Treatment With High-Dose Melphalan Linked to Mutational Load in Multiple Myeloma

Dr Samur and colleagues found that high-dose melphalan caused an approximately 2.5-fold greater mutation accumulation rate than that observed with RVD treatment alone.

Treatment with high-dose melphalan plus lenalidomide, bortezomib, and dexamethasone (RVD) prior to autologous stem cell transplant resulted in an approximately 2.5-fold higher rate of mutation accumulation at relapse in patients with multiple myeloma compared with treatment with RVD alone, according to data presented by Mehmet K. Samur, PhD, of Boston’s Dana-Farber Cancer Institute, at the virtual 62nd American Society of Hematology (ASH) Annual Meeting and Exposition.

“Although high-dose melphalan treatment has been around for almost 40 years now, there are still almost 90 ongoing clinical trials that are looking at different impacts of this treatment,” Dr Samur said.

Dr Samur and colleagues used whole-genome sequencing to analyze paired purified multiple myeloma cells collected at diagnosis and relapse from 68 patients treated in the IFM/DFCI 2009 study. Forty-three patients had been treated with RVD only and 25 with RVD plus high-dose melphalan.

There were a similar number of mutations at diagnosis between both arms, and mutational load increased in both arms following treatment administration. However, there was a significantly greater increase in the number of mutations and indels found at relapse in patients in the high-dose melphalan arm compared with those in the RVD-alone arm.

Using a model incorporating for new mutations, depth, and purity, Dr Samur and colleagues found that high-dose melphalan caused an approximately 2.5-fold greater mutation accumulation rate than the rate for RVD only.

There was no significant difference in structural variants or copy number alterations at diagnosis and relapse for patients treated with high-dose melphalan.

Clonal heterogeneity was also similar for both arms at the time of diagnosis; however, at relapse there was a significant increase in the subclonal mutation fraction for the patients treated with high-dose melphalan.

The researchers noted that DNA damage repair (DDR) pathway genes were frequently targeted in the high-dose melphalan group; 72% of these samples accumulated 1 or more DDR gene mutation compared with 17% of samples in the RVD-alone arm (P <.0001).

“This suggested that patients that got high-dose melphalan treatment either significantly accumulate mutations in this pathway, or the cells that [have] mutations in this pathway are significantly selected,” Dr Samur said.

Disclosures: Some of the presenters disclosed financial relationships with the pharmaceutical industry and/or the medical device industry. For a full list of disclosures, please refer to the presentation abstract.

Read more of MPR’s coverage of the ASH 2020 meeting by visiting the conference page.


Samur MK, Roncador M, Aktas-Samur A, et al. High-dose melphalan significantly increases mutational burden in multiple myeloma cells at relapse: results from a randomized study in multiple myeloma. Presented at:  the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition; December 5-8, 2020. Abstract 61.

This article originally appeared on Cancer Therapy Advisor