The FDA has granted approval to melphalan flufenamide in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma, who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody.
The FDA has granted approval to melphalan flufenamide (Melflufen) in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma, who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody.
“Melflufen offers a novel MOA which will provide patients with relapsed/refractory multiple myeloma with an important new option. Moreover, combination therapy with other standards of care – such as bortezomib (Velcade) and daratumumab (Darzalex)- are showing particular promise as a future direction,” said Paul G. Richardson, MD, Clinical Program leader and director of Clinical Research, Jerome Lipper Multiple Myeloma Center, and institute physician at Dana-Farber Cancer Institute and an RJ Corman Professor of Medicine at Harvard Medical School told Targeted Oncology, in an interview.
The New Drug application for melphalan flufenamide was backed by findings from the phase HORIZON clinical trial of melphalan flufenamide 40 mg plus dexamethasone 40 mg administered to patients with relapsed/refractory multiple myeloma (NCT02963493). The combination ultimately demonstrated clinically meaningful efficacy in the patient population along with a manageable safety profile, according to primary analysis results.2
In the study, the primary end point assessed was investigator-assessed overall response rate (ORR) which was later confirmed by independent review. The secondary end points were duration of response (DOR), progression-free survival (PFS), overall survival
(OS), and safety.
A total of 157 patients were enrolled to the intent-to-treat (ITT) population and of those enrolled 131 were treated with melphalan flufenamide and dexamethasone. At data cutoff, 26 patients were still on study treatment. The combination led to an ORR of 29% (95% CI 22%-37%) in the overall population and 26% (95% CI, 18%-35) in the triple-class refractory population. In the overall population, responses included 1 stringent complete response (sCR), 17 very good partial responses (VGPRs), 28 partial responses (PRs), and 25 minimal response for a clinical benefit rate (CBR) of 45% (95% CI, 37% -53%). Among the patients with triple-class refractory disease, there were 13 VGPRs, 18 PRs, and 16 patients with minimal responses, which calculated to a CBR of 39% (95% CI, 31%-49%).
DOR in the study was measured in patients with a PR or better. The median DOR 5.5 months in the all-treated population (95% CI, 3.9-7.6 months) and 4.4 months (95% CI, 3.4- 7.6 months) in the triple-class refractory population.
In terms of survival, the all-treated group had a median PFS of 4.2 months (95% CI, 3.4- 4.9 months), and the triple-class refractory group had a median PFS of 3.9 months (95% CI, 3.0-4.6 months). The median OS observed for the 2 cohorts was 11.6 months (95% CI, 9.3 to 15.4 months) and 11.2 months (95% CI, 7.7 to 13.2 months), respectively. It was also estimated that treatment with melphalan flufenamide plus dexamethasone would achieve a 1-year event-free survival (EFS) of 48.8% (95% CI, 39.6% -57.4%) in the all-treated cohort and 41.9% (95% CI, 31.6%-51.8%) in the triple-class refractory cohort.
A subgroup analysis of HORIZON evaluated responses in older patients with relapsed/refractory multiple myeloma and the results showed that in the age 65 to 74-year-old age group, 35% of patients achieved a PR or better. In the group of patients aged 75 years or older, 32% achieved a PR or better.
All patients in the study experienced treatment-emergent adverse events (TEAEs), and 90% had grade ≥ 3 TEAEs. The most common grade ≥ 3 TEAEs that were hematologic in nature were thrombocytopenia (76%), and anemia (43%). The most common nonhematologic treatment-emergent grade 3/4 events were pneumonia, and hypophosphatemia. The combination of melphalan flufenamide and dexamethasone also led to Any-grade and grade 3/4 bleeding events in 16% and 3% of patients, respectively.
Eleven percent of patients in the study experienced grade 3/4 neutropenia. In addition, gastrointestinal (GI) events of any grade occurred in 93%, and these events were grade 3 in 7%. There were no grade 3 GI events reported. The most common GI events of any grade included nausea (32%), diarrhea (27%), constipation (15%), and vomiting (13%).
There was only one case of mucositis in the study.
In 49% of patients, serious TEAEs occurred which were mainly pneumonia (9%) and febrile neutropenia (5%). Five patients developed secondary malignancies during the study, and 10 patients died as a result of TEAEs.
“The absence of alopecia and minimal non-hematologic toxicity, as well as the convenience of monthly infusion, is an important positive. Myelosuppression is the major side effect, but rates of infection and bleeding are very low, not least because mucositis is not seen. In addition, the use of growth factor support both for both neutrophils and platelets proved beneficial in our studies,” Richardson told Targeted Oncology about the safety profile of melphalan in the HORIZON study.
HORIZON is a single-arm, open-label study in which the cytotoxic activity against myeloma cell lines associated with the first-in-class anticancer peptide-drug conjugate, melphalan flufenamide, was indeed demonstrated in the relapsed/refractory population. Baseline data from the all-treated population showed that the group was predominantly male (59%), aged 65 years (range, 35-86), with an ECOG performance status of either 0 (25%), 1 (59%), or 2 (16%). Thirty-eight percent of patients had high-risk cytogenetics at baseline, which included more than 2 high-risk abnormalities for 13% of patients and del(17p) for 11% of patients.
On the International Staging System, 40% of the patients were stage I, 31% were stage II, and 25% were stage III. Data on stage was missing or unknown for 6 patients. Notably, 35% had extramedullary disease at baseline.
The population had a median of 5 (range, 2-12) prior lines of therapy, and patients were refractory to a number of different treatment types.
It was noted in the eligibility criteria that patients were required to have measurable disease and a life expectancy of at least 6 months to join the HORIZON study.
1. FDA approves Oncopeptides' PEPAXTO® ( melphalan flufenamide) for patients with relapsed or refractory multiple myeloma. News release. Oncopeptides, AB. Febraury 26, 20201. Accessed February 26, 2021.
2. Richardson PG, Oriol A, Larocca A, et al. Melflufen and dexamethasone in heavily pretreated relapsed and refractory multiple myeloma. J Clin Oncol. Published online December 09, 2020. doi: 10.1200/JCO.20.02259