Melphalan Flufenamide Emerges as Option for Heavily Pretreated Myeloma

Joseph Mikhael, MD, MEd, FRCPC, FACP

Combination therapies continue to improve outcomes for patients with multiple myeloma (MM), but innovative novel regimens are needed for those who become triple-class refractory. The addition of melphalan flufenamide (Pepaxto), a novel peptide-drug conjugate that rapidly delivers an alkylating payload into tumor cells, provides a new and effective treatment option for this heavily pretreated population.¹

On February 26, 2021, the FDA granted an accelerated approval to melphalan flufenamide in combination with dexamethasone for adult patients with relapsed or refractory MM who have received at least 4 prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody. The approval was based on findings in a subset of patients in the phase 2 HORIZON trial (NCT02963493).²

Results showed that melphalan flufenamide in combination with dexamethasone achieved an overall response rate of 23.7% (95% CI, 15.7%-33.4%) in the efficacy population (n = 97). Of these patients, 14.4% had a partial response and 9.3% had a very good partial response. The median duration of response was 4.2 months (95% CI, 3.2-7.6).³

In an interview with OncLive^®, Joseph Mikhael, MD, MEd, FRCPC,FACP, a professor of applied cancer research and drug discovery at the Translational Genomics Research Institute, an affiliate of City of Hope Cancer Center, in Phoenix, Arizona, discussed how melphalan flufenamide could potentially shift the treatment paradigm for patients with MM.

OncLive: Please put the efficacy data that led to this approval into the context of the MM landscape. 

Mikhael: The efficacy is considerable because these are very heavily pretreated patients; even though they [each] had 4 prior lines, the median was 6, so this is a pretty [ill] population of patients. Historically, when we’ve looked at this group, anything over 20% activity would be significant and this was 23.7% in that subgroup. One noteworthy feature is that this includes patients who previously had alkylator therapy, either melphalan itself or drugs like it. Seventy-five percent of those patients were refractory to prior alkylator therapy and 70% had an autologous stem cell transplant. That’s important because typically when a patient is treated with the same drug again, it tends not to be as effective. But this is a different delivery mechanism of that alkylator therapy. We know alkylators can be very effective in myeloma. We look at the pure efficacy number of a 24% response rate, but we also look carefully at who responded.

How does the mechanism of action of melphalan flufenamide influence its efficacy?

Melphalan flufenamide has a unique mechanism of action. It is an alkylator drug, but what makes [it] unique is that it’s really the first peptide-drug conjugate. This means that in addition to the actual alkylating payload drug, we have a peptide that carries it that has multiple steps along the way. The fact that it has a peptide carrying it [makes it] lipophilic, so it can pass into a cell. The peptide is bonded to the alkylator and in diseases like myeloma we have a high level of peptidases in those cancer cells.

The drug is leveraging these increased peptidases and hydrolyzes that bond so that the alkylator can be freed and then can help destroy the cell within the nucleus by interfering with the usual mechanisms of cell division and cell growth. Because of the conjugation, the drug can be brought into the cell for a more directed approach, as opposed to just giving an alkylator drug that may hit all sorts of cells.

What is the adverse event profile of this drug?

What toxicities are important to note? Melphalan flufenamide can cause significant low blood counts. White counts, platelet counts, and hemoglobin can all decrease and...at quite a high level. [Of those who had] grade 3 and 4 [adverse effects], 88% had a drop in white count, 80% in platelets, and about 50% in hemoglobin. This is not surprising because this is what we know alkylators do. There are also other adverse effects including nausea, fatigue, diarrhea, and fever.

How does this approval advance the MM treatment paradigm?

It’s important because we are seeing an increasing fraction of patients with myeloma meet criteria to go onto this drug that have triple-class refractory myeloma. As we’re combining our therapies earlier on in the disease course and using up the drugs from those 3 classes, it’s very common now for patients to have triple-class–refractory disease. It’s also important because we’re tending to use less alkylator therapy early on. We still use melphalan when we give a stem cell transplant, but there are a lot of patients who never go to transplant. Now that we’re not giving them oral versions of melphalan, like we did in the past, and we’re giving them these new novel drugs, it’s important because we have a lot of patients who have never seen any alkylator therapy who could benefit from this type of approach.

What are the next steps for melphalan flufenamide? 

As with many agents in the heavily relapsed setting, [melphalan flufenamide] proves itself as a single agent or in combination with dexamethasone, and then it starts to come earlier in the disease course, typically in combination. There have already been some presentations of combining this drug with daratumumab [Darzalex], with bortezomib [Velcade]. We all think that, with time, we’ll be using it earlier in the disease course and in combination with other myeloma therapies.

1. Mateos MV, Oriol A, Larocca A, et al. HORIZON (OP-106): an exploratory analysis of time-tonext treatment (TTNT) in patients (pts) with relapsed/refractory multiple myeloma (RRMM) who received melflufen plus dexamethasone (dex). J Clin Oncol. 2020;38(suppl 15):e20570. doi:10.1200/jco.2020.38.15_suppl.e20570
2. FDA grants accelerated approval to melphalan flufenamide for relapsed or refractory multiple myeloma. FDA. Updated March 1, 2021. Accessed April 2, 2021. https://bit.ly/3a2gcMf
3. Melphalan flufenamide. Prescribing information. Oncopeptides AB; 2021. Accessed April 2, 2021. https://bit.ly/3sTyfeQ.