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Melphalan Flufenamide for Relapsed or Refractory Multiple Myeloma


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In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

On February 26, 2021, the peptide-conjugated alkylating drug melphalan flufenamide was granted accelerated approval for use in combination with dexamethasone for adults 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.1,2

The safety and efficacy of melphalan flufenamide have not been established for use as a conditioning regimen in patients receiving transplantation. Melphalan flufenamide is not indicated and is not recommended for use as a conditioning regimen for transplantation outside of controlled clinical trials.

Supporting Efficacy Data

Approval was based on findings in the multicenter, phase II HORIZON trial (ClinicalTrials.gov identifier NCT02963493).2,3 In the trial, patients received melphalan flufenamide at 40 mg intravenously (IV) on day 1 and oral dexamethasone at 40 mg (20 mg for patients aged ≥ 75 years) on days 1, 8, 15, and 22 of each 28-day cycle until disease progression or unacceptable toxicity. Efficacy was evaluated in a subpopulation of 97 patients who received at least four prior lines of therapy and were refractory to at least one proteasome inhibitor, one immunomodulatory agent, and a CD38-directed antibody. The main efficacy outcome measure was investigator-assessed overall response rate and duration of response according to International Myeloma Working Group criteria.

OF NOTE

Melphalan flufenamide has warnings/precautions for thrombocytopenia, neutropenia, anemia, infections, increased risk of mortality at dosages higher than the recommended dosage, secondary malignancies, and embryofetal toxicity.

An objective response was observed in 23 patients (23.7%), with a partial response observed in 14 (14.4%) and a very good partial response in 9 (9.3%); no complete or stringent complete responses were observed. The median time to first response was 2.1 months (range = 1.0–6.1 months). Median duration of response was 4.2 months (95% confidence interval = 3.2–7.6 months).

How It Works

Melphalan flufenamide is a peptide-conjugated alkylating drug. Due to its lipophilicity, the agent is passively distributed into cells and thereafter enzymatically hydrolyzed to melphalan. Similar to other nitrogen mustard drugs, cross-linking of DNA is involved in the antitumor activity of melphalan flufenamide. In cellular assays, the study drug inhibited proliferation and induced apoptosis of hematopoietic and solid tumor cells. In addition, melphalan flufenamide showed synergistic cytotoxicity with dexamethasone in melphalan-resistant and nonresistant multiple myeloma cell lines.

How It Is Used

The recommended dose of melphalan flufenamide is 40 mg via 30-minute IV infusion on day 1 of each 28-day treatment cycle in combination with oral or IV dexamethasone at 40 mg on days 1, 8, 15, and 22 of each cycle, with treatment continuing until disease progression or unacceptable toxicity. The dose of dexamethasone should be reduced to 20 mg for patients aged ≥ 75 years. Use of a serotonin-3 (5-HT3) receptor antagonist or other antiemetics prior to and during treatment with melphalan flufenamide should be considered.

Recommended dose reductions for adverse reactions are sequentially to 30 mg and 20 mg; treatment should be permanently discontinued in patients unable to tolerate the 20-mg dose. Treatment should be withheld for neutrophil counts < 1 × 109/L or platelet counts < 50 × 109/L. Prescribing information provides details on dosage modification for myelosuppression and grade 2 and grade 3 or 4 nonhematologic adverse reactions.

Safety Profile

Safety data are from a total of 157 patients receiving melphalan flufenamide in the HORIZON trial. Overall, 29% of patients were exposed to treatment for at least 6 months and 6% for more than 1 year.

The most common adverse events of any grade (≥ 20%) were fatigue (55%), nausea (32%), diarrhea (27%), pyrexia (24%), and respiratory tract infection (24%). The most common grade 3 or 4 adverse events included pneumonia (11%), fatigue (6%), and upper respiratory tract infection (5%). The most common grade 3 or 4 laboratory abnormalities were decreased lymphocytes (95%), decreased leukocytes (88%), decreased neutrophils (82%), and decreased platelets (80%). Any-grade creatinine increase occurred in 68% (grade 3 in 1%).

KEY POINTS

  • The peptide-conjugated alkylating drug melphalan flufenamide was granted accelerated approval for use in combination with dexamethasone for 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 recommended dose of melphalan flufenamide is 40 mg via 30-minute IV infusion on day 1 of each 28-day treatment cycle in combination with oral or IV dexamethasone at 40 mg on days 1, 8, 15, and 22 of each cycle, with treatment continuing until disease progression or unacceptable toxicity.

Serious adverse events occurred in 49% of patients, the most common being pneumonia (10%), respiratory tract infection (6%), thrombocytopenia (5%), febrile neutropenia (5%), and sepsis (3.2%). Adverse events led to dose interruption in 62%, the most common causes being thrombocytopenia (43%), neutropenia (29%), anemia (10%), respiratory tract infection (7%), leukopenia (6%), and pyrexia (4.5%). Dose reductions due to adverse events occurred in 27%, the most common causes being thrombocytopenia (22%) and neutropenia (6%). Permanent treatment discontinuation due to adverse events occurred in 22%, with the most common cause being thrombocytopenia (11%). Fatal adverse events occurred in 10 patients (6%), with the most common being general physical health deterioration (1.9%) and respiratory failure (1.3%).

Melphalan flufenamide has warnings/precautions for thrombocytopenia, neutropenia, anemia, infections, increased risk of mortality at dosages higher than the recommended dosage, secondary malignancies, and embryofetal toxicity. Platelet counts, neutrophil counts, and red blood cell counts should be monitored at baseline, during treatment, and as clinically indicated. Patients should be monitored for signs/symptoms of infection and promptly treated. Dosages exceeding the recommended dose for melphalan flufenamide may be associated with mortality. Patients should have long-term monitoring for the development of secondary malignancies. Patients should be advised not to breastfeed while receiving melphalan flufenamide.The study drug is contraindicated for use in patients with a history of serious hypersensitivity reaction to melphalan flufenamide or melphalan. 

REFERENCES

1. U.S. Food and Drug Administration: FDA grants accelerated approval to melphalan flufenamide for relapsed or refractory multiple myeloma. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-melphalan-flufenamide-relapsed-or-refractory-multiple-myeloma. Accessed March 15, 2021.

2. Pepaxto (melphalan flufenamide) for injection, for intravenous use, prescribing information, Oncopeptides AB, February 2021. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214383s000lbl.pdf. Accessed March 15, 2021.

3. Richardson PG, Oriol A, Larocca A, et al: Melflufen and dexamethasone in heavily pretreated relapsed and refractory multiple myeloma. J Clin Oncol 39:757-767, 2021.


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