Multiple myeloma (MM), an incurable plasma cell malignancy of the bone marrow (BM), is a particularly heterogeneous cancer,1,2 whose progression from the well-defined precursor stages of monoclonal gammopathy of undetermined significance and smoldering MM is induced by marked evolution.3 The branching evolution pattern of MM tumor cells enables tumor clones with increased fitness to evolve in parallel and expand in various anatomical sites leading to increased genomic heterogeneity.4-6 Despite the significant improvement in progression-free survival and overall survival that has been achieved through high-dose chemotherapy with autologous stem cell transplantation (ASCT) and novel immunomodulatory therapies, MM remains an incurable disease, and the majority of patients will eventually relapse.7-9
One fascinating question for those who study this disease is whether new disease sites at relapse indicate pre-existing, though previously undetected, clones, or new dissemination of disease seeding. To that end, Dr. Heather J. Landau and colleagues made an effort to systemically investigate the development of relapsed MM over time. They performed whole-genome sequencing of 25 tissue samples collected at warm autopsy from four patients with relapsed/refractory MM, including 21 tumor and four nontumor samples taken from uninvolved skeletal muscle. They also interrogated an additional set of 125 whole exomes sequenced from 51 patients using previously published data.10 Similar to previously reported mutational signature SBS35, which is associated with treatment with platinum-based chemotherapy, they discovered a relapse-specific, new mutational signature named SBS-MM1 that is associated with high-dose melphalan exposure used for treating active MM and for conditioning before ASCT. This new signature is only acquired by each myeloma cell that was exposed to melphalan but managed to survive and expand, suggesting that exposure to distinct therapies influences the mutational landscape of relapsed MM.
Phylogenetic trees were created to define the timeline of mutational process for relapsed MM based on the clonal and subclonal composition of each patient in the whole-genome sequencing and whole-exome sequencing cohorts. The large number of SBS-MM1–related mutations shared by all the different biopsy sites could only be explained by the existence of a single clone surviving after high-dose melphalan therapy followed by ASCT. This single propagating clone then further disseminates to form different subclones at distinct anatomic sites, reflecting high spatial heterogeneity of MM. SBS3511 conversely, can only be observed in patients who received platinum-based chemotherapy, suggesting that distinct therapies trigger differences in mutational landscape of relapsed MM.
In Brief
Collectively, this study investigates an unanswered question in relapse about the origin of new disease development after therapy. This study reveals the genomic and mutational landscape of relapsed myeloma by showing how therapeutic treatments can introduce unique mutations in each surviving cancer cell, enabling the expansion of clonal tumor cells bearing the mutational signature. The high spatial and heterogenous anatomic dissemination is likely the result of selection for more aggressive or proliferative clones and treatment-related immunosuppression, which leads to much faster progression or dissemination than spontaneous evolution of tumor cells prior to initial diagnosis or exposure to therapy. Their findings suggest that post-transplantation reconstitution of the immune system could affect the efficacy of initial high-dose chemotherapy followed by ASCT. A comprehensive understanding of both genomic characterization of tumor cells and the immunologic milieu is therefore essential to the rational development of combined personalized therapies and immunotherapeutic interventions, while relapse remains the primary cause of treatment failure. The time between post-ASCT and relapse provides a critical window for immunotherapeutic modalities such as vaccines and checkpoint blockade agents to induce antitumor immune response for preventing the expansion of survived, more aggressive clones from earlier chemotherapy.
References
Competing Interests
Dr. Shen and Dr. Ghobrial indicated no relevant conflicts of interest.
