agent from clinical studies, as well as the potential implications of the FDA’s decision for both clinicians and patients. Richardson is the clinical program leader and director of Clinical Research at the Jerome Lipper Multiple Myeloma Center of Dana-Farber Cancer Institute, as well as the RJ Corman Professor of Medicine at Harvard Medical School, both in Boston, Massachusetts.

OncLive: What is the mechanism of action of melflufen and what makes it unique?

Richardson: It’s important to understand [melflufen] is a peptide drug conjugate. It’s an entirely first-in-class novel entity where a peptide drug conjugate construct is used to optimally deliver the drug into the [tumor] microenvironment, where it is more likely to work.

It’s a highly lipophilic drug and it delivers its payload into the bone marrow where myeloma is obviously dominant. By getting into this lipophilic bone marrow environment, the drug acts as a prodrug outside of the myeloma cell. Once it gets into the myeloma cell, it’s activated by the enzymes within the myeloma cell called aminopeptidases which activate the drug by cleaving the warhead.

The warhead is the traditional melphalan warhead but delivered in a very discreet way. An antibody drug conjugate uses an antibody to [deliver] a cytotoxic warhead and this uses a similar construct. It’s a peptide drug conjugate, which delivers the warhead into the cell and leverages a biological mechanism through aminopeptidases that turns on the warhead within the tumor cell. Not only does that provide a targeted delivery system, but also it changes the membrane characteristics of the tumor cell as that process unfolds, allowing more prodrug in.

What has been your experience using melflufen and what benefits have you seen patients derive from it?

Melflufen [uses] a highly targeted delivery system and what that means for patients is that it doesn’t cause alopecia [or] mouth sores. [Although] it does cause myelosuppression, it is generally well tolerated.

The preclinical work looked so convincing; it was able to overcome melphalan- and bortezomib [Velcade]-resistant myeloma in the laboratory and showed striking benefit in animal models. We took this to the clinic in a phase 1/2 study [NCT01897714] and defined an active dosing schedule of every 28 days combined with low doses of dexamethasone. It was [given] at a fixed dose of 30 mg and 40 mg.

We then took that into the phase 2 HORIZON study [NCT02963493], which was a larger effort, and the study findings showed a response rate of approximately 25% to 30%. More importantly, it showed single-agent activity in patients who were double refractory at that time who had become resistant to proteasome inhibitors and immunomodulatory drugs. This was an important signal.

We were also able to show activity in patients who were triple-class refractory. In the HORIZON trial, the majority of patients were triple-class refractory to immunomodulatory drugs and bortezomib, and also monoclonal antibodies and [anti]-CD38 [monoclonal antibodies]. We were excited because we saw an approximate 30% response rate in patients who were triple-class refractory.

What was particularly interesting to us in patients with triple-class refractory disease was that [those] with extramedullary disease, particularly after monoclonal antibody therapy had failed them, experienced benefit from melflufen. We [believe it’s] because melflufen is able to optimize delivery in extramedullary disease because aminopeptidases are enriched in myeloma cells that have extramedullary biology. We were able to see that melflufen was particularly active [in these patients] and that was exciting.

We also participated in the OCEAN trial at our center, and we were careful not to enroll patients who had had close proximity to prior transplant. We [thought] it wouldn’t be wise to use melflufen close to high-dose melphalan for obvious reasons. Sure enough, our own experience with melflufen was favorable in that context. Interestingly, if you look at the US subgroup of patients in the OCEAN study, the HR of the US patients was very good in favor of melflufen.

With that being said, we fully recognize the challenges of these trials and why there was such debate around OCEAN. I want to focus then on our real-world experience because when the drug was approved, we did use it. In our real-world experience, which isn’t massive [but still in] 12 patients, we had a response rate of 55%. We had a very good, manageable safety profile with no signals that were outside of the label. There was myelosuppression but it was manageable and our long-term outcomes for these patients were good. Per label, we were impressed with the drug, and we felt it helped our patients when we used it. We have to also be realistic; this wasn’t a controlled trial it was a real-world experience, but we were certainly encouraged by it.

Please discuss how the FDA decision to withdrawal melflufen varies from that of the EMA.

I’m very respectful of the FDA and EMA. Both organizations do amazing work under enormously challenging circumstances, especially during the pandemic, and as we move forward there are so many complexities to the regulatory landscape and it’s incredibly hard to navigate easily at the best of times.

The EMA looked at the same data and came to very positive conclusions. In contrast, the FDA clearly had their reservations and those were framed out very clearly by Peter Marks, MD, PhD, in his assessment of the appeal. What I’m left with is the need for more research. At the end of the day, the way forward here in the US is more clinical trials to address the questions that Marks identified.

In the European context, questions [on melflufen] have been answered to their satisfaction. Therefore, there the drug is commercially available, it’s been used, and the next steps there will revolve around further optimizing its use for its indication. In the US, we need to reset and renew clinical trials.

There are compelling data from the [phase 1/2] ANCHOR trial [NCT03481556], which showed melflufencan be very active when combined with bortezomib and that melflufen combined with daratumumab [Darzalex] is especially active. Then there’s the phase 3 LIGHTHOUSE study [NCT04649060]; even though it had to be closed early because of the regulatory issues identified after the initial readouts on OCEAN, the important point is that the trial—even with approximately 60 patients—was strikingly positive in favor of the melflufen-containing arm, and that was compared with daratumumab. There’s real merit to melflufen, it’s a question of identifying it to the FDA’s satisfaction and bringing it forward in a clinical research context, to address the concerns that the FDA have.

What would your response be to those who believe that melflufen can be effectively replaced by CAR T-cell therapy or bispecific antibodies?

We need all the drugs; it’s not one vs another. That’s an incredibly important principle. Right now, to onramp patients to new treatments, particularly immunotherapies, we have to have effective chemotherapeutic platforms and the existing ones we use are very powerful regimens that are quite toxic. I don’t think any clinician in the myeloma space would disagree with that. [Patients] have to be hospitalized [from] them typically and the adverse effect profile is challenging with infections, mucositis, myelosuppression, and alopecia.

This is real combination chemotherapy which can be very challenging for our patients because by the time they’re in the fourth-line space, the ability to access a relatively nontoxic, easy-to-give chemotherapeutic platform is not easy. In my mind, this is where the potential value of melflufen lies because it doesn’t cause alopecia or mucositis, and the infection signals are very manageable.

[However], it certainly causes myelosuppression and Dr Marks was quite right to say it’s something we have to be careful with, but it’s something we’re very used to dealing with. It’s not cardiac or central nervous system [toxicities], it’s hematologic [that we see with the drug]. In that context, understanding and making sure that that’s manageable will be an important future direction.

In the real-world practice of melflufen when it was available, and in our studies, myelosuppression was manageable—the rates of bleeding and febrile neutropenia were low. In the context of the infectious profile of patients for antibodies the rates of serious infections are very high, they [can be] over 50% to 60%. [With] melflufen, the experience is a fraction of that.

The reality is we need all of these drugs to be able to get our patients to the various bridges that they need to reach in the relapsed/refractory space. There’s another very important construct and that is what I call immune exhaustion. In the OCEAN study, there was a clue to that [as] younger patients getting pomalidomide did particularly well. Melflufen doesn’t require a potent immune [response] from the patient, it works without that. That’s perhaps why it shows such a promising signal in the elderly.


  1. FDA issues final decision to withdraw approval of Pepaxto (melphalan flufenamide). FDA. February 23, 2024. Accessed April 16, 2024.
  2. Final decision on the proposal to withdraw approval of pepaxto (melphalan flufenamide) for injection. FDA. February 23, 2024. Accessed April 16, 2024.
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