Numerical abnormalities of chromosome 1q (+1q21) are common in patients with newly diagnosed multiple myeloma (MM) but their prognostic impact remains a matter of debate. In addition, the impact of the number of copies of 1q21 is not known. We analyzed 912 consecutive patients with symptomatic MM to evaluate the prognostic implications of +1q21 and of their copy number variations, as assessed by FISH. At the time of initial diagnosis, 249 (27.3%) patients had +1q21, of which 150 (16.4%) had 3 copies and 99 (10.9%) had 4 or more copies. Presence of +1q21 was associated with advanced ISS stage (p = .003), concurrent presence of other cytogenetics aberrations and advanced R‐ISS stage (p < .001). Patients with +1q21 had inferior PFS (median 34 vs. 20 months, p < .001) and OS (median 75 vs. 44 months, p < .001) but the copy number of 1q21 had no additional prognostic impact. In multivariate analysis, adjusting for R‐ISS, age, treatment and HDM, +1q21 remained an independent prognostic factor both for PFS (p < .001) and OS (p = .008). The detrimental prognostic effect of +1q21 was more profound in R‐ISS‐3 patients, identifying a subgroup with OS of just 16 months (vs. 46 for R‐ISS‐3 without +1q21, p < .001). We further validated our findings in an independent cohort of 272 patients. In conclusion, the presence of +1q21 is associated with more advanced disease, inferior PFS, and OS but especially patients with R‐ISS‐3 disease and +1q21 have a very poor outcome comprising an ultra‐high‐risk group.

Background: Carfilzomib, an irreversible proteasome inhibitor approved for the treatment of relapsed/refractory Multiple Myeloma (MM) has been associated with Thrombotic Microangiopathy (TMA). Several pathogenetic mechanisms of carfilzomib-induced TMA have been proposed; however, recently, there has been a shift of focus on the potential contribution of complement dysregulation. Our aim was to explore whether patients with carfilzomib-induced TMA harbor germline variants of complement-related genes, which have been characterized as risk factors for TMA. Methods: We retrospectively recruited consecutive MM patients with carfilzomib-induced TMA and compared them to MM patients who received ≥4 cycles of carfilzomib and did not develop signs/symptoms of TMA, in a 1:2 ratio. Genomic DNA from peripheral blood was analyzed using next generation sequencing (NGS) with a complement-related gene panel; ADAMTS13 activity and soluble C5b-9 were measured using ELISA. Results: Complement-related variants were more common in patients with carfilzomib-induced TMA compared to non-TMA controls, regardless of patient and treatment characteristics; ADAMTS13 activity and C5b-9 were compatible with the phenotype of complement-related TMA. Conclusions: We confirmed the previous findings that implicated complement-related genes in the pathogenesis of carfilzomib-induced TMA. Most importantly, by incorporating a control group of non-TMA MM patients treated with carfilzomib-based regimens and functional complement assays, we enhanced the credibility of our findings.

We evaluated the efficacy and prognostic impact of bortezomib‐lenalidomide triplet (VRd) or daratumumab‐based quadruplets (DBQ) versus previous anti‐myeloma therapies, that is, bortezomib standard combinations (BSC) or conventional chemotherapy (CT), in a large cohort of patients with primary plasma cell leukemia (pPCL), including those fulfilling the revised diagnostic criteria, that is, circulating plasma cells (cPCS): ≥5%; 110 pPCL patients (M/F: 51/59; median age 65 years, range: 44–86) out of 3324 myeloma patients (3%), registered in our database between 2001 and 2021, were studied; 37% had cPCS 5%–19%; 89% received novel combinations including DBQ (21%), VRd (16%) and BSC (52%); 35% underwent autologous stem cell transplantation. 83% achieved objective responses. Treatment with VRd/DBQ strongly correlated with a higher complete response rate (41% vs. 17%; p = .008). After a median follow‐up of 51 months (95% CI: 45–56), 67 patients died. Early mortality was 3.5%. Progression‐free survival was 16 months (95% CI: 12–19.8), significantly longer in patients treated with VRd/DBQ versus BSC/CT (25 months, 95% CI: 13.5–36.5 vs. 13 months 95% CI: 9–16.8; p = .03). Median overall survival (OS) was 29 months (95% CI: 19.6–38.3), significantly longer in patients treated with VRd/DBQ versus BSC/CT (not reached vs. 20 months, 95% CI: 14–26; 3‐year OS: 70% vs. 32%, respectively; p < .001; HzR: 3.88). In the multivariate analysis VRd/DBQ therapy, del17p(+) and PLT <100.000/μL, independently predicted OS (p < .05). Our study has demonstrated that in the real‐world setting, treatment with VRd/DBQ induces deep and durable responses and is a strong prognostic factor for OS representing currently the best therapeutic option for pPCL.

Despite treatment improvements there is still a respectable proportion of newly diagnosed multiple myeloma (MM) patients that experience early progressive disease (EPD) defined as relapse or progression <18 months from start of therapy.

No abstract