Dispenzieri, Angela

Abstract Introduction Monoclonal B-cell lymphocytosis (MBL), monoclonal gammopathy of undetermined significance (MGUS), and clonal hematopoiesis (CH) are three common premalignant hematological conditions. MBL is a precursor to chronic lymphocytic leukemia (CLL), MGUS is a precursor to both multiple myeloma (MM) and Waldenström macroglobulinemia (WM), and CH is a possible precursor to myeloid disease. All three conditions are independently associated with aging. Furthermore, there is evidence that all three conditions are associated with increased risk of infection. The relationship among these conditions, the prevalence with which they co-exist, and the association between the number of premalignant conditions and risk of infection is unknown. Methods Study participants from the Mayo Clinic Biobank, a large-scale biorepository of adult patients, provided a peripheral blood sample between 7/14/2009 to 06/18/2015. Individuals were screened for MBL using eight-color flow cytometry capable of detecting clonal B-cells to the 0.005% level. MGUS was screened using a matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) assay. CH was screened using a targeted sequencing panel of 42 CH-associated genes with at least 1000x read depth and the ability to detect variant allele fractions down to 1%. All study participants resided in Olmsted County, Minnesota, the county that includes Mayo Clinic. Serious infection, defined as hospitalization due to infection, was abstracted from medical records from the time of sample collection through 12/31/2020 or date of death. The medical record abstractor collecting data was blinded to condition. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between each of the conditions. Cox regression was used to estimate hazard ratios (HR) and 95% CI to assess the association between number of premalignant conditions with risk of infection. All analyses were adjusted for age at sample collection and sex. Results A total of 407 individuals (55% male, median age 68 years) were screened for all three conditions. The prevalence was 19.9% (n=81) for MBL, 14.5% (n=59) for MGUS, and 25.6% (n=104) for CH. When we evaluated the association between each of the conditions, we found no evidence of an association between the prevalence of CH and risk of MBL (OR=0.79, 95% CI: 0.43-1.42), CH and risk of MGUS (OR=1.24, 95% CI: 0.66-2.27), or MGUS and risk of MBL (OR=1.32, 95% CI:0.66-2.52). The prevalence of co-existence of these conditions was assessed by grouping individuals based on their condition or conditions (Figure 1A). We found that 197 (48.4%) study participants had at least one premalignant condition and 10.6% had two or more. Individuals with 2 or more conditions were the oldest (median age 74 years), followed by 1 condition (median 69 years) and 0 conditions (median 67 years, P-trend <0.001). Sex was not significantly different across the groups, with 55%, 58%, and 47% male for 0, 1, and 2 conditions, respectively. Medical record abstraction identified 97 serious infection events in 80 individuals. Medical records were not available on 7 individuals. The most common infections were urinary tract (20 events), pneumonia (14 events), and cellulitis (14 events). Median follow-up time was 10.6 years (range 0.1-11.5 years). Compared to individuals with no condition, MBL (HR=1.75, 95% CI: 1.06-2.88) and MGUS (HR=1.75, 95% CI: 1.04-2.93) were associated with increased risk of serious infection. We found no evidence of an association with CH (HR=1.15, 95% CI: 0.71-1.87). When grouped by the number of conditions, we observed a significant trend (P-trend <0.01, Figure 1B) in risk of serious infections by the number of conditions: individuals with 1 condition had a 35% increased risk of infections (HR=1.35, 95% CI:0.83-2.20) and individuals with 2 or more conditions had a 2.6-fold increased risk (HR=2.58, 95% CI: 1.37-4.84). Discussion At least one premalignant condition was present in nearly 50% of the study population, with CH being the most prevalent. No evidence of a relationship between any of the three conditions was observed. However, we found increased susceptibility to serious infections as the number of conditions increased with individuals with at least two conditions had 2.6-fold increased risk of infections. Figure 1 Figure 1. Disclosures Parikh: Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding. Dispenzieri: Takeda: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. Murray: Mayo Clinic: Other: Has received patents for the Mass-Fix technology which has been licensed to the Binding Site with potential royalties.. Kumar: Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Oncopeptides: Consultancy; Beigene: Consultancy; Novartis: Research Funding; KITE: 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; Antengene: Consultancy, Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Roche-Genentech: Consultancy, Research Funding; Bluebird Bio: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: 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; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Cerhan: Regeneron Genetics Center: Other: Research Collaboration; Genentech: Research Funding; Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; NanoString: Research Funding. Kay: TG Therapeutics: Research Funding; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Targeted Oncology: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; MEI Pharma: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Research Funding; Genentech: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Behring: Membership on an entity's Board of Directors or advisory committees; CytomX Therapeutics: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees. Shanafelt: Genentech, Pharmacyclics: 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 >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 Background Recommendations for 2 nd line treatment for relapsed multiple myeloma (MM) patients have been changing over the past two decades, given the introduction of novel agents, different side-effect profiles, and attempts at more individualized treatment approaches. We designed this study to characterize how 2 nd line treatment strategies have evolved over the last two decades for MM patients. Methods Patients with MM with at least one relapse treated with a 2 nd line regimen, seen at Mayo Clinic between 2003-2021, were included. To visualize trends in treatment choices we divided the study period into 2-year intervals and for descriptive purpose the period was divided into three 6-year intervals. We used "100% stacked area" charts to show how the constituent parts of the whole have changed over time. The height of each colored stack represents the proportion of patients in that category at a given point in time. Results A total of 1439 patients were included. Patients were diagnosed between 2001 and 2018, the initiation of 2 nd line treatment occurred between June 2003 and February 2021. Median age at diagnosis was 62.7 years (interquartile range, 55.8-69.3), 60.0% were male. International Staging System stage I was present in 23.5% of patients, stage II in 32.9% and stage III in 28.8%. In the 1 st line therapy novel agents were used in 82.8% of cases, regimens based on proteasome inhibitors (PI) in 26.5%, immunomodulatory drugs (IMID) in 42.0% and combination of PI+IMID in 21.1%. Upfront autologous stem cell transplantation (ASCT) was performed in 50.1% of patients, and maintenance after 1 st line was used in 25.2%. For 2 nd line treatment, during 2003-2008 the majority were treated with doublets (70.5%), followed by triplets (14.8%) and salvage ASCT (7.7%) (Figure 1A). Patients were treated with IMID or PI-based therapy (50.7% and 21.8%, respectively); only 3.7% received PI+IMID and 20.1% of patients received alkylating agents/anthracyclines. The most frequently used regimens were lenalidomide-dexamethasone (RD, 32.2%) and bortezomib-dexamethasone (VD, 18.1%, Figure 1B). Between 2009-2014, the use of triplets in 2 nd line increased (43.0%), although doublets were still more common (50.9%). Like previous years, IMID-based therapy was most frequently used (37.3%), however, the use of PI-based therapy increased (36.0%). PI+IMID-based therapy was implemented in 17.9% of patient, and 27.3% received alkylating agents/anthracyclines. Most frequently used regimens included: RD (29.4%), bortezomib-cyclophosphamide-dexamethasone (CYBORD, 17.4%), bortezomib-lenalidomide-dexamethasone (VRD, 13.4%) and VD (13.3%). Finally, during 2015-2021, triplets were most common (68.9%), followed by doublets (23.0%). IMID- and PI+IMID-based therapies were most often implemented (34.2% and 31.1%, respectively), followed by PI-based therapy (26.8%). 28.1% of patients received monoclonal antibodies; only 15.9% received alkylating agents/anthracyclines. Most frequently used regimens include RD (13.8%), carfilzomib-RD (11.6%), daratumumab-RD (9.8%), CYBORD (9.3%), VRD (8.8%), daratumumab-pomalidomide-dexamethasone (5.9%) and daratumumab-VD (5.2%). Median time to next treatment (TTNT) from 2 nd line therapy has improved over the course of the three time periods (p<0.01; Figure 1C): years 2003-2008, 10.4 months; years 2009-2014, 13.2 months; and years 2014-2021, 16.6 months. Similarly, the median overall survival from 1 st relapse has increased over the three intervals: 30.9 months, 48.4 months, and 65.8 months, respectively. Conclusions Over the past two decades, the effectiveness of 2 nd line treatment has improved, reflected by improved TTNT from 2 nd line therapy. With the introduction of new agents in 2012-2015 (carfilzomib, pomalidomide and daratumumab) and favorable results for triplets demonstrated in randomized trials, the triplet therapies started to be used more frequently. Over time, the landscape of 2 nd line therapies has become more diverse, which may reflect a more individualized approach to each patient. Moreover, the large variety of treatment strategies makes comparisons more and more challenging. Figure 1 Figure 1. Disclosures Kapoor: Ichnos Sciences: Research Funding; Karyopharm: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Cellectar: Consultancy; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Dispenzieri: Pfizer: Research Funding; Alnylam: Research Funding; Takeda: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. 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; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Ionis Pharmaceuticals: Other: Advisory Board. Dingli: Sanofi: Consultancy; Apellis: Consultancy; Novartis: Research Funding; Alexion: Consultancy; Janssen: Consultancy; GSK: Consultancy. Kumar: Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Tenebio: Research Funding; Carsgen: Research Funding; Beigene: Consultancy; Antengene: Consultancy, Honoraria; Roche-Genentech: Consultancy, Research Funding; Janssen: 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; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy.

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<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<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 <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) <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 <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< 10 g/dL, calcium >11 mg/dL , LDH >222 U/L, β-2-microglobulin >5.5 mg/L, free light chain ratio >100, uric acid >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 >11 g/dL (OR: 11.5; 95%CI:1.78-74.9; p=0.01) and free light chain ratio>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 <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<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.

Abstract Background: MASS-FIX is a novel method for detection, characterization and quantification of serum and urine monoclonal proteins in multiple myeloma (MM) which uses immunoglobulin enrichment coupled with matrix-assisted laser desorption ionization time-of-flight mass-spectrometry (MALDI-TOF). MASS-FIX has been endorsed by the International Myeloma Working Group (IMWG) as an alternative to immunofixation electrophoresis for diagnosis and disease monitoring in MM and has replaced immunofixation electrophoresis in our institution. This technique has demonstrated superior sensitivity and specificity compared to conventional gel-based methods, but its prognostic value is still unknown. We designed this study to evaluate whether serum M protein monitoring by MASS-FIX has prognostic significance in predicting disease progression in patients with MM. Methods: In the first part of the study, we included patients with MM who had a documented negative MASSFIX after first-line treatment and had serial MASS-FIX data available (n=187). We then compared the time to next treatment (TTNT) between patients who became positive by MASS-FIX and those who remained negative by last follow up. In the second part, we included patients who were positive by MASS-FIX within 90 days from diagnosis and had available serial MASS-FIX data (n=203). We compared TTNT between patients who became negative by MASS-FIX and those who remained positive by last follow up. TTNT was defined as the time of initiation of the first-line treatment to the time of initiation of second-line treatment or last follow up. Results: Part 1: We included 155 patients diagnosed with MM between January 2013 and December 2019 who had a documented negative MASSFIX with first-line treatment and had serial MASSFIX data available. After a median follow up of 3.1 (95%CI: 2.6-3.5) years, 44 (28%) patients became MASSFIX positive, while 111 (72%) still had negative MASS-FIX. The median time from treatment start to negative MASSFIX was 18.0 (IQR: 6.4-33.5) months. The median TTNT was 4.1 (95%CI: 3.2 - NR) years in patients who became MASSFIX positive and not reached (NR) (95%CI: NR-NR) in patients who were MASS-FIX negative by last follow up (P<0.001). The 2-year OS was 97% and 100% in the 2 groups, respectively (P=0.27). Part 2: We included 203 patients who had positive MASSFIX within 90 days from diagnosis and available serial MASSFIX data. The median follow-up was 1.5 (95%CI: 1.5-1.7) years. By last follow up, 39 (19%) patients became MASSFIX negative while 164 (81%) still had positive MASSFIX. The median TTNT was NR (95%CI: 2.0-NR) years in patients who developed negative MASSFIX and 2.3 (95%CI: 1.9 - NR) years in patients who were still MASS-FIX positive by last follow up (P=0.03). The 2-year OS was 97% and 94% in the 2 groups, respectively (P=0.84) Conclusion: The utilization of MASS-FIX in disease monitoring of MM patients provides prognostic information; among patients who become MASS-FIX negative after first line treatment, an earlier conversion to positive MASS-FIX predicts disease progression. Similarly, persistent MASS-FIX positivity after treatment initiation predicts earlier disease progression. Larger studies and longer follow up are needed to evaluate whether the MASS-FIX is associated with overall survival. Disclosures Murray: Mayo Clinic: Other: Has received patents for the Mass-Fix technology which has been licensed to the Binding Site with potential royalties.. Dispenzieri: Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Pfizer: Research Funding; Alnylam: Research Funding; Takeda: Research Funding; 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. 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; Aurora Biopharma: Other: Stock option; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring. Dingli: Sanofi: Consultancy; GSK: Consultancy; Novartis: Research Funding; Apellis: Consultancy; Janssen: Consultancy; Alexion: Consultancy. Kumar: Amgen: Consultancy, Research Funding; Bluebird Bio: Consultancy; Antengene: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; KITE: 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; Carsgen: Research Funding; Merck: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Novartis: Research Funding; Tenebio: 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.

Abstract Introduction: A baseline involved to uninvolved free light chain ratio (FLCr) ≥100 with involved free light chain (iFLC) ≥10 mg/dL is considered a multiple myeloma (MM)-defining event (MDE). However, prior reports have demonstrated that the presence of multimeric light chain aggregates can contribute to falsely increased FLC levels due to impaired renal light chain clearance. Therefore, we aimed to compare the disease progression risk in patients with high versus low urine monoclonal protein (uMCP) excretion in the setting of an elevated serum FLCr. Methods: We retrospectively evaluated untreated smoldering MM (SMM) and asymptomatic MM patients diagnosed between January 1, 2000 and January 10, 2020. Included patients had a baseline bone marrow plasma cell (BMPC) burden of 10-59% without concomitant end organ damage (hypercalcemia, anemia, renal failure, or lytic lesions on x-ray or cross-sectional imaging; "CRAB" MDE). Patients with a baseline FLCr ≥100 and iFLC >10 mg/dL were included if they had a 24-hour urine collection and electrophoresis. Survival analyses were performed using the Kaplan-Meier method. Progression was defined as treatment for systemic AL amyloidosis or symptomatic MM (typical "CRAB" MDE). SMM patients treated due to evolving biomarkers or "SLiM" MDE (lytic lesions on MRI, BMPC ≥60%, or FLCr ≥100) were censored. Cox proportional hazards models were used for uni- and multivariable analyses. A two-sided p-value <0.05 was considered statistically significant. Results: We included 822 patients without MDE besides elevated FLCr (n=120 with FLCr ≥100, n=702 with FLC <100). Patients with a FLC ≥100 were grouped based on 24-hour uMCP excretion (≥200 mg/24h [n=35], <200 mg/24h [n=85]). Among included patients with a baseline FLCr ≥100, the median iFLC was 79.9 (IQR 42.9-131.5) mg/dL and median FLCr was 207.1 (IQR 137.7-400.3). Patients with a FLCr ≥100 and high (≥200 mg/24h) versus low (<200 mg/24h) uMCP excretion had a median iFLC of 101 versus 66.5 mg/dL (p=0.001), median estimated glomerular filtration rate (eGFR) 74.4 versus 74.6 mL/min/1.73m 2 (p=0.505), and median BMPC burden of 30% versus 21% (p=0.088), as shown in Table 1. The 2-year risk of progression to symptomatic MM or AL amyloidosis was significantly higher in patients with uMCP excretion ≥200 versus <200 mg/24h (36.2% versus 13.5%, respectively; HR 2.79, 95% CI 1.57-4.96, p<0.001, see Figure 1). However, the progression risk was similar in patients with a baseline FLCr <100 versus those with a FLCr≥100 and uMCP <200 mg/24h (log rank p=0.127). After adjusting for baseline eGFR, BMPC burden, iFLC, and light chain isotype, the progression risk was still 2.7 times higher in patients with high versus low uMCP excretion (HR 2.66, 95% CI 1.39-5.10, p=0.003). In patients with a baseline FLCr ≥100 that had cross-sectional imaging at diagnosis or prior to progression confirming the absence of osteolytic lesions, the risk of progression remained significantly higher in patients with a high versus low uMCP excretion (n=14 versus n=53, respectively; HR 4.20, 95% CI 1.86-9.49, p<0.001). In patients with FLCr ≥100, there were a total of 52 patients with end organ damage at progression (26 [50%] patients with anemia, 8 [15%] with renal failure, 21 [40%] with lytic lesions, 6 [12%] with systemic AL amyloidosis). Among patients who progressed, 5 (25%) of 20 patients with high uMCP excretion and 3 (9.4%) of 32 patients with low uMCP excretion presented with renal failure as the MDE. In patients with baseline high versus low uMCP excretion that experienced renal failure at progression, the median serum creatinine of 2.7 (range 1.9-4.1) versus 2.5 (range 1.9-3.2) mg/dL (p=0.653), median uMCP 4964 (range 738-5910) versus 512 (range 196-734) mg/24h (p=0.052), and median iFLC 388 (range 317-1640) versus 437 (range 199-1030) mg/dL (p=1.00). Conclusions: Increased uMCP excretion in the setting of a FLCr ≥100 is an unfavourable prognostic marker and is associated with an increased risk of progression. The progression risk in patients with a FLCr ≥100 and low uMCP excretion (<200 mg/24h) is similar to patients with a baseline FLCr <100. Our findings underscore the importance of conducting a 24-hour urine assessment at diagnosis and may help refine the subset of patients with FLCr ≥100 in whom pre-emptive therapy is warranted. Figure 1 Figure 1. Disclosures Kapoor: AbbVie: Research Funding; Takeda: Research Funding; Sanofi: Research Funding; Karyopharm: Research Funding; Glaxo SmithKline: Research Funding; Regeneron Pharmaceuticals: Research Funding; Ichnos Sciences: Research Funding; Amgen: Research Funding; Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: 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; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Ionis Pharmaceuticals: Other: Advisory Board. Dingli: Novartis: Research Funding; GSK: Consultancy; Alexion: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Apellis: Consultancy. Kumar: Antengene: Consultancy, Honoraria; Bluebird Bio: Consultancy; Roche-Genentech: Consultancy, Research Funding; Novartis: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Oncopeptides: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Tenebio: Research Funding; 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; 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.

Abstract Introduction: Light chain (AL) amyloidosis is a plasma cell disease characterized by the deposition of insoluble amyloid fibrils into organs leading to organ dysfunction and death. The analysis at 6 and 12 months of the ANDROMEDA study (NCT03201965) showed that the addition of subcutaneous (SC) daratumumab to the standard of care combination of bortezomib, cyclophosphamide, and dexamethasone (VCd) was superior to VCd alone, with higher rates of hematologic complete response (CR) and an acceptable safety profile. Based on these findings daratumumab with VCd (D-VCd) was approved for newly diagnosed AL amyloidosis in January 2021 in the US and June 2021 in the EU. Here, we present data from the analysis at 18 months of the ANDROMEDA study. Methods: ANDROMEDA is a randomized, open-label, active-controlled phase 3 study including patients with newly diagnosed AL amyloidosis with measurable hematologic disease, ≥1 involved organ, cardiac stage I-IIIA, estimated glomerular filtration rate ≥20 mL/min, and absence of symptomatic multiple myeloma. Patients were randomized (1:1) to D-VCd or VCd for 6 28-day cycles. Bortezomib (1.3 mg/m 2), cyclophosphamide (300 mg/m 2 up to 500 mg per week), and dexamethasone (20-40 mg) were administered weekly. SC daratumumab (1800 mg co-formulated with recombinant human hyaluronidase PH20 in 15 mL) was administered once weekly in cycles 1 and 2 and every 2 weeks in cycles 3 to 6. Patients in the D-VCd arm received only SC daratumumab after cycle 6, every 4 weeks (up to a total of 24 cycles from first dose). The primary endpoint was overall (ie, at any time) hematologic CR rate, defined here as normalization of free light chain (FLC) levels and ratio (FLCr) and negative serum and urine immunofixation, confirmed at a subsequent visit; normalization of uninvolved FLC level and FLCr were not required if involved FLC was lower than the upper limit of normal. Secondary endpoints included major organ deterioration progression-free survival (PFS), organ response rate, time to hematologic response, overall survival (OS), and safety. Results: A total of 388 patients were randomized to receive D-VCd (N=195) or VCd alone (N=193). At the May 2021 clinical cutoff, the median duration of treatment for D-VCd and VCd arms was 21.3 and 5.3 months, respectively. In the D-VCd arm, 149 patients (77.2%) received daratumumab monotherapy after completing 6 cycles of D-VCd; of those, 17 (11.4%) were still receiving treatment. The rates of deep hematological responses favored the D-VCd treatment arm (Table). At a median follow-up of 25.8 months, the rate of hematologic CR was significantly higher in the D-VCd arm vs the VCd arm (59.5% vs 19.2%; odds ratio [95% confidence interval (CI)], 6.03 [3.80-9.58]; P<0.0001). Similarly, more patients achieved a very good partial response or better (≥VGPR) (D-VCd vs VCd, 79.0% vs 50.3%; odds ratio [95% CI], 3.74 [2.39-5.86]; P<0.0001). Among patients who responded, the median time from randomization to ≥VGPR was shorter in the D-VCd arm (0.56 months) vs the VCd arm (0.82 months). Comparable to the cardiac response analysis at 6 months (D-VCd vs VCd, 42% vs 22%), greater cardiac response rates were achieved with D-VCd compared with VCd at 18 months (53% vs 24%). Similarly, renal response rates remained superior with D-VCd vs VCd alone at 18 months (58% vs 26% compared with 6 months [54% vs 27%]). A total of 79 deaths occurred (D-VCd, N=34; VCd, N=45). In the D-VCd arm, only 1 additional grade 3/4 treatment-emergent adverse event occurred over 18 months vs 12 months (119 [61.7%] vs 118 [61.1%] patients) and no additional infusion-related reactions were reported. OS will be analyzed and major organ deterioration PFS will be updated after approximately 200 events have occurred. Conclusions: These results demonstrate the sustained clinical benefits of D-VCd vs VCd in terms of hematologic and organ responses with longer follow-up, although it should be noted that many patients in the D-VCd arm received daratumumab monotherapy following 6 cycles of D-VCd, while patients in the VCd group stopped study treatment. Nevertheless, the study continues to support the use of D-VCd over VCd alone in patients with newly diagnosed AL amyloidosis. Following its recent approval, D-VCd represents a new SOC for patients with AL amyloidosis. Figure 1 Figure 1. Disclosures Comenzo: Prothena Biosciences: Consultancy, Research Funding; Takeda: Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Caelum: Consultancy, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Patents & Royalties: WO2016187546A1, Research Funding. Palladini: Pfizer: Honoraria; Siemens: Honoraria; Janssen Global Services: Honoraria, Other: advisory board fees. Kastritis: Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria. Minnema: Janssen: Consultancy; BMS: Consultancy; Kite/Gilead: Consultancy; Celgene: Other: Travel expenses; Alnylam: Consultancy; Cilag: Consultancy. Wechalekar: Amgen: Research Funding; Janssen: Consultancy; Takeda: Honoraria; Celgene: Honoraria; Caelum Biosciences: Other: Clinical Trial Funding; Alexion, AstraZeneca Rare Disease: Consultancy. Jaccard: Pfizer: Honoraria; Abbvie: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees. Dispenzieri: Janssen: Consultancy, Research Funding; Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Alnylam: Research Funding; Pfizer: Research Funding; Takeda: Research Funding. Lee: Karyopharm: Consultancy; Celgene: Consultancy; Takeda Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Sanofi: Consultancy; Genentech: Consultancy; Legend Biotech: Consultancy; Janssen: Consultancy, Research Funding; Oncopetides: Consultancy; Bristol Myers Squibb: Consultancy; Regeneron: Research Funding. Sanchorawala: Oncopeptide: Research Funding; Karyopharm: Research Funding; Sorrento: Research Funding; Pfizer: Honoraria; Proclara: Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Celgene: Research Funding. Gibbs: AbbVie: Consultancy; Janssen, Celgene, Amgen, Takeda, BMS and Pfizer: Consultancy, Honoraria. Mollee: Janssen, Pfizer: Research Funding; Amgen, BMS, Janssen, Caelum, EUSA, Pfizer, SkylineDx, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: No personal fees received. Venner: BMS: Honoraria; Amgen: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Schönland: Janssen: Honoraria, Other: Travel grants, Research Funding; Pfizer: Honoraria; Takeda: Honoraria, Other: Travel grants; Prothena: Honoraria, Other: Travel grants; Sanofi: Research Funding. Suzuki: Abie: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; ONO: Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Kim: BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Cibeira: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Akcea: Honoraria, Membership on an entity's Board of Directors or advisory committees. Beksac: Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Libby: Genentech: Research Funding; BMS: Research Funding; GSK: Research Funding; Janssen: Consultancy, Research Funding. Valent: Caelum Biosciences: Other: Clinical Trial Funding; Celgene Corporation: Speakers Bureau; Takeda Pharmaceuticals: Speakers Bureau; Amgen: Speakers Bureau. Hungria: Amgen, BMS, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings/travel ; Abbvie: Honoraria; Sanofi: Honoraria, Other: Support for attending meetings/travel ; Takeda: Honoraria. Wong: Amgen: Consultancy; Genentech: Research Funding; Fortis: Research Funding; Janssen: Research Funding; GloxoSmithKlein: Research Funding; Dren Biosciences: Consultancy; Caelum: Research Funding; BMS: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Rosenzweig: Janssen: Consultancy, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Akcea: Speakers Bureau; Takeda: Speakers Bureau; Onocopeptides: Speakers Bureau. Bumma: Amgen, Sanofi: Speakers Bureau; Janssen, Oncopeptides, Sanofi: Consultancy. Tran: Janssen: Current Employment, Current equity holder in publicly-traded company. Qin: Janssen: Current Employment. Khaled: Jazz: Honoraria; Astellas: Honoraria; Alexion: Honoraria, Speakers Bureau; Omeros: Honoraria; Janssen: Current Employment. Vermeulen: Janssen: Current Employment, Current equity holder in publicly-traded company.

Abstract Introduction: Renal light chain (AL) amyloidosis typically manifests as proteinuria with or without renal failure and is associated with a risk of progression to renal replacement therapy (RRT). A significant reduction in circulating amyloidogenic light chain is needed to achieve a renal response. Current renal response criteria are binary defining a renal response as >30% reduction in 24-h proteinuria without worsening estimated glomerular filtration rate (eGFR). Several studies suggest that greater reduction in proteinuria following successful therapy improves renal and overall survival. Methods: AL amyloidosis patients diagnosed between 2010 to 2015, achieving at least hematological partial response (hemPR) to therapy and with renal involvement (defined as 24-h non-selective proteinuria >0.5 g/24-h) were included. Four predefined renal response categories were formulated based on reduction level in pretreatment 24-h proteinuria in the absence of renal progression (≥25% decrease in eGFR): renal complete response (renCR, 24-h proteinuria ≤200 mg/24-h); renal very good partial response (renVGPR, >60% reduction in 24-h proteinuria); renal partial response (renPR, 31-60% reduction in 24-proteinuria); and renal no response (renNR, 30% or less reduction). Renal response was assessed at landmark (6-, 12-, and 24 months from treatment initiation) and as best renal response. Graded renal responses were assessed as predictors for time from diagnosis to RRT and overall survival. Results: Seven hundred and thirty-seven patients were included. The median age was 63. The breakdown of renal stage was: I, 34%; II, 52%; and III, 14%. Eighty percent of patients received 1 line of therapy within 12 months of their diagnosis. Bortezomib-based therapy was given to 60% of the patients; 28% received autologous stem cell transplantation (ASCT) as their first line therapy. Hematological CR was achieved in 44% of patients, followed by hematological very good partial response (38%) and hemPR (18%). RRT was required during follow-up in 15% of patients (n=108) with a median time from diagnosis to RRT of 18 (IQR 6-43) months. Twenty-eight percent of the patients died. The median follow-up of the surviving patients was 69 months (IQR 56-86). Reduction in 24-h proteinuria from baseline improved over time with a median reduction of 34%, 50% and 71% at 6-month, 12-month, and 24-months, respectively. At best response, renCR, renVGPR, renPR and renNR were achieved in 27% (n=199), 34% (n=247), 15% (n=112) and 24% (n=179) of patients, respectively. The median time to best renal response among renal responders was 17 (IQR 8-31) months, longer for renCR (23 months, IQR 10-40) compared to renVGPR (16 months, IQR 9-27) or renPR (11 months, IQR 6-19). A renal response as early as 6 months after therapy initiation was able to predict time to RRT with an increase in RRT risk with lower level of renal response at that time point (5-year RRT risk 0%, 3%, 9% and 16% for renCR, renVGPR, renPR and renNR, respectively, P<0.001, Figure 1A). Prediction of risk for RRT based on renal response depth improved at 12- and 24-months (Figure 1B-C) and at best renal response (Figure 1D). Overall survival discrimination based on renal response depth was noted as early as 12 months from therapy initiation and improved with time. Renal response criteria as best response were tested in a univariate analysis and multivariable proportional hazard models for time to RRT and OS. The graded renal response criteria demonstrated an independent prognostic role for time to RRT and OS. Along with renal stage, graded renal responses were the strongest predictors for time to RRT. Conclusions: We validated new graded renal response criteria based on reduction in 24-h proteinuria. These 4-level renal response criteria highlight the importance of achieving a deep renal response to improve renal and overall survival. These findings will allow clinicians to make decisions on therapy changes or augmentation based on response depth as early as 6-months, before irreversible renal failure develops. Figure 1 Figure 1. Disclosures Palladini: Janssen Global Services: Honoraria, Other: advisory board fees; Siemens: Honoraria; Pfizer: Honoraria. Milani: Celgene: Other: Travel support; Janssen-Cilag: Honoraria. Schönland: Sanofi: Research Funding; Prothena: Honoraria, Other: Travel grants; Janssen: Honoraria, Other: Travel grants, Research Funding; Takeda: Honoraria, Other: Travel grants; Pfizer: Honoraria. Hegenbart: Akcea: Honoraria; Alnylam: Honoraria; Janssen: Consultancy, Research Funding; Prothena: Research Funding; Pfizer: Consultancy, Honoraria. Dispenzieri: Oncopeptides: Consultancy; Alnylam: Research Funding; Sorrento Therapeutics: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding. Kumar: 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; Merck: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Carsgen: Research Funding; Beigene: Consultancy; Novartis: Research Funding; Bluebird Bio: Consultancy; Amgen: Consultancy, Research Funding; Roche-Genentech: Consultancy, Research Funding; Takeda: 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; Tenebio: Research Funding; Antengene: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Abbvie: Consultancy, 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. Kastritis: Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding. Dimopoulos: Takeda: Honoraria; Janssen: Honoraria; Beigene: Honoraria; BMS: Honoraria; Amgen: Honoraria. Liedtke: Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Alnylam: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Witteles: Pfizer: Honoraria, Research Funding; Alnylam: Honoraria, Research Funding; Eidos: Research Funding. Sanchorawala: Pfizer: Honoraria; Takeda: Research Funding; Celgene: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptide: Research Funding; Karyopharm: Research Funding; Sorrento: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding. Landau: Takeda, Janssen, Caelum Biosciences, Celgene, Pfizer, Genzyme: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Genzyme: Honoraria. Cibeira: Celgene: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Akcea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wechalekar: Caelum Biosciences: Other: Clinical Trial Funding; Amgen: Research Funding; Janssen: Consultancy; Celgene: Honoraria; Takeda: Honoraria; Alexion, AstraZeneca Rare Disease: Consultancy. 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.