Oral presentation by Dr. Paul Richardson
Most transplant-eligible and many transplant-ineligible patients will have been treated with an alkylator (such as cyclophosphamide or melphalan), a proteasome inhibitor (PI), and an immunomodulatory drug (IMiD) within the first one to two lines of therapy. Daratumumab is not currently available in many parts of Canada, but access is anticipated in the near future and many patients have also already taken daratumumab on clinical trial. This means that some patients are triple-class exposed, and sometimes triple-class refractory, by their third line of therapy. Current treatment approaches to relapsed disease in Canada may include repeating autologous stem cell transplant (ASCT) (if applicable and available) or using next-generation PIs and IMiDs, monoclonal antibodies (if available), and/or other novel agents. However, access to therapies and clinical trials varies across the country. Furthermore, treatment choice can be influenced by other factors such as frailty, frequency of clinic visits, and availability of supportive care. New treatment options are required that are effective in multi-class refractory patients, and tolerable and feasible to administer in our current practice setting.
Melflufen is a modified, peptidase-enhanced version of melphalan that selectively accumulates in malignant cells, such as myeloma cells, due to the overexpression of aminopeptidases in the malignant cells, while leaving peripheral blood mononuclear cells (such as T cells and B cells) relatively spared. This leads to accumulation of the melphalan metabolites in the malignant cells at levels up to 50 times or greater than if the same cells are exposed directly to melphalan. HORIZON is a phase II study of melflufen in combination with dexamethasone in patients who are PI- and IMiD-exposed and refractory to either daratumumab or pomalidomide, with 60% being refractory to both. Sixty-nine percent of patients had received at least one transplant, meaning that the majority were previously exposed to high-dose melphalan.
Despite this heavily pre-treated, multi-class refractory patient population, overall response rates were 33%, with 39% achieving minimal response or better, and 84% achieved at least stable disease or better. Progression-free survival was approximately 4 months but was 6.4 months in those achieving a partial response or better. This is similar to single-agent (or single-agent plus dexamethasone) results noted in other novel agents previously. These findings show a promising level of activity in patients who are refractory to currently available therapies.
There were grade 3/4 adverse events (AEs) in 62% of patients, predominantly cytopenias, with neutropenia and thrombocytopenia being the most common grade 4 AEs. There were no grade 4 infections and few clinically significant bleeds. These findings are consistent with the side effects of other alkylators as well as many other agents currently used in routine practice, such as PIs and IMiDs, and can be managed the same way as we currently manage these AEs, such as transfusion support for thrombocytopenia and granulocyte-colony stimulating factor or antibiotics/antivirals as indicated for neutropenia and infections. There were no unexpected or unusual safety signals noted in the results presented.
Alkylators continue to play an important role in the therapy of myeloma. Melphalan is still routinely used as a conditioning agent prior to ASCT. Melfuflen shows activity even in patients previously exposed to high-dose melphalan as well as other potent agents. This may make it an attractive agent in patients refractory to IMiDs and/or PIs, or patients who are intolerant of these agents and require an effective therapy. Early results of the phase I/II ANCHOR study of melflufen and dexamethasone in combination with either bortezomib or daratumumab in relapsed/refractory (R/R) multiple myeloma show evidence of efficacy with a reasonable safety profile, suggesting we may be able to incorporate this as part of triplet therapy in the future. The challenge will be determining when and how to best incorporate this therapy into the current treatment landscape.
One attractive thing about using melflufen in this setting is that it is given as a single infusion once monthly in the HORIZON and ANCHOR trials. Resource utilization, including clinic/infusion space and nursing time, is an important consideration when looking at cost effectiveness and the patient experience. Next to an oral agent, a once-monthly infusion with a low risk of reaction is a relatively easy regimen to administer and this may make it a good option for patients who have trouble traveling for weekly or biweekly intravenous or subcutaneous therapy.
Patients who are refractory to highly potent therapies, such as PIs, IMiDs, and anti-CD38 monoclonal antibodies, have limited effective options for treatment and continue to represent a therapeutic challenge. In the same way that PIs and IMiDs changed the landscape of myeloma therapy in the last two decades, I believe we will see new agents emerge that exploit myeloma biology in different ways to further improve outcomes. The ongoing challenge, which will only become more complex with time, is to know how to sequence these therapies to maximize their utility. The cost of the newer therapies, especially in combination, will also affect our access to therapy and influence if, how, and when these treatments are incorporated into practice.
Finally, the concentrated cytotoxicity of melflufen, leading to intracellular accumulation of melphalan in myeloma cells at rates up to 50-fold higher than administration of melphalan itself, begs the question of whether this may be an effective agent as conditioning for ASCT in the future.