Can Immunomodulatory Drugs Overcome CHIP’s Effects in Post-Transplant Multiple Myeloma?

Patients with multiple myeloma (MM) who harbor somatic mutations in hematopoietic cells, known as clonal hematopoiesis of indeterminate potential (CHIP), have better post–autologous hematopoietic cell transplantation (AHCT) survival if they receive firstline maintenance therapy with an immunomodulatory drug, according to a study presented at the 17th International Myeloma Workshop. The results suggest that assessment for and monitoring of CHIP mutations should be incorporated into treatment decisions for this patient population.

“CHIP status seems to have a prognostic role in myeloma and dictates the need for incorporating an immunomodulator in the treatment regimen,” said study author Tarek Mouhieddine, MD, from the Dana-Farber Cancer Institute (DFCI) in Boston, when asked about the clinical relevance of the findings. “Clinically, it looks like we might have to start screening for CHIP at the time of myeloma diagnosis before initiating therapy. Monitoring CHIP clones throughout therapy could also help identify patients at risk of developing a myeloid malignancy and thus direct our therapeutic regimen to [therapies] that do not allow clonal expansion.”

To determine how CHIP influences outcomes in patients with MM, Dr. Mouhieddine and co-authors performed targeted sequencing on cryopreserved peripheral blood from 629 patients who underwent AHCT at DFCI between 2003 and 2011. During this time, immunomodulatory maintenance therapy was not consistently offered to patients, and many patients were simply observed for post-transplant disease recurrence. The findings in this cohort were then validated against a cohort of 986 patients included in the Multiple Myeloma Research Foundation database.

In the DFCI cohort, 136 patients (21.62%) harbored a CHIP mutation at the time of AHCT. The most commonly mutated genes were:

  • DNMT3A
  • TET2
  • TP53
  • ASXL1
  • PPM1D

At a median of four years following AHCT (range = 1-10 years), 24 patients (3.8%) developed a second hematologic malignancy – 29% of whom had CHIP.

A total of 358 patients at DFCI received a firstline immunomodulatory drug after transplant, while 16 patients received maintenance with single-agent bortezomib.

Overall, 22% of patients underwent at least three years of firstline immunomodulatory drug maintenance (range = 0.06-12.8). Of those who did not receive immunomodulatory drugs, patients who harbored CHIP mutations had significantly worse overall survival (OS) and progression-free survival (PFS; p=0.001 and p<0.001, respectively), compared with those without CHIP. Conversely, there was no effect of CHIP on OS or PFS in patients who received immunomodulatory maintenance after transplant.

The effects on PFS were surprising, Dr. Mouhieddine said, but “this possibly reflects the presence of an interaction taking place between the myeloma cells and CHIP clones in the tumor microenvironment that is allowing myeloma to progress at a faster rate in myeloma patients with CHIP.”

Limitations of the study include its retrospective nature and the nonrandomized selection of a cohort of patients who underwent AHCT. According to Dr. Mouhieddine, the findings from this study “can generate only hypotheses and can’t really demonstrate causality between CHIP and treatment outcome” due to the study’s inherent limitations.

“Moreover, the tumor samples at the time of diagnosis were not available to sequence to exclude mutations coming from the tumor itself that could be infiltrating the stem cell products,” he added. “Yet, most of the CHIP mutations are well-known leukemia driver mutations rather than myeloma mutations and, thus, we have a certain degree of confidence that these mutations are indeed CHIP mutations.”

Further research could assess the status of CHIP clones after AHCT in both the presence and absence of immunomodulatory maintenance, he noted. “We believe that this study lays the groundwork for future investigations, particularly ones that examine the intricate myeloma-CHIP cellular interactions and the combinatorial effect of CHIP, transplant, and immunomodulators on treatment outcome in MM,” Dr. Mouhieddine concluded.

The authors report no relevant conflicts of interest.

Reference

Mouhieddine T, Tahri S, Park J, et al. Immunomodulatory therapy improves outcome in multiple myeloma patients with clonal hematopoiesis. Abstract OAB-020. Presented at the 17th International Myeloma Workshop, September 13, 2019; Boston, Massachusetts.

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