Zaucha, Jan Maciej

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10−9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10−4−5.79 × 10−14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10−4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10−4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10−4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3− B cells, CD5+IgD− cells, IgM− cells, IgD−IgM− cells, and CD4−CD8− PBMCs (p = 4.9 × 10−4−8.6 × 10−4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27− cells (p = 9.3 × 10−4). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3−, MCP-2−, and IL20-dependent pathways.

Abstract Background: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival. Methods: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed. Results: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P &lt; 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09–1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01–1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant. Conclusions: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. Impact: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.

BackgroundUpfront autologous hematopoietic stem cell transplantation (AHCT) remains an important therapy in the management of patients with multiple myeloma (MM), a disease of older adults.MethodsThe authors investigated the outcomes of AHCT in patients with MM who were aged ≥70 years. The Center for International Blood and Marrow Transplant Research (CIBMTR) database registered 15,999 patients with MM in the United States within 12 months of diagnosis during 2013 through 2017; a total of 2092 patients were aged ≥70 years. Nonrecurrence mortality (NRM), disease recurrence and/or progression (relapse; REL), progression‐free survival (PFS), and overall survival (OS) were modeled using Cox proportional hazards models with age at transplantation as the main effect. Because of the large sample size, a P value <.01 was considered to be statistically significant a priori.ResultsAn increase in AHCT was noted in 2017 (28%) compared with 2013 (15%) among patients aged ≥70 years. Although approximately 82% of patients received melphalan (Mel) at a dose of 200 mg/m2 overall, 58% of the patients aged ≥70 years received Mel at a dose of 140 mg/m2. On multivariate analysis, patients aged ≥70 years demonstrated no difference with regard to NRM (hazard ratio [HR] 1.3; 99% confidence interval [99% CI], 1‐1.7 [P = .06]), REL (HR, 1.03; 99% CI, 0.9‐1.1 [P = 0.6]), PFS (HR, 1.06; 99% CI, 1‐1.2 [P = 0.2]), and OS (HR, 1.2; 99% CI, 1‐1.4 [P = .02]) compared with the reference group (those aged 60‐69 years). In patients aged ≥70 years, Mel administered at a dose of 140 mg/m2 was found to be associated with worse outcomes compared with Mel administered at a dose of 200 mg/m2, including day 100 NRM (1% [95% CI, 1%‐2%] vs 0% [95% CI, 0%‐1%]; P = .003]), 2‐year PFS (64% [95% CI, 60%‐67%] vs 69% [95% CI, 66%‐73%]; P = .003), and 2‐year OS (85% [95% CI, 82%‐87%] vs 89% [95% CI, 86%‐91%]; P = .01]), likely representing frailty.ConclusionsThe results of the current study demonstrated that AHCT remains an effective consolidation therapy among patients with MM across all age groups.

Background: Autologous hematopoietic cell transplantation (AHCT) is an effective treatment to achieve deep and durable remission in multiple myeloma (MM). Typically, AHCT is offered to patients &lt;70 years of age, although the median age of diagnosis of MM is 70 years. We compared the outcomes of upfront AHCT across age groups for newly diagnosed MM in the era of novel therapies using the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Methods: We analyzed the outcomes of 15,999 MM patients aged 20 years and older from the USA who received a single AHCT with melphalan conditioning within 12 months of diagnosis between 2013 and 2017 and reported to the CIBMTR. Multivariate analysis was performed for non-relapse mortality (NRM), relapse/progression (REL), progression-free survival (PFS) and overall survival (OS) using Cox proportional hazards model with age at transplant in decades as the main effect. Hazard ratio (HR) with 95% confidence intervals (CI) are reported. Because of the large sample size, a p-value of &lt;0.01 was considered significant a priori. Results: Table 1 shows patient, disease and treatment characteristics by age group at diagnosis. All age groups had similar distribution of gender, race, ethnicity, Karnofsky performance score (KPS), comorbidity index (HCT-CI), stage III by Durie-Salmon/International Staging System. There was a higher proportion of high-risk cytogenetics in patients ≥70 years (30%), compared to age group 40-49 years (24%) and 20-39 years (20%) in this population. Older patients were more likely to be White compared to younger patients: 85% ≥70 compared to 64% 20-39 years. While 82% of the overall population received melphalan 200 mg/m2, 58% of the ≥70% received Mel 140 mg/m2. There were more ASCT performed in the ≥70-year age group in 2017 (28%) compared to 2013 (15%). Univariate outcomes by age groups shown in Table 2 revealed that 100-day NRM was higher in ≥70 years at 1% compared to younger patients (p &lt;0.01) and 2-year OS was lower in ≥70 years at 86 (85-88)% compared to 60-69 years, 89 (88-89)% (p&lt;0.01). When adjusted for other variables (Table 3), compared to reference age group of 60-69 years, patients ≥70 had similar NRM (HR 1.3, 95% CI 1, 1.7, p 0.06), REL (HR 1.03, 95% CI 0.9, 1.1, p 0.6), PFS (HR 1.06, 95% CI 1, 1.2, p 0.2), and OS (HR 1.2, 95% CI 1, 1.4, p 0.02). The leading cause of death across all age groups was primary disease. Among the ≥70 years cohort, melphalan dose was a surrogate for worse outcomes including NRM at 100 days (Mel 140, 1 (1-2)% vs Mel 200 0 (0-1)%, p 0.003, PFS at 2 years Mel 140 64 (60-67)% vs Mel 200 69 (66-73)%, p 0.003, and OS at 2 years (Mel 140 85 (82-87)% vs Mel 200 89 (86-91)%, p 0.01) (Figure). Conclusions: This is the largest study of AHCT in older adults with MM. More MM patients ≥70 years are being transplanted in the US over time. While our data may highlight referral and access biases regarding which older patients may be referred for ASCT, our results confirm that patients ≥70 years can undergo transplant safely and achieve similar benefits as 60-69 years' old patients. Our results also suggest that melphalan 200 mg/m2 may be given safely in the ≥70 years population. While melphalan conditioning dose 140 mg/m2 in the ≥70 group is associated with worse outcomes, this is likely a surrogate for higher frailty and comorbidities in this cohort of patients. Our analysis confirms that AHCT has similar benefits in terms of disease control (REL and PFS) in both young and older MM patients. This benefit is seen even in a contemporaneous era where proteasome inhibitors and/or immunomodulator drugs are used in upfront treatment. Thus, AHCT remains a safe consolidation therapy across all age groups of MM patients. Disclosures Hari: Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria. Kumar:Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. Shah:Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; University of California, San Francisco: Employment; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Qazilbash:Genzyme: Other: Speaker; Bioclinical: Consultancy; Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy. D'Souza:EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio: Research Funding; Prothena: Consultancy; Pfizer, Imbrium, Akcea: Membership on an entity's Board of Directors or advisory committees.