Abstract
Introduction: Multiple Myeloma (MM) is a clonal plasma cell malignancy, accounting for 10% of all hematological malignancies. Genetic analyses of large populations revealed that blood-specific somatic mutations in hematopoietic stem cells (HSCs) are commonly acquired during aging, a new entity labeled: clonal hematopoiesis of indeterminate potential (CHIP). We sought to determine the role of CHIP on survival of MM patients, specifically those receiving immunomodulator (IMiD) maintenance (Lenalidomide or Thalidomide) post autologous stem cell transplant (ASCT).
Methods: We collected the cryopreserved, growth factor mobilized peripheral blood of 629 MM patients who underwent ASCT between 2003 and 2011 at the Dana-Farber Cancer Institute (DFCI). Then, we performed targeted next-generation sequencing using a 224-gene panel at a mean depth of coverage of 978X and ultra-low pass whole-genome sequencing at 0.1X to account for tumor contamination. We downloaded (dbGAP # phs000748.v6.p4) the whole-exome sequencing (WES) data of a cohort of 1144 newly diagnosed, untreated MM patients from the Multiple Myeloma Research Foundation (MMRF) Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass, NCT0145429) study (MMRC) and the WES data of a cohort of 205 newly diagnosed, untreated MM patients from the Broad Institute dataset. We analyzed their peripheral blood (average coverage of 108X) and tumor (average coverage of 107X) data separately, looking for the same CHIP genes included in our target bait panel.
Results: The DFCI cohort had a median age of 58 years [range, 24-83] at time of ASCT and median follow up post ASCT of 8 years [range, 0.1-14.5]. 204 patients (32%) in the DFCI cohort had CHIP at time of ASCT. The most commonly detected mutated genes were DNMT3A, TET2, TP53, ASXL1 and PPM1D. 24 patients (3.8%) developed a second hematological malignancy at a median of 4 years [range, 1-10] post ASCT, half of whom had CHIP. Around 48% of the DFCI cohort received IMiDs as part of induction therapy. Different induction regimens had no effect on CHIP prevalence at time of ASCT. Around 56% of the DFCI cohort received IMiD maintenance, 22% of which received maintenance for at least 3 years [range, 0.06-12.8]. Among those who did not receive IMiD maintenance, patients with CHIP had worse progression free survival (PFS) (p-value < 0.001) and overall survival (OS) (p-value = 0.005). In patients receiving IMiD maintenance, having CHIP had no effect on PFS or OS. On the other hand, the MMRF cohort had a median age of 63 years [range, 27-93] and median follow up of 3.03 years [range, 0-5.9] from time of diagnosis. Around 52% of that cohort underwent ASCT and around 76% of those received IMiD maintenance with a median follow up of 2.7 years [range, 0-5.5] from time of ASCT. Furthermore, 200 patients of the MMRF cohort have follow-up samples of both tumor and peripheral blood that had targeted sequencing done by a 562-gene panel that included our genes of interest. Similarly, when studying the genomic results of 139 out of 1144 MMRF patients, as well as the 205 patients from the Broad Institute dataset, we detected CHIP in 25.6% of them and the top 5 most commonly mutated genes were similar to those of our cohort.
Conclusion: CHIP is a common entity among MM patients, reaching a prevalence of up to 32%, that predicts a worse PFS and OS in those who do not receive IMiD maintenance therapy post ASCT. As expected, IMiD maintenance improves outcome in MM patients, with and without CHIP. In patients with CHIP, the use of IMiDs abrogated the deleterious effect imposed by CHIP to a point that outcome is identical to that of patients without CHIP.
Bustoros:Dava Oncology: Honoraria. Munshi:OncoPep: Other: Board of director. Anderson:Gilead: Membership on an entity's Board of Directors or advisory committees; OncoPep: Equity Ownership, Other: Scientific founder; Celgene: Consultancy; C4 Therapeutics: Equity Ownership, Other: Scientific founder; Bristol Myers Squibb: Consultancy; Millennium Takeda: Consultancy. Richardson:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Soiffer:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Ghobrial:Celgene: Consultancy; Janssen: Consultancy; BMS: Consultancy; Takeda: Consultancy.
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