Hwa, Yi L.

AbstractAchievement of a complete response (CR) in multiple myeloma (MM) correlates with improvement in survival outcomes; however, its impact on prognostic variables at baseline outside of clinical trial settings is not well described. We sought to determine the impact of achieving a CR within 2 years from diagnosis, its effect on the prognostic value of fluorescence in situ hybridization (FISH) and International Staging System (ISS) risk, and examined additional predictors of outcome among those achieving a CR in a routine clinical setting. We evaluated 1869 newly diagnosed MM patients who had ≥ 2 monoclonal protein immunofixation studies in the serum and urine available within 24 months from diagnosis, categorizing those with ≥ 2 negative serum and urine immunofixations as achieving CR. With a landmark at 24 months, median progression‐free survival (PFS) for CR versus non‐CR patients was 29.8 versus 20.9 months (p ≤ .0002); median overall survival (OS) was 104 versus 70 months (p < .0001). The impact of achieving a CR was retained after adjusting for FISH, ISS, sex, transplant status, and involved heavy chain. Baseline FISH and ISS stage were not associated with PFS or OS among patients achieving a CR. The following variables were found as predictors of inferior OS within the CR cohort: age > 75 years, male gender, hypoalbuminemia, and non‐immunoglobulin G involved heavy chain. Our study confirms that achievement of CR within 2 years from diagnosis is associated with improvement in survival outcomes and neutralization of the impact of FISH and ISS risk, thereby confirming observations from the clinical trial setting among a clinical practice cohort.

AbstractThromboses are prevalent in POEMS syndrome, but few risk factors for POEMS‐associated thrombosis have been identified. The objective of this study is to identify novel risk factors for POEMS‐associated thrombosis. In this retrospective cohort of 230 POEMS patients, 27% developed thrombosis. Arterial events were slightly more common than venous. Stroke accounted for 26% of all thromboses and 53% of arterial events. There were differences in baseline features between the thrombosis group and the no thrombosis group, and these were driven by patients with arterial thrombosis. Risk factors for arterial thrombosis included thrombocytosis, elevated hemoglobin/hematocrit, extravascular volume overload, and splenomegaly. Hyperprolactinemia appeared to be a risk factor for venous thrombosis. The risk of thrombosis was most striking among men with elevated hemoglobin (32% vs. 5%, p < .001) and hematocrit (42% vs. 5%, p < .001) compared to men without. Most thromboses occurred prior to POEMS directed therapy, and most that occurred during therapy happened within 3 months of diagnosis. Twenty‐one percent of patients with thrombosis had recurrence. In recognition of high overall rates of thrombosis in this population, all patients with POEMS syndrome should receive prophylactic antiplatelet therapy, and clinicians should consider anticoagulation in patients with risk factors for POEMS‐associated thrombosis.

Abstract Background: There has been a steady improvement in the survival of patients with multiple myeloma (MM) due to better understanding of the pathophysiology, use of novel agents, and risk-adapted therapy. These improvements were largely observed in clinical trials and tertiary center populations and questions remain about the generalizability of these findings to patients in community settings. Here, we compared the experience of patients seen at Mayo Clinic, Rochester (MAYO) and those followed in the Surveillance, Epidemiology, and End Results Program (SEER), to gain a better understanding of current trends in survival. Methods: We studied all patients with MM diagnosed between 01/2004 and 12/2018 seen at MAYO and those followed in SEER (18 registry research data 2000-2018, 11/2020 submission). For comparison with SEER, MAYO patients who were alive at the end of SEER follow-up (12/31/2018) were censored. For the estimation of relative survival, patients alive at the end of 2019 were censored to align with the published United States general population rate tables. Overall survival (OS) estimates were calculated using the method described by Kaplan and Meier. Multivariable-adjusted proportional hazards regression models were used to assess the association between the 5-year interval of diagnosis and overall survival. Expected OS estimates were calculated based on United States general population rate tables from the Human Mortality Database using a conditional approach. Standardized mortality ratios (SMR) were calculated by dividing the number of observed deaths by the number of expected deaths in age- and sex-matched general United States population controls. Linear regression models were fit to test for trends in SMRs over time. Results: The median age at diagnosis was 3 years lower in patients seen at MAYO compared to patients followed in SEER. The proportion of patients 75 years and older at the time of diagnosis was higher in SEER (26.3%) compared to MAYO (15.3%). Median OS was 6.7 years (95% CI 6.3-7.1) for MAYO compared to 4.6 years (95% CI 4.5-4.7) in SEER (Figure 1). When stratifying OS by year of diagnosis (in 5-year-intervals: 2004-2008, 2009-2013, 2014-2018), improvements were seen in both patient populations over time, albeit to a greater extent in patients seen at MAYO (Figures 2 and 3). The results were consistent after adjusting for age and sex in both MAYO and SEER. There were improvements in OS across all three 5-year intervals and age groups in both patient populations. In MAYO, these improvements were most pronounced during the second 5-year interval for younger patients (&lt; 65 years) and more pronounced during the last 5-year interval for older patients (&gt; 65 years). In SEER, the improvements were more gradual across the three 5-year intervals, but it was noted that the relative improvements in younger patients were greater than in older patients during the last 5-year interval. Early mortality decreased over time in both patient populations: from 11% to 6% at MAYO and from 23% to 16% in SEER (Figure 4). To examine the observed improvements in the context of the survival trends of the general population, we stratified the SMRs by patient population, age at diagnosis, and year of diagnosis, and a lack of improvement in excess mortality was observed among older patients (&gt;75 years) in both populations over time (Figure 5). Three- and five-year overall survival estimates were higher in patients seen at MAYO compared to patients followed in SEER, but the survival advantage diminished with increasing follow-up time (Figure 6). On further sub-group analysis within MAYO patients, excess mortality was observed for all International staging system (ISS) stages and patients with high-risk (HR) cytogenetics. Stratifying the SMRs by age and risk group, decreases in excess mortality were most pronounced among older patients, particularly those with indolent disease (Figure 7). Conclusions: Survival outcomes in MM continued to improve in both patient populations. These improvements were more pronounced in MAYO compared to SEER, which may be partially explained by differences in access to specialized care. The most pronounced improvements were observed among younger patients and those with favorable disease characteristics. Future efforts need to focus on improving therapies for patients with unfavorable disease characteristics and on increasing access to specialized care in community settings. Figure 1 Figure 1. Disclosures Kapoor: Glaxo SmithKline: Research Funding; Takeda: Research Funding; Sanofi: Research Funding; Amgen: Research Funding; Sanofi: Consultancy; Pharmacyclics: Consultancy; Ichnos Sciences: Research Funding; BeiGene: Consultancy; Regeneron Pharmaceuticals: Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Karyopharm: Consultancy; Cellectar: Consultancy. Dingli: Alexion: Consultancy; Apellis: Consultancy; Janssen: Consultancy; Novartis: Research Funding; GSK: Consultancy; Sanofi: Consultancy. Gertz: Ionis Pharmaceuticals: Other: Advisory Board; Aurora Biopharma: Other: Stock option; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy. Lin: Novartis: Consultancy; Celgene: Consultancy, Research Funding; Juno: Consultancy; Takeda: Research Funding; Gamida Cell: Consultancy; Vineti: Consultancy; Merck: Research Funding; Bluebird Bio: Consultancy, Research Funding; Legend: Consultancy; Sorrento: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Dispenzieri: Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Research Funding; Oncopeptides: Consultancy; Alnylam: Research Funding; Pfizer: Research Funding. Kumar: Tenebio: Research Funding; Amgen: Consultancy, Research Funding; Oncopeptides: Consultancy; Bluebird Bio: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Beigene: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Antengene: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

Abstract INTRODUCTION: Belantamab mafodotin (BLMF) is a first-in-class, antibody-drug conjugate targeting B-cell maturation antigen on myeloma cells. BLMF was approved for use in patients (pts) with advanced multiple myeloma (MM). Due to the risk of ocular toxicity, it is made available through a restricted program under a Risk Evaluation and Mitigation Strategy. It is speculated that monomethyl auristatin F (MMAF), the cytotoxic payload of BLMF may be internalised by the corneal epithelium via an off-target mechanism, leading to epithelial changes. In the pivotal DREAMM-2 trial, only 1% of pts permanently discontinued treatment due to keratopathy. Data regarding BLMF-induced ocular toxicity following its commercial availability since August 2020, are sparse, and in this context, we evaluated our clinical experience with BLMF to determine the impact of its ocular toxicity on outcomes when utilized outside of stringent clinical trial settings. METHODS: We reviewed records of pts with advanced MM who were evaluated at Mayo Clinic between 09/01/2020-07/01/2021 and initiated on BLMF monotherapy following a baseline ophthalmic examination that was also performed prior to each dose, and as needed for worsening ocular symptoms. Data pertaining to ocular symptoms, best corrected visual acuity (BCVA) and corneal examinations were collected and analyzed with respect to patient outcomes. Adverse events were graded using the National Cancer Institute Common Toxicity Criteria for Adverse Events v5.0. RESULTS: Thirty-four pts, with median age of 67 (range:49-90) years who received BLMF at the approved 2.5 mg/kg dose as their first infusion and completed at least one cycle were included. All patients were instructed to use preservative-free lubricant eye drops at least 4 times a day, starting with the initial infusion and continuing until the end of therapy, and avoid contact lenses. The median number of prior lines of therapy was 8 (range: 2-15). The median time to BLMF initiation from the diagnosis of MM was 7.5 (range: 1.3-19.7) years. The median follow-up from initiation of BLMF was 7 [95% confidence interval (CI): 5.7-8.6] months, and the median number of BLMF doses administered was 2 (range: 1-6). Twenty-seven (79%) pts experienced ocular toxicity, comprising keratopathy [n=25 (74%)] and/or decreased visual acuity [n=21 (62%)]. Table 1 outlines the keratopathy-related details. Thirteen pts (38%) developed symptomatic xerophthalmia. A clinically significant decrease in BCVA of equal or worse than 20/40 in the better-seeing eye was observed in 12 (35%) pts at a median of 1.7 (95%CI: 1.4-2.2) months of commencing BLMF. In 7 (58%) pts, it improved to better than 20/40 within a median of 3 (range: 0.7-4) months from the time of documentation of impaired BCVA following withholding treatment (n=5), with or without subsequent dose reduction or its permanent discontinuation (n=2). Treatment was permanently discontinued in 5 (15%) pts after a median of 3 doses due to grade ≥2 keratopathy. It was withheld in 9 (26%) due to grade ≥2 keratopathy. Four (12%) pts required dose reduction due to keratopathy (Table 1). Of 14 pts in whom BLMF was held or permanently discontinued due to keratopathy, 10 (77%) had disease progression within a median of 1 month (range 0.4-2.5) following BLMF interruption. Among 11 pts (32%) responded to BLMF, 45% developed grade 2 or higher keratopathy after the first dose compared to 13% of pts who were refractory to BLMF (n=23). The median duration of response was 4 (95%CI: 0.7-NR) months. Among responders, 2 pts (18%) had to permanently discontinue BLMF due to keratopathy, with subsequent progression from partial remission at 1.4 and 4.6 months following its discontinuation. Additionally, 73% of responders required dose withholding due to keratopathy and of those, 50% had evidence of disease progression within a median of 1.2 month (range: 0.7-1.7) following BLMF interruption. DISCUSSION & CONCLUSIONS : Despite efficacy in pts with advanced MM, in routine practice, ocular toxicity of BLMF is a major challenge and a deterrent to its continuous use. While frequent ocular toxicity-related interruptions were observed at expected rates, permanent treatment discontinuation due to keratopathy was observed in a higher proportion of pts than that encountered in the DREAMM-2 trial. Larger prospective studies are warranted to accurately discern the effects of ocular toxicities on outcomes of pts treated with BLMF. Figure 1 Figure 1. Disclosures Patel: Emmecell: Consultancy; GlaxoSmithKline: Consultancy; Senju Pharmaceuticals: Consultancy; Santen, Inc.: Consultancy. Kumar: Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Roche-Genentech: Consultancy, Research Funding; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Antengene: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Ailawadhi: AbbVie: Consultancy; Xencor: Research Funding; Medimmune: Research Funding; Genentech: Consultancy; Ascentage: Research Funding; Takeda: Consultancy; Sanofi: Consultancy; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Cellectar: Research Funding; BMS: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Karyopharm: Consultancy; Beigene: Consultancy. Bergsagel: Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: human CRBN mouse; Genetech: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Gertz: Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Aurora Biopharma: Other: Stock option; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring. Kapoor: Karyopharm: Consultancy; AbbVie: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding.

Abstract INTRODUCTION POEMS syndrome is a paraneoplastic disorder that results in multi-organ disease, and Vascular endothelial growth factor (VEGF) is associated with disease activity. There is evidence that the cytokine Interleukin- 6 (IL-6) stimulates VEGF production in several cancer cell lines. It has also been suggested that patients with POEMS syndrome experience symptoms improvement when IL-6 levels are low. Our study aims to understand the role of IL-6 and whether it is a contributor to disease activity in POEMS syndrome. METHODS We conducted a retrospective study of patients (pts) seen at Mayo Clinic within 1 year of diagnosis for POEMS syndrome with an IL-6 level within 3 months of diagnosis between 01/01/2011-05/31/2021 were included. Our database comprised 358 pts,7 were excluded because did not have official diagnosis of POEMS syndrome. Two hundred and ninety-nine pts did not have IL-6 testing within 90 days of diagnosis and were excluded. Clinical data was abstracted from our electronic medical record. Descriptive statistics were used for IL-6 levels. The majority of IL-6 laboratory testing for pts utilized the same reference range. A minority of pts had alternate reference ranges; thus, all IL-6 values and reference ranges were fold-corrected to have a unified reference to determine elevation in IL-6. High IL-6 was considered any value above the normal range, also analyzed pts in quartiles and deciles. Hematologic, VEGF and PET response criteria were utilized to group pts into responders or non-responders. Time to progression (TTP) and overall survival (OS) was calculated using the Kaplan Meier method. Differences between curves were by log rank. Statistical analysis was conducted via JMP software package (SAS, Cary, NC, USA). Univariate analysis was done to determine the prognostic value of IL-6. Statistical significance is considered with p-values &lt;0.05. RESULTS 52 patients from among 352 met criteria and were included for analysis. Twenty-one patients (40%) had elevated IL-6 levels (IQR 5.67, 22.6) at the time of diagnosis. The fold elevation about normal was typically not very high, with a median of 3.1-fold elevation (IQR 1.3, 4.4; and range 1.0, 8.3). The percentage of males in the high IL-6 versus the normal Il-6 group were 90% versus 65%, p=0.03. Compared to normal IL-6, those with elevated IL-6 values had more instances of hepatomegaly (43% vs 16%, p=0.03), ascites (28% vs 6%, p=0 .04), abnormal DLCO (26% vs 3%, p=0.03), mixed bone lesions (57% vs 29%, p= 0.04), and lower serum albumin (range 2.3-3.5 vs 2.5-4.5 g/dL, p=0.0008).There was a trend for lower VEGF values among the high IL-6 group, but this did not meet statistical significance (median 250 vs 438 pg/mL). There was no significant difference in the time to progression between pts with high versus normal IL-6 levels (HR 1.36; p=0.456). Overall survival was significantly longer in pts with normal IL-6 compared to pts with high IL-6 levels (Median OS 67.4 vs 47.8 months, p=0.02). Forty-two pts were evaluated for VEGF response after treatment; there was a significant improvement in time to progression (85.5 vs 14.9 months, p=0.03) in pts who were VEGF responders. Among pts evaluable for a hematologic response (n=15), time to progression in pts with baseline high IL6 was longer in hematologic responders compared to non-responders (p=0.02). Conclusion Although OS was longer for pts with normal IL-6, elevated IL-6 at the time of diagnosis does not prevent pts from achieving disease remission. The study demonstrates that response to treatment rather than interleukin-6 levels in pts with POEMS syndrome is more prognostic. This study is an important initial step into understanding the utility of IL-6 in POEMS syndrome. Figure 1 Figure 1. Disclosures Gertz: Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Aurora Biopharma: Other: Stock option; Ionis Pharmaceuticals: Other: Advisory Board; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria. Kumar: Oncopeptides: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Merck: Research Funding; Antengene: Consultancy, Honoraria; Tenebio: Research Funding; Novartis: Research Funding; Roche-Genentech: Consultancy, Research Funding; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Dingli: GSK: Consultancy; Novartis: Research Funding; Janssen: Consultancy; Sanofi: Consultancy; Apellis: Consultancy; Alexion: Consultancy. Lin: Janssen: Consultancy, Research Funding; Merck: Research Funding; Novartis: Consultancy; Legend: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Vineti: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Sorrento: Consultancy; Gamida Cell: Consultancy; Takeda: Research Funding. Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Dispenzieri: Pfizer: Research Funding; Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Alnylam: Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding.

Abstract Background: Achievement of a complete response (CR) to therapy in multiple myeloma (MM) early in disease course correlates with improvement in clinical outcomes, reflective of therapeutically sensitive disease biology. While depth of response is known to impact overall survival (OS) and progression-free survival (PFS), the effect of known prognostic variables at baseline including FISH risk and International Staging System (ISS) score outside of clinical trial settings is not well described. We sought to determine the impact of known prognostic variables in MM including FISH and ISS risk in the context of NDMM patients achieving a CR to therapy and to also examine additional predictors of outcome among this cohort. Methods: A retrospective study was conducted on 1869 NDMM patients who had ≥ 2 consecutive monoclonal protein immunofixation (IFE) studies in the serum and urine available within 24 months from diagnosis. We identified the number of patients who had ≥ 2 negative serum and urine IFE as a surrogate for achieving CR (N=461), since a bone marrow biopsy is not routinely performed to confirm CR in the non-trial setting. A Kaplan-Meier model was used to compare median PFS and OS between patients achieving a CR vs. non-CR and a multivariate analysis was performed to adjust for known prognostic variables. A cox proportional hazards model was used to determine the prognostic impact of baseline FISH (high risk vs. standard risk) and ISS scores (3 vs.1 and 2) on PFS and OS, among patients achieving a CR vs. non-CR, and identify additional prognostically significant variables within the CR cohort. Results: The median length of follow-up for the entire cohort (n=1869) was 64 months (range: 1-199). The median time from diagnosis to achievement of CR among the CR cohort was 9.8 months (0.20-23.8 months). The median PFS for CR (n=461) vs. non-CR (n=1408) patients was 42.0 vs. 29.3 months (p&lt;.0001) and median OS was 124.4 vs. 85.6 months (p&lt;.0001), respectively (Figure 1). The impact of achieving a CR on outcomes was retained after adjusting for FISH, ISS, age, sex, autologous stem cell transplant, and involved heavy chain as follows: PFS HR 0.57 (0.43-0.76; p=0.0001); OS HR 0.56 (0.43-0.74; p&lt;0.0001). The baseline FISH and ISS risk on PFS and OS comparing CR vs. non-CR patients are shown in Table 1, with both variables having statistically insignificant impact on PFS and OS among the CR cohort. We examined several variables present at baseline and at the time of CR to determine their impact on PFS and OS, including age, sex, and non-IgG involved heavy chain (baseline), and thrombocytopenia (&lt;150,000), hypoalbuminemia (&lt;3.5 g/dL), and immunoparesis (at time of CR). The following variables were found as inferior predictors on PFS within the CR cohort with hazard ratios as follows: male gender, HR 1.36 (1.05-1.75; p=0.02) and non-IgG involved heavy chain, HR 2.2 (1.55-3.2).The following variables were found as predictors for inferior outcomes on OS within the CR cohort with hazard ratios as follows: Age&gt; 75 years, HR 2.7 (1.54-4.8; p=.0005); male gender, HR 1.5 (1.1-2.02; p=.008); serum albumin &lt;3.5, HR 1.54 (1.1-2.08; p=.004); and non-IgG involved heavy chain, HR 1.75 (1.23-2.47; p=.002). On multivariate analysis, age, hypoalbuminemia, and non-IgG involved heavy chain retained prognostic significance for OS. Conclusion: Attainment of an early CR in NDMM confers improvement in PFS and OS. Our study confirms these findings and suggests that achievement of CR neutralizes the impact of baseline FISH and ISS risk on PFS and OS. Among the CR cohort, age&gt; 75 years, male sex, non-IgG involved heavy chain, and hypoalbuminemia at the time of CR predict for inferior overall survival. Figure 1 Figure 1. Disclosures Dingli: Sanofi: Consultancy; Alexion: Consultancy; Novartis: Research Funding; GSK: Consultancy; Apellis: Consultancy; Janssen: Consultancy. Gertz: Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Aurora Biopharma: Other: Stock option; Ionis Pharmaceuticals: Other: Advisory Board; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy. Dispenzieri: Alnylam: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Janssen: Consultancy, Research Funding. Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Lin: Vineti: Consultancy; Bluebird Bio: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Juno: Consultancy; Merck: Research Funding; Sorrento: Consultancy; Celgene: Consultancy, Research Funding; Gamida Cell: Consultancy; Novartis: Consultancy; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Legend: Consultancy. Kumar: Merck: Research Funding; Antengene: Consultancy, Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Tenebio: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Roche-Genentech: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

Abstract Background: Treatment for multiple myeloma (MM) patients refractory to proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and monoclonal antibodies remains an unmet need. Belantamab mafodotin is a first in class antibody drug conjugates (ADCs) in MM utilizing a humanized monoclonal antibody targeting B cell maturation antigen (BCMA) conjugated to a microtubule-disrupting monomethyl auristatin F. The efficacy of belantamab in relapsed refractory MM (RRMM) patients has been reported in several randomized clinical trials. However, clinical trials have restricted patients' eligibilty. We report the "real world" efficacy and safety of belanatmab in patients treated at all three Mayo Clinic sites. Methods: We retrospectively reviewed all consecutive MM patients that received at least one dose of belantamab outside a clinical trial. The primary endpoints were PFS and OS, and the secondary endpoints included overall response rates (ORR) and safety. Results: Thirty-seven RRMM patients were treated with belantamab between September 2020 and June 2021. The median age at diagnosis was 61 (range 37-83) and 64% were male. The median age at belantamab administration was 67 (IQR 59-74) and 14 patients (38%) were 70 years or older. Fifteen of 34 patients (44%) had high-risk FISH and 13 patients of 33 (39%) had ISS 3. Two patients had a creatinine of &gt;2.5 mg/dL, and one patient was on dialysis. All three received full dose belantmab (2.5 mg/kg). The median time from diagnosis to belantamab initiation was 7 years (IQR 4-11), and the median prior lines of therapy was 8 (IQR 7-11). Twenty-seven patients (73%) underwent an autologous stem cell transplantation prior to belantamab therapy, and all patients were penta refractory (IMiD, PI, and anti CD38). Seven patients (19%) received CAR-T therapy prior to belantamab. The median number of belantamab doses administered was 3 (range 1-6). Thirty-one (84%) received belantamab monotherapy and 6 patients (16%) received belantamab in combination [pomalidomide (n=3), cyclophosphamide (n=2), or thalidomide (n=1)]. The overall response (ORR) rate to belantamab was 33% (out of 36 evaluable patients). Two patients (6%) achieved complete response (CR), 3 patients (8%) achieved very good partial response (VGPR), and 7 patients (19%) achieved partial response (PR). At data cutoff 20 patients (54%) are alive. Seventeen patients died of MM complications. The median follow-up was 6 months (IQR 3.5-7). The median PFS and OS for the whole cohort was 2 months (95% CI 1-3) and 7 months (95% CI 3--NR), respectively. Two patients died within the first cycle of belantamab (due to PD), and overall, 12 died within 100 days of belantamab therapy, all due to disease progression. Eleven patients (30%) were hospitalized during belantamab therapy. The reasons for hospitalization were related to MM in 4 patients (one patient with malignant ascites, one with hypercalcemia, 2 patients for pain management). Three patients were hospitalized due to thrombocytopenia (related to disease), and one due to an infusion-related reaction (IRR). Other reasons for hospitalization were infection (soft tissue abscess, n=1), proctitis (n=1) and tumor lysis (n=1). Keratopathy developed in 16 patients (43%). Keratopathy was grade 1 in 6 patients, grade 2 in 7 patients, and grade 3 in 3 patients. Only one patient had corneal erosions and 6 patients reported decreased visual acuity, (1 grade 3 keratopathy, 4 had grade 2 keratopathy, and 1 had grade 1 keratopathy). Two patients had IRR. Two patients reported gaining 3.5 kg each after therapy with belantamab was discontinued. Conclusions: The response rates are similar to those reported in randomized clinical trials. The role of belantamab in the era of other BCMA directed therapy (CAR-T, BiTEs) remains unclear. Disclosures Dispenzieri: Janssen: Consultancy, Research Funding; Pfizer: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Alnylam: Research Funding; Takeda: Research Funding. Kumar: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Oncopeptides: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Honoraria; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Bluebird Bio: Consultancy; Roche-Genentech: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Dingli: Novartis: Research Funding; GSK: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; Alexion: Consultancy; Apellis: Consultancy. Kapoor: Cellectar: Consultancy; BeiGene: Consultancy; Sanofi: Consultancy; Ichnos Sciences: Research Funding; Karyopharm: Consultancy; Amgen: Research Funding; Pharmacyclics: Consultancy; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Gertz: Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Ionis Pharmaceuticals: Other: Advisory Board; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Aurora Biopharma: Other: Stock option.

Abstract Introduction: Factors contributing to the antitumor activity of systemic oncolytic virotherapy (OV) include (i) generalized innate immune activation due to virus infusion; (ii) direct oncolytic and/or immune-mediated destruction of OV infected tumor cells due to intratumoral spread of the virus infection; (iii) collateral boosting of tumor antigen-specific T cell responses that target uninfected tumor cells. We investigated the relative contributions of these 3 factors T cell lymphoma (TCL) patients (pts) responding to a single intravenous infusion of Voyager-V1, an oncolytic vesicular stomatitis virus (VSV) encoding IFNβ and sodium iodide symporter (NIS) on NCT03017820. Of relevance, the virally encoded IFNβ enhances tumor specificity, boosts proinflammatory activity & serves as a convenient serum biomarker of infection. Methods: In a first in human trial, a single infusion of Voyager-V1 was administered to 15 pts with relapsed refractory hematologic cancers; 4 dose levels (DL) were tested (5x10 9, 1.7x10 10, 5x10 10, 1.7x10 11 TCID50); 7 pts had TCL. Cytokine levels and CRS symptoms were determined as a measure of generalized immune activation; serum IFNβ levels were monitored as a pharmacodynamic biomarker of virus infection; antitumor T cell responses were measured using ELISPOT assays. Results: Of 8 TCL pts, 3 had RECIST responses: PR at DL 2, a CR & PR at DL 4. Most pts experience short lived CRS typically resolving within 24 hours of virus infusion. Serum IFNβ levels increased post-therapy in all pts, typically peaking by 24 hours post virus infusion and returning to baseline by median day 10. T cell responses could not be accurately determined in most cases due to suboptimal T cell viability and/or function after thawing of frozen PBMC. Factors contributing to tumor regression in each of the responding pts appeared to differ significantly, as exemplified by the case reports below. Pt (I) with CTCL experienced grade 1 CRS followed by brisk regression of multiple cutaneous lesions. The PR lasted 3 mo, after relapse of an eye lesion, but responses at other sites deepened after the relapsed lesion was irradiated; pt remained off active therapy for the next 2 yrs. Peak serum IFNβ 4 hours post infusion was only 182 pg/ml suggesting that disease response may have been driven by nonspecific innate immune activation associated with the virus infusion. Pt (IV) (CD30+ PTCL/ cutaneous relapse) had short lived grade 2 CRS, then developed signs of IFNβ toxicity with AST elevation and thrombocytopenia. Oral ruxolitinib was administered for 5 days as IFNβ toxicity mitigation leading to normalization of AST and platelets. All PET-avid tumors regressed completely. This CR continues 16 months post virus infusion. Peak serum IFNβ was 18,213 pg/ml strongly suggesting that response was driven by extensive intratumoral amplification of the virus and oncolytic tumor destruction. Robust CTL responses to tumor neoantigens were detected in this pt at baseline indicating that collateral boosting of tumor-specific T cells may have been responsible for the long term maintenance of this CR Pt (V) (CD30+ PTCL) had short lived grade 2 CRS followed by response at all disease sites (including complete normalization of an enlarged FDG-avid spleen). Her PR ended after 6 months due to relapse in cervical lymph nodes. Peak serum IFNβ level was modest, 600 pg/ml & sustained over 48 hours suggesting slower intratumoral spread of the virus infection. The deepening of the response long after resolution of the oncolytic phase points strongly to a contribution from antitumor CTL but the assay was technically unsatisfactory in this pt. Conclusion: Analysis of the correlative data supports that intravenous Voyager-V1 therapy can recruit diverse antitumor effector mechanisms to impact tumor response in pts with heavily pretreated TCL. Importantly, intratumoral virus amplification, which results in high circulating concentrations of IFNβ, does not necessarily lead to tumor regression perhaps because of defective immune cell recruitment and/or activation in some tumors but not in others. This will be further evaluated in future study participants by performing CTL assays on fresh, rather than frozen PBMC. In conclusion, a single IV infusion of Voyager-V1 shows highly promising activity against treatment refractory TCL and should be further advanced as a new single-shot or combination therapy for this therapeutically challenging indication. Figure 1 Figure 1. Disclosures Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. Paludo: Karyopharm: Research Funding. Patnaik: StemLine: Research Funding; Kura Oncology: Research Funding. Dispenzieri: Takeda: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. Bennani: Kymera: Other: Advisory Board; Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Gertz: Aurora Biopharma: Other: Stock option; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Ionis Pharmaceuticals: Other: Advisory Board. Dingli: Janssen: Consultancy; Sanofi: Consultancy; GSK: Consultancy; Apellis: Consultancy; Novartis: Research Funding; Alexion: Consultancy. Kumar: Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Merck: Research Funding; Oncopeptides: Consultancy; Roche-Genentech: Consultancy, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Honoraria; Tenebio: Research Funding; Novartis: Research Funding; Bluebird Bio: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Bergsagel: Oncopeptides: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Genetech: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: human CRBN mouse; Janssen: Consultancy, Honoraria. Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Lin: Sorrento: Consultancy; Vineti: Consultancy; Legend: Consultancy; Novartis: Consultancy; Bluebird Bio: Consultancy, Research Funding; Merck: Research Funding; Juno: Consultancy; Celgene: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Gamida Cell: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Research Funding. OffLabel Disclosure: VSV-IFNβ-NIS is an oncolytic virus in clinical trial for systemic administration in hematologic malignancies

Abstract Background: Patients with multiple myeloma (MM) that are refractory to a proteasome inhibitors (PI), immunomodulatory drug (IMiDs) and CD38/SLAMF7 directed monoclonal antibodies are commonly referred to as triple class refractory (TCR). This is an increasingly common clinical problem and here we present the outcomes, prognostic markers and response to therapy for patients with TCR disease. Methods: Consecutive patients with MM diagnosed between 01/01/2013 and 12/31/2018 and seen at Mayo Clinic, Rochester, MN were included in this study after institutional review board approval. Refractoriness to therapy was defined as progression or non-responsiveness (failure to achieve at least a minimal response) to therapy within 60 days of discontinuation of therapy, based on the International Myeloma Workshop Consensus definition. Patients meeting the definition for refractory disease for at least 1 PI (bortezomib, carfilzomib or ixazomib), 1 IMiD (lenalidomide, pomalidomide or thalidomide) and 1 monoclonal antibody (daratumumab, isatuximab or elotuzumab) were considered to have TCR disease and included in the study population. The first date when patients satisfied the above-mentioned criteria for TCR was used to calculate the follow-up, progression free survival (PFS) and OS for TCR disease. The mSMART 3.0 (www.msmart.org) classification was used to characterize high-risk and standard-risk cytogenetics features in interphase fluorescence in situ hybridization (FISH). The currently prevalent international myeloma working group (IMWG) criteria were used for response assessment. The Kaplan-Meier method was used for estimation of time-to-event endpoints. Reverse censoring was used for estimation of follow-up time. Cox regression was used for multivariate analyses. Wilcoxon test was used for comparison of continuous variables and Chi square test or Fisher's exact test were used to compare categorical variables, respectively Results: In this retrospective study, 249 consecutive patients with TCR status were identified. The median follow-up from diagnosis of MM till date of last follow-up was 6.8 years (95% CI: 6.3-7.3 years) and 1.9 years (95% CI: 1.6-2.4) from TCR MM to last follow-up. The median age at diagnosis of MM was 61 years (range 31-89) and at TCR was 65 years (range 32-93). The median number of lines of therapy for the entire cohort were 8 (range 1-17); the patients were exposed to a median of 5 (range 1-12) lines of therapy prior to TCR status. Baseline characteristics for the cohort are depicted in Table 1. The median time to development of triple refractory disease was 2.9 years (95% CI: 2.6-3.2 years) from diagnosis of MM. The time to TCR disease was shorter for high-risk cytogenetics at 2.3 years (95% CI: 2-2.7) compared to 3.4 years (95% CI: 3.1-4.1) with a hazard ratio (HR) of 1.8 (95% CI: 1.4-2.4) p&lt;0.0001], Figure 1A. The median overall survival (OS) from TCR was 1.01 (95% CI: 0.9-1.3) years. High-risk cytogenetics at diagnosis of MM were associated with an inferior OS from TCR disease even after adjustment for age, and ISS stage [median 1.05 years (95% CI: 0.8-1.5) for high-risk vs 1.3 years (95% CI: 0.9-2.9) for standard-risk cytogenetics; hazard ratio 1.44 (95% CI: 1.01-2.05); p=0.04]. Of 249 patients, 227 had data available for therapy post TCR (initial therapy details post TCR status are depicted in Table 2) with a median PFS of 4 months (95% CI: 3.5-5) for the salvage therapy post attainment of TCR. Patients achieving a deeper response [≥partial response (PR)] were noted to have a significantly improved PFS with the initial therapy post TCR disease [median PFS 8.2 months (95% CI: 7.5-12.7)] compared to patients not achieving a PR [median PFS 2 months (95% CI: 1.6-2.7); HR 0.2 (95% CI: 0.13-0.27); p&lt;0.0001], Figure 1B. Deeper response (≥PR) to initial therapy at TCR disease was associated with an improved PFS [HR 0.23 (95% CI: 0.16-0.34); p &lt;0.0001] after adjusting for age at TCR status, ISS stage and cytogenetic risk categories at diagnosis. Conclusion: Patients with triple refractory MM have a guarded prognosis and demonstrate an underwhelming median PFS of 4 months and median OS of 1 year. Achievement of a deeper response to therapy at triple refractory status is associated with a prolonged PFS. High-risk cytogenetic features at diagnosis confer a negative prognosis in TCR patients. Newer therapies are the needed to sustain the improvement in outcomes for this group of patients. Figure 1 Figure 1. Disclosures Kapoor: Cellectar: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; BeiGene: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Karyopharm: Consultancy; Regeneron Pharmaceuticals: Research Funding; AbbVie: Research Funding; Takeda: Research Funding; Sanofi: Research Funding; Karyopharm: Research Funding; Glaxo SmithKline: Research Funding. Dispenzieri: Pfizer: Research Funding; Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Alnylam: Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding. Gertz: Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Aurora Biopharma: Other: Stock option; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria. Dingli: Apellis: Consultancy; GSK: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Novartis: Research Funding; Alexion: Consultancy. Kumar: Sanofi: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Beigene: Consultancy; Tenebio: Research Funding; Novartis: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Merck: Research Funding; Carsgen: Research Funding; Antengene: Consultancy, Honoraria; Oncopeptides: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Introduction Multiple myeloma (MM) is frequently accompanied by renal impairment (RI) in 30-40% patients at presentation (Dimopoulos et al, IMWG 2010). As per International Myeloma Working Group (IMWG), RI is defined as Creatinine clearance (CrCl) &lt;40 mL/min. Patients with RI at diagnosis have inferior overall survival (OS), however, over the years their outcome has improved due to treatment with novel agents. We examined the baseline clinical characteristics, and outcomes in patients with a new diagnosis of multiple myeloma at our institution to identify factors associated with baseline RI and study prognostic trend over the last 2 decades. Methods We retrospectively reviewed records for MM patients with a new diagnosis of MM who were seen at Mayo Clinic, Rochester between 1/2004 and 12/2018. RI was defined as per IMWG criteria. Categorical variables were compared using chi-square test and continuous variables using Wilcoxon test. Overall Survival (OS) was estimated using Kaplan-Meier method and difference between groups was assessed using log-rank test. Results In our cohort of 2702 patients, median age at diagnosis was 65 (range, 22-96) years and 61% were males. Number of patients with CrCl &lt;15, 15-29, 30-59 and ≥60 ml/min at diagnosis was 176 (6.5%), 204 (7.6%), 685 (25.3%) and 1637 (61%) respectively. RI was present in 557 (21%) of patients at the time of presentation. On univariate analysis, factors significantly associated with RI at diagnosis were higher age, ECOG PS ≥2, hemoglobin&lt; 10 g/dL, calcium &gt;11 mg/dL , LDH &gt;222 U/L, β-2-microglobulin &gt;5.5 mg/L, free light chain ratio &gt;100, uric acid &gt;8 mg/dL, higher ISS stage and cytogenetics [gain 1q, t (14;20), absence of any trisomy] as shown in table 1. However, on multivariate analysis, only elevated serum calcium &gt;11 g/dL (OR: 11.5; 95%CI:1.78-74.9; p=0.01) and free light chain ratio&gt;100 (OR: 4.17; 95%CI:1.29-13.4; p=0.016) had significant association with RI. The RI group had inferior OS when compared to patients with no RI at diagnosis (4.5 years vs 7.7 years, p-value &lt;0.001). However, use of novel agents was associated with improvement in OS in patients with RI (4.9 years vs 2.6 years; p=0.0001) (Figure 1). Looking at trends over time, the rate of RI at presentation had not changed. Over the last two decades, OS for the CrCl&lt;30 group had significantly improved in the last 5-year period (3.8 years in 2004-2014 vs not reached for 2014-2018; p= 0.0064) as shown in figure 2. Conclusion In our cohort of 2702 patient, frequency of RI at baseline was 21%, which corroborates with previous studies. Hypercalcemia and serum free light chain ratio were found to be independent factors associated with RI. RI at diagnosis is associated with inferior survival, however, use of novel agents in this population has led to improvement of patient outcomes. Figure 1 Figure 1. Disclosures Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Gertz: Aurora Biopharma: Other: Stock option; Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy. Dingli: Alexion: Consultancy; Novartis: Research Funding; Apellis: Consultancy; GSK: Consultancy; Sanofi: Consultancy; Janssen: Consultancy. Kumar: Roche-Genentech: Consultancy, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Novartis: Research Funding; Merck: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Bluebird Bio: Consultancy; Oncopeptides: Consultancy; Carsgen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Honoraria; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.