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Nitrogen mustards and oxazaphosphorinesIn useDerivative of an earlier drug

Melphalan

Also known as Alkeran, L-phenylalanine mustard, L-PAM, L-sarcolysin

A phenylalanine derivative of nitrogen mustard. The 2011 US tablet label lists palliative treatment of multiple myeloma and of non-resectable epithelial ovarian carcinoma; a liver-directed kit containing melphalan was approved in 2023 for uveal melanoma with liver metastases.

From discovery to approval

  1. 1953 · First described

    The 2011 US label says melphalan was first synthesized in 1953 by Bergel and Stock; their paper on cyto-active substituted phenylalanines is dated 1954. The racemic form is called merphalan or sarcolysin, and Blokhin and Larionov reported clinical experience with sarcolysin in 1958.[1][2][3]

  2. 1964-01-17 · FDA regular · 11 years after first description

    Alkeran tablets, NDA 014691, original approval, classed as a new molecular entity with priority review in the Drugs@FDA history, which lists this product as discontinued. The original label is not available there, so the indication at approval is not stated here; the 2011 label lists palliative treatment of multiple myeloma and of non-resectable epithelial carcinoma of the ovary. The type regular is an inference: no accelerated-approval wording was found.[4]

  3. 2023-08-14 · FDA regular · 70 years after first description

    Liver-directed treatment of adult patients with uveal melanoma with unresectable hepatic metastases affecting less than 50% of the liver and no extrahepatic disease, or extrahepatic disease limited to bone, lymph nodes, subcutaneous tissues or lung that is amenable to resection or radiation (NDA 201848; signature date from the letter). No accelerated-approval wording was found in the letter; regular is an inference.[5]

How it works

The 2011 US label calls it a bifunctional alkylating agent of the bischloroethylamine type whose cytotoxicity appears related to interstrand DNA cross-linking, probably at guanine N7. It is active against both resting and rapidly dividing tumour cells.[1]

Where it came from and why

No source states why it was made. The label calls it a phenylalanine derivative of nitrogen mustard, and the 1954 paper's title concerns cyto-active amino-acid and peptide derivatives.

Cancers

Worth knowing

  • The label gives the names L-phenylalanine mustard, phenylalanine mustard, L-PAM and L-sarcolysin for melphalan, and says the racemic form is called merphalan or sarcolysin.[1]
  • The label says the D-isomer, medphalan, is less active against certain animal tumours than the L-isomer, melphalan.[1]
  • Melphalan is also the active drug in a hepatic delivery kit that the FDA approved on 14 August 2023 for uveal melanoma with liver metastases.[5]
  • Drugs@FDA lists the Alkeran tablet product (NDA 014691) as discontinued.[4]

On this site

References

  1. U.S. Food and Drug Administration. Alkeran (melphalan) tablets, prescribing information, NDA 014691 supplement 030 (action date 2 May 2011 as listed in Drugs@FDA). Source
  2. Bergel F, Stock JA. Cyto-active amino-acid and peptide derivatives. Part I. Substituted phenylalanines. Journal of the Chemical Society (Resumed). 1954;:2409. DOI
  3. BLOKHIN N, LARIONOV L, PEREVODCHIKOVA N, CHEBOTAREVA L, MERKULOVA N. [Clinical experiences with sarcolysin in neoplastic diseases]. Ann N Y Acad Sci. 1958;68(3):1128-32. PubMedDOI
  4. U.S. Food and Drug Administration. Drugs@FDA: Approval date(s) and history, letters, labels, reviews for NDA 014691 (Alkeran tablets, melphalan). Page read 2026-10-26. Source
  5. U.S. Food and Drug Administration. NDA approval letter, NDA 201848, Hepzato Kit Hepatic Delivery System (melphalan). e-signed 14 August 2023. Source
  6. BERGSAGEL DE, SPRAGUE CC, AUSTIN C, GRIFFITH KM. Evaluation of new chemotherapeutic agents in the treatment of multiple myeloma. IV. L-Phenylalanine mustard (NSC-8806). Cancer Chemother Rep. 1962;21:87-99. PubMed
  7. McElwain TJ, Powles RL. High-dose intravenous melphalan for plasma-cell leukaemia and myeloma. Lancet. 1983;2(8354):822-4. PubMedDOI