Dimopoulos, Meletios Α.

TPS8075 Background: Standard of care for SMM includes active monitoring until progression to multiple myeloma (MM); however, recent evidence suggests pts with high-risk features may benefit from early treatment. DARA is a human IgGκ monoclonal antibody targeting CD38 that is approved as monotherapy for relapsed/refractory MM (RRMM) or in combination with standard of care for RRMM or newly diagnosed MM. Results from the phase 3 COLUMBA study showed that DARA SC demonstrated similar efficacy to intravenous (IV) DARA but with a lower rate of infusion-related reactions and shorter administration time. Based on the promising single-agent activity observed with IV DARA in intermediate- or high-risk SMM pts during the phase 2 CENTAURUS study, we hypothesized that DARA SC may delay progression to MM versus active monitoring in pts with high-risk SMM. Methods: AQUILA is an ongoing, randomized, open-label, multicenter phase 3 study of DARA SC versus active monitoring in pts with high-risk SMM. DARA SC (DARA 1,800 mg + recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; Halozyme]) is administered by manual injection over approximately 5 minutes at alternating locations on the abdomen weekly in Cycles 1 and 2, every 2 weeks in Cycles 3-6, and every 4 weeks thereafter until 39 cycles (28 days/cycle), up to 36 months, or until disease progression. Eligibility criteria include confirmed diagnosis of SMM for ≤5 years, factors indicating high risk of progression to MM (clonal bone marrow plasma cells [BMPCs] ≥10% and ≥1 of the following: serum M protein ≥30 g/L, IgA SMM, immunoparesis with reduction of 2 uninvolved Ig isotypes, serum involved:uninvolved free light chain ratio ≥8 to < 100, or clonal BMPCs > 50% to < 60% with measurable disease), and ECOG performance status ≤1. The primary endpoint is progression-free survival (PFS), assessed by an independent review committee, with disease progression defined according to International Myeloma Working Group diagnostic criteria for MM. Secondary endpoints include time to biochemical or diagnostic (SLiM-CRAB) progression, overall response rate, complete response rate, duration of response, time to response, time to first-line treatment for MM, PFS on first-line treatment for MM (PFS2), overall survival, and incidence of MM with adverse prognostic features. The study completed enrollment on May 6, 2019; 390 pts have been randomly assigned to DARA SC or active monitoring. The primary efficacy analysis will be performed after approximately 165 PFS events have been observed. Clinical trial information: NCT03301220.

7566 Background: Parenteral limited-duration BR chemoimmunotherapy and continuous orally administered Ibr, a Bruton tyrosine kinase inhibitor, dominate the treatment landscape of WM, a rare B cell lymphoma. No trials have assessed the comparative effectiveness of these 2 vastly different approaches. We conducted a multiinstitutional, international, collaborative study to compare BR and single-agent Ibr in patients (pts) with treatment naïve (TN) WM. Methods: Data from 347 pts with active TN WM, seen between 2011 and 2021 in the US and Europe, were analyzed. The pts on rituximab maintenance were excluded. The modified IWWM-6 criteria (based on IgM alone) were used for response assessment. All time-to-event analyses were performed from the frontline therapy initiation, using the Kaplan-Meier method. Results: The median age of the pts treated with BR (n=208) and Ibr (n=139) was 66 (range 40-86) years (y) and 69 (39-97) y, respectively, (p=0.005). With a median follow up of 4.2 y (95% CI 3.8-4.5), the 4-y progression free survival (PFS) was 73% in each group, p=0.6, and 4-y overall survival (OS) was 94% (95% CI 91-98) in the BR group versus ( v) 82% (95% CI 75-90) in the Ibr group, p=0.01. In a bivariate analysis adjusting for age and the treatment type, only age emerged as a predictor for OS (HR 7.2, p=0.0001). Therefore, a 1:1 age-matched analysis of 246 pts who received Ibr (n=123) or BR (n=123) was performed. Pts with a known MYD88WT status who had received Ibr and their age matched controls on BR were excluded. The international prognostic scoring system (IPSS) WM was comparable between the 2 groups (Table). A higher proportion of pts on BR attained very good partial or deeper response (≥VGPR) as the best response in comparison to the pts on Ibr (Table). The 4-y PFS for the BR and Ibr groups was similar [72% (95% CI 63-82) v 78% (95% CI 70-87), p=0.14] and 4-y OS was 95% (95% CI 91-99) with BR v 86% (95% CI 80-93) with Ibr (p=0.3). Premature discontinuation, during active treatment, due to adverse effects (AEs) or lack of response was noted in 13% and 33% of pts on BR and Ibr, respectively. A detailed assessment of the AEs will be presented at the meeting. Conclusions: Both BR and Ibr lead to comparable outcomes in pts with TN WM, although deeper responses are attained with BR. These findings require confirmation in prospective studies. For pts who harbor MYD 88L265P mutation, selection between the 2 approaches should be dictated by their potential toxicities, pt comorbidities, pt/clinician preference (parenteral fixed-duration v continuous oral) and access to therapies. [Table: see text]

Abstract Introduction: Multiple Myeloma (MM) is an incurable plasma cell malignancy commonly preceded by the asymptomatic stage smoldering multiple myeloma (SMM). MM is characterized with significant genomic heterogeneity of chromosomal gains and losses (CNVs), translocations, and point mutations (SNVs); alterations that are also observed in SMM patients. However, current SMM risk models rely solely on clinical markers and do not accurately capture progression risk. While incorporating some genomic biomarkers improves prediction, using all MM genomic features to comprehensively stratify patients may increase risk stratification precision in SMM. Methods: We obtained a total of 214 patient samples at SMM diagnosis. We performed whole-exome sequencing on 166 tumors; of these, RNA sequencing was performed on 100. Targeted capture was done on 48 additional tumors. Upon binarization of DNA features, we performed consensus non-negative matrix factorization to identify distinct molecular clusters. We then trained a random forest classifier on translocations, SNVs, and CNVs. The predicted clinical outcomes for the molecular subtypes were further validated in an independent SMM cohort of 74 patients. Results: We identified six genomic subtypes, four with hyperdiploidy (&gt;48 chromosomes, HMC, HKR, HNT, HNF) and two with IgH translocations (FMD, CND) (Table 1). In multivariate analysis accounting for IMWG (20-2-20) clinical risk stages, high-risk (HMC, FMD, HKR) and intermediate-risk (HNT, HNF) genetic subtypes were independent predictors of progression (Hazards ratio [HR]: 3.8 and 5.5, P = 0.016 and 0.001, respectively). The low-risk, CND subtype harboring translocation (11;14) was enriched for the previously defined CD-2 MM signature defined by the B cell markers CD20 and CD79A (FDR = 0.003 ), showed upregulation of CCND1, E2F1, and E2F7 (FDR = 0.01, 0.0004, 0.08), and was enriched for G2M checkpoint, heme metabolism, and monocyte cell signature (FDR = 0.003, 0.003, 0.003, respectively). The FMD subtype with IgH translocations (4;14) and (14;16) was enriched for P53, mTORC1, unfolded protein signaling pathways and plasmacytoid dendritic cell signatures (FDR = 0.01, 0.005, 0.008, respectively). The HKR tumors were enriched for inflammatory cytokine signaling, MYC target genes, T regulatory cell signature, and the MM proliferative (PR) signatures (FDR = 0.02, 0.03, 0.007, 0.02, respectively). The APOBEC mutational signature was enriched in HMC and FMD tumors (P = 0.005), while there was no statistical difference across subtypes in the AID signature. The median follow-up for the primary cohort is 7.1 years. Median TTP for patients in HMC, FMD, and HKR was 3.8, 2.6, and 2.2 years, respectively; TTP for HNT and HNF was 4.3 and 5.2, respectively, while it was 11 years in CND patients (P = 0.007). Moreover, by analyzing the changes in MM clinical biomarkers over time, we found that patients from high-risk subgroups had higher odds of developing evolving hemoglobin and monoclonal protein levels over time (P = 0.01 and 0.002, respectively); Moreover, the absolute increase in M-protein was significantly higher in patients from the high-risk genetic subtypes at one, two, and five years from diagnosis (P = 0.001, 0.03, and 0,01, respectively). Applying the classifier to the external cohort replicated our findings where intermediate and high-risk genetic subgroups conferred increased risk of progression to MM in multivariate analysis after accounting for IMWG staging (HR: 5.5 and 9.8, P = 0.04 and 0.005, respectively). Interestingly, within the intermediate-risk clinical group in the primary cohort, patients in the high-risk genetic subgroups had increased risk of progression (HR: 5.2, 95% CI 1.5 - 17.3, P = 0.007). In the validation cohort, these patients also had an increased risk of progression to MM (HR: 6.7, 95% CI 1.2 - 38.3, P = 0.03), indicating that molecular classification improves the clinical risk-stratification models. Conclusion: We identified and validated in an independent dataset six SMM molecular subgroups with distinct DNA alterations, transcriptional profiles, dysregulated pathways, and risks of progression to active MM. Our results underscore the importance of molecular classification in addition to clinical evaluation in better identifying high-risk SMM patients. Moreover, these subgroups may be used to identify tumor vulnerabilities and target them with precision medicine efforts. Figure 1 Figure 1. Disclosures Bustoros: Janssen, Bristol Myers Squibb: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria. Casneuf: Janssen: Current Employment. Kastritis: Amgen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Walker: Bristol Myers Squibb: Research Funding; Sanofi: Speakers Bureau. Davies: Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Beigene: Honoraria; Janssen: Honoraria. Bergsagel: Genetech: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: human CRBN mouse; GSK: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Yong: BMS: Research Funding; Autolus: Research Funding; Takeda: Honoraria; Janssen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; GSK: Honoraria; Amgen: Honoraria. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Getz: IBM, Pharmacyclics: Research Funding; Scorpion Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

Abstract Introduction: A number of cytogenetic abnormalities (CAs) are associated with poorer prognosis in MM, including del(17p), t(4;14), t(14;16), and amp1q21. There is a general consensus that treatment with proteasome inhibitors (PIs) benefits pts carrying these CAs (Sonneveld Blood 2016). This meta-analysis of four phase 3 studies assesses PFS benefit in pts receiving the oral PI ixa vs pbo regarding the specific adverse CAs. Methods: Pts in TOURMALINE-MM1 (N=722; relapsed/refractory MM; Moreau N Engl J Med 2016) and MM2 (N=705; newly diagnosed MM; Facon Blood 2021) received ixa plus lenalidomide-dexamethasone (Rd) vs pbo-Rd (1:1). Pts in TOURMALINE-MM3 (N=656; Dimopoulos Lancet 2019) and TOURMALINE-MM4 (N=706; Dimopoulos J Clin Oncol 2020) received ixa vs pbo (3:2) as maintenance following autologous stem cell transplant or as post-induction maintenance in transplant-ineligible pts, respectively. In TOURMALINE-MM1/MM2, CAs were centrally assessed on CD138 positive sorted cells from bone marrow samples collected at study entry using fluorescence in situ hybridization (FISH). Cutoff values for defining the presence of del(17p), t(4;14), and t(14;16) were 5%, 3%, and 3% positive cells, respectively, based on the false-positive rates (technical cutoffs) of the FISH probes used, and cutoff values of 3% (MM1) and 20% (MM2) were used for amp1q21. In TOURMALINE-MM3/MM4, cytogenetic assessment was performed locally using FISH or conventional karyotyping with locally defined thresholds for positivity. Results: 270/1227 (22%) vs 227/1019 (22%) evaluable pts receiving ixa-based vs pbo-based therapy had high-risk CAs [del(17p), t(4;14), t(14;16)]: 75 vs 62 in MM1, 60 vs 63 in MM2, 61 vs 54 in MM3, and 74 vs 48 in MM4. 957/1227 (78%) vs 792/1019 (78%) had complementary standard-risk CAs: 200 vs 216 in MM1, 231 vs 234 in MM2, 252 vs 152 in MM3, and 275 vs 190 in MM4. 555/1142 (49%) vs 479/955 (50%) evaluable pts receiving ixa-based vs pbo-based therapy had expanded high-risk CAs (high-risk CAs ± amp1q21): 155 vs 154 in MM1, 134 vs 146 in MM2, 116 vs 88 in MM3, and 150 vs 91 in MM4. 587/1142 (51%) vs 476/955 (50%) had complementary standard-risk CAs: 122 vs 126 in MM1, 164 vs 153 in MM2, 154 vs 89 in MM3, and 148 vs 108 in MM4. After a median follow-up in the pooled analysis of 25.6 months (mos; 12.7, 54.6, 29.7, and 21.3 mos in MM1, MM2, MM3, and MM4, respectively), the hazard ratio (HR) for PFS with ixa-based vs pbo-based therapy in pts with high-risk CAs was 0.74 (95% confidence interval [CI] 0.59-0.93; median 17.8 vs 13.2 mos) and 0.70, (95% CI 0.62-0.80; median 26.3 vs 17.6 mos) in pts with standard-risk CAs. In the subgroup analyses of expanded high-risk CAs, the HR for PFS with ixa-based vs pbo-based therapy in pts in the expanded high-risk group was 0.75 (95% CI 0.64-0.87; median 18.1 vs 14.1 mos; Figure 1) and 0.71 (95% CI 0.59-0.85; median 36.1 vs 21.4 mos) in the complementary standard-risk group. Analyses of PFS according to the presence of individual CAs (Figure 2) indicated differing magnitudes of PFS benefit. Notably, in pts with t(4;14) (n=124 vs n=102), the HR for PFS with ixa-based vs pbo-based therapy was 0.68 (95% CI 0.48-0.96; median 22.4 vs 13.2 mos), while for pts with amp1q21 (n=380 vs n=312), the HR was 0.77 (95% CI 0.63-0.93; median 18.8 vs 14.5 mos) and for pts with del(17p) (n=141 vs n=107) the HR was 0.80 (95% CI 0.59-1.09; median 15.7 vs 13.2 mos). Conclusions: This pooled analysis demonstrated a PFS benefit with ixa-based therapy vs pbo-based therapy regardless of the presence of specific adverse CAs, with a similar magnitude of benefit in pts with (expanded) high-risk CAs and the respective complementary standard-risk groups. However, due to the differences in study eligibility criteria and pt populations, ixa combined with Rd or as single-agent maintenance therapy may not abrogate the negative impact of high-risk CAs. Analyses of PFS in subgroups with specific CAs indicated that the greatest magnitudes of benefit (lowest HRs) with ixa-based vs pbo-based therapy were in pts with t(4;14) (HR 0.68) and pts with amp1q21 (HR 0.77), suggesting that the improved outcome with ixa-based vs pbo-based therapy in the expanded high-risk subgroup was primarily driven by PFS differences in pts with these more common CAs. Further study is needed, and additional sensitivity analyses will be presented in subsequent publications. Figure 1 Figure 1. Disclosures Chng: BMS/Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria; Abbvie: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria; Johnson and Johnson: Honoraria, Research Funding. Lonial: BMS/Celgene: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria. Morgan: Takeda: Honoraria. Iida: Amgen: Research Funding; Daiichi Sankyo: Research Funding; Glaxo SmithKlein: Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Chugai: Research Funding; Abbvie: Research Funding; Janssen: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding. Moreau: Sanofi: Honoraria; Celgene BMS: Honoraria; Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Oncopeptides: Honoraria. Kumar: Bluebird Bio: Consultancy; Carsgen: Research Funding; Janssen: 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; Antengene: Consultancy, Honoraria; Novartis: Research Funding; Oncopeptides: Consultancy; 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; Roche-Genentech: Consultancy, Research Funding; Beigene: Consultancy; Merck: 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; Amgen: Consultancy, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Twumasi-Ankrah: Takeda: Current Employment. Kumar: Takeda: Current Employment, Current holder of stock options in a privately-held company. Dash: Takeda: Current Employment, Current equity holder in publicly-traded company. Vorog: Takeda: Current Employment. Zhang: Takeda: Current Employment. Suryanarayan: Takeda: Current Employment. Labotka: Takeda: Current Employment. Dimopoulos: Janssen: Honoraria; Takeda: Honoraria; Beigene: Honoraria; BMS: Honoraria; Amgen: Honoraria. OffLabel Disclosure: Use of the oral proteasome inhibitor ixazomib for the initial treatment of multiple myeloma and as maintenance treatment following stem cell transplantation or induction therapy in newly diagnosed patients

Abstract Background: Two global, randomized, placebo (pbo)-controlled phase 3 studies of single-agent ixazomib (ixa) maintenance therapy are currently ongoing for newly diagnosed MM patients following primary therapy that included autologous stem cell transplantation (ASCT) (MM3, NCT02181413) or excluded ASCT (MM4, NCT02312258). Both trials have demonstrated statistically significant and clinically meaningful improvement in their primary endpoint of progression-free survival (PFS): for MM3, median 26.5 months (mos) ixa vs 21.3 mos pbo (hazard ratio [HR] 0.720, 95% confidence interval [CI] 0.582-0.890, P=0.002); for MM4, median 17.4 mos for ixa vs 9.4 mos for pbo (HR 0.659, 95% CI 0.542-0.801, P&lt;0.001). Data for the key secondary endpoint, OS, have not previously been published. Methods: Full methods have previously been reported (Dimopoulos, Lancet 2019; Dimopoulos, J Clin Oncol 2020). Eligible patients (MM3, N=656; MM4, N=706) were randomized 3:2 to receive maintenance therapy with single agent ixa or pbo for a maximum of approximately 24 mos (26 cycles, to the nearest complete cycle) or until progressive disease or unacceptable toxicity, whichever occurred first. Results: At the most recent data cut-off (MM3, 29 January 2021; MM4, 15 October 2020), with median follow up of 64 mos and 36 mos, respectively, 27% (MM3, 174/656) and 29% (MM4, 203/706) of the intention-to-treat (ITT) population had OS events. In MM3, the 5-year Kaplan-Meier estimate for OS was 74% for ixa and 73% for pbo, though the median OS had not yet been reached in either arm (HR 1.008, 95% CI 0.744-1.367, P=0.958; Figure). In MM4, the 5-year Kaplan-Meier OS estimate was 55% for ixa and 56% for pbo, though the median OS had also not yet been reached in either arm (HR 1.136, 95% CI 0.853-1.514, P=0.382; Figure). No new safety signals were identified, and the incidence of new primary malignancies in both studies was similar between ixa and pbo. Conclusions: These most current OS data for MM3 and MM4 have not demonstrated a statistically significant difference for the ixa or the pbo arm to date. After 64 mos of follow-up in MM3, the risk of OS does not differ between the study arms. After 36 mos of follow-up in MM4, the OS HR shows a trend that favors the pbo arm. Because interim analyses of OS may be overrepresented by deaths in patients who did not benefit from maintenance therapy, it is not known to what extent these results will be reflective of the ITT population at the time of the final analyses. As treatment options, including anti-CD38 mAb and other new mechanisms of action, for salvage therapies following progression continue to expand, OS is increasingly being confounded by subsequent therapies. Hence, demonstrating OS advantage for early line MM therapies is becoming increasingly challenging. OS data continue to be collected in these studies for later analyses. Figure 1 Figure 1. Disclosures Dimopoulos: Takeda: Honoraria; Amgen: Honoraria; Beigene: Honoraria; Janssen: Honoraria; BMS: Honoraria. Lonial: AMGEN: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Merck: Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Chng: Johnson and Johnson: Honoraria, Research Funding; BMS/Celgene: Honoraria, Research Funding; Takeda: Honoraria; Abbvie: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Iida: Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Chugai: Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Glaxo SmithKlein: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding. Mateos: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Oncopeptides: Honoraria. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Kumar: Takeda: Current Employment, Current holder of stock options in a privately-held company. Suryanarayan: Takeda: Current Employment. Vorog: Takeda: Current Employment. Fergus: Takeda: Current Employment. Labotka: Takeda: Current Employment. OffLabel Disclosure: Use of the oral proteasome inhibitor ixazomib as maintenance treatment for multiple myeloma following stem cell transplantation or induction therapy in newly diagnosed patients.

Abstract Introduction: Belantamab mafodotin (belamaf) is a B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate approved in the United States (US) and Europe as a monotherapy for triple-class refractory adult patients with relapsed or refractory multiple myeloma (RRMM). This hypothesis-generating post-hoc analysis of DREAMM-2 trial (NCT03525678) data examined relationships between corneal exam findings (superficial punctate keratopathy and/or microcyst like epithelial changes), best-corrected visual acuity (BCVA), and direct patient-reported ocular symptoms per the Ocular Surface Disease Index (OSDI) questionnaire. This approach could provide insight into the relationship between corneal exam findings, BCVA, and ocular symptoms and their impact on quality of life to help determine if BCVA decline and symptoms could guide dosing. Currently, in the US, eye exams with eye-care professionals (ECPs) are required for each belamaf treatment, which can add to patients' therapy-related burden. Identifying a surrogate marker for results from corneal exam findings would help providers determine if dosing adjustments are necessary. Methods: Eye exams (including a corneal exam and BCVA assessment using the Snellen chart) were performed on all patients receiving single-agent belamaf (2.5 mg/kg) by ECPs at baseline (BL) and before each dose, administered q3w. Corneal exam findings (keratopathy) and BCVA were assessed per protocol-defined criteria, and grade (GR) assessment was based on the worst finding in the worse eye. BCVA and keratopathy grading were relative to BL. Patient-reported ocular symptoms and vision-related functioning, as per the OSDI, were used to evaluate the impact of treatment-related ocular toxicity. The OSDI is a patient-reported outcome questionnaire that assesses eye symptoms and effects on vision-related function in the past week and was performed in all patients before each belamaf dose. Items 1-5 address the frequency of eye-related symptoms (eg, painful or sore eyes, blurred vision) while items 6-9 address the frequency of functional limitations (eg, driving at night or reading). OSDI was considered positive, clinically meaningful, and potentially associated with treatment when at least one question 1-5 (ie, sensitivity to light, gritty or painful eyes, blurred or poor vision) was reported as experienced "all of the time" and at least one question 6-9 (ie, driving at night, reading, working with PC, or watching TV) was reported as experienced "most of the time." Results: Overall, GR 3-4 (severe) keratopathy was observed only 5% of the time in patients who did not report frequent ocular symptoms as measured by the OSDI questionnaire (no items 1-9 ≥ "most of the time"). A further breakdown of the questions revealed that, in patients who reported no items 1-5 "all of the time" AND no items 6-9 ≥ "most of the time" (OSDI negative), GR 3-4 keratopathy was observed only 6% of the time (Table). When considering individual OSDI items, in patients who reported "no deterioration from BL" for any of the OSDI eye-related symptoms or functional limitations, GR 3-4 keratopathy was observed ~3%-7% of the time while GR 0-2 (mild) keratopathy was observed ~23%-34% of the time. Similar results were observed in patients with BCVA ≤20/30 at BL who reported "no deterioration from BL" for any eye-related adverse events (AEs) or functional limitations (GR 3-4 keratopathy: ~2%-6% of the time; GR 0-2 keratopathy: ~19%-28% of the time); patients with worse visual acuity at BL (BCVA &gt;20/30) who reported "no deterioration" for items 1-9 had lower incidence of GR 3-4 and GR 0-2 keratopathy (~0%-1% and ~3%-8%, respectively). Conclusions: The results from this hypothesis-generating post-hoc analysis suggest that hematologists/oncologists may be able to use clinical indicators/tools (eg, ocular symptoms, the OSDI tool) as potential surrogate markers for eye exam results to help determine whether dosing changes are needed. This approach will be explored in trials with other belamaf dose regimens that are currently under evaluation. If the results are validated, it may be possible for hematologists/oncologists to manage belamaf dose modifications, due to ocular AEs, without a confirmatory eye exam by the ECP, reducing the patient burden. Funding Source: GSK (205678). Drug linker technology licensed from Seagen; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Figure 1 Figure 1. Disclosures Popat: Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria; Abbvie, Takeda, Janssen, and Celgene: Consultancy; Janssen and BMS: Other: travel expenses. Badros: GlaxoSmithKline: Research Funding; BMS: Research Funding; Janssen: Research Funding; J&J: Research Funding. Kumar: Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Antengene: Consultancy, Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Roche-Genentech: Consultancy, Research Funding; Beigene: Consultancy; BMS: Consultancy, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Oncopeptides: Consultancy; Astra-Zeneca: 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; Novartis: Research Funding; Merck: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Rodríguez-Otero: Regeneron: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: 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; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and other expenses. Cohen: BMS: Research Funding; GlaxoSmithKline: Other: Personal fees and other association with, Research Funding; Novartis: Research Funding; Celgene: Honoraria, Other: Personal fees and other association with; Janssen: Honoraria; Kite Pharma: Honoraria; Oncopeptides: Honoraria; Seattle Genetics: Honoraria; Takeda: Honoraria. Manier: Regeneron: Consultancy, Research Funding; Oncopeptides: 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; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Celgene - Bristol Myers Squibb: 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; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Voorhees: Secura Bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gay: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria. Rifkin: Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Fresenius-Kabi: Membership on an entity's Board of Directors or advisory committees; Coherus: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb (Celgene): Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; McKesson: Current Employment, Current equity holder in publicly-traded company; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Martin: Janssen: Research Funding; Sanofi: Research Funding; Oncopeptides: Consultancy; Amgen: Research Funding; GlaxoSmithKline: Consultancy. Chari: Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Pharmacyclics: Research Funding; Millenium/Takeda: Consultancy, Research Funding; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Weisel: Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Farooq: Five Prime Therapeutics/Amgen: Consultancy; GlaxoSmithKline: Consultancy. Jeng: OysterPoint: Consultancy; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Eyegate: Current equity holder in publicly-traded company. Chng: Abbvie: Consultancy; GlaxoSmithKline: Consultancy; Takeda: Consultancy; BMS/Celgene: Consultancy, Research Funding; Sanofi: Consultancy; Novartis: Research Funding; Johnson & Johnson: Consultancy, Research Funding; Amgen: Consultancy; Antengene: Consultancy; Pfizer: Consultancy; Aslan: Research Funding. Lee: Takeda Pharmaceuticals: Consultancy, Research Funding; Oncopetides: Consultancy; Sanofi: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Legend Biotech: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy, Research Funding; Genentech: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Amgen: Consultancy, Research Funding; Regeneron: Research Funding. Berdeja: BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Celularity: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Kite Pharma: Consultancy; Legend Biotech: Consultancy; SecuraBio: Consultancy; EMD Serono: Research Funding; Genentech: Research Funding; GlaxoSmithKline: Research Funding; Ichnos Sciences: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Poseida: Research Funding; Bluebird bio: Consultancy, Research Funding; Astex Pharmaceuticals: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; Takeda: Consultancy; Sanofi: Research Funding; Acetylon: Research Funding; Teva: Research Funding; Lilly: Research Funding. Jadhav: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Tosolini: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Eliason: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Palumbo: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Dimopoulos: Beigene: Honoraria; BMS: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Lonial: Merck: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Trudel: Amgen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Amgen Canada: Honoraria; Sanofi: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Janssen: Honoraria, Research Funding; Genentech: Research Funding; Karyopharm: Honoraria. Richardson: Sanofi: Consultancy; Celgene/BMS: Consultancy, Research Funding; Protocol Intelligence: Consultancy; GlaxoSmithKline: Consultancy; Secura Bio: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Oncopeptides: Consultancy, Research Funding; Regeneron: Consultancy; AstraZeneca: Consultancy; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Terpos: Celgene: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, 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 &gt;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 &gt;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, &gt;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&lt;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 &gt;650 pg/mL or BNP &gt;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, &gt;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 &lt;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&lt;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&lt;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&lt;0.001; Figure 1C). These cardiac response criteria were independent predictors of survival and time to cardiac progression (&gt;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.