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Purpose The clinical outcome of multiple myeloma (MM) is heterogeneous. A simple and reliable tool is needed to stratify MM patients. We combined the International Staging System (ISS) with chromosomal abnormalities (CA) detected by interphase Fluorescence In Situ Hybridization (iFISH) after CD138 plasma cells purification and serum lactate dehydrogenase (LDH) to evaluate their prognostic value in newly diagnosed MM (NDMM). Methods Clinical and laboratory data from 4445 NDMM patients enrolled in eleven international trials were pooled together. The K-adaptive partitioning algorithm was used to define the most appropriate subgroups with homogeneous survival. Results ISS, CA, and LDH data were simultaneously available in 3060/4445 patients. We defined three groups: revised ISS (R-ISS) I (N=871), including ISS I (serum β2-microglobulin level <3.5mg/L and serum albumin level ≥3.5g/dL), no high-risk CA [del(17p) and/or t(4;14) and/or t(14;16)] and normal LDH level (below the upper limit of normal range); R-ISS III (N=295), including ISS III (serum β2-microglobulin level >5.5mg/L) and high-risk CA or high LDH level; R-ISS II (N=1894), including all the other possible combinations. At a median follow-up of 46 months, the 5-year OS was 82% in the R-ISS I, 62% in the R-ISS II, and 40% in the R-ISS III groups; the 5-year PFS was 55%, 36% and 24%, respectively. Conclusions The R-ISS is a simple and powerful prognostic staging system and we recommend its use in future clinical studies to stratify NDMM patients effectively with respect to the relative risk to their survival.

The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma. Daratumumab was associated with infusion-related reactions and a higher rate of neutropenia than the control therapy. (Funded by Janssen Research and Development; POLLUX ClinicalTrials.gov number, NCT02076009 .).

Patients with relapsed or refractory multiple myeloma who received a combination of elotuzumab, lenalidomide, and dexamethasone had a significant relative reduction of 30% in the risk of disease progression or death. (Funded by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT-2 ClinicalTrials.gov number, NCT01239797.).

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Lenalidomide maintenance after transplantation significantly prolonged progression-free and event-free survival among patients with multiple myeloma. Four years after randomization, overall survival was similar in the two study groups. (Funded by the Programme Hospitalier de Recherche Clinique and others; ClinicalTrials.gov number, NCT00430365.).

Multiple myeloma is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Here we use whole-exome sequencing, copy-number profiling and cytogenetics to analyse 84 myeloma samples. Most cases have a complex subclonal structure and show clusters of subclonal variants, including subclonal driver mutations. Serial sampling reveals diverse patterns of clonal evolution, including linear evolution, differential clonal response and branching evolution. Diverse processes contribute to the mutational repertoire, including kataegis and somatic hypermutation, and their relative contribution changes over time. We find heterogeneity of mutational spectrum across samples, with few recurrent genes. We identify new candidate genes, including truncations of SP140, LTB, ROBO1 and clustered missense mutations in EGR1. The myeloma genome is heterogeneous across the cohort, and exhibits diversity in clonal admixture and in dynamics of evolution, which may impact prognostic stratification, therapeutic approaches and assessment of disease response to treatment.