Paul G. Richardson, MD, clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center, institute physician at Dana-Farber Cancer Institute, and RJ Corman Professor of Medicine at Harvard Medical School, discusses the toxicity profile of melphalan flufenamide (melflufen; Pepaxto) in relapsed/refractory multiple myeloma. 

On February 26, 2021, the FDA approved melflufen for use in combination with dexamethasone in patients with relapsed/refractory multiple myeloma who have received at least 4 prior lines of therapy and whose disease is refractory to a proteasome inhibitor, immunomodulatory agent, and CD38-directed monoclonal antibody.

Regarding safety, myelosuppression is a challenging toxicity observed with melflufen, says Richardson. However, neutropenia appears to be well managed with growth factor support. Moreover, romiplostim (Nplate) can help control melflufen-associated thrombocytopenia, Richardson explains. Notably, although decreased blood counts are common with melflufen, the consequences do not appear to be limiting, Richardson adds. Additionally, the rate of pneumonia was relatively low among patients treated with melflufen in the pivotal trial, says Richardson.

As with any cytotoxic chemotherapy, the risk of secondary myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) is concerning, says Richardson. For example, melphalan (Evomela) has demonstrated significant activity as a cytotoxic agent but is associated with a risk of secondary MDS/AML. To date, the risk of secondary MDS/AML appears to be low with melflufen, concludes Richardson.

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Paul G. Richardson, MD, discusses the toxicity profile of melphalan flufenamide in relapsed/refractory multiple myeloma.  



Dr. Richardson on the Toxicity Profile of Melphalan Flufenamide in Multiple Myeloma 

Paul G. Richardson, MD, clinical program leader and director of clinical research, Jerome Lipper Multiple Myeloma Center, physician, Dana-Farber Cancer Institute, and RJ Corman Professor of Medicine at Harvard Medical School, discusses the FDA approval of melphalan flufenamide (Pepaxto; melflufen) in relapsed/refractory multiple myeloma.

FDA granted an accelerated approval to melphalan

 for use in combination with dexamethasone in patients with relapsed/refractory multiple myeloma who have received at least 4 prior lines of therapy and whose disease is refractory to a proteasome inhibitor, an immunomodulatory agent, and a CD38-directed monoclonal antibody.

The regulatory decision was based on findings from the phase 2 HORIZON study, in which the combination induced an overall response rate of 23.7% and a median duration of response of 4.2 months in this heavily pretreated, triple-class refractory patient population. 

Melphalan flufenamide is a novel peptide-drug conjugate that targets aminopeptidases and rapidly releases alkylating agents into myeloma cells, explains Richardson. The rationale to evaluate melphalan flufenamide was to improve upon the specificity of melphalan, which is a potent cytotoxic agent in multiple myeloma, Richardson says. In turn, melphalan flufenamide appears to confer low rates of infection and no alopecia. Although myelosuppression was observed with melphalan flufenamide, it was general manageable, concludes Richardson.

Paul G. Richardson, MD, discusses the FDA approval of melphalan flufenamide in relapsed/refractory multiple myeloma.  



Dr. Richardson on the FDA Approval of Melphalan Flufenamide in Relapsed/Refractory Multiple Myeloma 

Paul G. Richardson, MD, clinical program leader and director of clinical research, Jerome Lipper Multiple Myeloma Center; institute physician, Dana-Farber Cancer Institute; and RJ Corman Professor of Medicine at Harvard Medical School, discusses the next steps ​with the investigational cereblon E3 ligase modulator agent CC-92480 research in ​relapsed/refractory multiple myeloma.

A phase 2 expansion cohort evaluating CC-92480 in combination with dexamethasone (Decadron) in patients with heavily pretreated relapsed/refractory multiple myeloma ​is ongoing, says Richardson.

Preclinical data suggest that CC-92480 is synergistic with other standard of care agents, such as monoclonal antibodies, proteasome inhibitors, and steroids, Richardson adds. Moreover, exciting a combination strategy with bortezomib (Velcade) and daratumumab (Darzalex) has demonstrated encouraging results thus far, Richardson explains.

The combination could lead to improved outcomes for patients with relapsed/refractory multiple myeloma, concludes Richardson.

Paul G. Richardson, MD, discusses the next steps ​with the investigational cereblon E3 ligase modulator agent CC-92480 research in ​relapsed/refractory multiple myeloma.

Dr. Richardson on the Next Steps With CC-92480 Research in Relapsed/Refractory Multiple Myeloma

Paul Richardson, MD, clinical program leader, director of clinical research, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, RJ Corman Professor of Medicine, Harvard Medical School, discusses the FDA approval of selinexor (Xpovio) in multiple myeloma.

The has FDA granted an accelerated approval to selinexor in combination with dexamethasone for the treatment of adult patients with relapsed/refractory multiple myeloma who have received ≥4 prior therapies and whose disease is refractory to ≥2 proteasome inhibitors, ≥2 immunomodulatory agents, and a CD38-targeted monoclonal antibody. Data from Part 2 of the multicenter, single-arm, open-label, phase II STORM trial served as the basis for the approval. Findings demonstrated an overall response rate (ORR) of 25.3% (95% CI, 16.4-36.0) as assessed by an Independent Review Committee. Further, the stringent complete response rate was 1%, the very good partial response rate was 5%, and the partial response rate was 19%.

Selinexor is a first-in-class oral agent that has a unique mechanism of action. The agent is likely to have a broad effect, especially in settings of unmet need, says Richardson. 

Paul Richardson, MD, clinical program leader, director of clinical research, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, RJ Corman Professor of Medicine, Harvard Medical School, discusses the FDA approval of selinexor in multiple myeloma.

Dr. Richardson Discusses the FDA Approval of Selinexor in Myeloma

Paul Richardson, MD, clinical program leader, director of clinical research, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, RJ Corman Professor of Medicine, Harvard Medical School, discusses the synergy between immunomodulators and proteasome inhibitors in the treatment of patients with relapsed/refractory multiple myeloma (RRMM).

These data come from the phase III OPTIMISMM trial, which Richardson was the lead investigator of. OPTIMISMM evaluated the combination of pomalidomide (Pomalyst), bortezomib (Velcade), and low-dose dexamethasone versus the standard treatment of bortezomib and dexamethasone alone. Richardson says the concept of this trial has been a paradigm of myeloma treatment for a long time.

Patients on the pomalidomide arm received 4 mg/day of the agent for 14 days, in addition to the standard dose of bortezomib and dexamethasone. The primary endpoint of the study was progression-free survival (PFS).

Data showed that pomalidomide reduced PFS by 39% versus standard treatment. Overall survival data are not yet mature.

Dr. Richardson on the Synergy Between Immunomodulators and Proteasome Inhibitors

Paul Richardson, MD, clinical program leader, director of Clinical Research, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, RJ Corman Professor of Medicine, Harvard Medical School, discusses the results of the OPTIMISMM trial in patients with multiple myeloma.

The phase III OPTIMISMM trial compared pomalidomide (Pomalyst), bortezomib (Velcade), and low-dose dexamethasone (PVd) with bortezomib and low-dose dexamethasone in patients with relapsed or refractory multiple myeloma, previously treated with lenalidomide (Revlimid). Richardson says that is an interesting and important area, as lenalidomide is frequently used as upfront therapy, as well as in the maintenance setting. OPTIMISMM is the first of its kind, as it looks exclusively at lenalidomide-exposed patients, Richardson explains.

Results showed that the addition of pomalidomide to bortezomib and low-dose dexamethasone reduced the risk of disease progression or death by 39%. Additionally, the median progression-free survival at 16 months was 11.20 months with PVd compared with 7.10 months with bortezomib and low-dose dexamethasone alone (HR, 0.61; 95% CI, 0.49-0.77; 

Paul Richardson, MD, clinical program leader, director of Clinical Research, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, RJ Corman Professor of Medicine, Harvard Medical School, discusses the results of the OPTIMISMM trial in patients with multiple myeloma.
 

Paul Richardson, MD

Articles

Dr. Richardson on the Toxicity Profile of Melphalan Flufenamide in Multiple Myeloma

Dr. Richardson on the FDA Approval of Melphalan Flufenamide in Relapsed/Refractory Multiple Myeloma

Dr. Richardson on the Next Steps With CC-92480 Research in Relapsed/Refractory Multiple Myeloma

Dr. Richardson Discusses the FDA Approval of Selinexor in Myeloma

Dr. Richardson on the Synergy Between Immunomodulators and Proteasome Inhibitors

Dr. Richardson Discusses the Results of the OPTIMISMM Trial in Myeloma