Characteristics and outcomes of patients with multiple myeloma aged 21–40 years versus 41–60 years: a multi-institutional case-control study

We compared the outcomes of multiple myeloma (MM) patients aged 21–40 and 41–60 years in the novel agent era. This case-control study included 1089 patients between 2000 and 2015. Cases and controls were matched for sex, International Staging System (ISS) stage and institution. There were 173 patients in the younger group and 916 patients in the older group. Younger patients presented with a higher incidence of lytic lesions (82% vs. 72%; P = 0·04) and high-risk cytogenetic abnormalities (83% vs. 68%; P = 0·007), but lower rate of elevated lactate dehydrogenase (21% vs. 44%; P < 0·001). Five- and 10-year overall survival (OS) in younger versus older patients was 83% vs. 67% and 56% vs. 39%, respectively (P < 0·001). Similar results were seen when studying the subset of 780 patients who underwent autologous transplantation. Younger patients with ISS stage 1 had a better OS than older patients (P < 0·001). There was no survival difference between younger and older patients with ISS stage 2 or 3. Younger MM patients, aged 21–40 years, treated in the era of novel agents have a better OS than their counterparts aged 41–60 years, but the survival advantage observed in younger patients was lost in more advanced stages of MM

Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk

<div><p>The high-risk pedigree (HRP) design is an established strategy to discover rare, highly-penetrant, Mendelian-like causal variants. Its success, however, in complex traits has been modest, largely due to challenges of genetic heterogeneity and complex inheritance models. We describe a HRP strategy that addresses intra-familial heterogeneity, and identifies inherited segments important for mapping regulatory risk. We apply this new Shared Genomic Segment (SGS) method in 11 extended, Utah, multiple myeloma (MM) HRPs, and subsequent exome sequencing in SGS regions of interest in 1063 MM / MGUS (monoclonal gammopathy of undetermined significance–a precursor to MM) cases and 964 controls from a jointly-called collaborative resource, including cases from the initial 11 HRPs. One genome-wide significant 1.8 Mb shared segment was found at 6q16. Exome sequencing in this region revealed predicted deleterious variants in <i>USP45</i> (p.Gln691* and p.Gln621Glu), a gene known to influence DNA repair through endonuclease regulation. Additionally, a 1.2 Mb segment at 1p36.11 is inherited in two Utah HRPs, with coding variants identified in <i>ARID1A</i> (p.Ser90Gly and p.Met890Val), a key gene in the SWI/SNF chromatin remodeling complex. Our results provide compelling statistical and genetic evidence for segregating risk variants for MM. In addition, we demonstrate a novel strategy to use large HRPs for risk-variant discovery more generally in complex traits.</p></div

Prognostic indicators in primary plasma cell leukaemia: a multicentre retrospective study of 117 patients

We report a multicentre retrospective study that analysed clinical characteristics and outcomes in 117 patients with primary plasma cell leukaemia (pPCL) treated at the participating institutions between January 2006 and December 2016. The median age at the time of pPCL diagnosis was 61&nbsp;years. Ninety-eight patients were treated with novel agents, with an overall response rate of 78%. Fifty-five patients (64%) patients underwent upfront autologous stem cell transplantation (ASCT). The median follow-up time was 50&nbsp;months (95% confidence interval [CI] 33; 76), with a median overall survival (OS) for the entire group of 23&nbsp;months (95% CI 15; 34). The median OS time in patients who underwent upfront ASCT was 35&nbsp;months (95% CI 24·3; 46) as compared to 13&nbsp;months (95% CI 6·3; 35·8) in patients who did not receive ASCT (P&nbsp;=&nbsp;0·001). Multivariate analyses identified age ≥60&nbsp;years, platelet count ≤100&nbsp;×&nbsp;109 /l and peripheral blood plasma cell count ≥20&nbsp;×&nbsp;109 /l as independent predictors of worse survival. The median OS in patients with 0, 1 or 2-3 of these risk factors was 46, 27 and 12&nbsp;months, respectively (P&nbsp;&lt;&nbsp;0·001). Our findings support the use of novel agents and ASCT as frontline treatment in patients with pPCL. The constructed prognostic score should be independently validated. © 2018 John Wiley &amp; Sons Lt