Oncopeptides designed melflufen to specifically target enzymes called aminopeptidases in cancer cells. Once the drug is inside the cell, these enzymes cut away the peptides, freeing the 2 major metabolites, including an alkylator payload. Because these enzymes are more abundant in cancer cells, including myeloma, those cells will receive a much higher concentration of the drug.

“In myeloma cells you have more cleavage, so you have a higher concentration of the alkylator,” Dr Bakker said. “This should result in a broader therapeutic index and lead to less side effects, because the aminopeptidases are not expressed as much in normal cells.”

Serious adverse events occurred in 49% of patients, and led to dose reduction in 27%. The vast majority of grade 3/4 adverse events were hematologic effects, mostly thrombocytopenia, neutropenia, and anemia.

“Low blood counts are something we expect for this patient population,” said Dr Shah. “As hematologists, those are the things that don’t scare us as much. It does put the patient at risk for bleeding and infection, but it doesn’t necessarily make the patient feel bad.”


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Bleeding events accompanied thrombocytopenia in 3% of patients, while infections concurrent with neutropenia occurred in 11%.

Like many myeloma therapies, melflufen is given in combination with dexamethasone, a steroid that inhibits inflammation. Dexamethasone has been in the news recently as a possible treatment for COVID-19, and there have been concerns about a possible shortage as a result.2 But because it’s available as a generic from multiple suppliers, Dr Bakker said, it’s unlikely to become too scarce. “Prednisone would be a viable alternative, should there be supply problems with dexamethasone,” he added.

Some oncologists remain skeptical that melflufen will have a major impact. “The big question is, how does melflufen fit in the current landscape of myeloma treatment, with so many wonderful immunotherapy options that are in clinical trial[s]?” said hematologist/oncologist Saad Usmani, MD, of Atrium Health in Charlotte, North Carolina.  “If we did not have any of those other options in clinical studies, perhaps we would be more excited about melflufen.”

However, when all else fails, it can be useful to have another tool in the toolbox. In a recent comment for Lancet Haematology,3 María-Victoria Mateos, MD, PhD, and Verónica González-Calle, MD, PhD, of the University Hospital of Salamanca, Spain, addressed this question of whether there is a role for melflufen in the current treatment landscape. Dr Mateos was also an author on the HORIZON trial.

“Most patients will reach the third line of therapy already exposed to PIs, IMiDs, and [monoclonal antibodies] targeting CD38, and refractory to 1 or more than 1 of them and, overall, the expected overall survival is of approximately 9 months,” they wrote. “This is the rationale for the need of novel agents with different mechanisms of action, and melflufen represents an option as a first-in-class peptide-conjugated alkylator that uses high aminopeptidase levels to target myeloma cells.”

However, they also pointed out, “we cannot forget the alkylating properties of this compound, thus incidence of second primary malignancies should be collected in the long-term follow-up in all trials.”

Oncopeptides is currently in the middle of a phase 3 study, called OCEAN (ClinicalTrials.gov Identifier: NCT03151811), comparing melflufen plus dexamethasone vs pomalidomide plus dexamethasone, measuring PFS as the primary endpoint. The randomized, open-label trial began enrolling in 2017 and will include 450 patients with RRMM.

References

  1. Richardson PG, Oriol A, Larocca A, et al. Melflufen plus dexamethasone in relapsed/refractory multiple myeloma (RRMM) refractory to pomalidomide and/or an anti-CD38 monoclonal antibody – primary and subgroup analysis. Paper Presented at: Virtual Edition of the 25th European Hematology Association (EHA) Annual Congress; June 2020. Abstract EP945.
  2. Cahan E. Drug recently shown to reduce coronavirus death risk could run out, experts warn [published online June 21, 2020]. Science. doi: 10.1126/science.abd4447
  3. Mateos MV, González-Calle V. Is there a role for new drugs with alkylating properties in multiple myeloma? [published online March 23, 2020]. Lancet Haematol. doi: 10.1016/S2352-3026(20)30073-9