Melflufen and Dexamethasone for Triple-Class Refractory Multiple Myeloma

Peter Voorhees, MD: Melphalan flufenamide is a novel peptide-drug conjugate. Basically, this is a peptide that is conjugated to an alkylator agent. This is a lipophilic product. Once it’s infused, it readily enters cells. Once inside a cell, aminopeptidases in the cell will cleave the peptide off, liberating the alkylating agent payload. In this case, that also includes melphalan. Melphalan is hydrophilic. In other words, it basically becomes trapped inside the cell where it can bind DNA, cause DNA damage, and mediate cell death. The reason we think melphalan flufenamide is a relatively targeted strategy is that aminopeptidases are upregulated in cancer cells, including multiple myeloma cells. In fact, there are data suggesting that in relapsed/refractory multiple myeloma, the levels of aminopeptidases are even higher. The idea is that you get more clipping of the peptide and release of the alkylating agent payload inside myeloma cells relative to normal tissues, which are then trapped inside the myeloma cell. That’s thought to be the basis for the relative specificity of the alkylating agent against the multiple myeloma.

The initial O-12-M1 study was the phase 1 study that established the optimal dose and schedule of melphalan flufenamide with dexamethasone. But it was the phase 2 HORIZON trial that led to its FDA accelerated approval. This was a single-arm study that looked at melphalan flufenamide given intravenously once every 4 weeks with a weekly dose of oral dexamethasone. Patients were allowed to stay on treatment until the emergence of unacceptable adverse effects or disease progression. Eligibility criteria were such that this group of patients was heavily pretreated and refractory to the majority of myeloma agents that are available. The majority of patients on this study were triple-class refractory.

In this study, the overall response rate was 29%. The majority of responses were very good partial responses and partial responses. The minimal responses, or what we call the clinical benefit rate, was 45%. Close to 50% of the patients achieved benefit and reduction of disease burden with this 2-drug combination. One of the other nice things we saw in this study was that response rates were very similar whether you had high-risk cytogenetics or not. The response rate was very similar whether you had extramedullary multiple myeloma or not. There was a fairly high percentage of patients in this trial who had extramedullary myeloma, which we know is a high-risk disease situation. That’s essentially what led to FDA approval of this combination.

Suzanne Lentzsch, MD, PhD: Melflufen is a peptidase-enhanced cytotoxic agent. I usually compare it with alkalines. It’s an important additional medication for the treatment of relapsed multiple myeloma, especially when patients failed antibody treatment, immunomodulatory drugs, and also proteasome inhibitors. We know that medications like Cytoxan, bendamustine, and melphalan are very potent in relapsed/refractory multiple myeloma. We use melphalan as treatment when patients receive high-dose chemotherapy and stem cell transplantation. Melflufen is a more potent, modified melphalan that has a high potency and can induce remissions in relapse/refractory multiple myeloma, which is important.

Don’t forget that if patients are resistant to all IMiDs [immunomodulatory imide drugs], proteasome inhibitors, and CD38 antibodies, the situation is pretty grim. Having a drug that can induce another remission is really important. Unfortunately, this is also associated with a high number of cytopenias, especially thrombocytopenias and neutropenias, which is a bit of a challenge because patients in that situation often start with lower blood counts. That might make it a little more challenging to treat patients in the relapse situation with melflufen.

Peter Voorhees, MD: From the adverse-effect perspective, the combination of melphalan flufenamide and dexamethasone is good. The nonhematologic toxicity with the combination is fairly low. That speaks to the aminopeptidase-driven relative targeting of the agent to the multiple myeloma. But there was a very high rate of grade 3 and 4 neutropenia and thrombocytopenia with this agent, which is not all that surprising given that it is in the class of alkylating agents. Obviously, hematopoietic precursor cells in the bone marrow must make aminopeptidases as well, because we’re certainly seeing cytopenias as an adverse effect of this agent. That has to be managed carefully. Neutropenia can be managed with GCSF, for example. You must monitor counts closely to determine whether a patient needs red blood cell or platelet transfusion support. For now, melphalan flufenamide needs to be administered through a central venous catheter. There’s an ongoing study to determine whether it can safely be given through a peripheral line.

Transcript Edited for Clarity