Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The mutagenic impact of melphalan in multiple myeloma


The introduction of whole genome and exome sequencing partnered with advanced bioinformatic pipelines has allowed the comprehensive characterization of mutational processes (i.e., mutational signatures) in individual cancer patients. Studies focusing on multiple myeloma have defined several mutational processes, including a recently identified mutational signature (called “SBS-MM1”) directly caused by exposure to high-dose melphalan (i.e., autologous stem cell transplant). High-dose melphalan exposure increases both the overall and nonsynonymous mutational burden detected between diagnosis and relapse by ~10–20%. Nevertheless, most of these mutations are acquired within the heterochromatin and late-replicating regions, rarely involving key myeloma driver genes. In this review, we summarize key studies that made this discovery possible, and we discuss potential clinical implications.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: History of melphalan mutational signature in multiple myeloma.
Fig. 2: Melphalan mutational signatures.
Fig. 3: SBS-MM1 is detectable only in relapsed multiple myeloma exposed to melphalan.
Fig. 4: Scheme summarizing the single cell expansion and engraftment models.


  1. 1.

    Barlogie B, Jagannath S, Desikan KR, Mattox S, Vesole D, Siegel D, et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood. 1999;93:55–65.

    CAS  Article  Google Scholar 

  2. 2.

    Tacchetti P, Pantani L, Patriarca F, Petrucci MT, Zamagni E, Dozza L, et al. Bortezomib, thalidomide, and dexamethasone followed by double autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GIMEMA-MMY-3006): long-term follow-up analysis of a randomised phase 3, open-label study. Lancet Haematol. 2020;7:e861–e873.

    Article  Google Scholar 

  3. 3.

    Barlogie B, Tricot GJ, van Rhee F, Angtuaco E, Walker R, Epstein J, et al. Long-term outcome results of the first tandem autotransplant trial for multiple myeloma. Br J Haematol. 2006;135:158–64.

    Article  Google Scholar 

  4. 4.

    Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, et al. Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma. N Engl J Med. 2017;376:1311–20.

    CAS  Article  Google Scholar 

  5. 5.

    Paiva B, Puig N, Cedena MT, Rosinol L, Cordon L, Vidriales MB, et al. Measurable Residual Disease by Next-Generation Flow Cytometry in Multiple Myeloma. J Clin Oncol. 2020;38:784–92.

    CAS  Article  Google Scholar 

  6. 6.

    Joseph NS, Kaufman JL, Dhodapkar MV, Hofmeister CC, Almaula DK, Heffner LT, et al. Long-Term Follow-Up Results of Lenalidomide, Bortezomib, and Dexamethasone Induction Therapy and Risk-Adapted Maintenance Approach in Newly Diagnosed Multiple Myeloma. J Clin Oncol. 2020;38:1928–37.

    CAS  Article  Google Scholar 

  7. 7.

    Engelhardt M, Ihorst G, Landgren O, Pantic M, Reinhardt H, Waldschmidt J, et al. Large registry analysis to accurately define second malignancy rates and risks in a well-characterized cohort of 744 consecutive multiple myeloma patients followed-up for 25 years. Haematologica. 2015;100:1340–9.

    CAS  Article  Google Scholar 

  8. 8.

    Maclachlan K, Diamond B, Maura F, Hillengass J, Turesson I, Landgren CO, et al. Second malignancies in multiple myeloma; emerging patterns and future directions. Best Pr Res Clin Haematol. 2020;33:101144.

    Article  Google Scholar 

  9. 9.

    Razavi P, Rand KA, Cozen W, Chanan-Khan A, Usmani S, Ailawadhi S. Patterns of second primary malignancy risk in multiple myeloma patients before and after the introduction of novel therapeutics. Blood Cancer J. 2013;3:e121.

    CAS  Article  Google Scholar 

  10. 10.

    Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6633 patients from 27 randomized trials. Myeloma Trialists’ Collaborative Group. J Clin Oncol. 1998;16:3832–42.

  11. 11.

    Cavo M, Gay F, Beksac M, Pantani L, Petrucci MT, Dimopoulos MA, et al. Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study. Lancet Haematol. 2020;7:e456–e468.

    Article  Google Scholar 

  12. 12.

    Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371:895–905.

    Article  Google Scholar 

  13. 13.

    Gay F, Musto P, Rota Scalabrini D, Galli M, Belotti A, Zamagni E, et al. Survival Analysis of Newly Diagnosed Transplant-Eligible Multiple Myeloma Patients in the Randomized Forte Trial. Blood. 2020;136:35–37.

    Article  Google Scholar 

  14. 14.

    Perrot A, Lauwers-Cances V, Corre J, Robillard N, Hulin C, Chretien ML, et al. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. Blood. 2018;132:2456–64.

    CAS  Article  Google Scholar 

  15. 15.

    Goicoechea I, Puig N, Cedena MT, Burgos L, Cordon L, Vidriales MB, et al. Deep MRD profiling defines outcome and unveils different modes of treatment resistance in standard and high risk myeloma. Blood. 2020;137:49–60.

  16. 16.

    Alexandrov LB, Kim J, Haradhvala NJ, Huang MN, Tian Ng AW, Wu Y, et al. The repertoire of mutational signatures in human cancer. Nature. 2020;578:94–101.

    CAS  Article  Google Scholar 

  17. 17.

    Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–21.

    CAS  Article  Google Scholar 

  18. 18.

    Maura F, Degasperi A, Nadeu F, Leongamornlert D, Davies H, Moore L, et al. A practical guide for mutational signature analysis in hematological malignancies. Nat Commun. 2019;10:2969.

    Article  Google Scholar 

  19. 19.

    Bolli N, Avet-Loiseau H, Wedge DC, Van Loo P, Alexandrov LB, Martincorena I, et al. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat Commun. 2014;5:2997.

    Article  Google Scholar 

  20. 20.

    Walker BA, Wardell CP, Murison A, Boyle EM, Begum DB, Dahir NM, et al. APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma. Nat Commun. 2015;6:6997.

    CAS  Article  Google Scholar 

  21. 21.

    Maura F, Petljak M, Lionetti M, Cifola I, Liang W, Pinatel E, et al. Biological and prognostic impact of APOBEC-induced mutations in the spectrum of plasma cell dyscrasias and multiple myeloma cell lines. Leukemia. 2017;32:1044–1048.

  22. 22.

    Weinhold N, Ashby C, Rasche L, Chavan SS, Stein C, Stephens OW, et al. Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma. Blood. 2016;128:1735–44.

    CAS  Article  Google Scholar 

  23. 23.

    Bolli F, Maura M, Minvielle M, Gloznik D, Szalat R, Fullam A, et al. Genomic patterns of progression in smoldering multiple myeloma. Nat Commun. 2018;9:3363.

  24. 24.

    Degasperi A, Amarante TD, Czarnecki J, Shooter S, Zou X, Glodzik D, et al. A practical framework and online tool for mutational signature analyses show inter-tissue variation and driver dependencies. Nat Cancer. 2020;1:249–63.

    Article  Google Scholar 

  25. 25.

    Rustad EH, Nadeu F, Angelopoulos N, Ziccheddu B, Bolli N, Puente XS, et al. mmsig: a fitting approach to accurately identify somatic mutational signatures in hematological malignancies. Commun Biol. 2021;4:424.

    CAS  Article  Google Scholar 

  26. 26.

    Rustad EH, Yellapantula V, Leongamornlert D, Bolli N, Ledergor G, Nadeu F, et al. Timing the initiation of multiple myeloma. Nat Commun. 2020;11:1917.

    CAS  Article  Google Scholar 

  27. 27.

    Kucab JE, Zou X, Morganella S, Joel M, Nanda AS, Nagy E, et al. A Compendium of Mutational Signatures of Environmental Agents. Cell. 2019;177:821–36.

    CAS  Article  Google Scholar 

  28. 28.

    Landau HJ, Yellapantula V, Diamond BT, Rustad EH, Maclachlan KH, Gundem G, et al. Accelerated single cell seeding in relapsed multiple myeloma. Nat Commun. 2020;11:3617.

    CAS  Article  Google Scholar 

  29. 29.

    Ziccheddu B, Biancon G, Bagnoli F, De Philippis C, Maura F, Rustad EH, et al. Integrative analysis of the genomic and transcriptomic landscape of double-refractory multiple myeloma. Blood Adv. 2020;4:830–44.

    CAS  Article  Google Scholar 

  30. 30.

    Lee-Six H, Olafsson S, Ellis P, Osborne RJ, Sanders MA, Moore L, et al. The landscape of somatic mutation in normal colorectal epithelial cells. Nature. 2019;574:532–7.

    CAS  Article  Google Scholar 

  31. 31.

    Pich O, Cortes-Bullich A, Muiños F, Pratcorona M, Gonzalez-Perez A, Lopez-Bigas N. The evolution of hematopoietic cells under cancer therapy. bioRxiv. 2020.

  32. 32.

    Pich O, Muinos F, Lolkema MP, Steeghs N, Gonzalez-Perez A, Lopez-Bigas N. The mutational footprints of cancer therapies. Nat Genet. 2019;51:1732–40.

    CAS  Article  Google Scholar 

  33. 33.

    Samur MK, Roncador M, Aktas-Samur A, Fulciniti M, Bazarbachi AH, Szalat R, et al. High-Dose Melphalan Significantly Increases Mutational Burden in Multiple Myeloma Cells at Relapse: Results from a Randomized Study in Multiple Myeloma. Blood. 2020;136:4–5.

    Article  Google Scholar 

  34. 34.

    Poos AM, Giesen N, Catalano C, Paramasivam N, Huebschmann D, John L, et al. Comprehensive Comparison of Early Relapse and End-Stage Relapsed Refractory Multiple Myeloma. Blood. 2020;136.

  35. 35.

    Wuilleme S, Lok A, Robillard N, Dupuis P, Stocco V, Migne H, et al. Assessment of tumoral plasma cells in apheresis products for autologous stem cell transplantation in multiple myeloma. Bone Marrow Transpl. 2016;51:1143–5.

    CAS  Article  Google Scholar 

Download references


This work was supported by the Sylvester Comprehensive Cancer Center NCI Core Grant (P30 CA 240139), by the Memorial Sloan Kettering Cancer Center NCI Core Grant (P30 CA 008748), by the Multiple Myeloma Research Foundation (MMRF), by the Perelman Family Foundation, and by the Riney Family Multiple Myeloma Research Program Fund. FM is supported by the American Society of Hematology, the International Myeloma Foundation and The Society of Memorial Sloan Kettering Cancer Center. BD is supported by Myeloma Crowd and Conquer Cancer.

Author information




FM, NW, GM, LR, DK, BD and OL designed and supervised the study, collected and analyzed the data and wrote the paper.

Corresponding authors

Correspondence to Francesco Maura or Ola Landgren.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Maura, F., Weinhold, N., Diamond, B. et al. The mutagenic impact of melphalan in multiple myeloma. Leukemia 35, 2145–2150 (2021).

Download citation


Quick links