Clinical Outcomes and Evolution of Clonal Hematopoiesis in Patients with Newly Diagnosed Multiple Myeloma

Abstract

Clonal hematopoiesis (CH) at time of autologous stem cell transplant (ASCT) has been shown to be associated with decreased overall survival (OS) and progression-free survival (PFS) in patients with multiple myeloma not receiving immunomodulatory drugs (IMiD). However, the significance of CH in newly diagnosed patients, including transplant ineligible patients, and its effect on clonal evolution during multiple myeloma therapy in the era of novel agents, has not been well studied. Using our new algorithm to differentiate tumor and germline mutations from CH, we detected CH in approximately 10% of 986 patients with multiple myeloma from the Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass) cohort (40/529 transplanted and 59/457 non-transplanted patients). CH was associated with increased age, risk of recurrent bacterial infections and cardiovascular disease. CH at time of multiple myeloma diagnosis was not associated with inferior OS or PFS regardless of undergoing ASCT, and all patients benefited from IMiD-based therapies, irrespective of the presence of CH. Serial sampling of 52 patients revealed the emergence of CH over a median of 3 years of treatment, increasing its prevalence to 25%, mostly with DNMT3A mutations.

Significance: Using our algorithm to differentiate tumor and germline mutations from CH mutations, we detected CH in approximately 10% of patients with newly diagnosed myeloma, including both transplant eligible and ineligible patients. Receiving IMiDs improved outcomes irrespective of CH status, but the prevalence of CH significantly rose throughout myeloma-directed therapy.

FIGURE 1

Classification of mutation origins. A, Scatterplot of observed VAFs in the PB and BM samples (n = 151). Colors specify the classification of each mutation by the winning model: CH (blue), germline (orange), or tumor (green). The scatterplot is in the log scale, with a small offset artificially labeled at y = 0 to visualize VAFs of 0 in select BM samples. B, Bar graph depicting total number of mutations classified as either CH, germline, or tumor.

FIGURE 2

The mutational spectrum of CH in 986 patients with multiple myeloma. A, The total number of patients harboring one or more mutations in each gene. B, Number of patients harboring mutations in one or two different genes. C, Commutation plot showing CH, tumor and germline mutations present in 129 patients: each column represents a single patient. The top row denotes the maximum VAF in each patient, with darker shades of red indicating higher VAF. The bar graph on the right designates the percentage of the different mutation subtypes for each gene out of all detected mutations.

FIGURE 3

Mutational properties. A, The maximum VAF attained by each of the 99 patients with CH. B, Distribution of VAF among different variants. C, Distribution of the types of single-nucleotide bp changes seen in all detected mutations.

FIGURE 4

OS and PFS of non-transplanted and transplanted patients with multiple myeloma with respect to CH and IMiD treatment. OS (A) and PFS (B) of all patients with CH versus those who do not have CH. OS (C) and PFS (D) of non-transplanted patients with CH versus those who do not have CH. OS (E) and PFS (F) among transplanted patients with CH versus those who do not have CH.