Defining and Managing High-Risk Multiple Myeloma: Current Concepts

Abstract

Multiple myeloma is a very heterogeneous disease. Despite advances in diagnostics and therapeutics, a subset of patients still experiences abbreviated responses to therapy, frequent relapses, and short survival and is considered to have high-risk multiple myeloma (HRMM). Stage III diagnosis according to the International Staging System; the presence of del(17p), t(4;14), or t(14;16) by fluorescence in situ hybridization; certain gene expression patterns; high serum lactic dehydrogenase level; and the presence of extramedullary disease at diagnosis are all considered indicators of HRMM. More recent evidence shows that patients who experience response to therapy but with a high burden of measurable residual disease or persistence of abnormal FDG uptake on PET/CT scan after initial therapy also have unfavorable outcomes, shaping the concept of dynamic risk assessment. Triplet therapy with proteasome inhibitors, immunomodulatory agents, and corticosteroids and autologous hematopoietic cell transplantation remain the pillars of HRMM therapy. Recent evidence indicates a benefit of immunotherapy with anti-CD38 monoclonal antibodies in HRMM. Future trials will inform the impact of novel immunotherapeutic approaches, including T-cell engagers, CAR T cells, and nonimmunotherapeutic approaches in HRMM. Those agents are likely to be deployed early in the disease course in the setting of risk- and response-adapted trials.

Autologous Stem Cell Transplantation in Multiple Myeloma: Where Are We and Where Do We Want to Go?

“…The correct definition of “high-risk MM” is very difficult in the modern era, when not only stage ISS, cytogenetic abnormalities [t(4;14), t(14;16), t(14;20), copy number abnormalities such as gain(1q) and del(17p)], elevated LDH value, renal failure, the presence of extramedullary disease or plasma cell leukemia are considered markers of HR MM. Now it could be necessary to evaluate other novel aspects such as gene expression profiling, somatic mutations at diagnosis, chromothripsis, TP53 biallelic inactivation, and some dynamic characteristics such as deepness of response to therapy through MRD assessment (in bone marrow samples, imaging PET-CT or circulating plasma cells) in order to build a dynamic risk assessment [ 81 , 82 ]. Indeed, patients experiencing relapse within 18 months of diagnosis are considered to have functional HR MM.…”

Multiple Myeloma: Molecular Pathogenesis and Disease Evolution

“…Despite the recent improvements in therapy for MM patients, a group of high-risk disease patients consistently demonstrates poor outcomes upon standard therapy [56]. High-risk disease, which is present in 20–30% of all cases, cannot be defined by a single pathogenic mechanism, but rather arises from the interplay of several genetic lesions leading to high proliferation rates, evasion of apoptosis, and therapy resistance [20].…”

Aggressive Plasmablastic Myeloma With Extramedullary Cord Compression and Hyperammonemic Encephalopathy: Case Report and Literature Review

“…Similarly, chromosome 1q addition (+1q), one of the most common chromosomal abnormalities seen in MM, has been shown to be an independent negative prognosticator for poor overall survival (19,20). Its negative effect on survival appears to be more profound in the presence of other co-occurring chromosomal abnormalities, such as deletion 1q or 1q tetrasomy (20,21). Although our patient had no 17p deletion or translocations t(4;14) and t(14;16), he unfortunately had +1q together with deletion 1q and 1q tetrasomy.…”