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This pilot study assessed the safety and efficacy of letetresgene autoleucel (lete-cel; GSK3377794), a genetically modified autologous T-cell therapy targeting New York esophageal squamous cell carcinoma-1 (NY-ESO-1)/L antigen family member 1 isoform A (LAGE-1a)–positive myeloma cells, alone or in combination with pembrolizumab in patients with relapsed/refractory multiple myeloma. Eligible patients expressed NY-ESO-1 and/or LAGE-1a and either HLA-A∗02:01, ∗02:05, or ∗02:06. Patients received lete-cel single infusion alone (arm 1) or with pembrolizumab (arm 2). 127 patients were screened, and 6 patients (3 per arm) were enrolled; patients in arm 1 and 2 received lete-cel alone, or with pembrolizumab, respectively. All patients exhibited grade 3/4 cytopenias, which resolved or improved to grade 1. One patient (arm 1) had grade 3/4 lete-cel–related adverse events (AEs); 2 patients (arm 2) had grade 3/4 AEs related to lete-cel and lymphodepletion. Three patients with grade 1/2 cytokine release syndrome (CRS) exhibited elevated post–lete-cel interleukin-6 levels versus those without CRS. Pooled overall response rate was 50% including 1 patient each with confirmed clinical response, very good clinical response, and partial response, and progression-free survival ranged from 1.3 to 5.2 months. Responders (arm 1: n = 1; arm 2: n = 2) had a time-to-response of 3 weeks, duration of response of 2.1 months. Two responders, but no nonresponders, exhibited elevated cytokine levels after lete-cel infusion. Lete-cel had a manageable safety profile and demonstrated clear but transient antitumor activity in patients with relapsed/refractory multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT03168438.

What is this plain language summary about? This summary presents the results from an ongoing, long-term extension study that followed an earlier study called ATTR-ACT. People who took part in this extension study and ATTR-ACT have a type of heart disease known as transthyretin amyloid cardiomyopathy (ATTR-CM for short), which causes heart failure and death. In ATTR-ACT, people took either a medicine called tafamidis or a placebo (a pill that looks like the study drug but does not contain any active ingredients) for up to 2½ years. So far, in the long-term extension study, people have continued taking tafamidis, or switched from taking a placebo to tafamidis, for another 2½ years. Researchers looked at how many people died in ATTR-ACT and the extension study. The long-term extension study is expected to end in 2027, so these are interim (not final) results. What did researchers find out? In the extension study of ATTR-ACT, the risk of dying was lower in people who took tafamidis continuously throughout ATTR-ACT and the extension study than in people who took placebo in ATTR-ACT and switched to tafamidis in the extension study. What do the results mean? Taking tafamidis increases how long people with ATTR-CM live. People with ATTR-CM who take tafamidis early and continuously are more likely to live longer than those who do not. These results highlight the importance of early detection and treatment in people with ATTR-CM. Clinical Trial Registration: NCT01994889 ( ClinicalTrials.gov ) Clinical Trial Registration: NCT02791230 ( ClinicalTrials.gov )

What is this plain language summary about? This plain language summary describes some results of a study called ATTR-ACT. This was the first large study to include people with wild-type and hereditary transthyretin amyloid cardiomyopathy (ATTR-CM for short). ATTR-CM is a type of heart disease that happens when abnormal clumps of protein build up in the heart. This build-up prevents the heart from working properly, causing a condition called heart failure. Wild-type ATTR-CM happens for unknown reasons in some people as they get older. Hereditary ATTR-CM can happen because of changes in people's genes (known as gene variants or mutations). Important information about ATTR-ACT In this study, 441 people with ATTR-CM took either a medicine called tafamidis or a placebo (a capsule that looked like tafamidis but didn't contain any active medicine) by mouth for 30 months, once a day. The researchers' main aim was to find out how tafamidis treatment affected the risk of people dying or being admitted to the hospital for heart problems. They found that tafamidis lowered these risks by about one-third compared with placebo. What else did researchers find out in ATTR-ACT? As described in this summary, after ATTR-ACT was completed, researchers looked back at the results from people who took placebo to learn how ATTR-CM progressed without treatment. The researchers found that about 4 in 10 people with wild-type ATTR-CM who took placebo died and 6 in 10 were admitted to the hospital because of heart problems over 30 months. People who took placebo also could not walk as far at the end of the study as they did at the start because their heart function worsened over time. Why are these results important? By showing how ATTR-CM affects people's health when they do not take treatment, these results highlight the benefits of early diagnosis and treatment of ATTR-CM. ClinicalTrials.gov NCT number: NCT01994889

This plain language summary describes some results of a study called ATTR-ACT. This was the first large study to include people with wild-type and hereditary transthyretin amyloid cardiomyopathy (ATTR-CM for short). ATTR-CM is a type of heart disease that happens when abnormal clumps of protein build up in the heart. This build-up prevents the heart from working properly, causing a condition called heart failure. Wild-type ATTR-CM happens for unknown reasons in some people as they get older. Hereditary ATTR-CM can happen because of changes in people's genes (known as gene variants or mutations).In this study, 441 people with ATTR-CM took either a medicine called tafamidis or a placebo (a capsule that looked like tafamidis but didn't contain any active medicine) by mouth for 30 months, once a day. The researchers' main aim was to find out how tafamidis treatment affected the risk of people dying or being admitted to the hospital for heart problems. They found that tafamidis lowered these risks by about one-third compared with placebo.As described in this summary, after ATTR-ACT was completed, researchers looked back at the results from people who took placebo to learn how ATTR-CM progressed without treatment. The researchers found that about 4 in 10 people with wild-type ATTR-CM who took placebo died and 6 in 10 were admitted to the hospital because of heart problems over 30 months. People who took placebo also could not walk as far at the end of the study as they did at the start because their heart function worsened over time.By showing how ATTR-CM affects people's health when they do not take treatment, these results highlight the benefits of early diagnosis and treatment of ATTR-CM. ClinicalTrials.gov NCT number: NCT01994889.

Clinical features of soft tissue amyloid light-chain (AL) amyloidosis include macroglossia, arthropathy, muscle pseudohypertrophy, skin plaques, and carpal tunnel syndrome. Vascular manifestations of AL amyloid include periorbital ecchymosis, jaw or limb claudication, and even myocardial infarction caused by occlusion of small vessel coronary arteries. Some of these features, such as macroglossia, periorbital ecchymosis, and the so-called shoulder-pad sign, are pathognomonic for AL amyloidosis. These findings may be the initial presenting features of the disease, and the recognition of these red flag symptoms is very important for the diagnosis and early intervention on the underlying plasma cell disease.

Technetium-labeled cardiac scintigraphy (i.e., Tc-PYP scan) has been repurposed for the diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM). Validated in cohorts of patients with heart failure and echocardiographic and/or cardiac magnetic resonance imaging findings suggestive of cardiac amyloidosis, cardiac scintigraphy can confirm the diagnosis of ATTR-CM only when combined with blood and urine testing to exclude a monoclonal protein. Multisocietal guidelines support the nonbiopsy diagnosis of ATTR-CM using cardiac scintigraphy, yet emphasize its use in the appropriate clinical context and the crucial need to rule out light chain amyloid cardiomyopathy. Although increased awareness of ATTR-CM and the advent of effective therapy have led to rapid adoption of diagnostic scintigraphy, there is heterogeneity in adherence to consensus guidelines. This perspective outlines clinical scenarios wherein findings on technetium-labeled cardiac scintigraphy have been misinterpreted, reviews causes of false-negative and false-positive results, and provides strategies to avoid costly and potentially fatal misdiagnoses.

Background Selinexor is an oral, selective nuclear export inhibitor. STORM was a phase 2b, single-arm, open-label, multicenter trial of selinexor with low dose dexamethasone in patients with penta-exposed relapsed/refractory multiple myeloma (RRMM) that met its primary endpoint, with overall response of 26% (95% confidence interval [CI], 19 to 35%). Health-related quality of life (HRQoL) was a secondary endpoint measured using the Functional Assessment of Cancer Therapy – Multiple Myeloma (FACT-MM). This study examines impact of selinexor treatment on HRQoL of patients treated in STORM and reports two approaches to calculate minimal clinically important differences for the FACT-MM. Methods FACT-MM data were collected at baseline, on day 1 of each 4-week treatment cycle, and at end of treatment (EOT). Changes from baseline were analyzed for the FACT-MM total score, FACT-trial outcome index (TOI), FACT-General (FACT-G), and the MM-specific domain using mixed-effects regression models. Two approaches for evaluating minimal clinically important differences were explored: the first defined as 10% of the instrument range, and the second based on estimated mean baseline differences between Eastern Cooperative Oncology Group performance status (ECOG PS) scores. Post-hoc difference analysis compared change in scores from baseline to EOT for treatment responders and non-responders. Results Eighty patients were included in the analysis; the mean number of prior therapies was 7.9 (standard deviation [SD] 3.1), and mean duration of myeloma was 7.6 years (SD 3.4). Each exploratory minimal clinically important difference threshold yielded consistent results whereby most patients did not experience HRQoL decline during the first six cycles of treatment (range: 53.9 to 75.7% for the first approach; range: 52.6 to 72.9% for the second). Treatment responders experienced less decline in HRQoL from baseline to EOT than non-responders, which was significant for the FACT-G, but not for other scores. Conclusion The majority of patients did not experience decline in HRQoL based on minimal clinically important differences during early cycles of treatment with selinexor and dexamethasone in the STORM trial. An anchor-based approach utilizing patient-level data (ECOG PS score) to define minimal clinically important differences for the FACT-MM gave consistent results with a distribution-based approach. Trial registration This trial was registered on ClinicalTrials.gov under the trial-ID NCT02336815 on January 8, 2015.

Clinical features of soft tissue amyloid light-chain (AL) amyloidosis include macroglossia, arthropathy, muscle pseudohypertrophy, skin plaques, and carpal tunnel syndrome. Vascular manifestations of AL amyloid include periorbital ecchymosis, jaw or limb claudication, and even myocardial infarction caused by occlusion of small vessel coronary arteries. Some of these features, such as macroglossia, periorbital ecchymosis, and the so-called shoulder-pad sign, are pathognomonic for AL amyloidosis. These findings may be the initial presenting features of the disease, and the recognition of these red flag symptoms is very important for the diagnosis and early intervention on the underlying plasma cell disease.

Multiple myeloma is a hematologic malignancy that classically manifests with hypercalcaemia, renal insufficiency, anaemia and lytic bone lesions. Liver dysfunction in multiple myeloma is a lesser known complication that occurs through biliary obstruction, liver infiltration by plasma cells, amyloid/light chain deposition or due to liver injury from medications. Although transfusion-related hepatic iron overload—leading to significant liver disease—is a recognised complication in certain hematologic malignancies, little is known about transfusional iron overload in patients with multiple myeloma. We present a case of a 49-year-old female with relapsed/refractory multiple myeloma who presented with rapid onset liver failure, due to both iron deposition and malignant plasma cell infiltration of the liver as a terminal event. A review of the literature on hepatic complications in multiple myeloma patients is presented.

A towering figure in experimental psychology, Charles W. Eriksen, passed away in February this year. “Erik” made extensive original and lasting contributions to both research methods and theories in several areas of psychology, especially involving visual information processing. His research exhibited consistent concerns with experimental methods for distinguishing among alternative explanations and distinguishing perception from behavior. Erik pioneered many research methods now in common use—including converging operations, visual search, rapid serial presentations, the stop-signal paradigm, temporal integration in form perception, spatial cues for guiding selective attention, and the flankers task. He also introduced and tested many theories of selective attention. Erik was the founding editor of Perception & Psychophysics, and served for 23 years as its principal editor. An impressive and unforgettable person, Erik was a compelling personification of “the greatest generation.”

Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease). The primary end point was overall response rate (ORR). Results Of 79 patients, 48 had quad-refractory and 31 had penta-refractory myeloma. Patients had received a median of seven prior regimens. The ORR was 21% and was similar for patients with quad-refractory (21%) and penta-refractory (20%) disease. Among patients with high-risk cytogenetics, including t(4;14), t(14;16), and del(17p), the ORR was 35% (six of 17 patients). The median duration of response was 5 months, and 65% of responding patients were alive at 12 months. The most common grade ≥ 3 adverse events were thrombocytopenia (59%), anemia (28%), neutropenia (23%), hyponatremia (22%), leukopenia (15%), and fatigue (15%). Dose interruptions for adverse events occurred in 41 patients (52%), dose reductions occurred in 29 patients (37%), and treatment discontinuation occurred in 14 patients (18%). Conclusion The combination of selinexor and dexamethasone has an ORR of 21% in patients with heavily pretreated, refractory myeloma with limited therapeutic options.

Background: Tafamidis is approved in many countries for the treatment of transthyretin amyloid cardiomyopathy. This study reports data on the long-term efficacy of tafamidis from an ongoing long-term extension (LTE) to the pivotal ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial). Methods: Patients with transthyretin amyloid cardiomyopathy who completed ATTR-ACT could enroll in an LTE, continuing with the same tafamidis dose or, if previously treated with placebo, randomized (2:1) to tafamidis meglumine 80 or 20 mg. All patients in the LTE transitioned to tafamidis free acid 61 mg (bioequivalent to tafamidis meglumine 80 mg) following a protocol amendment. In this interim analysis, all-cause mortality was assessed in patients treated with tafamidis meglumine 80 mg in ATTR-ACT continuing in the LTE, compared with those receiving placebo in ATTR-ACT transitioning to tafamidis in the LTE. Results: Median follow-up was 58.5 months in the continuous tafamidis group (n=176) and 57.1 months in the placebo to tafamidis group (n=177). There were 79 (44.9%) deaths with continuous tafamidis and 111 (62.7%) with placebo to tafamidis (hazard ratio, 0.59 [95% CI, 0.44–0.79]; P P =0.05) and wild-type transthyretin amyloidosis (0.61 [0.43–0.87]; P =0.006); and baseline New York Heart Association class I and II (0.56 [0.38–0.82]; P =0.003) and class III (0.65 [0.41–1.01]; P =0.06). Conclusions: In the LTE, patients initially treated with tafamidis in ATTR-ACT had substantially better survival than those first treated with placebo, highlighting the importance of early diagnosis and treatment in transthyretin amyloid cardiomyopathy. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01994889 and NCT02791230.

Background: Outcomes remain poor for patients with relapsed and refractory multiple myeloma (RRMM) progressing on conventional therapy (proteasome inhibitors, IMiDs, anti-CD38 antibodies, BCMA targeting agents, corticosteroids). Lete-cel, an autologous T-cell therapy, targets NY-ESO-1/LAGE-1a+ tumors using a genetically modified, high-affinity T-cell receptor. NY-ESO-1 and LAGE-1a are immunogenic cancer/testis antigens frequently overexpressed in MM and are linked to poor clinical outcomes. Additionally, PD-1 expression, which may limit adaptive immune response, has been observed previously in RRMM patients following treatment with lete-cel (Stadtmauer et al. Blood Adv, 2019; 3: 2022-2034). This open-label, pilot study evaluated the safety and efficacy of lete-cel +/- pembrolizumab (pembro) in patients with RRMM. Study design and methods: Key eligibility criteria include: age ≥18 yr; HLA-A*02:01; A*02:05, and/or A*02:06; NY-ESO-1+ and/or LAGE-1a+; protocol-required prior regimens; specified washouts from prior therapy; no active/chronic/intercurrent illness. Following lymphodepletion (LD), patients received lete-cel (Arm 1) or lete-cel + pembro (Arm 2). Planned pembro dosing was 200 mg/dose Q3 weeks (wks) starting at Wk 3. Primary endpoint was safety and tolerability. Key efficacy endpoint was investigator-assessed overall response rate (ORR) by International Myeloma Working Group uniform response criteria for MM (2016); response was assessed Q3 wks from Wk 3 to Wk 24, then Q6 wks to Wk 72, then every 3 months (mo) to disease progression/death/withdrawal. NY-ESO-1/LAGE-1a expression was assessed by qRT-PCR on myeloma cells. Transduced cell kinetics were assessed by qPCR of transgene vector copies in DNA from peripheral blood mononuclear cells. Results: Six patients (all male; median age 63 yr) were enrolled; 3 per arm. All had prior systemic anti-cancer therapy; 3 patients had received ≥5 prior regimens. Five of 6 patients received systemic anti-cancer therapy between leukapheresis and LD. All received reduced LD due to age and, in some patients, renal impairment. Patients in each arm received similar numbers of transduced T cells. Each of the 3 patients in Arm 2 received a median of 3 pembro doses (range: 3-4 doses). Start of pembro dosing was delayed to Wk 6 in 2 patients due to ongoing toxicities. There were no Grade 5 AEs. Grade 3/4 T-cell related AEs were reported in 3 patients, and all patients had Grade 3/4 LD-related AEs. Hematopoietic cytopenias were the most common treatment-emergent and treatment-related Grade 3/4 AE, occurring in all patients. All cytopenias were reported to have resolved for 4 patients or to have improved to Grade 1 at final patient follow-up for 2 patients. Three patients had cytokine release syndrome (Arm 1: 1 patient, Grade 2; Arm 2: 2 patients; 1 Grade 1 and 1 Grade 2); all patients recovered. There was 1 event of graft vs host disease (GvHD skin; Grade 1) and, in a separate patient, 1 event of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) (Grade 1). Both events resolved. All patients had reduction in tumor burden. Arm 1 (lete-cel alone) had an ORR of 33.3% (1 CR, 2 SD) and median progression-free survival (PFS) of 2.79 mo, while Arm 2 (combination) had an ORR of 66.7% (1 VGPR, 1 PR, 1 SD) and median PFS of 2.78 mo. Time to response for all responders was 3 weeks. Pembro dosing for the 2 Arm 2 responders began at Wk 6. Duration of response in each responder was 2.1 mo. Overall survival data are not mature. Two of 3 responders exhibited clearance of antigen positive myeloma cells in the bone marrow for up to 6 weeks after lete-cel infusion. T cell kinetics trended toward higher peak expansion (Cmax) and area under the curve (AUC) over the first 28 days post-dose (AUC0-28d) in responders vs. non-responders. Serum cytokine profiles in relation to response and CRS will be discussed. Conclusions: A single lete-cel infusion was associated with antitumor activity in 6/6 heavily pretreated RRMM patients, including 1 CR, 1 VGPR, 1PR. Both responses in Arm 2 occurred prior to pembro initiation. The associated safety profile was manageable and consistent with that seen in other lete-cel studies. Responders showed a trend toward higher Cmax and AUC0-28d as compared to non-responders. The study was closed in November 2020 due to protracted enrollment. This study (208470; NCT03168438) was funded by GlaxoSmithKline. Submission support was provided by Fishawack Health. Disclosures Nishihori: Novartis: Research Funding; Karyopharm: Research Funding. Kaufman: Janssen: Honoraria; Heidelberg Pharma: Research Funding; Fortis Therapeutics: Research Funding; Tecnofarma SAS, AbbVie: Honoraria; Amgen: Research Funding; BMS: Consultancy, Research Funding; Incyte, celgene: Consultancy; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech, AbbVie, Janssen: Consultancy, Research Funding; Novartis: Research Funding; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Sutro, Takeda: Research Funding. Huff: GSK: Current Employment, Current equity holder in publicly-traded company. Snape: Veramed: Current Employment. Jain: Butterfly Network: Current equity holder in publicly-traded company; Marker Therapeutics: Current equity holder in publicly-traded company; 23 and Me: Current equity holder in publicly-traded company; Sema4 Holdings: Current equity holder in publicly-traded company; GSK: Current Employment, Current equity holder in publicly-traded company. Kapoor: GSK: Current equity holder in publicly-traded company. Zajic: GSK: Current Employment, Current equity holder in publicly-traded company. Suchindran: GSK: Current Employment, Current equity holder in publicly-traded company. Chisamore: Merck & Co. Inc: Current Employment, Current equity holder in publicly-traded company. Rapoport: GSK: Other: Support received as site principal investigator for this study.

The genomic landscape of Waldenström Macroglobulinemia (WM) is characterized by recurrent somatic mutations in MYD88, with a lower incidence of mutations affecting CXCR4, ARID1A, CD79B and the NFKB signaling pathway (Hunter et. al. Blood 2014). We aimed to characterize the relationship between single base substitutions (SBS), mutational signatures, copy number aberrations (CNA) and structural variants (SV) in WM. We performed whole genome sequencing (WGS) on 14 primary samples from WM patients at various clinical stages, including IgM monoclonal gammopathy (n=1), smoldering (n=5), newly diagnosed (n=7) and relapsed WM (n=1). We identified a median of 2806 clonal SBS per sample (IQR 1870-3079), and 12/14 (85%) samples harbored MYD88 mutations. To investigate which mutational processes are involved in shaping the genomic landscape of WM we performed a mutational signature analysis. Four previously reported SBS signatures were detected: SBS1 and SBS5 (aging), SBS9 (germinal center; GC) and SBS8, with the contribution of age-related signatures SBS1/SBS5 being directly correlated with age at presentation (R 2=0.44, p=0.014). The GC signature SBS9 demonstrated sustained GC activity, as evidenced by the same proportion of mutations attributable to SBS9 at both the clonal and subclonal level (24%). At the immunoglobulin loci, we observed evidence of clustered SBS84 (AID), reflecting somatic hypermutation, with SBS84 accounting for 30% of signature contribution from subclonal mutations. Overall, these data suggest that, similarly to MM and other hematological malignancies, the interaction between WM and the GC is sustained over time. We have previously demonstrated that SV and complex events are critical in the pathogenesis and clinical outcomes of multiple myeloma. In contrast, in this WM WGS cohort, we found a low prevalence of complex SV, with no chromothripsis detected, and a single chromoplexy event found in 3 patients (21%), all of whom had progressed to symptomatic WM. To explore WM CNA features in a larger cohort, we examined the WGS data together with 38 MYD88-mutated WM samples for which targeted sequencing was available (MSK-IMPACT-Heme 400 gene panel). In this combined dataset (n=52), GISTIC analysis identified significantly deleted regions at 6q16.1, 7q34, 17p13.1 (TP53) and 21q22.2, along with significant amplification at 6p22.1 (HLA-A). To better characterize the HLA loci using the loss of heterozygosity in human leukocyte antigen (LOHHLA) tool (McGranahan et. al. Cell 2017) we found the presence of HLA-specific loss of heterozygosity in 1 sample, while 4 samples had HLA CN >2.5 (all from patients who progressed to symptomatic WM). CNA analysis demonstrated that while some samples harbored typical CNA features, others had minimal changes, with MGUS / smoldering WM samples having less CNA compared with those who progressed to symptomatic WM. The 2 MYD88 wild type WGS contained a clonal gain affecting chromosome 12, which is typically an early event in chronic lymphocytic leukemia. Molecular time analysis (the corrected ratio between duplicated and non-duplicated clonal mutations within large chromosomal gains [Maura et al. Nat Comm 2019]) demonstrated that these 2 chromosomal gain events occurred early in cancer development (relative timing 0.5) and tended to be subclonal. This data suggests that, while MYD88-mutations are central to WM clone establishment and can be observed in precursor disease, CNA may contribute to later phases and disease progression. In summary, WGS in WM allows the demonstration that germinal center activity is sustained over time. CNA in WM are not random in distribution, with specific loci being significantly amplified or deleted, and a potential role for HLA CNA. In contrast to MYD88 mutations, which are carried by stable precursor patients, the subclonal status and late molecular time of most CNA changes suggest a late role in cancer progression. Disclosures Kastritis: Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Diamond: Sanofi: Honoraria; Medscape: Honoraria. Kazandjian: Arcellx: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Papaemmanuil: Isabl Technologies: Divested equity in a private or publicly-traded company in the past 24 months; Kyowa Hakko Kirin Pharma: Consultancy. Dogan: Roche: Consultancy, Research Funding; Seattle Genetics: Consultancy; EUSA Pharma: Consultancy; Peer View: Honoraria; Takeda: Consultancy, Research Funding; Physicians' Education Resource: Honoraria. Lesokhin: Trillium Therapeutics: Consultancy; Serametrix, Inc: Patents & Royalties; Genetech: Research Funding; Iteos: Consultancy; bristol myers squibb: Research Funding; Behringer Ingelheim: Honoraria; pfizer: Consultancy, Research Funding; Janssen: Honoraria, Research Funding. Landgren: Janssen: Other: IDMC; Janssen: Honoraria; Celgene: Research Funding; Amgen: Honoraria; Janssen: Research Funding; Amgen: Research Funding; Takeda: Other: IDMC; GSK: Honoraria. Palomba: Rheos: Honoraria; Pluto: Honoraria; Lygenesis: Honoraria; Ceramedix: Honoraria; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Nektar: Honoraria; PCYC: Consultancy; Wolters Kluwer: Patents & Royalties; Notch: Honoraria, Other: Stock; Priothera: Honoraria; Kite: Consultancy; Novartis: Consultancy; Magenta: Honoraria; WindMIL: Honoraria; BeiGene: Consultancy; Juno: Patents & Royalties. Maura: OncLive: Honoraria; Medscape: Consultancy, Honoraria. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; BeiGene: Honoraria.

Background Despite recent advances in treatment options, multiple myeloma (MM) remains incurable. We previously presented preliminary data from an ongoing Phase 1/2 trial (NCT03761108) demonstrating that REGN5458 (a BCMAxCD3 bispecific antibody) monotherapy had an acceptable safety and tolerability profile with early, deep, and durable responses in heavily pretreated patients (pts), with at least triple-refractory RRMM, (Madduri, ASH 2020, O291). Here we describe updated safety, overall response, and response durability in pts treated in the Phase 1 portion of this study. Methods The primary objectives of the Phase 1 portion of the study are to assess the safety, tolerability, and occurrence of dose-limiting toxicities of REGN5458 and to determine a recommended Phase 2 dose regimen (RP2DR). Key secondary objectives include: assessment of objective response rate as determined by the investigator, duration of response (DOR), and minimal residual disease status; pharmacokinetic (PK) evaluation; and characterization of immunogenicity. Pts with progressive RRMM, who were triple-refractory, or intolerant to prior lines of systemic therapy including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 antibody are treated with REGN5458 monotherapy following a modified 3+3 dose-escalation design (4+3). Treatment consists of 16 weekly infusions of REGN5458, followed by q2w dosing, until disease progression. Response assessments are measured using modified International Myeloma Working Group criteria. Results As of data cut-off (June 10, 2021), 68 pts were treated with REGN5458 in the dose escalation cohort with full doses ranging from 3-400 mg. The median age at enrollment was 64 years (range, 41‒81) and 20.6% pts were ≥75 years. As per Revised International Staging System, stage was 1, 2 or 3 in 14.7%, 60.3% and 23.5% of pts respectively. Pts had a median of 5 prior lines of systemic therapy (range, 2-17) with the majority of pts (51.5%) being penta-refractory (see Table). The median duration of follow-up was 2.4 months (range, 0.1-20.8). Treatment-emergent adverse events (TEAE) were reported in 66 pts (97.1%), and Grade (Gr) ≥3 TEAEs in 52 (76.5%) pts. The most frequent TEAEs were fatigue in 29 pts (42.6%), Gr 1/2 in 26 pts (38.2%), Gr 3 in 3 pts (4.4%); cytokine release syndrome (CRS) in 26 pts (38.2%), CRS was Gr 1 in 23 pts (33.8%) and Gr 2 in 3 pts (4.4%). No pt had Gr ≥3 CRS or discontinued treatment due to CRS. There were no Gr ≥3 neurotoxicity events. Nausea was reported in 22 pts (32.4%). The severity of nausea was Gr 1 in 23.5% of pts and Gr 2 in 8.8% of pts. Treatment-related adverse events (TRAE) were reported in 56 patients (82.4%). The most frequent hematologic TRAE was neutropenia in 11 pts (16.2%), with Gr ≥3 severity in 9 of these pts (13.2%). The most frequent non-hematologic TRAEs were CRS (38.2%) and fatigue (20.6%). The safety profile was consistent across all dose levels, and there was no correlation between CRS and the full dose of REGN5458. Responses were observed at all dose levels. Amongst pts treated at the 96 and 200 mg dose levels, the response rate was 73.3% (11/15). Across all dose levels, 92.6% (n=25) of all responders achieved at least a very good partial response and 48.1% (n=13) of responders had a complete response (CR) or stringent CR. Pts without extramedullary plasmacytomas (EMP) responded more frequently than those with EMP. The Kaplan-Meier estimated median DOR was not reached and the probability of DOR ≥8 months was 92.1% (95% confidence interval: 72.1, 98.0), with responses ongoing up to 19 months at the latest data cut-off. Disease response was not impacted by level of BCMA expression in the core biopsy, as assessed by immunohistochemistry. Additional PK and biomarker data will be available at the time of presentation. Updated safety and efficacy data will also be presented. Conclusions In this updated analysis of the first-in-human study, REGN5458 continues to show an acceptable safety and tolerability profile, with Gr 2 CRS in only 4.4% of patients, and no Gr ≥3 CRS or neurotoxicity events. No new safety signals were observed during the additional follow-up period. Early, deep, and durable responses were seen in triple- to penta-refractory patients with RRMM, with a 73.3.% response rate at the combined 96 and 200 mg dose levels. The Phase 2 portion of the study is currently recruiting. Figure 1 Figure 1. Disclosures Zonder: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; Alnylam: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Caelum Biosciences: Consultancy; Intellia: Consultancy; Regeneron: Consultancy. Richter: BMS, Karyopharm, Antengene: Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Speakers Bureau; Janssen, Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Tisch Cancer Institute: Icahn School of Medicine at Mount Sinai: Current Employment. Bumma: Amgen, Sanofi: Speakers Bureau; Janssen, Oncopeptides, Sanofi: Consultancy. Hoffman: BMS, Celgene: Honoraria. Bensinger: BMS, Janssen, Poseida, Regeneron, Trillium: Research Funding; Amgen, BMS, Janssen, Sanofi: Speakers Bureau. Xu: Regeneron Pharmaceuticals, Inc: Current Employment; Regeneron Pharmaceuticals, Inc: Current holder of stock options in a privately-held company. Chokshi: Regeneron Pharmaceuticals, Inc: Current holder of stock options in a privately-held company; Regeneron Pharmaceuticals, Inc: Current Employment. Boyapati: Regeneron Pharmaceuticals, Inc: Current Employment; Regeneron Pharmaceuticals, Inc: Current holder of stock options in a privately-held company. Sharma: Regeneron Pharmaceuticals, Inc.: Patents & Royalties: US17/112,564: Methods of Treating Multiple Myeloma with Bispecific anti-BCMA X anti-CD3 Antibodies (Status: Pending). Rodriguez Lorenc: Regeneron Pharmaceuticals, Inc: Current Employment; Regeneron Pharmaceuticals, Inc, Novartis Pharmaceuticals: Current holder of stock options in a privately-held company. Kroog: Regeneron Pharmaceuticals, Inc: Current Employment; Regeneron Pharmaceuticals, Inc: Current holder of stock options in a privately-held company. Lentzsch: Magenta Therapeutics: Current equity holder in publicly-traded company; Ossium Health: Consultancy; Caelum Biosciences: Consultancy, Current holder of individual stocks in a privately-held company; Oncopeptides: Consultancy; Sanofi: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy; GSK: Consultancy; AbbVie: Consultancy; Celularity: Consultancy; Janssen: Consultancy; Kadmon: Current equity holder in publicly-traded company. Jagannath: Janssen Pharmaceuticals: Consultancy; Takeda: Consultancy; Legend Biotech: Consultancy; Karyopharm Therapeutics: Consultancy; Bristol Myers Squibb: Consultancy; Sanofi: Consultancy. OffLabel Disclosure: The data described in the abstract will report on use of REGN5458 in a Phase 1 clinical trial of patients with relapsed/refractory multiple myeloma

Introduction: Treatment combinations involving CD38 targeted monoclonal antibodies have significantly prolonged the median duration and depth of response in myeloma (MM), reflected in minimal residual disease-negativity (MRD-) rates of over 70% in newly diagnosed patients (Landgren et al. JAMA Onc 2021). Key to improving our understanding of treatment failures is the combined use of single cell analysis of the microenvironment with genome wide assessment of tumor genetics to decipher the mechanisms of disease resistance. Methods: We isolated malignant plasma cells from bone marrow (BM) samples using CD138+magnetic or flow (CD38, CD138, and CD45) sorting from 60 newly diagnosed MM patients treated with KRd with daratumumab (D-KRd n=46; NCT03290950) and without daratumumab combination therapy (KRd, n=14; NCT01402284). Fifty-five baseline samples underwent whole genome sequencing (WGS), median coverage of 80x using somatic DNA as a normal comparator. The BM cellular content of 22 patients (44 samples-5 failed) treated with D-KRd (10 MRD+ and 12 MRD-) underwent 5'single cell RNA-sequencing with an additional capture of the TCR and surface protein markers (CITEseq) to interrogate the single cell composition of the immune microenvironment at baseline (T1, n=20) and at the end of induction (T2, n=19). Paired (T1/T2) single-cell data were obtained in 17 patients and paired WGS and single cell data (T1) were available in 15 patients. MRD-, sustained MRD- (defined as two MRD- results, the first at the end of the induction (T2) and the subsequent at the first year of follow-up (T3)) and progression/loss of MRD- were used as clinical endpoints for this study. Results: After a median follow up of 29 months, 36 (54%) patients achieved MRD-; 34 (51%) had sustained MRD- >1 year after completion of combination therapy. Overall, 10 (15%) patients had clinical progression and two conversions from MRD- to MRD+. A comprehensive catalogue of MM-genomic events associated with these three clinical endpoints was defined. Deletion (del) 13, biallelic loss CYLD, del XBP1, del 20q13.12 (CD40), and 8q gains were associated with MRD+ and failure to achieve sustained MRD-. Presence of del RPL5 and multiple chromothripsis events significantly correlated with early progression and loss of MRD-. Interestingly, structural variants (SV) involving IKFZ3 were seen in all three negative clinical endpoints (p We interrogated the BM microenvironment at baseline and correlated its composition with the tumor genomic architecture. Across 15 evaluable patients, del XBP1 were associated with fewer memory B-cells (p=0.03), naïve B-cell (p=0.01) and dendritic cells (p=0.03) compared to the wild type. Also, low dendritic cell at baseline cases were observed in patients with del 20q13.12 (CD40) (p=0.03). Interestingly, low level of plasmacytoid dendritic cells at baseline was associated with failure to achieve MRD- and sustained MRD-. Patients with 6p24 amplification showed a reduced number of CD8 effectors 1 and 2 (p When comparing baseline (T1) and end of induction (T2), significant differences were seen between sustained MRD+ and MRD-. We identified significantly depleted NK, and naïve and memory B-cell after D-KRd MRD- patients had significantly more CD14+ monocytes both at T1 and T2 than their MRD+ counterparts (Fig. 1). Differential expression suggests that inflammatory response genes including IL1B are upregulated in the absence of sustained MRD- whereas genes implicated in IL2, IL6, and IFNα response as well as adipocyte differentiation are associated with sustained MRD response. Conclusion: We show, for the first time, evidence of complex interplay between MM tumor genetics and the microenvironment in the context of D-KRd treated patients. Our results highlight the importance of genomic-based mechanisms in the persistence of disease (IKZF3, XBP1) as well as heterogeneity in the composition of the BM microenvironment, with the monocytes pointing towards the importance of inflammation. Figure 1 Figure 1. Disclosures Maura: OncLive: Honoraria; Medscape: Consultancy, Honoraria. Hassoun: Celgene, Takeda, Janssen: Research Funding. Mailankody: Jansen Oncology: Research Funding; Allogene Therapeutics: Research Funding; Bristol Myers Squibb/Juno: Research Funding; Legend Biotech: Consultancy; Takeda Oncology: Research Funding; Fate Therapeutics: Research Funding; Physician Education Resource: Honoraria; Plexus Communications: Honoraria; Evicore: Consultancy. Hultcrantz: Intellisphere LLC: Consultancy; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Curio Science LLC: Consultancy; Amgen: Research Funding; Daiichi Sankyo: Research Funding. Scordo: Omeros Corporation: Consultancy; i3 Health: Other: Speaker; Kite - A Gilead Company: Membership on an entity's Board of Directors or advisory committees; Angiocrine Bioscience: Consultancy, Research Funding; McKinsey & Company: Consultancy. Kazandjian: Arcellx: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shah: Janssen Pharmaceutica: Research Funding; Amgen: 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. Giralt: SANOFI: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees; JANSENN: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Dogan: Physicians' Education Resource: Honoraria; Seattle Genetics: Consultancy; EUSA Pharma: Consultancy; Roche: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Peer View: Honoraria. Lesokhin: Behringer Ingelheim: Honoraria; pfizer: Consultancy, Research Funding; Janssen: Honoraria, Research Funding; Iteos: Consultancy; Genetech: Research Funding; bristol myers squibb: Research Funding; Trillium Therapeutics: Consultancy; Serametrix, Inc: Patents & Royalties. Davies: Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Korde: Amgen: Research Funding; Medimmune: Membership on an entity's Board of Directors or advisory committees. 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. Landgren: Janssen: Other: IDMC; Celgene: Research Funding; Amgen: Honoraria; Janssen: Research Funding; Janssen: Honoraria; Amgen: Research Funding; Takeda: Other: IDMC; GSK: Honoraria.

Translocation t(11;14) multiple myeloma (MM) is sensitive to the apoptosis-inducing drug venetoclax, yet the drug lacks FDA approval in MM. Selinexor is an inhibitor of nuclear export that is approved in relapsed/refractory MM. Here, we report that in patients with t(11;14) MM, the combined administration of venetoclax and selinexor was safe and resulted in clinically meaningful responses. This prompted preclinical studies to investigate synergism and molecular mechanisms of action. The combination was synergistic in t(11;14) MM cell lines and caused decreased levels of Cyclin D1 when given in combination as compared to single agents. A 58-year-old African American man and an 81-year-old Caucasian woman with relapsed, refractory t(11;14) MM with CCND1-IGH fusion confirmed by FISH and progression of disease after multiple lines of therapy were treated with venetoclax based on previous data showing efficacy of venetoclax in t(11;14) MM. Both patients responded initially to venetoclax, however, developed resistance and progressive disease. The addition of selinexor recaptured responses (VGPR and MR, respectively) suggesting a beneficial effect of the combination over single agent venetoclax. The treatment course of the 58-year-old man is shown in Figure A and free kappa light chain response in Figure B. Based on these observations, we hypothesized that selinexor with venetoclax was synergistic in patients bearing the t(11;14) translocation. We therefore studied the combination in MM cell lines with (U266-B1, KMS-12-BM, SK-MM2), and without (RPMI-8226, LP-1, OPM-2) t(11;14) translocations. We performed cell viability assays in increasing concentrations of selinexor, venetoclax, and a combination of the two drugs at 72 hours. Synergy was analyzed via the Bliss independence model using Synergy Finder software as well as via the Chou-Talalay method by using CompuSyn software. Average Bliss model synergy scores were -0.5 in non-t(11;14) and 10.2 in t(11;14) MM cells (>10 indicates synergistic effects and 1 are antagonistic. Cell lines that possessed t(11;14) were more sensitive to the drug combination and showed enhanced synergy in those cell lines bearing the CCND1-IGH translocation (Figure C). To better understand molecular mechanisms underlying the observed synergistic effect, we performed western blot analysis in these six cell lines, treating with selinexor (200nM), venetoclax (1μM), the combination, or DMSO control for 24 hours. We measured protein expression with antibodies against Cyclin D1, which is overexpressed in t(11;14) and a cargo of XPO1. Additionally, we measured levels of XPO1, p53, MCL-1, and p65, which we have previously shown to be altered by selinexor treatment (Figure D). We confirmed Cyclin D1 overexpression in t(11;14) cells lines but not in non-t(11;14) cells. Cyclin D1 levels decreased with selinexor, and the reduction was enhanced by adding venetoclax. Similarly, XPO1 levels decreased to a further degree in t(11;14) cell lines with the combination when compared to either drug alone. There was no difference in XPO1 reduction with the treatment combination in non-t(11;14) cell lines. P53 levels increased as a result of selinexor and combination treatment, and the combination also caused decreased levels of p65 in cell lines with and without t(11;14). Venetoclax upregulated MCL-1, but this was mitigated with the addition of selinexor. These effects were statistically more significant in t(11;14) cell lines (Figure E). The combination of selinexor and venetoclax has shown preclinical synergy in other cancer types and is in Phase 1b clinical trials for relapsed, refractory non-Hodgkin lymphoma or acute myeloid leukemia (NCT03955783; NCT04607772). To our knowledge, this is the first report of patients with MM treated with the combination of selinexor and venetoclax. The mechanism behind the preferential synergy in t(11;14) MM is still under investigation; however, the result of our studies suggests a role for Cyclin D1, which is a cargo protein of XPO1. Additionally, while the effect of venetoclax on Cyclin D1 is not well defined, prior studies suggest the interplay between Cyclin D1, BCL2, and other anti- and pro-apoptotic proteins as having a role in oncogenesis. Based on our results, further clinical evaluation of this combination in MM is planned. Figure 1 Figure 1. Disclosures Bradley: AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Maura: OncLive: Honoraria; Medscape: Consultancy, Honoraria. Kazandjian: Arcellx: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Landgren: Janssen: Other: IDMC; Takeda: Other: IDMC; Celgene: Research Funding; Amgen: Honoraria; Janssen: Honoraria; Janssen: Research Funding; Amgen: Research Funding; GSK: Honoraria. OffLabel Disclosure: Venetoclax for myeloma is not yet FDA approved, but is used at clinician's discretion in patients who possess t(11;14) based upon the previous sub-group analysis of trials with venetoclax.

Background: Patients treated with cytotoxic chemotherapies and/or autologous stem-cell transplantation (ASCT) are at risk for therapy-related myeloid neoplasms (tMN). As these agents yield increased mutation burden in relapsed malignancies and leave evidence of exposure via mutational signatures, we studied the genomic and temporal relationship between chemo exposure and progression of clonal hematopoiesis (CH) to tMN. Methods: We analyzed 32 tMN whole genomes (WG) from 31 patients [27 acute myeloid leukemias (AML), 4 myelodysplastic syndromes]. For 7 patients with tMN post-high-dose melphalan/ASCT, we investigated the presence of antecedent CH using targeted sequencing (MSK-IMPACT; Bolton et al. Nat Gen 2020) on pre-melphalan blood mononuclear cells, granulocytes, or CD34+ apheresis samples. Results: TMN was diagnosed a median of 4.2 years (IQR, 2.6-6.6) following primary treatment. When compared to data from 200 de novo AML from TCGA (NEJM, 2013), tMNs had fewer mutations in FLT3 (9.7% v 28.0%; p = 0.028) and NPM1 (3.2% v 27.0%; p = 0.003). TP53 loss was enriched in tMNs (25.8% v 10.5%; p = 0.035 ). Mutational signature analysis revealed 5 known single base substitution (SBS) signatures in tMN: the hematopoietic stem-cell (SBS-HSC), aging (SBS1), melphalan (SBS-MM1), and platinum signatures (E-SBS1, E-SBS20) (Rustad et al. Nat Comm 2020, Pich et al. Nat Gen 2019). Complex structural variants (SV), defined as ≥3 breakpoint pairs involved in simultaneous copy number changes (Rustad et al. Blood Can Disc 2020), were observed in 7 tMNs; including chromothripsis in 6 tumors (19.4%), chromoplexy in 2 (6.5%), templated insertion in 1 (3.2%), and unspecified complex SV in 2 (6.5%). Chromothripsis has not been previously reported in de novo AML and, in 4 cases, involved chromosome 19 with hyper-amplification of the SMARCA4 locus (≥5 copies). CH variants that became clonal in tumor were seen in 5/7 pre-melphalan/ASCT samples and included mutations in TP53, RUNX1, NCOR1, NF1, CREBBP, DNMT3A, and PPM1D. Chemotherapy introduces hundreds of mutations, leaving each exposed cell with a unique catalogue (i.e., barcode). In fact, TMNs with evidence of chemo signatures had a higher mutation burden (median 1574 single nucleotide variants) than those without (median 938; p = 0.004). Detection of chemo signatures in bulk genome sequencing relies on one cell, with its catalogue of mutations, to expand to clonal dominance (Fig 1a, Landau et al. Nat Comm 2020). Given the long latency between exposure and tMN diagnosis, this single-cell expansion model was expected for all samples exposed to melphalan or platinum-based regimens (i.e., agents with a measurable signature). Strikingly, all patients with pre-tMN platinum exposure (n=7) had evidence of platinum SBS signatures whereas only 2 of 7 patients with prior melphalan/ASCT had a melphalan signature (SBS-MM1). As all platinum-exposed tMN had mutational evidence of exposure, a CH clone must have existed prior to exposure, supporting a single-cell expansion model. Absence of a chemo signature for 5/7 post-melphalan/ASCT tumors despite exposure implies tumor progression driven either by multiple clones in parallel (Fig 1b) or by an unexposed clone. As latency largely excludes the former, this suggests pre-tMN CH clones were re-infused during SCT, thus avoiding chemo exposure (Fig 1c). This is supported by two lines of evidence: 1) tMNs from 2 patients exposed to sequential platinum and melphalan/ASCT had platinum but not melphalan signatures confirming single-cell expansion of the pre-tMN CH clone post-platinum but with escape from exposure to melphalan in the ASCT (Fig 1d); 2) targeted sequencing of pre-tMN samples from melphalan/ASCT patients identified tMN genomic mutations at the CH level in 5/7 cases, including in all 3 tested apheresis samples - one of which (TP53) expanded to dominance without a melphalan signature. Conclusion: WG sequencing identified novel features of tMN revealing the key driver role of complex SV. Mutational signature analyses and targeted sequencing of pre-tMN samples can increase our understanding of tMN pathogenesis and demonstrate that tMNs arising post-ASCT are often driven by CH clones that re-engraft after escaping melphalan exposure. This mode of expansion suggests that a permissive, immunosuppressed, post-transplant environment might play a more important role than chemotherapy-induced mutagenesis in tMN pathogenesis. Figure 1 Figure 1. Disclosures Diamond: Sanofi: Honoraria; Medscape: Honoraria. Watts: Rafael Pharmaceuticals: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Aptevo Therapeutices: Research Funding. Kazandjian: Arcellx: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bradley: AbbVie: Consultancy, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bolli: Amgen: Honoraria; Takeda: Honoraria; Janssen: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria. Papaemmanuil: Isabl Technologies: Divested equity in a private or publicly-traded company in the past 24 months; Kyowa Hakko Kirin Pharma: Consultancy. Scordo: Kite - A Gilead Company: Membership on an entity's Board of Directors or advisory committees; i3 Health: Other: Speaker; Omeros Corporation: Consultancy; Angiocrine Bioscience: Consultancy, Research Funding; McKinsey & Company: Consultancy. Lahoud: MorphoSys: Membership on an entity's Board of Directors or advisory committees. Stein: Jazz Pharmaceuticals: Consultancy; Foghorn Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Gilead Sciences, Inc.: Consultancy; Abbvie: Consultancy; Janssen Pharmaceuticals: Consultancy; Genentech: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; Novartis: Consultancy; Astellas: Consultancy; Syndax Pharmaceuticals: Consultancy; PinotBio: Consultancy; Daiichi Sankyo: Consultancy; Syros Pharmaceuticals, Inc.: Consultancy. Sauter: Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Gamida Cell: Consultancy; Celgene: Consultancy, Research Funding; Genmab: Consultancy; Novartis: Consultancy; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. Hassoun: Celgene, Takeda, Janssen: Research Funding. Mailankody: Bristol Myers Squibb/Juno: Research Funding; Physician Education Resource: Honoraria; Plexus Communications: Honoraria; Takeda Oncology: Research Funding; Jansen Oncology: Research Funding; Fate Therapeutics: Research Funding; Allogene Therapeutics: Research Funding; Legend Biotech: Consultancy; Evicore: Consultancy. Korde: Medimmune: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Hultcrantz: Daiichi Sankyo: Research Funding; Intellisphere LLC: Consultancy; Curio Science LLC: Consultancy; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding. Shah: Bristol Myers Squibb: Research Funding; Janssen: Research Funding. Shah: Janssen Pharmaceutica: Research Funding; Amgen: Research Funding. Park: Servier: Consultancy; Affyimmune: Consultancy; Autolus: Consultancy; Minerva: Consultancy; PrecisionBio: Consultancy; BMS: Consultancy; Novartis: Consultancy; Kura Oncology: Consultancy; Curocel: Consultancy; Artiva: Consultancy; Innate Pharma: Consultancy; Intellia: Consultancy; Amgen: Consultancy; Kite Pharma: Consultancy. Landau: Genzyme: Honoraria; Takeda, Janssen, Caelum Biosciences, Celgene, Pfizer, Genzyme: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Sekeres: BMS: Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Ho: Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees. Roshal: Celgene: Other: Provision of services; Auron Therapeutics: Other: Ownership / Equity interests; Provision of services; Physicians' Education Resource: Other: Provision of services. Lesokhin: pfizer: Consultancy, Research Funding; Janssen: Honoraria, Research Funding; Iteos: Consultancy; Serametrix, Inc: Patents & Royalties; Genetech: Research Funding; Trillium Therapeutics: Consultancy; bristol myers squibb: Research Funding; Behringer Ingelheim: 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. Landgren: Janssen: Other: IDMC; Janssen: Research Funding; Amgen: Honoraria; Celgene: Research Funding; Janssen: Honoraria; Amgen: Research Funding; Takeda: Other: IDMC; GSK: Honoraria. Maura: OncLive: Honoraria; Medscape: Consultancy, Honoraria.

Introduction: In cardiac amyloidosis (CA), immunoglobulin-derived light chains (AL) and transthyretin (TTR) are the most common amyloidogenic proteins infiltrating the heart. 1 Identification of the specific precursor protein leading to amyloid deposition is needed to establish the correct therapeutic approach. 2 In both AL- and TTR-related CA, an early and accurate diagnosis is critical to achieving the best treatment outcomes. TTR amyloid cardiomyopathy (ATTR-CM) is often misdiagnosed as other causes of heart failure (HF), including AL CA. 3 While almost all patients with AL amyloidosis have elevated serum free light-chain (sFLC) levels and abnormal free kappa:lambda (κ:λ) ratios, 4 patients with ATTR-CM can also have abnormal sFLC levels due to either an unrelated monoclonal gammopathy or relative κ-predominance in renal dysfunction. 2,5 Because ATTR-CM most often occurs in elderly adults and is commonly accompanied by renal comorbidity, we theorized that patients with ATTR-CM may have κ:λ ratios that approach, or exceed, the upper limit of the normal reference range (0.26-1.65 6). High light-chain ratios in these patients have the potential to increase the likelihood of misdiagnosis of a monoclonal plasma cell disorder and may lead to unnecessary referrals to hematologists and/or inappropriate treatments. To explore this theory, we evaluated κ:λ ratios in patients with biopsy-proven ATTR-CM who were enrolled in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). 7 Methods: In ATTR-ACT, a double-blind, placebo-controlled, randomized study, patients with biopsy-proven ATTR-CM, and without light-chain amyloidosis, received tafamidis or placebo for 30 months. In the current analysis, sFLC levels and κ:λ ratios were assessed in the intent-to-treat population (N=441), excluding patients with a prior diagnosis of monoclonal gammopathies (n=13; defined by MedDRA preferred terms: 'monoclonal gammopathy', 'plasma cell myeloma', 'plasma cell disorder', and 'hypergammaglobulinemia benign monoclonal'). Subgroup analyses were performed by estimated glomerular filtration rate (eGFR) category (≥60 vs ≥40 to Results: In 422 patients with ATTR-CM and available sFLC data, and without a prior diagnosis of monoclonal gammopathies, the mean κ:λ ratio was 1.45 (median, 1.20 [IQR, 0.98, 1.47]) (Figure). The ratio increased with declining renal function: eGFR ≥60 mL/min/1.73 m 2, mean, 1.25 (median [IQR], 1.11 [0.94, 1.38]); ≥40 to Conclusions: In patients with biopsy-proven ATTR-CM without known monoclonal gammopathies who were enrolled in ATTR-ACT, the mean κ:λ ratio showed a κ-predominance, often exceeding the upper range of normal in patients with more advanced kidney dysfunction. The findings suggest that individuals with ATTR-CM can have higher sFLC levels than those normally seen in the general population, and such elevations do not necessarily indicate the presence of monoclonal gammopathy of undetermined significance or AL CA. In an era when most patients with ATTR-CM and without monoclonal gammopathies are diagnosed noninvasively using bone scintigraphy, age- and renal-function-based sFLC norms are critical to ensure appropriate use of diagnostic testing modalities. References: 1. Maleszewski JJ. Cardiovasc Pathol. 2015;24:343-50. 2. Donnelly JP, et al. Cleve Clin J Med. 2017;84:12-26. 3. Witteles RM, et al. JACC Heart Fail. 2019;7:709-716. 4. Falk RH, et al. J Am Coll Cardiol. 2016;68:1323-41. 5. Geller HI, et al. Mayo Clin Proc. 2017;92:1800-5. 6. Katzmann JA, et al. Clin Chem. 2002;48:1437-44. 7. Maurer MS, et al. N Engl J Med. 2018;379:1007-16. Figure 1 Figure 1. Disclosures Hoffman: BMS, Celgene: Honoraria. Sultan: Pfizer: Current Employment, Current equity holder in publicly-traded company. Gundapaneni: Pfizer: Current Employment, Current equity holder in publicly-traded company. Witteles: Pfizer: Honoraria, Research Funding; Alnylam: Honoraria, Research Funding; Eidos: Research Funding.

Background Patients (pts) with relapsed/triple-class refractory (R/R; refractory to a proteasome inhibitor, immunomodulatory drug or anti-CD38 antibody) multiple myeloma (MM) have limited treatment options. A need remains for novel combination therapies with manageable toxicity and non-cross-resistant mechanisms of action. B-cell maturation antigen (BCMA) is expressed in most MM pt tumors. SEA-BCMA is an investigational, humanized, nonfucosylated IgG1 monoclonal anti-BCMA antibody. Proposed mechanisms of action of SEA-BCMA include blocking of BCMA-mediated pro-survival and proliferative signaling, mediating antibody-dependent cellular phagocytosis, and displaying enhanced antibody-dependent cellular cytotoxicity. Preclinical data demonstrate promising antitumor activity and versatile combinability. Here, we present preliminary data from the first-in-human Phase 1 clinical trial. Methods SGNBCMA-001 (NCT03582033) is an ongoing phase 1, open-label, multicenter, dose-escalation and expansion study to evaluate the safety, tolerability and antitumor activity of SEA-BCMA in adults with R/R MM not previously exposed to any other BCMA-directed therapy. Part A tested monotherapy safety and tolerability with dose escalation (100-1600 mg flat dosing once every 2 weeks [Q2W] by intravenous infusion), and dose expansion at the highest tolerated dose. Parts B and C aim to optimize efficacy by testing intensified dosing (Part B; weekly [Q1W] induction dosing of SEA BCMA for 8 weeks is followed by Q2W maintenance dosing) and dexamethasone (DEX) combination therapy (Part C) in pts who have received ≥3 prior lines of therapy for MM and are triple-class refractory. Responses are assessed per the 2016 International Myeloma Working Group criteria. Results As of June 15, 2021, Part A completed enrollment. A total of 55 pts received SEA-BCMA (see Table 1 for pt characteristics). SEA-BCMA was generally well tolerated, and the maximum tolerated dose was not reached in the 5 dose levels tested in Part A (100, 200, 400, 800, or 1600 mg Q2W; n=2, 2, 2, 7, and 7, respectively). At 800 mg, 1 of 7 pts reported a Grade 3 infusion-related reaction (IRR), which met dose-limiting toxicity (DLT) criteria by lasting >24 hours despite supportive care. This constituted the single DLT observed during dose escalation. Subsequently, dose expansion (n=15) proceeded at 1600 mg Q2W. The most common treatment-emergent adverse events (TEAEs) observed with 1600 mg Q2W (n=22) were fatigue (32%), pyrexia (23%), IRR (23%), and hypertension (23%) for non-hematological events, and anemia (14%) for hematologic events. The most common ≥Grade 3 TEAEs with 1600 mg Q2W were anemia and syncope (9% each). Following a safety monitoring review, premedication with acetaminophen + antihistamine was introduced to mitigate IRRs in expansion cohorts. Parts B and C completed parallel safety run-ins (n=6 each) at the 1600 mg dose with no DLTs observed and with similar tolerability. Pharmacokinetic (PK) analyses indicate serum SEA-BCMA exposures increased proportionally with increasing dose with a half-life of approximately 10 days. Preliminary analyses suggest the PK profile of SEA-BCMA in combination therapy with DEX (n=5) is comparable to monotherapy and is unaltered with a change in schedule from Q2W to Q1W. Three of 22 pts who received 1600 mg SEA-BCMA Q2W monotherapy (Part A) achieved a confirmed objective response (OR; OR rate: 14% [95% confidence interval: 2.91, 34.91]; 2 partial responses [PR], 1 very good PR [VGPR]). To date, 3 pts remain on treatment (2 PRs and 1 stable disease). The median duration of treatment was 12 weeks (Figure 1; range 4-88). In Parts B and C, 2 of 8 (2 PR) and 2 of 12 (1 VGPR, 1 PR) pts reported a confirmed OR; 3 of the 4 responding pts remain on treatment in cycle 7, 8, and 9, respectively. Conclusions Preliminary results for SGNBCMA-001 suggest a favorable safety profile and combination potential. SEA-BCMA also showed encouraging duration on treatment and initial antitumor activity in a heavily pre-treated late-line R/R MM pt population. Expansion cohorts testing intensified SEA-BCMA dosing and the addition of DEX are underway to further assess the safety, tolerability, and estimate of SEA-BCMA activity in the context of these treatment approaches. An additional expansion cohort (Part D), testing the combination of SEA-BCMA with pomalidomide and DEX in pts who have received ≥2 prior lines of therapy, is now enrolling. Figure 1 Figure 1. Disclosures Hoffman: BMS, Celgene: Honoraria. Lipe: Seagen Inc.: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; sanofi: Consultancy; GlaxoSmithKline: Consultancy; amgen: Research Funding; Cellectar: Research Funding; Karyopharm: Research Funding; Harpoon: Research Funding. Melear: Astrazeneca: Speakers Bureau; TG Therapeutics: Speakers Bureau; Janssen: Speakers Bureau. Liedtke: Pfizer: Honoraria; 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; Alnylam: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: 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; Kite: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Niesvizky: Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; GSK: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding. Tomasson: Pfizer, Inc.: Research Funding; Rafael Pharmaceuticals: Research Funding; syros Pharmaceuticals: Research Funding; Janssen R&D: Research Funding; Seagen, Inc.: Research Funding. Yasenchak: Seagen Inc.: Research Funding. Green: Seagen Inc.: Research Funding; bristol myers squibb: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Cellectar Biosciences: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen Biotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Patents & Royalties, Research Funding; Legend Biotech: Consultancy; Neoleukin Therapeutics: 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; SpringWorks Therapeutics: Research Funding. Li: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Wang: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Ho: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company.

Background: Chromosomal abnormalities in multiple myeloma (MM) patients, identified by either conventional metaphase cytogenetics or fluorescence in situ hybridization (FISH), stratify those at high risk of relapse and poorer survival after treatment. However the prognostic value of high-risk (HR) features in regard to survival after autologous hematopoietic stem cell transplantation is unclear. In addition, recent epidemiologic studies describe difference between Hispanic and non-Hispanic whites (NHW) in incidence, age at presentation, time to initial treatment, and rate of auto-HSCT within one year of diagnosis, but the presence of cytogenetic abnormalities as a prognostic factor in Hispanic patients has not yet been described. Methods: We conducted a retrospective analysis of 367 MM patients at the University of Miami Sylvester Comprehensive Cancer center who underwent auto-HSCT between January 2014 and December 2020. Patients were classified as HR if either conventional cytogenetics or FISH demonstrated at least one of the following: 1q+, 1p-, 17p-, 13q-, t(4;14), or t(14;16). All other patients with normal chromosomal studies or with trisomies and/or hyperdiploidy were considered standard risk (SR). Survival analysis were performed using the log-rank test, with significance at p-value < 0.05. Results: Male patient comprised 58% of our patient population with 43% of patients of Hispanic ethnicity. Of the 367 patients who underwent auto-HSCT, 183 (50%) had at least one HR cytogenetic abnormality. Overall, HR patients exhibited inferior PFS (32.9m vs 50.6m, p=0.017) and OS (median not reached/NR for both, p=0.0086) compared to SR patients. When evaluating outcomes with specific HR cytogenetic abnormalities, we identified cohorts that did not exhibit survival benefit, either in overall survival (OS) or progression-free survival (PFS) after transplant compared to SR patients, in particular patients with 17p-, 13q-, or 1q+ (Table 1). Patients with 1p-, t(14;16) or t(4;14) derived partial benefit from transplant in terms of PFS but not OS. Notably, patients with 1p- exhibited significantly worse OS compared to other HR patients (38.3m vs NR, p=0.007). We next evaluated differences in outcome when stratifying across ethnicity. Of the 183 patients with HR cytogenetic abnormalities, 75 (41%) were of Hispanic ethnicity, while 58 (32%) were NHW and 46 (25%) were of African-American (AA) ethnicity. The proportion of patients with SR or each individual HR cytogenetic abnormality was mostly equivalent amongst each ethnicity with the exception of 13q- (35% of Hispanic patients, vs. 44% of NHW and 26% of AA patients). Nevertheless, we observed that Hispanic patients with either t(4;14) or 13q- had significantly worse OS and PFS than their NHW and AA counterparts, and similarly observed inferior OS in Hispanic patients with 1q+ (Table 2). Conclusion: In our single-center retrospective analysis of HR MM patients undergoing auto-HSCT, we have identified specific patient populations that derive some survival benefit from transplant as well as populations that did not derive any benefit. Additionally, we demonstrate that despite similar incidence of certain HR abnormalities when comparing across ethnicities, Hispanic patients with particular chromosomal abnormalities have inferior overall survival outcomes after transplant. Further investigation is warranted to identify patient-specific and treatment-related factors leading to inferior outcomes in this patient population. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

In the emotion induced blindness (EIB) paradigm, participants search for a single target picture embedded in a rapidly presented sequence of “background” pictures. When the sequence also contains a task-irrelevant, emotional distractor appearing shortly before the target, awareness for the target is severely impaired (Most, Chun, Widders, & Zald, 2005). This temporary “blindness” for the target is thought to reflect attention capture by the emotionally salient distractor which blocks the target's access to the attention system. However, there are also reasons to suspect that physical salience may play an important role in the initial attention capture process. The emotional pictures consist of close-ups of people and animals while the background pictures are wide-angle views of landscapes and cityscapes. These physical differences might result in pop-out of the distractor picture that is at least partially based on physical and not emotional salience. We investigated the role of physical salience in emotional capture by comparing the typical EIB paradigm, which uses dissimilar distractors, with one in which the background pictures consist of people and animals in non-emotional settings (similar distractors). If emotional salience is the basis of attention capture in EIB, we should see similar amounts of target suppression in both conditions. Instead, we found that the EIB effect was reduced and possibly eliminated in the similar background condition. A control experiment revealed that emotional information was still available in the similar background condition because the blink was restored when the emotional picture was designated for report by a salient cue. These findings are clearly inconsistent with current theories of EIB (e.g., McHugo, Olatunji, & Zald, 2013) which assume that initial attention capture is driven by emotional not physical salience.

Background: Light chain (AL) amyloidosis is a rare disease in which deposits of insoluble amyloid derived from immunoglobulin light chains accumulate and cause dysfunction of organs including the heart and kidneys. In order to reverse organ damage and improve overall survival, treatment must provide rapid, deep, and sustained hematologic responses. Although therapies approved for the treatment of multiple myeloma have demonstrated some efficacy, there are currently no health authority-approved treatments for AL amyloidosis. A retrospective observational study was undertaken to characterize patients and describe treatment patterns in patients with AL amyloidosis from real-world data in the US. Methods: Data were extracted from Optum Electronic Health Records (EHR) and Optum Clinformatics Data Mart (claims) databases. Eligible patients had (1) a diagnosis of AL amyloidosis (ICD-10 code E85.81) on or after January 1, 2008 or (2) a diagnosis of amyloidosis (ICD-9 codes 277.30, 277.39; ICD-10 codes E85.89, E85.9) on or after January 1, 2008 and at least one line of therapy (LOT) comprising one or more of the following treatments: bendamustine bortezomib, carfilzomib, cyclophosphamide, daratumumab, dexamethasone, doxorubicin, elotuzumab, etoposide, interferon alfa-2a, interferon alfa-2b, ixazomib, lenalidomide, melphalan, panobinostat, pomalidomide, prednisone/prednisolone, thalidomide, vincristine, or autologous stem cell transplant. Patients were required to have continuous medical enrollment during the 365 days prior to the index amyloidosis diagnosis date (claims data) or have first active date at least 365 days prior to index amyloidosis date (EHR data), must not have had prior cancer in the 365-day period prior to the index amyloidosis diagnosis date, and must have been age ≥18 years at time of amyloidosis diagnosis. Patients treated with dexamethasone only or dexamethasone and prednisolone only for ≤90 days and those treated with prednisone/prednisolone only irrespective of duration were excluded. LOTs were defined by a start date, an end date, and a distinct regimen made up of ≥1 drugs. Patients may have multiple sequential LOTs during the available follow-up period. Comorbidities were scored according to the Charlson Comorbidity Index (CCI). A score of 0 reflects no comorbidities; higher scores reflect increased mortality risk and the maximum score is 24. Descriptive statistics are provided for patient characteristics at index diagnosis date for patients who had ≥1 LOT, distribution of regimens in each LOT, treatment attrition, and duration of treatment in each line of therapy and by regimen. Results: Data from 1688 patients (Optum claims, n=624; Optum EHR, n=1064) were included in the analysis (Figure). Median age at diagnosis was 67 years and 55.7% of patients were male. Almost 70% of patients had an index diagnosis date between 2013 and 2019. The median CCI score at index diagnosis date (based on comorbidities in the 365-day pre-index diagnosis period) was 1 and 10.9% of patients had a stem cell transplant on or after the index diagnosis date. The three most common comorbidities were hypertension (50.8%), renal failure (26.2%), and congestive heart failure (24.6%). Median follow-up period was 28 months. Treatment information for regimens used by ≥5% of patients for LOT1 is summarized in the Table. The most common treatment regimen for LOT1 was a proteasome inhibitor (PI), an alkylating agent, and a steroid (n=392, 23.2%); this combination was used for an average of 111 days. Of patients treated with this combination, the most common regimen was bortezomib, cyclophosphamide, and dexamethasone (VCd), used by 358 patients. Steroid only (dexamethasone for ≥90 days) regimens accounted for 16.4% and a PI ± steroid for 13.2% of LOT1. A limitation of the study is that assumptions were used to classify AL amyloidosis vs other types of amyloidosis. Conclusions: VCd is the most commonly used regimen in patients with newly-diagnosed AL amyloidosis. This is consistent with clinical guidelines and real world data from Europe (Palladini et al, EHA 2020), supporting this regimen as the current standard of care for treatment of patients with newly-diagnosed AL amyloidosis. Disclosures Dispenzieri: Celgene: Research Funding; Pfizer: Research Funding; Alnylam: Research Funding; Intellia: Research Funding; Janssen: Research Funding; Takeda: Research Funding. Zonder:Intellia, Amgen, Takeda, Janssen, Regeneron, Alnylam, Caelum, Oncopeptides: Consultancy; BMS, Celgene: Research Funding. Hoffman:Loxo: Current equity holder in publicly-traded company; Celgene: Honoraria, Speakers Bureau. Wong:Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Fortis: Research Funding; Roche: Research Funding; GSK: Research Funding; Amgen: Consultancy; Bristol Myers Squibb: Research Funding. Liedtke:Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Abonour:BMS: Consultancy, Research Funding; Takeda: Consultancy; Janssen: Honoraria, Research Funding; Celgene: Consultancy. D'Souza:Amgen, Merck, TenoBio: Research Funding; Akcea, Imbrium, Janssen, Pfizer: Consultancy. Lee:Janssen: Current Employment. Nair:Janssen: Current Employment. Potluri:SmartAnalyst Inc.: Current Employment. Weiss:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Lam:Janssen: Current Employment. Mehra:Janssen: Current Employment.

BACKGROUND: Stratification using cytogenetics (CG), either metaphase karyotyping or fluorescence in situ hybridization (FISH) is used to identify patients (pts) with multiple myeloma (MM) who are at higher risk of relapse and tend to have poorer survival. It is largely unknown if autologous stem cell transplantation (auto-HCT) after high dose melphalan (200 mg/m2) is able to modify the survival of some of these high-risk MM pts and to make it comparable to standard risk. METHODS: Pts were classified as high risk (HR) if either conventional cytogenetics or FISH demonstrated at least one of the following 1q+, 1p-, 17p-, 13q-, t(4;14), or t(14;16), realizing that the inclusion of 13q- by FISH alone and 1p- in the HR MM definition is controversial. Pts with normal chromosomes or those with trisomies and hyperdiploidy were considered standard-risk (SR). We compared progression-free survival (PFS) and overall survival (OS) via a retrospective analysis of pts at the University of Miami Sylvester Comprehensive Cancer Center who underwent auto-HCT between January 2014 and December 2017 for MM. Survival analyses were performed using the log-rank test, with significance at p-value < 0.05. RESULTS: Male pts comprised 56% of the population, and 40% of pts were of Hispanic ethnicity. Of 205 pts undergoing auto-HCT, 108 (53%) had at least one HR cytogenetic abnormality. Interestingly, the depth of response to pre-transplant induction was higher in pts classified as HR, with 71% (77 of 108) achieving at least a very good partial response (VGPR), while 24% (23 of 96) SR pts achieved VGPR. While OS remained largely unaffected in HR pts (34.0 m vs. 35.1 m, p = 0.27); HR pts had an inferior PFS compared to SR pts (21.9 m vs. 25.7 m, p = 0.041). The presence of trisomies did not negate the poorer PFS of HR pts. When we evaluated specific HR CG abnormalities, OS and PFS in patients with 1q+ or t(4;14) were surprisingly comparable to SR pts, indicating a significant benefit from auto-HCT. On the other hand, OS was significantly decreased in pts with 1p- when compared to standard risk (16.5 m vs. 35.1 m, p = 0.004) or other high-risk patients (16.5 m vs. 35.4 m, p = 0.01), implying that 1p- group derive no benefit from auto-HCT. Similarly, OS was shorter in pts with t(14;16) (16.5 m vs. 34.4 m, p = 0.025) and with 17p- (26.6 m vs. 35.1 m, p=0.01), however the PFS was not affected in these populations. In pts with 13q-, PFS was significantly shorter (20.3 m vs. 25.7 m, p=0.023) compared to SR pts without affecting OS. CONCLUSION: At our center in a retrospective analysis of 205 pts: a) patients with HR MM responded better and faster than SR pts to induction, b) those with 1p- did not derive any benefit from transplant and c) pts with 17p- and t(14;16) had some short term benefit (similar PFS to SR group) but at the end their OS remained inferior. Nevertheless, we consider a very important finding the fact that, by having auto-HCT, pts with 1q+ and t(4;14), equalized their PFS and OS to those of SR pts. Based on these findings, patients with 1q+ and t(4;14) should still have a transplant in CR1 even after optimal induction. Whether 17p- and t(14;16) pts can extend PFS benefit after transplant into OS benefit with maintenance regimens stronger than lenalidomide alone remains to be determined. Disclosures Hoffman: Celgene: Honoraria, Speakers Bureau; Loxo: Current equity holder in publicly-traded company; Seattle Genetics: Research Funding.

Introduction NY-ESO-1 TCR T (GSK3377794) are autologous polyclonal T cells transduced by a self-inactivating lentiviral vector to express an affinity-enhanced TCR recognizing NY-ESO-1 or LAGE-1a antigenic peptides in complex with HLA-A2. NY-ESO-1 and LAGE-1a are immunogenic cancer/testis antigens overexpressed in mutiple myeloma (MM) and linked to poor clinical outcome. Patients (pts) with MM who received GSK3377794 after autologous stem cell transplant (ASCT) showed encouraging clinical activity. PD-1 expression on CD8 T cells can occur in GSK3377794-treated MM pts and may limit adaptive immune response; this is a mechanism of resistance/relapse in CD19 CAR T-cell trials. Combining GSK3377794 with an anti-PD1 inhibitor (pembrolizumab) may have synergistic antitumor activity. Objective Evaluate safety and efficacy of GSK3377794 alone or in combination with pembrolizumab in pts with relapsed MM. Methods This is an open-label, pilot study (NCT03168438) of GSK3377794 in pts who are HLA-A*02:01, 05, ± 06 positive and have NY-ESO-1+/LAGE-1a+ relapsed/refractory MM. Twenty pts who have received ≥3 prior therapies containing ≥1 (separately or combined; including ASCT) of an IMiD, PI, alkylator, CD38 monoclonal antibody, and glucocorticoid, will be assigned to 1 of 2 arms: GSK3377794 as a single infusion (Arm 1, n=10) or GSK3377794 as a single infusion + pembrolizumab 200 mg IV every 3 wk (Arm 2, n=10). Arm 1 enrollment will complete before enrolling Arm 2. Pembrolizumab treatment will start from Wk 3 (Wk 6 if precluded by toxicity). Each patient will undergo leukapheresis to obtain cells for autologous NY-ESO-1-specific T-cell manufacturing, followed by lymphodepleting chemotherapy with fludarabine + cyclophosphamide, then GSK3377794 infusion of 1−8 × 109 transduced T cells. Study objectives are to assess safety and tolerability (primary) and antitumor activity (secondary) of GSK3377794 treatment (± pembrolizumab). At each visit, pts will be monitored for AEs and treatment-limiting toxicities, efficacy (using IMWG criteria), and biomarkers. Arm 2 enrollment will pause for a 3-wk safety review period after the first 3 pts receive their first pembrolizumab dose. Treatment will continue until disease progression or 108 wk after GSK3377794 infusion. After completing treatment, pts will transfer to long-term follow-up (NCT03391778) to continue safety/survival monitoring for up to 15 years. As of Jan 27, 2019, 50 pts have been screened. Half have tested positive for HLA-A*02:01, 05, ± 06; bone marrow samples from 12/21 (57%) tested positive for NY-ESO-1 ± LAGE-1a. To date, 3 pts have received GSK3377794. Further work is ongoing to enhance patient eligibility. These data are presented on behalf of the original authors with their permission. A similar presentation will be presented at the ASH Annual Meeting, Orlando, FL, USA, Dec 7-10, 2019. This study (NCT03168438) is funded by GSK.

Background Transthyretin cardiomyopathy (ATTR-CM) is an underdiagnosed, fatal disease caused by the deposition of transthyretin amyloid fibrils in the heart leading to heart failure (HF). It can be hereditary due to mutations in the TTR gene (ATTRm) or acquired (wild-type [ATTRwt]). Tafamidis is a selective transthyretin stabilizer which prevents tetramer dissociation and amyloidogenesis. The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) was an international, multicenter, double-blind, placebo-controlled, randomized trial of Tafamidis in patients with ATTR-CM. Objectives Given the limited number of patients with ATTR-CM, a novel study design was utilized to enable rigorous testing of the efficacy of tafamidis on hard cardiovascular (CV) endpoints in a study of relatively modest size compared with traditional CV trials. The primary results of this trial were further supported through the application of pre-specified sensitivity analyses. Methods Patients with ATTR-CM were randomized (2:1:2) to tafamidis (80 mg or 20 mg of tafamidis meglumine), or placebo (orally, once daily), for 30 months. Enrollment was stratified by NYHA class and genotype. The primary efficacy analysis was a hierarchical combination of all-cause mortality and frequency of CV-related hospitalizations comparing the pooled tafamidis groups (20 mg and 80 mg) vs. the placebo group using the Finkelstein-Schoenfeld (F-S) method. The primary efficacy analysis result was examined using a series of sensitivity analyses. Key secondary endpoints were change from baseline to Month 30 in the six-minute walk test distance and the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall score. Safety assessments included adverse events, vital signs, and clinical laboratory tests. Results A total of 441 patients were randomized (tafamidis=264, placebo=177). Tafamidis was associated with a significant reduction in the hierarchical combination of all-cause mortality and CVrelated hospitalizations (P Conclusions ATTR-ACT, the largest randomized controlled trial in ATTR-CM, showed that tafamidis is the first treatment to improve survival and quality of life in ATTR-CM. Significant and clinically meaningful improvements were observed in functional capacity as measured by the six-minute walk distance and quality of life by KCCQ overall score. Sensitivity analyses confirmed the robustness of these results. Tafamidis was safe and well tolerated. The primary trial results, along with the sensitivity analyses described here, provide strong rationale for the use of tafamidis as first-line therapy in ATTR-CM.

Background Transthyretin amyloid cardiomyopathy (ATTR-CM), is an underdiagnosed, fatal disease caused by the deposition of transthyretin amyloid fibrils in the heart leading to heart failure. The Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), an international, multi-center, double-blind, placebo-controlled, randomized study, demonstrated the efficacy and safety of tafamidis treatment for patients with ATTR-CM due to variant (ATTRm) or wild-type (ATTRwt) TTR. Purpose This is a pooled analysis of data from ATTR-ACT and interim data from the ongoing, long-term, extension study to evaluate longer term data on the efficacy of tafamidis in patients with ATTR-CM. Methods Patients who completed ATTR-ACT (which had a duration of 30 months) were eligible to be enrolled in a long-term, extension study in which patients either continued to receive tafamidis meglumine at the same dose (the tafamidis/tafamidis [T/T] group) or, for patients previously treated with placebo, were randomised (in a 1:2 ratio) to tafamidis meglumine 20 mg or 80 mg (the placebo/tafamidis [P/T] group) for up to 60 months. The primary efficacy outcome was all-cause mortality. This analysis combined data from the completed ATTR-ACT with interim data from the extension study (cut-off date: 15 Feb, 2018), and included patients treated with tafamidis meglumine across the two studies with a median follow up of 36 months. Results All-cause mortality was significantly lower in the T/T group (n=264; 88 events, 33.3%) compared with the P/T group (n=177; 88 events, 50.3%); hazard ratio (95% CI), 0.64 (0.47, 0.85); P=0.001. In the subgroup of ATTRwt patients, all-cause mortality was significantly reduced in the T/T group (55/201; 27.4%) compared with the P/T group (60/134; 44.8%); 0.64 (0.44, 0.92); P=0.002. In the 106 (24.0%) ATTRm patients, there was a trend towards a reduction in all-cause mortality in the T/T group (33/63; 52.4%) compared with the P/T group (29/43; 67.4%); 0.66 (0.39, 1.09); P=0.17. In patients who were NYHA Class I or II at baseline, all-cause mortality was significantly reduced in the T/T group (38/186; 20.4%) compared with the P/T group (45/114; 39.5%); 0.49 (0.32, 0.75); P=0.001. In those patients with more severe symptoms at baseline (NYHA Class III), there were fewer deaths in the T/T group (50/78; 64.1%) compared with the P/T group (44/63; 69.8%); 0.80 (0.53, 1.21), but this difference was not statistically significant (P=0.50). Conclusions In ATTR-ACT, tafamidis was shown to significantly improve survival, functional capacity, and quality of life in patients with ATTR-CM. This pooled analysis with data from the ongoing extension study further supports the efficacy of tafamidis in patients over a longer period of time and the importance of early diagnosis and treatment. Acknowledgement/Funding This study was sponsored by Pfizer.