Exploring Increase of Point Mutations Associated with High-Dose Melphalan in Multiple Myeloma

Mehmet K. Samur, PhD

High-dose melphalan (Evomela) followed by autologous stem cell transplant (ASCT) has demonstrated significant efficacy for the treatment of patients with multiple myeloma. The agent has improved progression-free survival (PFS) in patients when administered as upfront therapy to patients aged 66 years or younger.

The median PFS shown with melphalan plus ASCT in a phase IFM/DFCI 2009 study was 50 months versus 26 months when compared with the standard of care treatment regimen lenalidomide (Revlimib), bortezomib (Velcade), and dexamethasone (RVD) alone hazard ratio for disease progression or death, 0.65; P <.001). As the treatment strategy continues to be explored in patients with multiple myeloma, researchers have now begun to investigate an outstanding biological question of whether the alkylating agent causes an increased amount of DNA damage.

An analysis presented during the virtual 2020 American Society of Hematology (ASH) Annual Meeting showed that between the time of diagnosis and relapse, patients treated with high-dose melphalan had an increased number of point mutations. It was unclear from this research how this result translated to treatment selection and sequencing.

In an interview with Targeted Oncology, Mehmet Samur, PhD, senior research scientist, Dana-Farber Cancer Institute, discussed the investigation of high-dose melphalan following ASCT in patients with multiple myeloma and shared insights into how the ongoing questions can be explored in the future.

TARGETED ONCOLOGY: Can you explain what was demonstrated prior with high-dose melphalan followed by ASCT in patients with multiple myeloma?

Sumar: The clinical part of the phase 3 study was published previously. It showed that when you do RVD plus high-dose melphalan following by stem cell treatment, patients do significantly better than patients who get RVD alone. Adding high-dose melphalan increased the PFS benefit by around 12 months.

TARGETED ONCOLOGY: Can you provide background on your analysis of Melphalan for patients with multiple myeloma?

Sumar: Melphalan is an alkylating agent. Because of the way the agent works, we always think that it creates more DNA damage. The study that we presented at ASH was questioning whether this was true or not.

We collected DNA sequencing data from patients who were treated with RVD followed by high-dose Melphalan and a bone marrow transplant. We had a total of 25 patients, and we collected data at the time of diagnosis and the time of relapse. To compare this compilation, we also collected data from 43 patients from the IFM/DFCI 2009 study who only received RVD. We also collected data at diagnosis and relapse in the 43 patients. Genomic alterations were compared at diagnosis and relapse for patients who were injected with high-dose Melphalan and RVD versus patients who were only treated with RVD.

TARGETED ONCOLOGY: What were the findings from this study?

Sumar: We found that patients who got high-dose melphalan plus RVD followed by transplant accumulated more point mutations. To be precise, they accumulated around 10,000 new mutations between diagnosis and relapse at 5 years. For RVD patients, there were around 4500 new point mutations. The study showed that treating patients with high-dose Melphalan is increasing the mutational load by about 2.9-fold at the time of relapse.

TARGETED ONCOLOGY: What are the implications of these findings?

Sumar: There are a couple of things that we see from our study. One point is that we only saw point mutations. We didn’t see any large-scale DNA alterations. This suggests that our patients who are treated with high-dose melphalan are more likely to experience changes.

In terms of the pathways that are mutated, the DNA damage repair pathway is more frequently mutated between diagnosis and relapse in patients treated with high-dose melphalan. We think that if we combine inhibitors that can overcome the selection of DNA damage repair pathway mutations, those patients may get additional benefit from the treatment.

We don’t have clear data yet on whether this increased mutational load is something that is bad for patients. Even though these patients have more mutations, overall survival times are similar between the 2 arms. C outcomes are not impacted by the increased number of mutation so far.

TARGETED ONCOLOGY: What plan are underway to further this research?

Sumar: We are expanding our study in multiple ways. There is no clear data set we can get answers to our ongoing questions yet. We have reached out to our partners around the world to see if we can come up with a cohort to investigation. Also, we are looking at impact of these mutational load increase on other features like secondary cancer rate.

TARGETED ONCOLOGY: The understanding of gene mutations in myeloma is evolving. Can you discuss the current role of genomic testing?

Sumar: It has been shown in many studies that genetic testing at diagnosis can tell us which patients are high risk and which are low risk. Studies have also shown that patients who have loss of p53 or with deletion 17p will have bad outcomes.

There was a study published last year in the Journal of Clinical Oncology showing which patients with myeloma would have a lower risk. The study also shows that there are certain genomic features prolong survival time in patients.

We have different genomic tools that we can use to look at these different alterations and assess patient risk. Today, I think people are looking at these alterations from all different angles to plan stratification in upcoming clinical trials.

TARGETED ONCOLOGY: In your opinion, what change will we see in the myeloma treatment landscape in the next 5 years?

Sumar: There are a lot of studies looking at new treatment. Everyone is carefully watching out for data on new treatment options like chimeric antigen receptor T-cell therapy, bispecific antibodies, and monoclonal antibodies. It looks like these agents are providing benefit to patients, but they are at the very early stages of research.

Reference:Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017; 376(14):1311-1320. doi: 10.1056/NEJMoa1611750