Muchtar, Eli

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: 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.

Abstract Introduction: Binary cardiac response assessment using NT-proBNP is prognostic in light chain (AL) amyloidosis. Previous studies suggested that refining the criteria to multi-level cardiac responses improves prognostic prediction. We validate a graded cardiac response assessment tool in AL amyloidosis using NT-proBNP or BNP. Methods: In this retrospective, multicenter study AL amyloidosis patients who were diagnosed between 2010 and 2015, achieving at least a hematological partial response (PR) within 12 months of diagnosis and were evaluable for cardiac response (defined as baseline NT-proBNP >650 pg/mL or BNP >150 pg/mL) were included. The following response criteria were tested: cardiac complete response (carCR, nadir NT-proBNP≤350 pg/mL or BNP≤80 pg/mL); cardiac very good partial response (carVGPR, >60% reduction in NT-proBNP/BNP); Cardiac PR (carPR 31-60% reduction); and cardiac non response (carNR, ≤30% reduction). Response was assessed at fixed time points (6, 12 and 24 months from therapy initiation) and at best response. The primary outcome was overall survival based on depth of cardiac response. Multivariate Cox proportional models were analyzed to determine independent prognostic factors for OS and time to cardiac progression using variables with p-value <0.1 in a univariate analysis. Results: Six hundred and fifty-one patients were included. The median age was 64 years. Mayo 2004 cardiac stage II, IIIA and IIIB was present in 47.5%, 38% and 14.5% of patients, respectively (by definition, patients with Mayo stage I do not have cardiac amyloidosis evaluable for response). Seventy-six percent of patients received only one line of therapy within the initial 12 months of diagnosis. Bortezomib-based therapy was the most common (70.2% of patients) followed by autologous stem cell transplantation (ASCT) in 15.7% of patients. Hematological CR, hematological VGPR and hematological PR as best response was achieved in 38%, 39% and 23% of patients, respectively. Forty-three percent of the patients have died, with 36% of the patients dying within 5-years of diagnosis. The median follow-up of the surviving patients is 70 months (IQR 56-84). Cardiac response was evaluable using NT-proBNP in 494 patients (75.9%), BNP in 109 patients (16.7%) and both NT-proBNP and BNP in 48 patients (7.4%). The latter two were grouped together for further analysis. The median time to best cardiac response among responders was 12 months (IQR 7-21 months; 18 months for carCR, 11.5 months for carVGPR and 9.5 months for carPR). Cardiac response improved over time with a median percentage reduction in NT-proBNP/BNP compared to baseline of 15%, 37% and 54%, at 6, 12 and 24 months respectively. Cardiac responses at 6-, 12- and 24-months are depicted in Figure 1A. At best cardiac response, carCR, carVGPR, carPR and carNR were achieved in 16%, 26%, 23% and 35% of patients, respectively. Patients who achieved a carCR had lower cardiac stage at diagnosis compared to patients who achieved carVGPR or carPR (stage II 65% vs 47% vs 47%, respectively; P<0.001). At least carPR at 6 and 12 months and at least carVGPR at 24-months was associated with better survival compared with a lower depth of response. At best cardiac response, deeper cardiac response was associated with a longer survival (5-year OS 93%, 80%, 62% and 35% for carCR, carVGPR, carPR and carNR, respectively; P<0.001, Figure 1B). A 2-year landmark analysis (excluding early deaths not evaluable for cardiac response depth) confirmed improved survival with a deeper cardiac response (5-year OS 93%, 82%, 70% and 58%, P<0.001; Figure 1C). These cardiac response criteria were independent predictors of survival and time to cardiac progression (>30% rise in NT-proBNP/BNP) in multivariate analysis that included age, type of first line therapy, light chain burden, cardiac stage, and hematological response. Conclusions: We validated the prognostic value of graded cardiac response. These response criteria allow better discrimination of patient populations and assessment of treatment effectiveness in an era of improved therapies for AL amyloidosis. The study emphasizes the importance of early diagnosis which increases the likelihood of deep and durable cardiac responses. Figure 1 Figure 1. Disclosures Dispenzieri: Oncopeptides: Consultancy; Pfizer: Research Funding; Sorrento Therapeutics: Consultancy; Takeda: Research Funding; Alnylam: Research Funding; Janssen: Consultancy, Research Funding. Palladini: Siemens: Honoraria; Pfizer: Honoraria; Janssen Global Services: Honoraria, Other: advisory board fees. Schönland: Janssen: Honoraria, Other: Travel grants, Research Funding; Takeda: Honoraria, Other: Travel grants; Sanofi: Research Funding; Pfizer: Honoraria; Prothena: Honoraria, Other: Travel grants. Hegenbart: Alnylam: Honoraria; Janssen: Consultancy, Research Funding; Prothena: Research Funding; Pfizer: Consultancy, Honoraria; Akcea: Honoraria. Kumar: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Novartis: Research Funding; Merck: Research Funding; Tenebio: Research Funding; Bluebird Bio: Consultancy; 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; Roche-Genentech: Consultancy, Research Funding; Antengene: Consultancy, Honoraria; Oncopeptides: Consultancy; Amgen: Consultancy, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Janssen: 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; BMS: Consultancy, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Kastritis: Genesis Pharma: Honoraria; Takeda: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Dimopoulos: Beigene: Honoraria; Takeda: Honoraria; BMS: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Liedtke: GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; 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; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees; Alnylam: 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; 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; Kura Oncology: Membership on an entity's Board of Directors or advisory committees. Witteles: Eidos: Research Funding; Alnylam: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Sanchorawala: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Proclara: 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; Abbvie: 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; Regeneron: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Karyopharm: Research Funding; Oncopeptide: Research Funding; Pfizer: Honoraria; Sorrento: Research Funding. Landau: Genzyme: Honoraria; Takeda: Research Funding; Takeda, Janssen, Caelum Biosciences, Celgene, Pfizer, Genzyme: Membership on an entity's Board of Directors or advisory committees. Cibeira: 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; Celgene: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gertz: 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; Aurora Biopharma: Other: Stock option.

Abstract Background: Systemic light chain (AL) amyloidosis is a plasma cell disorder characterized by multisystem deposition of misfolded immunoglobulin light chains produced by clonal plasma cells. Hematologic and organ responses with treatment have been shown to correlate with survival as early as 3 months from initiation of first-line treatment. Our group recently developed and validated a model integrating organ and hematologic responses for assessment of treatment outcomes at 6 months. Although current organ response criteria do not consider the depth of organ response, this has been shown to have prognostic utility in newly diagnosed patients. So, we designed this study to evaluate a composite hematologic and organ scoring system that also considers the depth of organ response at 1 to 6 months from initiation of first-line treatment. Methods: We included patients with AL amyloidosis who had at least one major organ involvement (cardiac, renal and/or liver involvement) and who had not started a second line treatment by 6 months from the time of initiating first-line treatment. For each patient, we calculated an organ response score and a hematologic response score at 1, 2, 3, 4, 5, and 6 months from initiation of first-line treatment. A score was assigned for each depth of hematologic response as follows: complete response=0, very good partial response=1, partial response=2, and no response/progressive disease=3). To calculate organ response, a score was assigned to each organ based on the depth of organ response (Muchtar et al. 2018): non-evaluable=0, complete response=1, very good partial response=2, partial response=3, and no response=4. The final organ response score was obtained by calculating the average of the individual involved organ scores. We then calculated the composite hematologic and organ response (HOR) score by adding the organ and hematologic responses at each interval and compared overall survival (OS) between patients with HOR score ≤ 5 (group 1) and those with score > 5 (group 2). Results: The cohort included 730 patients diagnosed with AL amyloidosis between February 10 th, 2006 and July 9 th, 2019. Median age was 63 (IQR: 56-69), and 65% were male. The involved light chain was Lambda in 75% of cases. Cardiac, renal, and liver involvement were found in 81%, 61%, and 17% of patients, respectively. Among all patients, 28% underwent autologous stem cell transplantation during their disease course. The median follow up in the entire cohort was 7.0 (95%CI: 6.4-8.0) years and OS was 3.6 (95%CI: 2.6-4.4) years. At 1 to 4 months, we observed a statistically significant difference in OS between patients with HOR score ≤5 vs. >5. However, there was no difference in OS between the 2 groups at 5 and 6 months. These results are presented in Table 1. Conclusion: A composite hematologic and organ response score that takes into consideration the depth of organ response can discriminate 2 groups of patients with distinct survival outcomes as early as 1 month from treatment initiation and maintains its predictive ability for up to 4 months. The lack of predictive ability beyond 4 months in this study may be due to limited sample size especially in group 2 as more patients achieve deeper responses with time. This approach can provide the basis for early changes in treatment but needs validation in future studies. Figure 1 Figure 1. Disclosures Dispenzieri: Janssen: Consultancy, Research Funding; Takeda: Research Funding; Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Pfizer: Research Funding; Alnylam: Research Funding. Gertz: 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; Aurora Biopharma: Other: Stock option; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring. Kapoor: Ichnos Sciences: Research Funding; Karyopharm: Consultancy; Glaxo SmithKline: Research Funding; Pharmacyclics: Consultancy; Amgen: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy; BeiGene: Consultancy; Regeneron Pharmaceuticals: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Dingli: GSK: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Novartis: Research Funding; Apellis: Consultancy; Alexion: Consultancy. Kumar: Oncopeptides: Consultancy; Merck: Research Funding; Antengene: Consultancy, Honoraria; Bluebird Bio: Consultancy; Roche-Genentech: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Research Funding; Carsgen: Research Funding; Tenebio: Research Funding; Celgene: 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; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; 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.

AbstractGain of 1q22 at diagnosis portends poorer outcomes in multiple myeloma (MM), but the prognostic significance of acquired 1q22 gain is unknown. We identified 63 MM patients seen at Mayo Clinic from 1/2004 to 12/2019 without 1q22 gain at diagnosis who acquired it during follow up and compared them to 63 control patients who did not acquire 1q22 gain with similar follow up. We also compared outcomes in the acquired 1q22 gain group with outcomes in 126 patients with 1q22 gain present at diagnosis. The incidence of acquired 1q22 gain was 6.1% (median follow‐up 6.8 years); median time to acquisition was 5.0 years (range: 0.7–11.5 years). Abnormalities on baseline fluorescence in situ hybridization (FISH) included trisomies (54%) and monosomy 13 (39%); 16 (25%) had high‐risk (HR) translocations or del(17p). Median progression‐free survival with front line therapy was 29.5 months in patients with acquired 1q22 gain, versus 31.4 months in control patients (p = .34) and 31.2 months in patients with de novo 1q22 gain (p = .04). Median overall survival (OS) from diagnosis was 10.9 years in patients with acquired 1q22 gain, versus 13.0 years in control patients (p = .03) and 6.3 years in patients with de novo 1q22 gain (p = .01). Presence of HR FISH at baseline increased risk of 1q22 gain acquisition. We demonstrate that acquisition of 1q22 gain is a significant molecular event in MM, associated with reduced OS. Among HR patients for whom this clonal evolution is determined, a risk‐adapted approach and/or clinical trial should be considered.

AbstractMonoclonal B‐cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL) are clonal B‐cell disorders associated with an increased risk of infections and impaired vaccination responses. We investigated the immunogenicity of recombinant zoster vaccine (RZV) in these patients. Individuals with MBL/untreated CLL and Bruton tyrosine kinase inhibitor (BTKi)‐treated CLL patients were given two doses of RZV separated by 2 months. Responses assessed at 3 and 12 months from the first dose of RZV by an anti‐glycoprotein E ELISA antibody assay and by dual‐color Interferon‐γ and Interleukin‐2FLUOROSPOT assays were compared to historic controls matched by age and sex. About 62 patients (37 MBL/untreated CLL and 25 BTKi‐treated CLL) were enrolled with a median age of 68 years at vaccination. An antibody response at 3 months was seen in 45% of participants, which was significantly lower compared to historic controls (63%, p = .03). The antibody response did not significantly differ between MBL/untreated CLL and BTKi‐treated CLL (51% vs. 36%, respectively, p = .23). The CD4+ T‐cell response to vaccination was significantly lower in study participants compared to controls (54% vs. 96%, p < .001), mainly due to lower responses among BTKi‐treated patients compared to untreated MBL/CLL (32% vs. 73%, p = .008). Overall, only 29% of participants achieved combined antibody and cellular responses to RZV. Among participants with response assessment at 12 months (n = 47), 24% had antibody titers below the response threshold. Hypogammaglobulinemia and BTKi therapy were associated with reduced T‐cell responses in a univariate analysis. Strategies to improve vaccine response to RZV among MBL/CLL patients are needed.

AbstractMultiple myeloma (MM) remains an incurable disease despite incorporation of novel agents. Venetoclax, a B‐cell lymphoma 2 (BCL‐2) inhibitor is approved for some hematologic malignancies but not yet for MM, although clinical trials have shown efficacy in patients with MM, particularly those harboring t(11;14). We reviewed the medical records of relapsed and/or refractory MM patients to study the efficacy and safety of venetoclax used outside of clinical trials at Mayo Clinic between December, 2016 and March, 2019. The data cut‐off date was August 06, 2020. We identified 56 patients of whom 42 (75%) harbored t(11;14). The median number of prior therapies was six (range 1–15) and 14% of patients had received ≥10 prior lines of therapy. Fifty‐three (95%) patients were refractory to an immunomodulatory drug and proteasome inhibitor. Venetoclax was used as monotherapy or doublet, in combination with dexamethasone in 55% (n = 31) and a triplet or quadruplet in 45% of patients. No patient experienced tumor lysis syndrome. Overall response rate in 52 evaluable patients was 44%. The median time to best response was 2 months and median duration of response was 13.6 months. The median PFS for the entire cohort was 5.8 (95% CI 4.9–10.3) months and median OS was 28.4 (95% CI 14.6‐not reached) months. The presence of t(11;14) was associated with improved PFS (median 9.7 months vs. 4.2 months, p = 0.019) and OS (median not reached vs. 10.8 9 months, p = 0.015). Venetoclax demonstrates encouraging activity in heavily‐treated patients with relapsed/refractory MM, particularly the t(11;14) patient‐population.

e20016 Background: An elevated serum LDH level is an adverse prognostic factor in NDMM. However, this category includes quantitative serum LDH levels that range from just over the upper limit of normal (ULN) to levels that may be 2 or more-fold higher than the ULN. This binary classification of serum LDH level of “normal versus elevated” fails to discriminate between the different disease biology that exists among NDMM patients with elevated serum LDH levels. Thus, we attempted to further stratify NDMM patients by the level of their serum LDH and determine its impact on OS. Methods: The cohort included patients diagnosed with NDMM from the Mayo Clinic, Rochester from 2003 - 2017 who were treated with novel agent induction therapy and had serum LDH levels measured at the time of diagnosis. The serum LDH levels were stratified into three levels: Normal (LDH < 222 U/L), Elevated (LDH 223-444 U/L), and Very Elevated (LDH >444 U/L or >2x upper limit of normal). Survival analysis was performed using the Kaplan-Meier survival analysis and compared via the log-rank method. Results: The cohort consists of 1,196 NDMM patients with a median age of 65 (22 – 95). R-ISS classification and cytogenetic risk were available for 968 and 970 patients respectively. The median serum LDH level was (162 U/L (3- 1260)) and an elevated LDH was present in 199 patients (17%). The median OS for patients with normal (N = 997; 83%), elevated (N = 170; 13%) and very elevated (N = 29; 3%) LDH levels were 76 months, 57 months and 23 months respectively (P < 0.001). The impact of these different levels of LDH on OS by R-ISS stage and cytogenetic risk is shown in the Table. Conclusions: A very small subset of NDMM patients has very elevated LDH levels that confer an exceptionally poor OS irrespective of R-ISS stage and cytogenetic risk. Future studies elucidating their disease biology responsible for such poor OS outcomes are warranted.[Table: see text]

e20000 Background: In the novel agents’ era, refractoriness to induction in Multiple Myeloma (MM) is relatively rare. This population remain an unmet need and are often excluded from clinical trials. In the current era, chemotherapy-induced stem cell collections are used at Mayo Clinic in “poor responders” to induction, such as patients that progress prior to ASCT or patients with significant disease burden after induction. Methods: This is a retrospective study that includes all MM patients the underwent chemo-mobilization between January 2012 and September 2020 at Mayo Clinic. We compared our cohort to a cohort of 125 matched patients that were transplanted over the same time period and underwent mobilization with G-CSF and “on-demand” plerixafor. We matched the cohorts by level of response by IMWG at pre-transplant evaluation. Results: 125 newly diagnosed MM patients who received novel agents’ induction and had a poor response to induction were mobilized using IV intermediate-dose cyclophosphamide (83%) or VDT-PACE (17%) plus G-CSF and “on-demand” plerixafor. The median PFS and OS of the chemo-mobilized cohort were 16 months (95% CI 11-20) and 47 months (95% CI 37-71), respectively. Patients receiving chemo-mobilization had higher stem cell yields than the growth factor only cohort (median 9.88X106 cells/kg versus median 8.77X106 cells/kg, respectively (P<0.001)). The safety profile of chemo-mobilization was favorable, with no difference between the two groups in length of hospitalization during ASCT (P=0.95), days to neutrophil or platelet engraftment, and risk of bacteremia (P=0.38). 29% of the chemo-mobilized cohort and 66% of the matched cohort required plerixafor for adequate mobilization (P<0.001). Conclusions: Chemo-mobilization enhances stem cell collection in MM patients with a suboptimal response to induction and reduces the need for plerixafor without adversely impacting the post-transplant clinical course. [Table: see text]