High-risk disease in newly diagnosed multiple myeloma: beyond the R-ISS and IMWG definitions

Abstract

Multiple myeloma (MM) is an acquired malignant plasma cell disorder that develops late in life. Although progression free and overall survival has improved across all age, race, and ethnic groups, a subset of patients have suboptimal outcomes and are labeled as having high risk disease. A uniform approach to risk in NDMM remains elusive despite several validated risk stratification systems in clinical use. While we attempt to capture risk at diagnosis, the reality is that many important prognostic characteristics remain ill-defined as some patients relapse early who were defined as low risk based on their genomic profile at diagnosis. It is critical to establish a definition of high risk disease in order to move towards risk-adapted treatment approaches. Defining risk at diagnosis is important to both effectively design future clinical trials and guide which clinical data is needed in routine practice. The goal of this review paper is to summarize and compare the various established risk stratification systems, go beyond the R-ISS and international myeloma working group risk stratifications to evaluate specific molecular and cytogenetic abnormalities and how they impact prognosis independently. In addition, we explore the wealth of new genomic information from recent whole genome/exome sequencing as well as gene expression data and review known clinical factors affecting outcome such as disease burden and early relapse as well as patient related factors such as race. Finally, we provide an outlook on developing a new high risk model system and how we might make sense of co-occurrences, oncogenic dependencies, and mutually exclusive mutations.

Fig. 1. High-risk clinical features.

^*Large FLs (diameter >2.5 cm) associated with site-specific enrichment of HiR driver mutations consistent with them being key mediators of drug resistance and treatment failure [–100]. ^**Certain EME sites seemed to carry worse prognosis with 3-year PFS differing according to involved organs: kidney (59.5%), skin (20.1%), lymph nodes (37.6%), CNS (47.9%), lung/respiratory tract (44.4%), GI/liver (22.5%), and spleen, ovaries, and testes (60.0%). BM bone marrow, CA cytogenetic abnormalities, CPCs circulating plasma cells, EBMT European Society for Blood and Marrow Transplantation, EME extramedullary myeloma that is extra-osseous (results from hematogenous spread and involving only soft tissues, the incidence in NDMM 1.7–3.5%), EMB extamedullary myeloma that is paraskeletal or paraosseous plasmacytomas (consists of tumor masses adjacent to bones and arising from focal skeletal lesions, incidence in NDMM 6–34.4%), EMM extramedullary myeloma, FL focal lesion, HR hazard ratio, ISS international staging system, MRI magnetic resonance imaging, MV multivariate, NDMM newly diagnoses multiple myeloma, NR not reached, OS overall survival, PC plasma cells, PCPI plasma cell proliferation index, PET-CT 18-fluoro-deoxyglucose emission tomography, PFS progression-free survival, R-ISS revised international staging system, TT total therapy.