Survival Of Multiple Myeloma Patients Research Articles

E3 ubiquitin ligase ASB8 promotes selinexor-induced proteasomal degradation of XPO1

Selinexor (KPT-330), a small-molecule inhibitor of exportin-1 (XPO1, CRM1) with potent anticancer activity, has recently been granted FDA approval for treatment of relapsed/refractory multiple myeloma and diffuse large B-cell lymphoma (DLBCL), with a number of additional indications currently under clinical investigation. Since selinexor has often demonstrated synergy when used in combination with other drugs, notably bortezomib and dexamethasone, a more comprehensive approach to uncover new beneficial interactions would be of great value. Moreover, stratifying patients, personalizing therapeutics and improving clinical outcomes requires a better understanding of the genetic vulnerabilities and resistance mechanisms underlying drug response. Here, we used CRISPR-Cas9 loss-of-function chemogenetic screening to identify drug-gene interactions with selinexor in chronic myeloid leukemia, multiple myeloma and DLBCL cell lines. We identified the TGFβ-SMAD4 pathway as an important mediator of resistance to selinexor in multiple myeloma cells. Moreover, higher activity of this pathway correlated with prolonged progression-free survival in multiple myeloma patients treated with selinexor, indicating that the TGFβ-SMAD4 pathway is a potential biomarker predictive of therapeutic outcome. In addition, we identified ASB8 (ankyrin repeat and SOCS box containing 8) as a shared modulator of selinexor sensitivity across all tested cancer types, with both ASB8 knockout and overexpression resulting in selinexor hypersensitivity. Mechanistically, we showed that ASB8 promotes selinexor-induced proteasomal degradation of XPO1. This study provides insight into the genetic factors that influence response to selinexor treatment and could support both the development of predictive biomarkers as well as new drug combinations.

The prognostic role of 1q21 gain/amplification in newly diagnosed multiple myeloma: The faster, the worse.

The prognostic value of additional copies of chromosome 1q (1q gain/amplification [amp]) in multiple myeloma (MM) remains controversial. In the meantime, the kinetics of the response to MM therapy has long been an area of debate. Few studies have pointed out the relationship of response kinetics with cytogenetic abnormalities (CAs) in MM. The authors retrospectively analyzed the data of 1068 real-world newly diagnosed MM patients from a Chinese national medical center. Overall, 405 (51.9%) patients had 1q gain/amp, with aggressive clinical characteristics and significant inferior survival. The variation in copy number (CN) of 1q (CN=3 or CN>3) had no significant impact on the survival of MM patients with 1q abnormalities. No difference was found in the outcome of 1q gain/amp patients treated with doublet or triplet regimens. Upfront autologous stem cell transplantation could eliminate the adverse prognostic effect of 1q gain but not 1q amp. The duration from diagnosis to the first time achieving very good partial response (VGPR) or better was significantly shorter in patients with 1q gain/amp (77days vs. 100days, p=.001). Finally, multifactor regression analysis was performed to construct a new risk stratification model in MM patients with 1q gain/amp, which was validated in the Multiple Myeloma Research Foundation CoMMpass study cohort and worked better than the Revised International Staging System and Second Revision of the International Staging System (Harrell's concordance index: 0.631 vs. 0.598 and 0.537). In the setting of novel therapy, 1q gain/amp still acts as an independent adverse prognostic factor. Patients with 1q gain/amp achieved VGPR rapidly but had inferior survival.

A prognostic model incorporating inflammatory cells and cytokines for newly diagnosed multiple myeloma patients.

Peripheral blood cell counts and cytokines can be used as predictors of multiple myeloma (MM) patients' outcomes. 313 newly diagnosed MM patients treated with novel agents were divided into training and validation cohorts. We selected the common peripheral blood cell counts, including the lymphocyte/monocyte ratio (LMR), neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio (PLR), systemic inflammation response index (SIRI), and serum cytokines which contained tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-2 receptor (IL-2R), interleukin-8 (IL-8), interleukin-6 (IL-6), and interleukin-10 (IL-10) as related variables. The least absolute shrinkage and selection operator (LASSO) regression was conducted to sort the predictor variables in the training cohort, and then the developed nomogram was assessed in the training and validation cohort. Our study showed that SIRI, PLR, and IL-8 were independent prognostic factors for the survival of MM patients. Patients with lower SIRI (≤ 0.87) had superior survival than patients with higher SIRI (> 0.87). Further, according to the LASSO regression, a nomogram embracing LMR (> 3.78), SIRI (> 0.87), PLR (≤ 106.44), and IL-8 was established. The nomogram demonstrated a better correlation with the outcomes of MM patients in the training cohort than International Staging System (ISS) and Revised-International Staging System (R-ISS). The same results were verified in the validation cohort. The nomogram incorporating inflammatory cells and cytokines could be a helpful tool to stratify MM patients in the era of novel agents.

The Correlation of miR-671-5p with Diagnosis and Prognosis in Multiple Myeloma.

This study aimed to investigate the value of miR-671-5p in multiple myeloma (MM) in diagnostics and prognosis and developed a potential biomarker to improve the prognosis of MM. Plasma cells were isolated from bone marrow samples of 80 MM patients, in which miR-671-5p levels were determined. The correlation between miR-671-5p expression with serum creatinine, β-2-microglobulin, lactate dehydrogenase, bone lesions, International Staging System staging, chromosomal abnormalities, and albumin was analyzed. The association between miR-671-5p expression with progression-free survival and overall survival in MM patients was determined. miR-671-5p expression was reduced and predicted an increased risk of MM. miR-671-5p expression was negatively correlated with serum creatinine, β-2-microglobulin, lactate dehydrogenase, bone lesions, International Staging System staging, and chromosomal abnormalities, and positively correlated with albumin. miR-671-5p expression was augmented in complete response patients and overall response rate patients, and differentiated CR and ORR patients from Non-CR and Non-ORR patients. Furthermore, miR-671-5p low expression was associated with unfavorable progression-free survival and overall survival in MM patients. In a word, miR-671-5p is associated with worsening clinical properties, increased ISS staging, unfavorable chromosomal abnormalities, and poor prognosis in MM patients.

Systematic discrimination of the repetitive genome in proximity of ferroptosis genes and a novel prognostic signature correlating with the oncogenic lncRNA CRNDE in multiple myeloma.

Emerging insights into iron-dependent form of regulated cell death ferroptosis in cancer have opened a perspective for its use in cancer therapy. Of interest, a systematic profiling of ferroptosis gene signatures as prognostic factors has gained special attention in several cancers. Herein, we sought to investigate the presence of repetitive genomes in the vicinity of ferroptosis genes that may influence their expression and to establish a prognostic gene signature associated with multiple myeloma (MM). Our analysis showed that genes associated with ferroptosis were enriched with the repetitive genome in their vicinity, with a strong predominance of the SINE family, followed by LINE, of which the most significant discriminant values were SINE/Alu and LINE/L1, respectively. In addition, we examined in detail the performance of these genes as a cancer risk prediction model and specified fourteen ferroptosis-related gene signatures, which identified MM high-risk patients with lower immune/stromal scores with higher tumor purity in their immune microenvironment. Of interest, we also found that lncRNA CRNDE correlated with a risk score and was highly associated with the majority of genes comprising the signature. Taken together, we propose to investigate the molecular impact of the repetitive genome we have highlighted on the local transcriptome of ferroptosis genes in cancer. Furthermore, we revealed a genomic signature/biomarker related to ferroptosis that can be used to predict the risk of survival in MM patients.

Expression of SIL-2R in Patients with Multiple Myeloma and Its Clinical Significance

To investigate the expression and clinical significance of soluble interleukin-2 receptor(sIL-2R) in patients with multiple myeloma(MM). 54 newly diagnosed MM patients in the Second Affiliated Hospital of Fujian Medical University from February 2020 to December 2021 were selected as the observation group, and 60 healthy people in our hospital in the same period were selected as the control group. The expression levels of sIL-2R in the serum of the two groups were detected by enzyme-linked immunosorbent assay. The differences of sIL-2R expression level among different clinical parameter groups in MM patients were compared. The clinical parameters include:gender, age, ISS stage, hemoglobin, albumin, serum creatinine, lactate dehydrogenase and β2-microglobulin, blood calcium, bone marrow plasma cell ratio and treatment response. The relationship between sIL-2R expression level and progression-free survival(PFS) and overall survival(OS) in MM patients were analyzed. The expression of serum SIL-2R in MM patients was significantly higher than that in healthy control group (P<0.05). The expression of sIL-2R in MM patients who did not achieve complete remission(CR) was significantly higher than those of CR patients (P=0.037). There was no significant difference in the expression of serum sIL-2R between the groups of different sex, age, ISS stage, hemoglobin concentration, albumin content, serum creatinine level, lactate dehydrogenase level, the content of β2-microglobulin, the concentration of blood calcium, and the proportion of bone marrow plasma cells(P>0.05). The PFS of sIL-2R high expression group(15 months) was shorter than that of sIL-2R low expression group (22 months), which was significant difference (P=0.041). But there was no significant difference in OS between sIL-2R high expression group and sIL-2R low expression group (P=0.124). Univariate analysis results showed that the high expression of serum sIL-2R was associated with poor PFS in MM patients. Multivariate analysis results showed that the high expression of serum sIL-2R was still an independent adverse prognostic factor for PFS in MM patients, However, the expression of serum sIL-2R was not statistically significant in evaluating OS in MM patients by univariate and multivariate analysis. The expression of serum sIL-2R in MM patients was significantly higher than that in healthy people. Serum sIL-2R is an independent prognostic factor of PFS in MM patients.

Survival analysis of transplant-eligible newly-diagnosed multiple myeloma patients harboring t(4;14), t(14;16), and/or del(17p) in the real-world setting

Cytogenetic abnormalities (CA) such as t(4;14), t(14;16), and del(17p), are associated with a poor prognosis in Multiple Myeloma (MM) patients. However, there is scarce information regarding the Latin-American population. This study aims to analyze the impact of t(4;14), t(14;16), and del(17p) on the progression-free survival (PFS) and overall survival (OS) of transplant-eligible newly-diagnosed MM (NDMM) patients in Latin America. Retrospective survival analysis based on the Grupo de Estudio Latinoamericano de MM (GELAMM) registry, including all adult patients with NDMM harboring CA t(4;14), t(14;16), and/or del(17p). Fifty-nine patients were included; the median age was 57 years, 55.9% males, 22% ISS-I, 25.4% ISS-II, and 47.5% ISS-III. The majority (89.8%) had one alteration, whereas 10.2% had del(17p) and t(4;14). The frequencies of CA were del(17p) in 61.0%, t(4;14) in 25.4%, and t(14;16) in 3,4%. Autologous stem cell transplantation was performed in 36 cases, 20 patients did not use this consolidative strategy, and this data was missed in three cases.Five-year OS for the entire cohort was 60.8% and 5-year PFS was 28.1%. Bortezomib-based induction regimen (BBR) (p=0.029), consolidation with ASCT (p<0.001), and maintenance therapy (p=0.004) were associated with an improved 5-year OS. In the multivariate analysis, ASCT was the only variable with a positive impact on OS (HR 0.11, 95% CI 0.033 to 0.34, p<0.001). The median PFS presented a non-statistically significant benefit in BBR, ASCT, and maintenance therapy groups. BBR induction, ASCT, and maintenance therapy were associated with improved OS in high-risk NDMM patients.

Long-Term Outcomes of Delayed Neutrophil Engraftment Following Autologous Hematopoietic Cell Transplant in Multiple Myeloma

Introduction: AHCT remains a standard of care in multiple myeloma (MM) patients especially in the frontline setting. Studies exploring the long-term effect of the time to neutrophil engraftment on survival post-AHCT in MM patients remains scarce. In addition, a better understanding of the implication of certain demographic, clinical and cytogenetic factors on the engraftment process is needed. Here, we studied patient and disease specific factors impacting the engraftment processes as well as its effect on survival in MM patients. Methods: The electronic medical records of all MM patients who underwent AHCT between 2011 and through 2020 at Cleveland clinic were reviewed. Patient specific characteristics that were analyzed included age at diagnosis, age at AHCT, sex, smoking history (current, ex- or never), time to transplant (<12 vs ≥12 months), albumin level at diagnosis (<3.5 g/dL or ≥3.5 g/dL), cytogenetic risk abnormalities (High risk: HR or Standard risk: SR), ECOG performance status (0, 1, 2, 3 or 4), International scoring system stage (I, II or III), pre-AHCT number of treatments (1 or ≥2), disease status pre-AHCT (PR: partial response; VGPR: very good partial response; CR: complete response), CD34+ dose used, and days to engraftment. Neutrophil engraftment was defined as an absolute neutrophil count (ANC) of 500/mm3 or more for three consecutive days. A cut-off 20 days was chosen and tested for long-term outcomes using Kaplan-Meier survival analysis, whereas chi-square and t-tests were followed by multivariate analysis to confirm factors that independently influence engraftment. Results: A total of 431 patients were included in our study, of whom cytogenetics and ISS were available in 346 and 352, respectively. Our cohort had a median age at AHCT of 61.3 years (range 33.1-77.8 years), male preponderance of 56.6%, median time to neutrophil engraftment of 12 days (range 9-61 days), and median follow up of 32.5 months (range 0.6-117.8 months). Applying Kaplan Meier survival analysis when dividing patients into early engraftment (<20 days, n=405) and delayed engraftment (≥20 days, n=26) groups yielded a remarkably significant difference in mOS post-AHCT (88.8 vs 33.2 months, P<0.0001) (Fig 1). This was consistent with 1-year and 3-year mortality rates of 38.46% (vs 14.22%, P=0.0031) and 88.46% (vs 52.45%, P=0.0003) for the ≥20 as opposed to the <20 days to engraftment groups, respectively. Subgroup analysis further emphasized the lower survival in the ≥20 days vs <20 days in the setting of non-relapse (medians unreached, P=0.0096) as well as relapsed disease (mOS 25.4 vs 77.2 months, P<0.0001), respectively. A lower, albeit non-significant, median progression free survival (mPFS) was also seen in the ≥20 days engraftment group (36.8 vs 46.6 months, P=0.5). Looking into factors that may affect time to engraftment, delayed engraftment (≥20 days) was associated with female sex (73 vs 41%, P<0.0001), ISS stage III (31.6 vs 22% P<0.0001), HR cytogenetics (44.4 vs 29.5%, P<0.0001), and IgA MM (52.4 vs 22.2%, P<0.0001) compared to early engraftment (<20 days). No difference was seen with regards to age at AHCT (median 61.6 vs 60.7 years, P=0.5), history of smoking (23 vs 38.3%, P=0.3), ECOG performance status pre-AHCT (P=0.2), albumin levels at diagnosis (<3.5 g/dL in 25 vs 26.6%, P=0.9), disease status pre-AHCT (PR 42.3 vs 40.2%, VGPR 34.6 vs 33.8%, CR 23.1 vs 26% P=0.9), mobilization regimen (G-CSF + Plerixafor in 92.3 vs 90.6%, P=0.9), time to transplant of ≥ 12 months (34.6 vs 29%, P=0.5), recent immunomodulatory drugs use (69.2 vs 66.9%, P=0.9), pre-AHCT lines of treatment (≥ 2 in 42.3 vs 35.8%, P=0.6). Delayed engraftment was associated with a lower, though not statistically significant, median CD34+ dose (4.7 vs 5.2 x106, P=0.08). Multivariate analysis further confirmed the association of HR cytogenetics with delayed engraftment (HR 5.2, 1.2-27.8 95% CI). Conclusion: Early engraftment, defined as in less than 20 days, confers better overall survival rates post-AHCT, including among both relapsed and non-relapsed patients. Time to engraftment is mainly associated with patients' cytogenetic risk categorization. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Suppression of Multiple Myeloma Via Inhibition of EFNB2 Reverse Signaling

Multiple myeloma (MM) cells display a reciprocal relationship with neighboring niche cells in the bone marrow (BM), particularly vascular endothelial cells (BM ECs). This relationship drives disease initiation, progression, and therapy resistance, but the mechanisms underlying this interaction remain incompletely understood. Here, we show that silencing ephrin B2 (EFNB2) blocked MM cell proliferation and survival in vitro and abrogated MM engraftment and repopulation in vivo. EFNB2 expression is also increased in MM patients with adverse-risk cytogenetics and decreased survival, suggesting an important role for EFNB2 in MM disease progression. To identify novel regulators of MM pathogenesis, we performed transcriptome analyses of ECs from multiple human tissues and analyzed their capacity to promote MM growth. The EPH receptor, EPHB1, was overexpressed in human ECs that support MM expansion in culture. Silencing EPHB1 expression in ECs using siRNA or a lentiviral shRNA abrogated MM cell expansion compared to EC co-cultures treated with non-targeting shRNA and blocked the expansion of MM cells capable of in vivo repopulation in immune deficient mice. Additionally, transgenic Vk*MYC mice, which develop indolent murine MM through activation-induced deaminase-dependent MYC activation in germinal B cells, displayed increased expression of EPHB1 and EPHB4 in BM ECs compared to wild type BM ECs. We found that expression of EFNB2, an EPHB1/4 binding partner, is upregulated in 3 human MM cell lines and in primary MM cell populations from patients, whereas other EPHB1/4 binding partners were either not detected or expressed at a low level. shRNA-mediated inhibition of EFNB2 in MM cells blocked MM cell cycling, leading to a near 70-fold reduction in MM cell growth at day 12 of culture, and blunted MM cell repopulation when transplanted into NSG mice. In order to determine the therapeutic potential of targeting EFNB2 in MM in vivo, we transplanted irradiated NSG mice with MM cells and subsequently administered a single chain variable fragment (scFv) targeting EFNB2 on days +4, +6, +10 and +12. Mice treated with the EFNB2 scFv displayed significantly decreased engraftment of MM cells in vivo compared to control mice. MM reconstitution in vivo. Silencing EFNB2 expression in MM cells downregulated several pathways including those involved in cellular movement, cell death and survival, cellular assembly, cell cycle and DNA repair. Several STAT5 target genes were also downregulated in MM cells treated with shRNA-EFNB2, supporting the notion that STAT5 signaling is activated by ephrin B proteins (Bong et al. Proc Natl Acad Sci. 2007;104(44):17305-17310). Consistent with these findings, EFNB2 overexpression via dCas9-VPR increased MM cell survival, proliferation and STAT5 phosphorylation. Conversely, silencing EFNB2 decreased STAT5 activation, increased MM apoptosis, and decreased MM proliferation. Importantly, STAT5 inhibition in MM cells overexpressing EFNB2 blocked EFNB2-mediated MM cell proliferation, suggesting that EFNB2-mediated MM growth is dependent on STAT5. Overexpressing a mutant form of human EFNB2 with GFP replacing the intracellular cytoplasmic PDZ signaling domain did not result in cell growth comparable to overexpressing the full-length EFNB2. Silencing EPHB4, the main EFNB2 binding partner expressed on MM cells, resulted in significant impairment of growth in wild-type MM cells but not those with full-length EFNB2 overexpression. Updated downstream signaling and in vivo data of these will be presented at the meeting. Interrogation of MM clinical databases, including the Total Therapy studies (Zhan F. et al. Blood. 2006;108(6):2020-2028) and the CoMMpass data (Multiple Myeloma Research Foundation, https://research.themmrf.org/, accessed on 20 October 2021, n = 773 patients), revealed that EFNB2 expression is increased in MM patients with adverse risk cytogenetics, including t(4;14) and gain of chromosome 1q, while lower EFNB2 expression is associated with the more favorable, "standard risk" disease category, hyperdiploid MM. Increased EFNB2 expression is also associated with advanced stage disease and decreased survival in MM patients. Our analyses suggest that EFNB2 signaling represents an important new mechanistic target in MM. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Exonuclease 1 Drives Growth and Genomic Instability in Multiple Myeloma through Interaction with CAD, a Key Protein Involved in De Novo Pyrimidine Biosynthesis

Human exonuclease 1 (Exo1) plays important roles in DNA replication and repair including the resection of DNA ends during homologous recombination (HR). Based on our previous data demonstrating the role of HR in genomic instability and growth of cancer cells, we investigated role of EXO1 in multiple myeloma (MM). Expression of EXO1 and pRPA32 (a marker of DNA end resection) was elevated in all myeloma cell lines tested (N=10) relative to normal peripheral blood mononuclear (PBMC) cell samples. We developed a fluorescence-based EXO1 activity assay and observed elevated (~1.5- to > 5-fold; p < 0.05) Exo1 activity in all twelve MM cell lines tested relative to normal PBMCs. Moreover., elevated expression of EXO1 correlated with poor overall and event-free survival in MM patients (MMRF dataset; p < 1x10-5). Transgenic suppression of EXO1 in MM cell lines caused a time-dependent loss in cell viability. Evaluation at day 5 after selection indicated that, relative to control cells, EXO1 suppression in RPMI, MM1S, MM1R and U266 cells was associated with ∼95%, 85%, 60% and 40% cell death, respectively. Apoptosis, as evaluated by annexin-labeling, was detected in ~50% of EXO1-knockdown cells compared to 11.9% of control MM1S cells. Conditional knockdown in H929 cells evaluation at 48 h after adding doxycycline demonstrated apoptosis in 18% of EXO1-suppressed cells vs. 4.9% of control cells. To investigate the mechanisms by which EXO1 impacts MM cell viability, the proteins interacting with EXO1 in MM cell lines (MM1S and H929) were identified using Exo1 pull-down and mass spectrometry. Interaction of EXO1 with CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase), a trifunctional protein involved in the first three steps of de novo pyrimidine biosynthesis, was identified and its binding confirmed with co-immunoprecipitation. We found that EXO1 overexpression increased the growth rate of non-cancerous cell types (HS5 - bone marrow stromal cells and normal fibroblasts), whereas suppression of CAD inhibited the spontaneous and EXO1-mediated increase in growth rate as well as DNA replication in both normal cell types. Consistently, the CAD-knockdown increased apoptosis in HS5 cells by ∼5-fold, whereas EXO1 overexpression reduced it by ~2-fold. Conversely, suppression of CAD also increased apoptosis in EXO1-overexpressing cells by 3-fold. In normal diploid fibroblast cells with a limited lifespan, EXO1 overexpression increased DNA replication by 32%, whereas CAD-knockdown reduced it by ∼65%. Importantly, CAD-knockdown in EXO1-overexpressing cells also reduced DNA replication by 26%. These data indicate that CAD is involved in EXO1-dependent cell proliferation and survival. Investigating the molecular events associated with EXO1, we observed that its suppression in MM cells inhibits DNA end resection, DNA breaks, HR activity and genomic instability (as assessed by a micronucleus assay); whereas overexpression in normal cells increased those activities. Moreover, inhibition of CAD reduced spontaneous as well as EXO1-induced HR activity and genomic instability in both hematopoietic and solid tumor cell types. Since CAD is involved in the first three steps of pyrimidine biosynthesis, our data suggest that interaction with CAD enables EXO1 to drive DNA replication, HR and associated genomic instability. Functional relevance of this interaction and possible regulation of de novo pyrimidine biosynthesis by EXO1 is being further investigated. Inhibitors of CAD may provide a novel therapeutic target in myeloma as well as other Exo1 overexpressing malignancies.

Limited Long-Term Benefit of Upfront Autologous Stem Cell Transplant on Survival in Severe Renal Impairment in Multiple Myeloma in Novel Drug Era, a Retrospective Multi-Center Study in China

Background Renal impairment (RI) is a common complication of multiple myeloma (MM) affecting approximately 20%-30% of the patients at diagnosis. The presence of severe RI is associated with an increased risk of early death and poor prognosis in myeloma. The impact of autologous stem cell transplant (ASCT) on outcome in severe RI patients remains controversial. Therefore, we performed a retrospective real-world analysis to clarify the effect of ASCT on the survival of MM patients with severe RI. Methods Clinical data of 337 MM patients with severe RI at diagnosis were collected from three centers in China from April 2004 to January 2020. Severe RI was defined as an increase creatinine ＞177 umol/L (or 2mg/L) or an estimated glomerular filtration rate ≤40 ml/min/1.73 m2 using the simplified modification of diet in renal disease (MDRD) formula. RI caused by other confirmed pathological diagnosis except for tubular nephropathy was excluded. We excluded patients underwent salvage ASCT (6 cases), patients older than 65 years (107 cases), and traditional introduction therapy (2 cases). At last, there were 232 cases for analysis, containing 59 cases received ASCT. All enrolled patients were treated with novel-agent introduction. Patients were divided into the ASCT group and the non-ASCT group. Hematological and renal response were assessed based on the International Myeloma Working Group (IMWG) criteria. Results The median age for all patients at diagnosis was 55 years old (range: 37-65 years old). 37% presented with free light chain myeloma. There were 4 patients underwent double-ASCT in the ASCT group. All dialysis patients in ASCT group were off dialysis after induction therapy. Baseline profiles between ASCT and non-ASCT group were matched in sex, M-protein isotype, ISS stage, and induction therapy. More patients were on dialysis at diagnosis in non-ASCT group (34.7% vs 19.3%, P=0.04). There were 59/159 patients presented unfavorable cytogenetic abnormality (del(17p), t(4;14), t(14;16)), including 40 cases (34.2%) in non-ASCT group and 19 cases (41.3%) in ASCT group (P=0.47). The 1q amplification presented 21.4% in non-ASCT group and 22.2% in ASCT group (P=0.56). In terms of hematological response, at least VGPR accounts for 88.1% in the ASCT group and 50.3% in the non-ASCT group (P<0.001). The overall renal response was significantly higher in the ASCT group than that in the non-ASCT group (94.9% vs 54.3%, P<0.001). There was the similar tendency for at least renal PR between ASCT and non-ASCT groups (88.1% vs 41.3%, P<0.001). The transplant-related mortality (within 3 months after ASCT) was 6.8%. Early mortality within 1 year was 6.7% in the ASCT group and 19.8% in the non-ASCT group (P=0.002). The median follow-up for all patients was 37.6 months (range: 1-157 months) and the median overall survival (OS) was 49.5 months (95% CI：42-57 months). In the ASCT group, the median OS was much longer than ASCT group (57.3 months vs 42.8 months, P =0.052). But there was no difference in PFS between the two groups (36.9 months vs 26.5 , p=0.348). As the log-rank test didn't hold the proportional hazards assumption, it would have low power. We use the two-stage landmark analysis to further determine the effect of ASCT on survival. In landmark analysis, 3-year PFS rate in ASCT group was significantly higher (54.0% vs 41.9%, P=0.024). Within 5-year follow-up, OS was significantly longer in the ASCT group than that in non-ASCT group (OR=0.61, 95%CI: 0.39-0.97, P=0.04). Beyond the 5-year time point, OS was similar between the two groups (OR=1.59, 95%CI: 0.60-4.20, P=0.35). In univariate analysis, at least renal MR, at least hematological VGPR, PLT＞100×109/L, and BMPC ≥60% were correlated with longer OS. In multivariate analysis, at least renal MR (HR=0.61, 95%CI: 0.39-0.96, P=0.031), at least hematological VGPR (HR=0.41, 95%CI: 0.27-0.63, P<0.001), and PLT＞100×109/L (HR=0.43, 95%CI: 0.28-0.66, P<0.001) were independent predictor of OS. Although upfront ASCT could remarkably prolong OS in severe RI myeloma, it was not confirmed in multivariate analysis. Conclusions In the novel agent era, role of upfront ASCT in myeloma with severe RI remains uncertain. In our analysis, it seems the benefit of the OS from novel-drug induction and upfront ASCT was observed in the first 5-year, but the long-term survival benefit was limited. Instead, deep hematological response and renal recovery was strong predictors for OS.

EZH2 Targeting Induces CD38 Upregulation and Response to Anti-CD38 Antibodies in Multiple Myeloma

Multiple myeloma (MM) is the second most common hematological malignancy characterized by the accumulation of tumor plasma cells within the bone marrow. MM is characterized by high molecular and clinical heterogeneity. During the last 10 years new therapeutic classes including targeted immunotherapies significantly improved the overall survival of MM patients. However, drug resistance and relapse remain major challenges in MM. In MM, marked reduction of CD38 expression via exocytosis, endocytosis, degradation of the antigen-antibody complex and trogocytosis has been associated with resistance to CD38 targeted immunotherapies. Our group previously described a link and a negative correlation between CD38 and EZH2 (Enhancer of Zeste homolog 2) expression during normal B to plasma cell differentiation in association with a transcriptional control of CD38 expression involving the polycomb PRC2 complex (Herviou et al. Leukemia. 2019). Here we identified a significant negative correlation between CD38 expression and EZH2 expression in 2 independent cohorts of MM patients (p<0.05; Montpellier cohort n=198; Compass cohort n=631). Thus, we hypothesized that PRC2 targeting using EZH2 inhibitor could result in CD38 re-expression to overcome daratumumab resistance. We first characterized the membrane CD38 expression by calculating the Antibody Binding Capacity in our unique panel of 40 Human Myeloma Cell lines (HMCL) representative of MM heterogeneity. We observed a heterogeneous expression of the membrane CD38 expression on MM cell lines with cell lines demonstrating no membrane expression and cell lines demonstrating high membrane expression. Next, we selected 3 HMCLs with low (JJN3), intermediate (XG2), and high (XG7) CD38 expression, and treated these cell lines with sublethal concentration of EZH2 inhibitor (EPZ-6438) for 9 days. CD38 membrane expression was characterized at Day 3, Day 6 and Day 9. Interestingly, EZP-6438 treatment induced upregulation of cell surface CD38 expression on all the HMCLs tested with the highest effect measured at day 9. Similar re-expression pattern was observed by western blot at these timing in the JJN3 CD38low cell line. Remarkably, ChIPseq analyses underlined a significant association of H3K27me3 mark at CD38 promoter in CD38neg and CD38low cell lines compared to CD38highcells. In addition, we investigated the efficiency of CD38 monoclonal antibodies (Daratumumab and Isatuximab) lysis through ADCC (Antibody dependent cellular cytotoxicity) assay after 9 days of EPZ-6438 pretreatment. Using JJN3 CD38low HMCL, EPZ-6438 pretreatment significantly improved the ADCC lysis induced by low doses of Daratumumab and Isatuximab treatment, in presence of purified Natural Killer (NK) from healthy donor, together with CD38 re-expression (p<0.05; n=3). Finally, we searched to validate these results using primary MM cells from patients at relapse after Daratumumab treatment. EPZ-6438 pretreatment resulted in a significant CD38 membrane expression upregulation with a 2 fold difference compared to the control condition together with improved ADCC toxicity of anti-CD38 antibodies in vitro. Altogether we demonstrated that treatment of MM cells with EZH2 inhibitor leads to significant upregulation of membrane CD38 expression in cell lines and primary MM cells from patients. CD38 re-expression was linked to an improvement of Daratumumab and Isatuximab ADCC efficiency. Thus, EZH2 targeting may be of therapeutic interest to overcome resistance to anti-CD38 targeted immunotherapies in Multiple Myeloma.

Baseline Systemic Inflammatory Markers Interleukin 6 and Ferritin Are Associated with Toxicities and Progression-Free Survival in Multiple Myeloma Patients Treated with Idecabtagene Vicleucel

Introduction: A challenge of chimeric antigen receptor (CAR) T-cell therapy is the en-masse activation of tumor-reactive T-cells that can lead to cardiovascular, respiratory, and neurologic toxicities, including cytokine release syndrome (CRS) and neurotoxicity (NT). Recent studies found that elevated levels of cytokines and inflammatory markers pre-treatment are associated with severe toxicities in B cell lymphoma patients receiving axicabtagene ciloleucel. However, less is known about patients with relapsed/refractory multiple myeloma (RRMM) treated with commercial idecabtagene vicleucel (ide-cel). We evaluated the associations of serum cytokines and inflammatory biomarkers with immune-mediated toxicities and progression-free survival (PFS) in RRMM patients treated with commercial ide-cel. Methods: Serum samples were collected at baseline (within 45 days of lymphodepleting chemotherapy) and daily from infusion until hospital discharge. The Ella automated simple plex immunoassay system (ProteinSimple) was used to measure cytokines including GM-CSF, IL2, IL6, IL15, IFNγ, TNFα, and Angiopoietin 1&2. Standard clinical tests were used to measure ferritin and C-reactive protein at baseline (pre-lymphodepleting chemotherapy), infusion, and daily until hospital discharge. Treatment-related toxicities were graded based on ASTCT guidelines and managed according to institutional policies. Treatment responses were graded based on IMWG response criteria. Chi-square and Kruskal-Wallis tests were used to examine the distribution of each cytokine and inflammatory biomarker at baseline, infusion, and peak (highest level between day one post infusion and last day of hospitalization) by any grade and ≥ grade 2 CRS and NT. For cytokines or inflammatory biomarkers associated with CRS and NT, maximally selected rank statistics were used to determine optimal cut-points for PFS, and Kaplan-Meier survival curves and log-rank tests were used to examine PFS by optimal cut-points of selected cytokines and inflammatory biomarkers. Results: 28 patients who received ide-cel by May 1st, 2022 were included. Median age was 65 years. 38% of patients had high-risk cytogenetics and 54% had penta-refractory disease. Median number of prior lines of therapy was 6 (range 4-13). CRS was seen in 79% (≥ grade 2: 14%) and NT in 11% (≥ grade 2: 7%) of patients. Tocilizumab and steroids were used in 79% and 32% of patients, respectively. With a median follow up of 6.2 months, best overall response rate was 82%, with 57% of patients achieving a complete response or better. Of those, 69% were minimal residual disease negative. Four patients died of myeloma progression. Patients with any grade versus no CRS had higher levels of baseline ferritin (402 vs 133 ng/mL; P=0.045), peak ferritin (2804 vs 191 ng/mL; P<0.001), and peak IL6 (3681 vs 20 pg/mL; P<0.001). Patients with ≥ grade 2 vs < grade 2 CRS had higher levels of baseline IL6 (19 vs 5 pg/mL; P=0.04; Figure 1). A positive but not statistically significant association was observed for baseline IL6 with ≥ grade 2 vs < grade 2 NT (19 vs 6 pg/mL; P=0.12). There were positive correlations between baseline and peak ferritin (r=0.43; P=0.02) and baseline ferritin and IL6 (r=0.58; P=0.005), but no correlation between baseline and peak IL6 (r=-0.06; P=0.8). Using optimal cut-points for baseline ferritin (1700 ng/mL) and IL6 (10 pg/mL), patients with high (n=5) vs low (n=23) baseline ferritin had an inferior PFS (median PFS of 4.8 months vs not reached [NR]; P=0.0005), and patients with high (n=6) vs low (n=16) baseline IL6 had an inferior PFS (median PFS of 3 months vs NR; P=0.069). When combining baseline ferritin and IL6, patients with either high (n=8) vs low (n=20) ferritin or IL6 had an inferior PFS (median PFS of 4.8 months vs NR; P=0.021; Figure 1). No other differences in inflammatory biomarkers or cytokines by toxicities or PFS were identified. Conclusions: In our single center experience, we found associations between ferritin and IL6 with CRS and NT. Median PFS was inferior in patients with elevated baseline ferritin and IL6. This suggests that a pre-existing pro-inflammatory state puts ide-cel patients at risk for toxicities in addition to inferior PFS. Tailoring toxicity and additional therapeutic management to patient risk may mitigate morbidity and mortality. D.K.H. and L.C.P contributed equally; M.A. and M.L.D contributed equallyFigure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Retrospective Analysis of Prognostic Factors and Survival in Multiple Myeloma Patients Aged 65 Years or Older at Diagnosis in a Real-Life Setting and a Proposed New Staging System

Introduction: The incidence of multiple myeloma (MM) increases with age. Novel agents provide better treatment results. However, adults >65 years of age are often underrepresented in clinical trials making it difficult to assess treatment outcomes in older patients. Appropriate strategies are necessary and treatment must be individualized in this heterogeneous population. Methods: We retrospectively reviewed the charts of 534 patients diagnosed with MM between January 2010 and January 2020 who presented to our department. One hundred twenty-three of them were aged 65 years or older at diagnosis and were included in the study. Clinical and laboratory data were collected and potential prognostic factors of overall survival (OS) were evaluated by univariate and multivariate analyses. Results: Of 123 patients analyzed 54.5% (67) were male and 45.5% (56) were female. The median age was 71 years and 32.5% of patients were equal or older than 75 years. Median follow-up time was 28 months (1-117). Median OS and progression free survival (PFS) were 46 and 17 months, respectively. Of the patients 63.4% (78) died during the study period. The patients were divided into 3 groups according to age: 65-69 (47 patients, median OS 68 months), 70-74 (36 patients, median OS 45 months) and ≥75 (40 patients, median OS 36 months) years old (p: 0.022). International Staging System (ISS) stage could be defined in 117 patients (19 had ISS I, 40 ISS II and 58 had ISS III disease). Revised ISS (R-ISS) could also be defined in 117 patients (17 R-ISS I, 82 R-ISS II and 18 R-ISS III). Both ISS and R-ISS could not identify statistically significant differences regarding OS and PFS. Chromosomal abnormalities were detected by fluorescence in situ hybridization (FISH) and conventional cytogenetics in 56 and 39 patients respectively. Eleven of 56 patients and 4 of 39 patients had unfavorable genetic features and due to the small number these patients are not included in the survival analyses. Bortezomib based doublet and triplet induction regimens were given in 86% of patients. Univariate analysis revealed that age, hemoglobin, creatinine, calcium, albumin, extramedullary disease and bone marrow plasma cell (BMPC) percentage were strongly associated with OS. Receiver operating curve (ROC) analysis determined the optimal cut-off value of BMPC 26.5%. On multivariate analysis albumin, extramedullary disease and BMPC ratio retained prognostic value. Presence of none, one, two or all three of these factors could identify 4 patient subgroups showing median OS rates of 108, 55, 25 and 12 months, respectively (p: <0.001) (Figure). Conclusions: MM primarily affects older adults. Hence, there is a need for simple and reliable staging systems for elderly MM patients. We propose a prognostic scoring method for outcome incorporating easy to use variables such as albumin, extramedullary disease and BMPC ratio. Hypoalbuminemia (≤ 3.5 g/dl), presence of extramedullary disease and BMPC ratio ≥ 26.5% predicted different OS ratios in the study population. A validation of the score in an independent series of patients is planned. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Autologous Transplantation for Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis

Background: The relevance of autologous hematopoietic cell transplantation (ASCT), a crucial part of multiple myeloma (MM) therapy for eligible patients, has been questioned in light of improvements in induction therapy that result in excellent responses. To increase progression free and overall survival, it is crucial to continue developing first-line treatments using non-ASCT and ASCT-based methods. In addition, it is important to determine if a specific patient population might benefit from a given strategy to develop personalized cancer care based on risk stratification. In our meta-analysis, we assessed the efficacy outcomes of HDT/ASCT in combination with standard induction treatment as compared to standard-dose therapy alone for newly diagnosed MM. Materials & Methods: A comprehensive literature search was carried out on PubMed (Medline), EMBASE, CENTRAL (Cochrane Library), and Google Scholar from inception till 20th July 2022. HDT/ASCT versus standard-dose therapy (SDT) employing novel therapies was evaluated in phase 3 RCTs. The inclusion criteria were randomized controlled trials (RCTs) that directly compared combination chemotherapy followed by consolidation with HDT/ASCT(high-dose therapy with melphalan followed by autologous stem cell transplant) to SDT(Standard Dose therapy) alone without ASCT in patients with newly diagnosed MM(Multiple Myeloma). We included papers which reported PFS and OS as their endpoints using intention-to-treat analysis and had a minimum of 2 years of follow-up. All the original studies, review articles, and clinical trials with a sample size of <100 were excluded from the review. Review Manager Software (RevMan, version 5.3) was employed for statistical analyses, and forest plots were created to analyze the results visually. The Mantel-Haenszel random effect model was applied. Higgins's I2 test was used to evaluate heterogeneity across the studies. Results: A total of five Randomized Controlled Trials consisting of 3,294 participants were included in the meta-analysis. Only four studies included in the analysis reported OS. The pooled analysis reported no significant benefit for overall survival in the HDT/ASCT group compared to SDT (OR: 0.77, 95% CI; 0.49, 1.23, I2= 76%, P=0.28); however, the results were limited by significant heterogeneity. (Forest Plot 1). The combined odds ratio(OR) for complete response(CR) was 1.18 (OR: 1.18, 95%CI; 0.96-1.44, I2=21%, P= 0.11) with SDT compared with HDT/ASCT, although it is not statistically significant. (Forest Plot 3). Similarly, the combined odds ratio for a complete response did not favor any treatment group (OR: 1.18, 95%CI; 0.96-1.44, I2=21%, P= 0.11). All five studies reported PFS. Our results indicated statistically significant PFS in HDT/ASCT group as compared to the SDT alone group (OR: 0.57, 95% CI; 0.46-0.70, I2= 66%, P <0.00001). (Forest Plot 2) Conclusion: HDT/ASCT was linked with a better PFS as compared to SDT without ASCT in newly diagnosed multiple myeloma. The OS was comparable for both HDT/ASCT and SDT without ASCT in all RCTs. Overall survival for multiple myeloma patients has gradually improved over the last two decade. Overall survival benefit will be difficult to demonstrate between the two approaches as new and better treatments are getting available for salvage and bridging multiple myeloma patients to receive ASCT. ASCT in any line of treatment results in deeper remission and better outcomes, as well as equalizes the PFS benefit seen in using ASCT in first line treatment. Based on data from our meta-analysis, use of HDT/ASCT should be individualized based on disease risk group and patient's preference. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long Term Survival in Multiple Myeloma Patients: A Multicenter Italian Experience

Long Term Survival in Multiple Myeloma Patients: A Multicenter Italian Experience

Impact of Dialysis Dependence on Survival for Multiple Myeloma Patients with Renal Impairment: A Multicenter Retrospective Study in China

Impact of Dialysis Dependence on Survival for Multiple Myeloma Patients with Renal Impairment: A Multicenter Retrospective Study in China

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

BRD9 Is Essential for Ribosome Biogenesis and the Survival of Multiple Myeloma Cells

BRD9 is a component of the noncanonical SWI/SNF (ncSWI/SNF) complex, which is a chromatin-remodeling complex that modulates genomic architecture and DNA accessibility. Since BRD9 has been shown to play a critical tumor-promoting role in various cancers, we investigated its biologic impact in multiple myeloma (MM) cells. We found that BRD9 was highly expressed in patient MM cells compared to normal plasma cells (GSE39754, P = 0.045). Moreover, higher BRD9 expression was associated with poor overall survival (GSE39754, P = 0.049) in MM patients. We next confirmed that genetic (shRNA) and pharmacological (dBRD9-A) depletion of BRD9 significantly reduced growth in a panel of MM cell lines and patient MM cells. Furthermore, dBRD9-A induced G1 cell-cycle arrest and apoptosis in OPM2 and H929 cells, even in the presence of anti-apoptotic cytokines (IL-6, IGF-1), or bone marrow stromal cells. In a murine xenograft model, dBRD9-A treatment significantly inhibited OPM2 tumor growth compared with vehicle control (P = 0.001 and P < 0.001, respectively) without significant body weight loss. Kaplan-Meier curves and log-rank analysis showed a significantly prolonged overall survival in the dBRD9-A treatment cohort compared with the vehicle control cohort (P < 0.001). Having nominated BRD9 as a potential therapeutic target, we next investigated the cellular mechanisms impacted by BRD9 depletion by RNA-seq analyses. After BRD9 knockdown (shRNA) or dBRD9-Aapplication, a total of 162 and 197genes were commonly up- or downregulated, respectively, compared with DMSO-treated control cells (Padj < 0.05). Importantly, we identified that ribosome biogenesis and rRNA processing were the most significantly downregulated pathways. Notably, target genes of MYC, the master regulator of ribosome biogenesis, were also markedly downregulated. Furthermore, we observed that the expression of representative proteins (i.e., MYC, RRS1, and BOP1) was also consistently decreased by dBRD9-A in vitro and in vivo. Indeed, we observed a significant decrease in total pre-rRNA levels and nucleolar number by dBRD9-A treatment in OPM2 and H929 cells, indicating ribosome biogenesis was positively regulated, at least in part, by BRD9. OPM2 cells treated with dBRD9-A had fewer ribosomal subunits and fewer actively translating polysomes compared with DMSO-treated controls, as determined by polysome profiling of cytosolic extracts. Furthermore, AgNOR staining of tumors harvested from our murine xenograft model demonstrated that dBRD9-A treatment reduced the number of nucleolar organizer regions in vivo. To understand how BRD9 regulates the expression of ribosome biogenesis genes, we next performed ChIP-seq. We found that many of the genes downregulated by dBRD9-A had BRD9 occupancy at their promoters compared to other intact genes. Notably, genes with BRD9 signals in their promoter regions were enriched for ribosome biogenesis and rRNA processing and were downregulated by dBRD9-A treatment. Although GLTSCR1, another ncBAF-specific component, was still able to form a complex even after BRD9 depletion, ChIP-seq revealed a significant loss of GLTSCR1 binding throughout the genome after treatment with dBRD9-A. Thus, we hypothesized that BRD9 is required for the localization of the ncSWI/SNF complex to target gene regions. Indeed, BRD9 co-immunoprecipitated with the positive transcription elongation factors, RNAPII, BRD4, and MYC in MM cells. Interestingly, the interaction between BRD9 and BRD4 was enhanced by an HDAC inhibitor, while BRD9 depletion attenuated the interaction between GLSTCR1 and BRD4, suggesting that BRD9 interacts with the acetylated form of BRD4, stabilizing its binding to the ncBAF complex and thereby supporting the initiation of transcription of target genes. Indeed, ChIP-seq analysis demonstrated that BRD9-bound sites preferentially co-localized with ChIP peaks of BRD4, MYC, and RNAPII to the promoter regions of all ribosome biosynthesis genes. In summary, our data identify a novel function for BRD9 in promoting ribosome biogenesis in MM. BRD9 depletion impairs ncBAF localization to its genomic targets, thereby disrupting ribosome biogenesis machinery, resulting in significant cell growth inhibition. Our study therefore provides the rationale for further evaluation of BRD9 degraders as a novel treatment strategy in MM.

Impact of academic medical center access on outcomes in multiple myeloma.

Treatment at academic cancer centers (ACs) is associated with improved survival across hematologic malignancies, though the benefit in multiple myeloma (MM) has not been examined. This study aims to evaluate survival outcomes at Commission on Cancer accredited ACs compared to non-academic centers (NACs) for patients receiving MM-directed therapy. The National Cancer Database (NCDB) was used to identify demographics and overall survival (OS) of MM patients diagnosed from 2004 to 2017 and to compare outcomes by facility type. Survival analysis was repeated in a propensity score matched cohort, with NACs matched 1:1 to ACs by age, race, comorbidity score, insurance, year of diagnosis, distance traveled, and income. Of 163 375 MM patients, 44.5% were treated at ACs. Patients at ACs were more likely to receive MM-directed therapy compared to NACs (81% vs. 73%, p < .001). For patients receiving treatment, median OS at ACs was 71.3months versus 41.2 months at NACs (p < .001). When adjusted for baseline demographics, patients treated at ACs had reduced mortality; hazard ratio (HR) 0.79 (95% CI 0.78-0.81, p < .001). The propensity score matched cohort maintained this survival benefit with a median OS of 59.9months at ACs versus 37.0 months at NACs (p < .001), HR of 0.66 (95% CI 0.64-0.67, p < .001). ACs treated younger patients with fewer comorbidities and were more likely to treat racial minorities and patients with Medicaid or private insurance, and the uninsured. In this analysis, MM patients treated at ACs have significantly improved survival. While potentially related to access to specialized care, socioeconomic factors that drive facility selection may also contribute.