Overall Survival In Multiple Myeloma Research Articles

Abstract 6157: Population-specific 5-hydroxymethylcytosine signatures in circulating cell-free DNA and overall survival among Blacks and Whites with multiple myeloma

Abstract Background: Epigenetic modifications play important roles in the prognosis of multiple myeloma (MM). To date, DNA methylation (i.e., 5-methylcytosine) is the most extensively studied cytosine modification. Emerging evidence suggests that 5-hydroxymethylcytosine (5hmC), a product of 5mC through demethylation, in circulating cell-free DNA (cfDNA) is associated with the overall survival (OS) of MM. We also showed that African Americans (AAs) and European Americans (EAs) with MM have distinct genome-wide 5hmC profiles. However, no study has evaluated whether the association between 5hmC profiles and OS in MM differs between EAs and AAs. Methods: A total of 586 newly diagnosed patients with MM at the University of Chicago Medical Center were prospectively enrolled between 2010-2019. The current study profiled genome-wide 5hmC in plasma-derived cfDNA for 303 patients using the 5hmC-Seal and next-generation sequencing. Data cutoff was February 28, 2022. Vital status was ascertained using the National Death Index. OS was defined as the time from diagnosis until death from any cause. The 5hmC-Seal data were mapped to the human genome reference (hg19) and annotated to gene bodies. In each population, patients were randomly divided into a training set (EAs, n=147; AAs, n=64) and a testing set (EAs, n=64; AAs, n=28). After selecting the top 10% candidate genes associated with OS in age-adjusted univariate Cox proportional hazards model, we applied multivariable Cox models with elastic net regularization for feature selection through leave-one-out cross-validation. The optimal “alpha” and “lambda” were evaluated to maximize model performance measured by the Harrell’s Concordance Index. The differential 5hmC enrichment levels of selected genes were used to compute a weighted prognostic score (wp-score). The associations between the wp-scores and OS were evaluated in the testing sets, adjusting for established prognostic factors (e.g., age, stage). Results: Of the 303 MM patients, 94 (30.92%) were AA and 210 (69.08%) were EA. The median follow-up was 108 months. Our preliminary analyses identified 26 and 10 5hmC marker genes associated with OS in EAs and AAs, respectively. Importantly, none of these genes overlap between the two groups. We used these genes to compute wp-scores in EAs and AAs. In the training sets, patients with a higher wp-score had worse OS. The same trend was observed in the testing sets: hazard ratios (HR) in EAs: 1.31, 95% CI: (0.83, 2.06) and HR in AA: 11.94, 95% CI: (1.88, 75.68) after controlling for established prognostic factors. Conclusions: Our findings suggest that different epigenetic modifications in cfDNA might be associated with OS between EAs and AAs with MM and the 5hmC marker gene-based wp-scores are independent prognostic factors for MM. Citation Format: Bei Wang, Zhou Zhang, Benjamin Derman, Krissana Kowitwanich, Jason Cheung, Andrezej Jakubowiak, Chuan He, Wei Zhang, Brian Chiu. Population-specific 5-hydroxymethylcytosine signatures in circulating cell-free DNA and overall survival among Blacks and Whites with multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6157.

Enhancing prognostic power in multiple myeloma using a plasma cell signature derived from single-cell RNA sequencing

Multiple myeloma (MM) is a heterogenous plasma cell malignancy, for which the established prognostic models exhibit limitations in capturing the full spectrum of outcome variability. Leveraging single-cell RNA-sequencing data, we developed a novel plasma cell gene signature. We evaluated and validated the associations of the resulting plasma cell malignancy (PBM) score with disease state, progression and clinical outcomes using data from five independent myeloma studies consisting of 2115 samples (1978 MM, 65 monoclonal gammopathy of undetermined significance, 35 smoldering MM, and 37 healthy controls). Overall, a higher PBM score was significantly associated with a more advanced stage within the spectrum of plasma cell dyscrasias (all p < 0.05) and a shorter overall survival in MM (hazard ratio, HR = 1.72; p < 0.001). Notably, the prognostic effect of the PBM score was independent of the International Staging System (ISS) and Revised ISS (R-ISS). The downstream analysis further linked higher PBM scores with the presence of cytogenetic abnormalities, TP53 mutations, and compositional changes in the myeloma tumor immune microenvironment. Our integrated analyses suggest the PBM score may provide an opportunity for refining risk stratification and guide decisions on therapeutic approaches to MM.

Abstract B114: Population differences in the associations between chromosomal abnormalities and overall survival among Blacks and Whites with multiple myeloma

Abstract Background: Several primary and secondary cytogenetic abnormalities (e.g., translocation t(4;14) and 1q copy number changes) are associated with poor prognosis and worse survival of multiple myeloma (MM). Some of the aberrations (e.g., t(11;14), t(14;16), and t(14;20)) have been suggested, albeit inconclusively, to be enriched in Blacks. However, whether the associations between chromosomal abnormalities and overall survival (OS) of MM differ by race/ethnicity remains largely unknown. Methods: We prospectively enrolled 586 patients with newly diagnosed MM between 2010-2019 at the University of Chicago Medical Center. Of the 561 subjects identified as Black or White, 181 had chromosomal abnormalities determined by fluorescence in situ hybridization (FISH), which used CD138+ plasma cells enriched from bone marrow aspirates collected within 180 days of diagnosis. We analyzed data for 19 aberrations, including IGH/FGFR3 fusion [t(4;14)(p16,q32)]; IGH/CCND1 fusion [t(11;14)(q13,q32)]; IGH/MAF [t(14;16)(q32,q23)]; IGH/MAFB [t(14;20)(q32,q12)]; trisomies of chromosome 3, 7, 9, and 12; chromosome 13 deletion; loss of ATM [11q22.3]; gain of ATM; loss of TP53 [17p13.1]; gain of TP53; loss of CDKN2C [1p32.3]; gain of CKS1B [1q21]; IGH translocation with uncommon chromosome partners; IGH locus rearrangement; loss of IGH; and tetraploidy. Vital status was ascertained using the National Death Index. Baseline clinical and laboratory data were retrieved from electronic medical records. We used proportions and Chi-square tests to compare the distributions of cytogenetic abnormalities in Blacks and Whites. In each population, we evaluated the associations between cytogenetic abnormalities and OS using hazard ratios (HRs) and 95% confidence interval (CIs) from Cox proportional hazards models, adjusting for prognostic factors including age, international staging system, elevated lactate dehydrogenase, and estimated glomerular filtration rate. We used the Wald test of the cross-product terms to assess potential heterogeneity of effect in the HRs by race. Results: Of the 181 MM patients, 55 (30.39%) were Black and 126 (69.61%) were White. The median follow-up was 69 months. The frequencies of the 19 cytogenetic abnormalities did not differ between Blacks and Whites. However, we observed population differences in the associations between two chromosomal abnormalities and OS: the presence of t(4;14) was associated with worse OS in Blacks (HR=14.34 [2.17-94.58]; N=38) but not Whites (HR=2.04 [0.70-5.88]; N=99, p-heterogeneity = 0.08), whereas gain of 1q was associated with poorer OS in Whites (HR: 3.38, 95% CI: [1.25- 9.09], N=77), but not Blacks (HR=1.32 [0.31-5.68]; N=32; p-heterogeneity=0.02). Conclusions: Although we found similar frequencies of primary and secondary chromosomal abnormalities between Blacks and Whites, our data show population differences in the associations between two established high-risk cytogenetic abnormalities and the OS of MM. Our findings suggest that cytogenetic features may have varying impacts on the OS of MM based on race. Citation Format: Bei Wang, Benjamin A. Derman, Jason Cheung, Wei Zhang, Andrzej Jakubowiak, Brian C. Chiu. Population differences in the associations between chromosomal abnormalities and overall survival among Blacks and Whites with multiple myeloma [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B114.

Low Erythropoietin to Albumin Ratio in the Serum Predicts Less Reversibility of Renal Impairment with Poorer Prognosis in Multiple Myeloma

Background: Renal impairment (RI) is one of the most common clinical presentations in patients with multiple myeloma (MM) and contributes to its morbidity and mortality. In consistent with this, renal injury is an important factor considered high risk for MM in recently updated NCCN clinical practice guideline. It has been demonstrated that RI is reversible in about half the patients with MM and reversal of renal dysfunction significantly affects the prognosis of MM (Blood Cancer J. 2014 Aug 1;4(8):e235). Because reversibility of RI was a more important prognostic factor than response to anti-myeloma therapy in patients with MM with RI (Clin Lymphoma Myeloma Leuk. 2022 Aug;22(8):626-634; Eur J Haematol. 2000 Sep;65(3):175-81), identification of accurate non-invasive predictive markers for differentiating reversible / irreversible RI in MM patients treated with anti-myeloma therapy is undoubtedly needed. Methods: We conducted a retrospective study to evaluate the predicting value of serum erythropoietin (EPO) to albumin ratio (EPO/albumin) of MM patients treated with anti-myeloma therapy for reversibility of RI and overall survival (OS). RI was defined as an estimated glomerular filtration rate (eGFR) that was measured before treatment ≦50 ml/min per 1.73 m 2 by the simplified Modification of Diet in Renal Disease formula, and the definition of the reversibility of RI were also based on eGFR measurements, as previous publications described (J Clin Oncol. 2010 Nov 20;28(33):4976-84). Renal complete response (CRrenal) was defined as a sustained improvement from an eGFR baseline value of lower than 50 to ≥60 mL/min/1.73 m 2. Partial renal response (PRrenal) was defined as a sustained recovery of eGFR at the time of diagnosis of less than 15 to 30-59 mL/min/1.73 m 2; when achieved CRrenal or PRrenal, the MM patients with RI is defined as the renal responder group, otherwise, the MM patients with RI is defined as the renal non-responder group. Total 52 newly diagnosed MM patients with RI were analyzed in this study, 27 cases in the renal responder group and 25 cases in the renal non-responder group. Bortezomib with high-dose dexamethasone were used as the treatment of choice for such patients. Serum EPO levels were determined using chemiluminescence immunoassay. In our research, mean ± standard deviation (SD) was used to describe the normally distributed variables data while median with interquartile range (IQR) was used to describe the nonparametric variables data. P&amp;lt;0.05 was taken to indicate significance in all analyses. Results: There were significant differences in serum EPO and albumin, hemoglobin and RDW between the renal responder group and the non-responder group. The renal responder group had higher EPO [median: 44.06 (IQR: 160.96) vs 13.58(26.49)] and RDW [median:53(IQR:15) vs 48(9)], lower serum albumin (mean:30.21±SD: 7.78 vs 35.79±6.01) and hemoglobin. (mean:66.56±SD:16.42 vs 78.76±19.79), compared with the non-responder group. Of note, there were no significant differences in serum β2-Microglobulin, creatinine and eGFR at baseline between the two groups. As expected, serum EPO was negatively correlated with serum albumin (r = -0.257, P = 0.033). Likewise, EPO/albumin was negatively correlated with albumin (r = -0.42, P = 0.002); In contrast, EPO/albumin was positively correlated with serum EPO (r = 0.98, P &amp;lt; 0.001). Importantly, our study showed that EPO/albumin were independent predictor of the reversal of RI in MM patients. The optimal cutoff for EPO/albumin was determined via ROC analysis and was determined to be 1.77 U/g. The area under the curve was 0.784. According to the optimal cutoff value, low and high EPO/albumin groups were defined. The data confirmed that the group (n=36) with low EPO/albumin in the serum had shorter OS in MM with RI, compared with the group (n=16) with high EPO/albumin. Conclusions: Our findings demonstrated that low EPO/albumin in the serum predicts less reversibility of RI with poorer prognosis in MM, it is a reliable biomarker for predicting reversibility of RI in MM patients before anti-myeloma therapy. Figure 1

A Prospective, Multinational Study of Clinical and Biological Factors Associated with Short Overall Survival in Multiple Myeloma

Introduction: Multiple myeloma (MM) is an incurable cancer, but a subset of patients can achieve long-term remission and overall survival (OS). We aimed to study the clinical and biological factors associated with short OS defined as less than 3 years. Methods: A prospective, observational, multinational study was conducted by Australian and New Zealand (ANZ) and Asia-Pacific (APAC) Myeloma and Related Disease Registry (MRDR) from January 2013 to January 2023, across 5 countries (Australia, New Zealand, Korea, Singapore, Malaysia). Eligible patients were ≥18 years old, diagnosed with MM per International Myeloma Working Group (IMWG) criteria, received a bortezomib-containing triplet, and had at least 3 years of follow-up or had deceased within 3 years. Descriptive analysis was completed using chi-squared test for categorical variables and Wilcoxon rank-sum test for continuous variables. The Kaplan-Meier method was used for analysing OS and follow-up data. The ‘stepwise’ function in Stata was used for the forward stepwise logistic regression, with the p-value set to 0.1. All analyses were completed using Stata 16. Results: Of the 1539 patients enrolled, majority were from ANZ (1071 and 359, respectively), with male preponderance (61.0%). Half were above 65 years old. High risk cytogenetic abnormalities, a criterion of the Revised International Staging System (R-ISS), was unknown for half of the patients (49.4%). 45.3% patients presented as ISS stage 1, 21.9% stage II, and 32.8% stage III, respectively at study entry . The most frequent front-line agent used in combination with bortezomib-based triplet was cyclophosphamide [VCd, 1380 (89.7%)], followed by thalidomide [VTd, 92(6.0%)], lenalidomide [VRd, 63 (4.1%)] and daratumumab [DVd, 4 (0.3%)]. The median follow-up was 29.9 months (95%CI: 28.3-31.8) and the median OS was 87.7 months (95%CI: 80.9-93.2). Thirty percent patients had OS&amp;lt;3 years. Clinical and biological factors associated with long OS (≥3 years) were compared with those &amp;lt;3 years (Table 1). Baseline factors associated with higher odds of short OS included age≥65, Eastern Cooperative Oncology Group performance status (ECOG PS)≥2, ISS III, lower creatinine clearance and platelet count, high LDH and poor cytogenetic abnormalities (Table 1). In a multivariate analysis, age≥65 (OR:2.50; p&amp;lt;0.001), ECOG≥2 (OR:2.08; p&amp;lt;0.001), ISS III (OR:2.48; p&amp;lt;0.001), t(4;14)[OR:2.04; p=0.004], t(14;16)[OR:6.33; p=0.004] and 17p deletion (OR:2.77; p =0.001) were associated with a significantly shorter OS. Conclusion: From clinician perspective, identifying patients with an increased likelihood of shorter OS through the determination of patient- and disease-specific risk factors might be clinically relevant to facilitate better treatment decisions.

Patterns of Change in Multiple Myeloma (MM) Clone Size with Autologous Hematopoietic Stem Cell Transplantation (ASCT) Assessed By Next Generation Sequencing (NGS) in Patients (pts) Receiving Modern Therapy

Background Measurable residual disease (MRD) is a quantitative, dynamic prognostic marker of progression free and overall survival in MM. With modern triplet and quadruplet induction strategies deep responses are the norm and the incremental effect of ASCT impact may vary substantially among pts and be influenced by disease and treatment features. However, the accurate characterization of the impact of ASCT is diluted by measuring a disease surrogate (paraprotein) instead of clone size. We examine the quantitative impact of ASCT on MM clone size by serial NGS testing before and after ASCT and evaluate disease and induction treatment features that modulate this impact. Methods We included pts with newly diagnosed MM from five US centers, who received modern triplet and quadruplet induction followed by single melphalan ASCT between 3/2018 and 5/2023 with MRD testing (ClonoSEQ®) pre and post ASCT. ClonoSEQ® platform utilizes NGS to quantify unique immunoglobulin genes rearrangements associated with MM clone, therefore directly capturing clone size. We excluded pts with clone size &amp;lt;10 -5 prior to ASCT. We explored patient-, disease-, and treatment features influencing clone size reduction with AHCT by 1 log 10. We used binary logistic regression to identify factors associated with ≥1 log 10 clone reduction (60-100 days post ASCT). Results One hundred and forty-nine pts with NDMM had pre and post ASCT results and pre ASCT MRD ≥10 -5 and met the inclusion criteria. The median age was 63 years (35-79), 37 pts (25%) ≥70 years, 62% male, 27% Black, 23% ISS3 and 16% RISS3. Seventy-three pts (49%) had high risk chromosomal abnormalities [HRCA, gain/amp(1q), t(4;14), t(14;16), t(14;20) or del(17p)]); 72 pts (48%) had 0 HRCA, 50 (34%) had 1 HRCA, and 23 (15%) had 2+ HRCA. AntiCD38 monoclonal antibody (mAb) was part of induction in 125 (84%) pts [68 pts quadruplet containing carfilzomib; 53 pts quadruplet containing bortezomib], 28 pts received triplets. Eighty-seven pts (58%) had &amp;gt;1log 10 reduction in MRD burden with ASCT. The median log reduction in MRD burden was 1.15 (IQR 0.65-1.75). For pts with 0, 1 and 2+ HRCA, 47% (34/72), 68% (34/50), 74% (17/23) had a &amp;gt;1 log 10 reduction in clone size and the median reduction was 0.96 log 10 (IQR 0.47-1.66), 1.24 log 10 (IQR 0.89-1.91) and 1.5 log 10 (IQR 0.89-2.20), respectively (Figure). Among pts without HRCA, those with hyperdiploid MM had a trend towards less frequent ≥1 log 10 clone size reduction with ASCT (38% vs. 57%, p=0.18). Overall, we saw reduction ≥1 log 10 in clone size in 61% of pts receiving anti-CD38 mAb in induction (N=125) vs. 46% among those who did not (N=24, p= 0.18). Among pts treated with melphalan 200 mg/m 2 (N=113) compared to those who received 140 mg/m 2 (N=36), ≥1 log 10 reduction in clone size was noted in 61% vs. 50% (p=0.25), respectively. In multivariable analysis that included stage, antiCD38 mAb in induction, use of carfilzomib in induction, HRCA and melphalan dose, the presence of HRCA was the only factor associated with greater than 1 log 10 reduction in MRD burden with ASCT [1 HRCA, OR 2.34 (1.07-5.14); ≥2 HRCA, OR 2.71 (0.91-8.03); p=0.049]. Conclusions The impact of high dose melphalan and AHCT on MM clone size is heterogeneous, of greater magnitude in pts with one or more high-risk chromosome abnormalities, and less pronounced in pts with standard risk disease, particularly hyperdiploid MM. The use of antiCD38 mAb in induction regimens or dose of melphalan does not impact the effect of ASCT on MM clone size, likely owing to the distinct mechanism of action of melphalan. This dataset provides context to explore risk- and response-adapted use of ASCT and use of new cellular and non-cellular immunotherapies as post-induction consolidative strategies.

P-186 Proteasome regulatory ATPase PSMC2 promotes drug resistance by mitigating ER stress and portends reduced overall survival in multiple myeloma

P-186 Proteasome regulatory ATPase PSMC2 promotes drug resistance by mitigating ER stress and portends reduced overall survival in multiple myeloma

High expression of HOXC6 predicts a poor prognosis and induces proliferation and inflammation in multiple myeloma cells.

Multiple myeloma (MM) is a common blood system malignance accompanied by monoclonal plasma cell hyperplasia. Homeobox C6 (HOXC6) acts as an oncogene in various cancers, but its function on MM is elusive. The role of HOXC6 on MM development was clarified in this study. HOXC6 expression and its clinical significance were determined in the peripheral blood samples collected from forty MM patients and thirty healthy adult volunteers. The overall survival was evaluated by Kaplan-Meier analysis with the log-rank test. Cell viability, proliferation and apoptosis were measured by CCK-8, EdU assay and Flow cytometry in U266 and MM.1R cells. Tumor growth was estimated by a xenograft assay. The apoptosis of tumor tissues was evaluated using TUNEL staining. The protein level in tissues was tested by immunohistochemistry. The HOXC6 expression was elevated in MM and high HOXC6 level was associated with the poor overall survival of MM. Besides, the HOXC6 expression was associated with hemoglobin level and ISS stage. Furthermore, silencing HOXC6 suppressed cell proliferation, induced cell apoptosis, and restrained the secretion of inflammatory factors (TNF-α, IL-6, and IL-8) in MM cells through inactivating the NF-κB pathway. Moreover, silencing HOXC6 suppressed the tumor growth of MM, the inflammatory factors levels, and the activation of NF-κB pathway but enhanced apoptosis in vivo. HOXC6 was elevated in MM and associated with poor survival. Knockdown of HOXC6 suppressed proliferation, inflammation and tumorigenicity of MM cells via inactivating the NF-κB pathway. HOXC6 may be a meaningful target for MM therapy.

Abstract LB188: Discovery and development of fully human TACI/BCMA bispecific armored CAR for the treatment of relapsed/refractory multiple myeloma

Abstract Background: The introduction of novel targeted therapies and immunotherapies has dramatically improved responses and overall survival in multiple myeloma (MM) patients. However, greater than 50% MM achieve refractory or relapse (r/r) within five-year due to MM target heterogeneity and bone marrow tumor microenvironment (TME). The approved B-cell maturation antigen (BCMA) -directed CAR T therapies have shown unprecedented efficacy in advanced r/r MM, yet relapse remains to occur. The shedded soluble BCMA, target escape and bone marrow TME may contribute to the r/r MM mechanism through compromising clinical efficacy and durability. TACI and BCMA are co-expressed on the tumors of ~78% MM patients, and therefore, dual targeted TACI/BCMA CAR therapy could be an attractive strategy in addressing challenges of BCMA mono-CAR therapy. We have developed EPC-004, a fully human anti-TACI and BCMA bispecific armored tandem CAR, aiming to overcome BCMA target escape mechanism, reduce immunosuppression within the bone marrow tumor microenvironment, and be more persistent with engineered armor and the improved cell manufacturing process. Methods: Fully human anti-TACI, anti-BCMA and anti-PDL1 scFv antibodies with a broad affinity range and epitope coverage have been discovered by proprietary mRNADisTM mRNA display and live cell selection platform. The T cell modulatory activity fine-tuned IL2 was discovered by the mSCAFoldTM technology through the structure guided mutagenic library design and high throughput systemic screening. The anti-PDL1 scFv was then fused to the engineered IL2 to generate an armor molecule to enhance CAR activities and persistence. Finally, EPC-004, an optimal bispecific tandem TACI/BCMA armored CAR candidate, was developed by precision engineering of multiple pairs of anti-TACI and BCMA scFvs with monospecific and bispecific target binding properties, spacers and scFv orientation. Results: EPC-004 demonstrated both mono-specific and bispecific TACI and BCMA target cell engagement and effective cytotoxic cancer cell killing activities. EPC-004 showed potent anti-tumor activity in MM1R, BCMA knock out or TACI knock out MM1R -luciferase orthotopic animal models, which validated the mechanism of EPC-004 in overcoming BCMA or TACI target escape resistance. Furthermore, EPC-004 showed strong persistent CAR-T activity against tumor cells in re-challenging models in mice. Importantly, the secreted armor molecule selectively activates central memory T cells and contributed to the enhanced anti-tumor activity and persistence in vivo. Conclusion: EPC-004, engineered with multi-modules and multi-mechanisms is a promising candidate which enhances anti-tumor activity, prevents target escape, reduces immunosuppression within the bone marrow tumor microenvironment. These novel mechanisms could potentially translate EPC-004 into durable clinical efficacy in treating R/R multiple myeloma. Citation Format: Garima Agrahari, Wenle Liang, Katie O'Callaghan, Keming Zhang, Ning Jiang, Xiaoyi Jin, Ryan Feng, Jenna Nguyen, Sam Hassan, Annie Luu, Tony Ruan, Kehao Zhao, Yan Chen. Discovery and development of fully human TACI/BCMA bispecific armored CAR for the treatment of relapsed/refractory multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB188.

Impaired Plasma B Cell Markers in CD138+ Cells Predict Prognosis in Multiple Myeloma

Background: Multiple myeloma (MM), characterized by the proliferation of clonal plasma B-cell in the bone marrow, is the second most common hematologic malignancy in the US. MM represents the final stage in a continuum of plasma cell dyscrasias, arising from the premalignant conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). Despite therapeutic advances, MM remains incurable with the prognostic improvement observed only in a subset of patients. The variations in clinical course are largely caused by the underlying intertumoral heterogeneity between different patients. To further improve the clinical outcome of MM patients, biomarkers that can effectively stratified patients are critically needed for directing personalized treatment. In this study, we hypothesize that the magnitude of plasma B cell malignancy is a primary factor that determines the clinical phenotypes of MM patients, which can be reflected by gene expression in CD138+ cells. Methods: Using single-cell RNA sequencing (scRNA-seq) data, we develop a plasma B gene signature and apply it to gene expression profiles of CD138+ cells from MM patients (Figure 1 A). The resulting score, denoted as plasma B cell malignancy (PBM) score, indicates the degree of plasma B cell malignancy of MM samples with a higher value indicating higher malignancy status. Genomic and/or transcriptomic data from five MM studies (i.e., MMRF CoMMpass, UAMS, MAQC-II and APEX phase 3 trial and Chng study) were used to examine the associations between PBM score and known MM driver genes, and its clinical impact on MM progression and prognosis. Univariate and multivariate Cox regression models were constructed to evaluate the prognostic value of patient specific PBM scores when used alone or combined with established clinical factors. Results: Survival analysis indicates that the PBM score defined based on plasma B cell markers are significantly associated with patient overall survival. In contrast, gene signatures charactering other immune cells are less (other three B cell types) or not prognostic (non-B immune cell types) (Figure 1 B). Then we investigated the effects of PBM score on MM development and prognosis. Overall, a higher PBM score was significantly associated with a more advanced stage in the spectrum of plasma cell dyscrasias (all P < 0.05, Figure 1C). Higher PBM score was also associated with shorter overall survival (OS) in patients with MM (HR = 1.72, P < 0.001) (Figure 1D) and its prognostic effect was independent of the currently available clinical prognostic model, such as the International Staging System (ISS) (Figure 1E). Mutation status of TP53 gene has been found to be associated with patient prognosis. Investigations on the relationships between PBM score and MM driver genes found that the PBM score was significantly increased in patients carrying TP53 mutations compared to those with mild-type alleles. Of note, PBM scores could predict patients’ survival even among those who don't carry TP53 mutations, with log-rank P values of 0.002 (Figure 1F). The model based on the PBM score alone had a c-index of 0.62 to predict the OS of MM. The clinical model based on age, sex, race, and (ISS) stage had a c-index of 0.67 to predict OS. Incorporating PBM score into the models based on clinical factors significantly improved the prognostic performance of the models, with the c-index increased to 0.70 for the model that combined PBM and clinical factors (P < 0.001) (Figure 1G).Conclusions: There may be a clinical utility of the PBM score to predict MM outcomes in combination with more standard clinical parameters. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

African American Race Is a Potential Favorable Biologic Factor That Impacts Clinical Outcome for Patients with Multiple Myeloma

Multiple myeloma (MM) remains an incurable malignancy characterized by plasma cells that are nurtured and proliferate within the permissive bone marrow milieu. It has a greater incidence in African Americans (AA) compared to whites (13.8 vs. 6.5/100,000). The five-year age adjusted mortality rate, according to SEER database, is greater in AA compared to white Pts (5.8 vs. 2.9/100,000), which is likely explained by a greater incidence in the AA population. However, recent reports have also shown that AAs with equal access to care have an even better survival than their white counterparts [Fiala et al. Cancer. 2017]. Conversely, results from the CoMMpass registry database showed that OS was shorter for AA compared with Whites (age-adjusted hazard ratio (HR) 1.7, 95% confidence interval 1.2-2.4, P = 0.003) [Derman et al. Blood Cancer J. 2020]. Here, we report the interplay of race and other dimensions of MM care using the National Cancer Database (NCDB). Methods: NCDB is the largest cancer database in the US including >70% of all newly diagnosed cancer patients. The International Classification of Diseases for Oncology (ICD-O) code of 9732 was used. OS was calculated from the date of MM diagnosis. Given that Smoldering MM (SMM) does not have specific ICD code, we defined patients who did not receive any treatment within 3 months after the diagnosis as SMM, similar to other authors (Ravindran et al. Blood Cancer J. 2016). Initiation of systemic treatment was considered as a surrogate of progression to symptomatic MM. Overall survival (OS) of SMM patients was calculated from initiation of systemic treatment after they progressed to MM, estimated by the Kaplan-Meier method, and compared with the log-rank test. Cumulative incidence of progression from SM to MM was calculated with death as a competing risk and compared with the Gray's test. Multivariable Cox and logistic regression analysis were performed to identify independent predictors of OS and progression to MM, respectively. Results: We identified 56,021 patients with MM and 11,485 with SMM between 2010 to 2014 in this database. Among MM patients, 42,836 (76%) were white and 11,255 (20%) self-identified as AA. For AA patients, there was a lower proportion of Medicare (46 vs. 56%), and private insurance (35 vs. 36%) and a higher percentage of Medicaid (11 vs. 5%) and uninsured Pts (6 vs. 3%) compared to Pts that self-identified as white. A larger proportion of AAs had a Charlson score ≥1 (30 vs. 24%, p<0.001). The percentage of Pts who underwent radiation was higher among whites compared to AA (23 vs 8%). However, unadjusted OS was greater for AA compared to white Pts, 55 vs. 48 months, respectively (P < 0.0001). Among SMM patients, 8,324 (72%) were white and 2,756 (24%) were AA. SMM was diagnosed in AA patients at a median of 3.7 years younger than in white patients. Similar socioeconomic disparities were observed in SMM as in MM cohort. The time from diagnosis of SMM to first therapy which is indicative of progression from SMM to MM is the same among AA and white (median time in days 136 vs 135 days, p=0.672) with comparable OS. Multivariable Cox and logistic regression analysis showed that lower age, AA race, Female gender, ASCT, living in a higher income area and having Medicare or Private insurance compared to no insurance were independent predictors for better OS in MM. Although other predictive factors persisted for patients with SMM, race did not reach statistical significance. Conclusion: Taken together, our results utilizing one of the largest available datasets in the US, reflect a similar outcome for AA and white patients with MM despite a clear disparity in healthcare access and SES. This finding might suggest a more favorable biology of the disease among AA Pts. The lower rate of radiation among AA is also an indirect measure of bone complications. AA enjoy less bone loss and fractures under physiologic and pathologic conditions. Further studies to elucidate the role of bony compartment of the MM microenvironment at the cellular and molecular levels might be able to explain this disparity and help advance a more personalized treatment options to improve outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Cancer-Related Circrna Cirs-7 (CDR1-AS) Is Differentially Expressed in CD138+ Cells of Patients with Plasma Cell Disorders and Predicts Unfavorable Overall Survival in Multiple Myeloma

Introduction: During the last decades, different non-coding RNAs have been implicated in the biology and prognosis of multiple myeloma (MM). Circular RNAs (circRNAs) constitute a class of non-coding RNAs with a high potential as molecular biomarkers. Recently, ciRS-7 (also known as CDR1-AS), an important circRNA regulating miR-7-5p and other cancer-related miRNAs, was shown to be downregulated in MM patients’ cells exhibiting acquired resistance to immunomodulatory drugs (IMiDs). Our goal was to study the expression of this circRNA in MM, compare the results with those of patients with smoldering myeloma (SMM) and monoclonal gammopathy of undetermined significance (MGUS) and evaluate its prognostic significance. Methods: Bone marrow aspirate (BMA) samples were collected from 177 adult patients with plasma cell disorders. The presence of high-risk cytogenetic abnormalities, namely del(17p), t(4;14), t(14;16), and (+1q), was assessed using fluorescence in situ hybridization (FISH). MM patients were classified according to the ISS and revised ISS (R-ISS) staging systems. Whole-body low-dose computed tomography was used to assess osteolysis. Next, CD138-positive selection of plasma cells among mononuclear cells of BMA samples was performed. Moreover, three human MM cell lines (L-363, H929 and U266) were propagated. Total RNA was extracted from CD138+ enriched BMA samples and the MM cell lines, and reverse-transcribed. A first-round PCR was used to pre-amplify ciRS-7 and GAPDH (i.e. reference gene) transcripts, before their quantification via real-time qPCR. In both reactions for ciRS-7 amplification, divergent PCR primers were used, to achieve high specificity and accuracy. ciRS-7 expression was measured in relative quantification units (RQU). Results: The cohort of patients consisted of 111 newly diagnosed MM, 35 SMM and 31 with MGUS. In total, 107 out of the 177 cases (60.5%) were male and 70 (39.5%) were female. The median age of all patients at diagnosis was 70 years (range: 35-93 years). According to the R-ISS staging system, 24 (21.6%) MM patients had R-ISS stage I, 62 (55.9%) R-ISS stage II and 25 (22.5%) had R-ISS stage III. Seventy-seven (69.4%) MM patients presented with osteolytic disease at diagnosis. Regarding front-line therapy of MM patients, 12/111 (10.8%) received proteasome inhibitor (PI)-based therapy, 7 (6.3%) received IMiD-based treatment, 74 (66.7%) were treated with combinations of PI and IMiD, and 18 (16.2%) received anti-CD38-based treatment. The intracellular levels of the ciRS-7 circRNA were different between MM, SMM and MGUS patients’ CD138+ plasma cells (median values were: for MM patients 0.40 RQU vs. 1.74 RQU for SMM patients vs. 2.79 RQU for MGUS patients; P<0.001). Moreover, ciRS-7 levels in U266 and H929 cells were much lower (2,165- and 26,616-fold) than in L-363 cells. ROC analysis showed that ciRS-7 expression can effectively discriminate between MM and SMM patients (AUC=0.65, 95% CI=0.56-0.75, P=0.007). ciRS-7 levels did not significantly differ among MM patients with different ISS or R-ISS stages and were not associated with any assessed cytogenetic abnormality or the presence of osteolytic lesions. Regarding the progression-free (PFS) and overall survival (OS), out of 106 MM patients with survival data, patients with high levels of ciRS-7 have lower survival probabilities. As shown in Figure 1, the median PFS of MM patients with high ciRS-7 (high: defined as higher of the median value) was 19 months vs. 25 months for patients with low ciRS-7 (lower values than the median) (P=0.046); similarly, the mean OS of ciRS-7 (high) MM patients was 25 months vs. 30.5 months for ciRS-7 (low) MM patients (P=0.008). Bootstrap multivariate Cox regression analysis showed that the unfavorable prognostic value of ciRS-7 expression with regard to OS is independent of R-ISS stage and age of MM patients (HR=2.6, BCa 95% CI=0.91-4.75, bootstrap P=0.041). Conclusions: Expression levels of ciRS-7, a cancer-related circRNA, in CD138+ plasma cells are significantly different among patients with MM, SMM and MGUS. Most likely, high ciRS-7 levels predict an unfavorable prognosis in MM, independently of the R-ISS stage and age. Combining our results with the limited existing literature providing evidence for ciRS-7 implication in response to IMiD therapy, its biological role in MM deserves further elucidation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Proteasome Regulatory Atpases PSMC2 and PSMC6 Modulate Proteosome Inhibitor Sensitivity and Correlate with Survival in Multiple Myeloma

Background: Multiple myeloma (MM) cells synthesize and secrete massive amounts of immunoglobulins and thus are exquisitely sensitive to therapeutics that disrupt proteostasis. The 26S proteasome complex is a 2.5-MDa holoenzyme comprised of >32 individual subunits responsible for the bulk of intracellular protein degradation. 26S proteasomes are comprised of barrel-shaped proteolytic core complex, the 20S core particle (CP), capped at either or both ends by 19S regulatory particles (RPs), which confer ATPase activity and specificity for ubiquitinated proteins. Six distinct ATPases (PSMC1-6) form a heterohexameric ring-like structure that rests atop the 20S CP's α-subunits and is responsible for unfolding and shuttling target proteins for degradation within the 20S CP. The proteasome inhibitor (PI) bortezomib (BTZ) is a potent, selective, and reversible drug that dramatically improved the prognosis of multiple myeloma (MM) patients and remains the backbone of induction therapy for transplant-eligible new diagnosis MM (NDMM), but response to therapy remains highly variable. Here, we predicted that gene expression analysis of publically available datasets could identify components within the ubiquitin-proteasome system (UPS) that areprognostic in patients treated with BTZ, suggesting potential new targets in MM. Methods: We interrogated gene expression profiles (GEP) from the randomized, phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study that compared BTZ with high-dose dexamethasone (DEX) in RRMM patients who had received 1-3 prior therapies. APEX datasets served as a test cohort to identify genes that influenced survival in patients treated with BTZ. Patients consented to genomic analyses of pretreatment tumor samples. CD138+ cells were isolated from BM aspirates and analyzed by RNA microarrays to generate GEP datasets. We correlated gene expression with response to BTZ or DEX and overall survival (OS). We then validated individual genes identified from the APEX analysis using the MM Research Foundation (MMRF) CoMMpass study, a longitudinal observational analysis of the clinical and molecular data for >1000 NDMM patients receiving various standard approved treatments. Finally, we used shRNA to knockdown PSMC2 in RPMI8226 and ARH77 cells and tested their sensitivity to BTZ and carfilzomib (CFZ). Results: Analysis of the APEX dataset revealed that increased expression of genes PSMC2 and PSMC6, members of the heterohexameric ATPase ring of the 19S RP, correlated with poorer OS (PSMC2- Figure 1A, PSMC6- Median OS 320 versus 620 days for upper and lower tertile PSMC6, respectively). Using the CoMMpass database, increased PSMC2 expression also correlated with a worse OS (Figure 1B), while increased PSMC6 correlated with worse OS as well as progression free survival (PFS) (OS- HR= 2.29 p=0.0014, PFS- HR=1.63 p=0.0109). PSMC6 displayed greater expression in 50 patients above the median RNA expression (Fragments per Kb transcript per million mapped reads (FPKM)= 1 to 100) while PSMC2 expression was elevated in 400 patients above the median (FPKM= 25 to 100). shRNA-mediated PSMC2 knockdown (KD) increased PI susceptibility in ARH77 and the RPMI8226 MM cells. In ARH77 cells, the BTZ LD50 decreased from 11 nM to 2.5 nM and the CFZ LD50 decreased from 11 to 9 nM in control and KD cells, respectively. In RPMI8226 cells, the BTZ LD50 decreased from 30 nM to 20 nM and the CFZ LD50 decreased from 28 to 17 nM in control and KD cells, respectively. Conclusion: Taken together, our results indicate that increased PSMC2 and PSMC6 correlates with OS in MM in both patients treated with BTZ in the APEX and with a variety of standard therapies in the CoMMpass database. Analysis in this validation cohort extends the clinical significance of PSMC2/PSMC6 beyond the landmark APEX trial and suggests they may inform survival in patients treated with modern triplet anti-myeloma therapies. In addition to the prognostic importance across our test and validation datasets, point mutations in each ATPase subunit have been associated with PI resistance. Consistent with these findings, PSMC2 KD increased sensitivity to PI therapy. Controlled inhibition or degradation of proteasome 19S ATPase subunits using small molecules, PROTACs or RNA-based modalities now provides an opportunity to therapeutically target proteostasis in MM and other malignancies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Causal AI in silico Patient Model Identifies Minichromosome Maintenance (MCM) Family Genes As Novel Predictors for Overall Survival in Multiple Myeloma

The minichromosome maintenance (MCM) complex is among the best-known protein families involved in eukaryotic replication initiation. The six conserved proteins of the MCM complex, namely MCM2-MCM7, have been well studied and form a DNA helicase. Dysregulation of members of the MCM complex has been demonstrated in multiple cancer types, including gastric cancer, liver cancer, cervical cancer, and prostate cancer, among others. However, comparatively little is currently known about the role of the MCM complex in hematological oncology. We show here the first evidence of a causal link between members of the MCM complex, specifically MCM2, MCM3, and MCM4, and overall survival of multiple myeloma patients. This result was further validated in a separate, externally collected cohort of patients. In this study, an in-silico patient model of Multiple Myeloma Research Foundation (MMRF) IA19 CoMMpass data was developed using GNS Healthcare's Causal AI technology, REFSTM. REFSTM has been previously used to analyze MMRF data to identify the epigenetic regulator PHF19 as a marker of aggressive disease. Simulated genetic perturbations performed on the in-silico model identified changes in the expression of DNA replication genes MCM2, MCM3, and MCM4 as strong causal drivers of overall survival (OS) in MM patients (MCM2 and MCM4 shown in figure 1). These targets were validated using a Cox proportional-hazards model on an out-of-cohort Dana-Farber Cancer Institute MM dataset (DFCI). We report Cox hazard ratios of 1.62 (1.41, 1.85), 1.72 (1.42, 2.10), and 1.75 (1.50, 2.05) respectively, for MCM2, MCM3 and MCM4 in the MMRF IA19 dataset. Among patients in the DFCI dataset, we report Cox hazard ratios of 1.40 (1.09, 1.79), 1.50 (1.14, 1.99), and 1.56 (1.17, 2.08), respectively for MCM2, MCM3 and MCM4. In addition, causal modeling indicated large negative prognostic median effect sizes for overall survival. In summary, this work demonstrates MCM2, MCM3, and MCM4 as candidate genes involved in MM pathology. These genes are known targets in other cancers due to their role in DNA replication and cell cycle pathways. We could not identify any existing Open Targets literature related to these genes as drug targets or predictive markers in MM. Our results, validated out-of-cohort, suggest that MCM2, MCM3, and MCM4 are newly discovered predictors of overall survival among multiple myeloma patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Association of Socioeconomic Status with Adherence, Progression Free and Overall Survival to Oral Agents in Multiple Myeloma Patients

Background: The introduction of novel oral immunomodulatory drugs has improved overall survival (OS) rates of patients with multiple myeloma (MM). Poor adherence to oral therapies may lead to drug resistance, poor response to treatment and other untoward effects. The purpose of this study was to examine the impact of socioeconomic status (SES) on adherence to oral MM medications, progression-free survival (PFS) and OS. Methods: This is a retrospective cohort study from 9/1/18-9/1/21 of data from a large national healthcare payor in the United States. Eligibility criteria include adult patients who had ≥ 2 visits with ICD-10 patient disease codes C90.X, received an oral oncolytic for MM with ≥ 3 fills and had continuous enrollment for six months post-study inclusion. We created SES bands based on the American Community Survey (ACS) and the Behavioral Risk Factor Surveillance System (BRFSS) data and combined "Very Low” and 'Low” and "Very High” and "High” into "Low” and "High” categories, respectively. We measured adherence using the medication possession ratio (MPR), calculated as the total days supplied in the period/length of the period; we defined optimal adherence as an MPR ≥ 0.8. We computed PFS for the entire cohort and defined it as the time from inclusion until the first date of visit with an ICD-10 code of C90.X3 indicting relapse, or date of death, whichever occurred first. We computed OS for the Medicare Advantage (MA) sub-population only (we did not have date of death for the Commercial population) and defined it as the time from inclusion until the date of death, defined as the date of disenrollment with the reason listed as "death.” We used multivariable logistic regression to assess the impact of SES on adherence. We estimated PFS and OS using the Kaplan-Meier method. We used Cox proportional hazard regression analysis and Aalen's additive hazard model to determine which variables correlated with PFS and OS; p-values less than 0.05 were significant. Results: 1,351 patients met the inclusion criteria; most 755 (55.9%) were adherent. The mean (SD) age was 71.5 (10.4) years, 736 (54.5%%) were men, 779 (57.7%) were White, 656 (48.6%) had a low SES and 972 (77.6%) had MA coverage. The median National Cancer Institute (NCI) comorbidity index was 0.47 (Interquartile range (IQR) 0 to 1.03). There were high rates of polypharmacy, with 29.2% of the population receiving 5-7 different classes of therapies. In the multivariate model, age was the only factor significantly associated with increased odds of adherence. Patients between the age of 65 to 73 years and 74 to 79 years of age were significantly more likely to be adherent to oral MM agents 1.55 (95% CI, 1.12-2.14) (p< 0.001) and 1.49 (95% CI, 1.05-2.11) (p< 0.001), respectively when compared to patients < 65 years of age. Patients with a low SES, compared with a high SES, were less likely to be adherent 0.77 (95% CI, 0.57-1.03); however, this association was not statistically significant. When examining PFS by adherence, significantly more patients experienced progression in the non-adherent cohort (25.7% vs. 19.9%; p = 0.13) compared to the adherent cohort. The proportion of patients who did not progress to disease at 36 months was 71.3% in adherent patients and 58.3% in non-adherent patients (p=0.03) (Figure 1). Adherence was significantly associated with a lower hazard of progression, controlling for SES, NCI score and being a new MM patient, p = 0.016. There was no significant association between PFS and SES. OS was calculated for the MA subpopulation only. Death was significantly less likely to occur in the adherent cohort (7.0% vs. 17.8%; p < 0.001) compared to the non-adherent cohort. The proportion of patients still alive at 36 months was 84.7% in adherent patients and 69.0% in non-adherent patients (p<0.01) (Figure 2). Adherence was associated with a lower hazard of death, controlling for SES, NCI score and age, p <0.01. There was no significant association between OS and SES. Conclusions: SES was not associated with adherence, PFS or OS in this study. However, adherent patients experienced significantly longer PFS and OS. To the authors’ knowledge, this is the first study evaluating drug adherence in MM oral agents across the United States. Future studies are needed to determine risk factors influencing non-adherence to oral MM agents so that vulnerable patients are identified and corrective actions are taken to maximize adherence and increase therapeutic success. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Body Mass Index and Overall Survival of Patients with Newly Diagnosed Multiple Myeloma.

Obesity is associated with survival in several solid tumors and non-Hodgkin lymphoma, but its impact on multiple myeloma (MM) survival is unclear. We examined the associations between body mass index (BMI) at different periods of life up to the time of diagnosis and overall survival (OS) among 563 patients newly diagnosed with MM in 2010-2019. BMI at diagnosis was calculated using measured height and weight from electronic medical records (EMR). BMIs at age 20, maximum during adulthood, and 5 years before diagnosis were calculated using self-reported weights and measured height from EMR. Over a median follow-up of 49.3 months, 191 (33.93%) deaths were identified. We used multivariable Cox proportional-hazards models to examine the associations between BMIs and OS. Height as well as BMI before and at diagnosis was not associated with OS, but there is a U-shape association between weight and OS. Higher BMIs at diagnosis were associated with better OS among females (HR = 0.39 [0.22-0.71]), irrespective of race. In conclusion, our results suggest that BMI at different periods of life up to the time of diagnosis may not be associated with OS in MM, except that a higher BMI at diagnosis was associated with superior OS for females.

NAIRscore as a biomarker for the quality of immune response to neoantigens is related with an increased overall survival in multiple myeloma

Neoantigen provides a promising breakthrough in tumor immunotherapy, although only a subset of patients responds well due to the quality of their immune response. However, few biomarkers have been reported to measure the quality of immune response to neoantigens and to predict prognosis of patients with multiple myeloma (MM). Here, we first developed a neoantigen-prediction pipeline starting from outcomes of somatic mutations and gene-expression profiles. Given the expression of some specific marker genes, the human leukocyte antigen (HLA)-I score and the cytolytic score were evaluated respectively to reflect HLA-I molecular expression and CD8+ T/natural killer (NK) cell abundance. According to the process of the immune response to neoantigens, we comprehensively took neoantigen load, cytolytic score, and HLA-I score to construct a neoantigen immune response score (NAIRscore), in which the HLA-I score presented a hazard ratio (HR) of less than 1, while the cytolytic score and neoantigen load presented a HR of greater than 1. Meanwhile, NAIRscore presented a competitive advantage to stratify MM samples. Especially, those exhibiting high NAIRscore correlated with an increased overall survival (OS), echoing the underlying molecular signatures of lower driver-gene mutations and down-regulated immune response. Notably, an online tool based on this study is provided to identify neoantigens and predict OS.

Does a Multiple Myeloma Polygenic Risk Score Predict Overall Survival of Patients with Myeloma?

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. 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. 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. Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.

Body mass index and overall survival in multiple myeloma.

e20007 Background: Elevated body mass index (BMI) is associated with a higher risk of multiple myeloma (MM), but its influence on survival is unclear. Studies evaluating BMI and mortality of MM have reported conflicting findings and most have limited data on clinical prognostic factors. We evaluated the associations between BMI at different life stages up to the time of diagnosis and overall survival (OS) in a cohort of newly diagnosed patients with MM. Methods: A total of 583 newly diagnosed MM patients were prospectively enrolled between 2010-2019 at the University of Chicago Medical Center. Epidemiology questionnaire and blood samples were collected at the time of diagnosis. We collected baseline clinical, laboratory, cytogenetic, and treatment data from electronic medical records. Vital status was ascertained using the National Death Index. Patients were followed through 31 December 2020 with an average follow-up length of 77.8 months. BMI was calculated using height and weight information collected from electronic health records and questionnaires. OS was defined as time from diagnosis until death from any cause. Chi-squared test and t-test were used to compare characteristics of patients by vital status. Hazard Ratios (HR) and 95% confidence intervals (CI) were derived from Cox proportional hazards models to examine the associations between BMI at different times and OS, adjusting for potential confounders. Stratified analyses were done to examine sex- and race-specific associations. Results: The median age at diagnosis was 63 years, 45% (n = 258) were female, and 27% (n = 150) were African Americans. Of the 572 MM patients, 176 (31%) deaths were identified during the follow-up. There was no significant association between elevated BMI at different time points (i.e., at diagnosis, 5 years before diagnosis, age 20, and maximum adulthood BMI) and OS after adjusting for age, race, sex, and prognostic variables (e.g., stage, serum lactate dehydrogenase levels). No association was found for both African Americans and European Americans. However, for women, obesity (BMI &gt; = 30) at the time of diagnosis was associated with a better OS (HR = 0.25; 95% CI = 0.12-0.54 for obese vs. normal weight) whereas in men, obesity at the time of diagnosis was associated with worse OS (HR = 2.54; 95% CI = 1.18-5.49). Conclusions: We found no association between BMI and OS in MM, irrespective of race. Our data showed that, compared to subjects with normal BMI at the time of diagnosis, female patients with elevated BMI had better survival, whereas a higher BMI was associated with inferior OS among male patients. Our findings of an effect modification by sex are novel and warrant further investigations. These findings might have clinical significance because BMI is amenable to lifestyle modification.

Second Revision of the International Staging System (R2-ISS) for Overall Survival in Multiple Myeloma: A European Myeloma Network (EMN) Report Within the HARMONY Project.

Patients with newly diagnosed multiple myeloma (NDMM) show heterogeneous outcomes, and approximately 60% of them are at intermediate-risk according to the Revised International Staging system (R-ISS), the standard-of-care risk stratification model. Moreover, chromosome 1q gain/amplification (1q+) recently proved to be a poor prognostic factor. In this study, we revised the R-ISS by analyzing the additive value of each single risk feature, including 1q+. The European Myeloma Network, within the HARMONY project, collected individual data from 10,843 patients with NDMM enrolled in 16 clinical trials. An additive scoring system on the basis of top features predicting progression-free survival (PFS) and overall survival (OS) was developed and validated. In the training set (N = 7,072), at a median follow-up of 75 months, ISS, del(17p), lactate dehydrogenase, t(4;14), and 1q+ had the highest impact on PFS and OS. These variables were all simultaneously present in 2,226 patients. A value was assigned to each risk feature according to their OS impact (ISS-III 1.5, ISS-II 1, del(17p) 1, high lactate dehydrogenase 1, and 1q+ 0.5 points). Patients were stratified into four risk groups according to the total additive score: low (Second Revision of the International Staging System [R2-ISS]-I, 19.2%, 0 points), low-intermediate (II, 30.8%, 0.5-1 points), intermediate-high (III, 41.2%, 1.5-2.5 points), high (IV, 8.8%, 3-5 points). Median OS was not reached versus 109.2 versus 68.5 versus 37.9 months, and median PFS was 68 versus 45.5 versus 30.2 versus 19.9 months, respectively. The score was validated in an independent validation set (N = 3,771, of whom 1,214 were with complete data to calculate R2-ISS) maintaining its prognostic value. The R2-ISS is a simple prognostic staging system allowing a better stratification of patients with intermediate-risk NDMM. The additive nature of this score fosters its future implementation with new prognostic variables.