Rosenthal, Adam

Background: Isatuximab is an IgG1κ monoclonal antibody that binds with high affinity to CD38 expressed on plasma cells in light chain (AL) amyloidosis. Anti-CD38 antibodies have shown efficacy alone and in combination in a variety of settings for patients with multiple myeloma and light chain (AL) amyloidosis. Here we report the final analysis of a multi-center, cooperative group prospective phase II study of isatuximab in previously treated patients with AL amyloidosis (NCT03499808). Methods: Eligibility included: age ≥18 years, relapsed or refractory systemic AL amyloidosis, ≥1 prior line of therapy, measurable disease, ≥1 organ involved, not refractory to daratumumab, Eastern Cooperative Oncology Group performance status ≤2, creatinine clearance ≥25 mL/min, and NT-proBNP ≤8500 pg/mL. Patients received isatuximab intravenously 20 mg/kg weekly during the first 28-day cycle and every other week during cycles 2 through 24 for a maximum of 24 cycles. The primary objective was hematologic response with secondary objectives of organ response, safety, progression free survival, and overall survival. Results: Forty-three patients were registered, with 35 patients being eligible for response. The median age of the evaluable patients was 70 years (range, 40.1-79.5) with the majority (66%, n=23) having a lambda clonal plasma cell dyscrasia. The most common cytogenetic abnormality using fluorescence in situ hybridization was translocation t(11;14) observed in ten patients (29%). The most common prior treatment was a proteasome inhibitor (94%, n=33) while 46% (n=16) had undergone autologous stem cell transplant. Eighteen patients (51%) had single organ involvement while 17 (49%) had multiple organs involved. The distribution of organ involvement was typical for AL amyloidosis with cardiac involvement in 25 patients (71%) and renal involvement in 14 (40%). As of December 30, 2022, no new safety concerns were identified. The most common treatment related grade ≥3 adverse events included lymphopenia (n=3, 8.5%) and infection (n=2, 6%). The overall hematologic response rate was 77.1% with a rapid median time to partial response or better of 1.1 months. Two patients (6%) achieved a hematological complete response (CR), 18 (51%) had a very good partial response (VGPR), and 7 (20%) had a partial response (PR). At 24 months from hematologic response, the rate of patients still in response was estimated at 81% (95% confidence interval (CI): 67, 96). The 24-month estimated overall survival was 85% (95% CI: 73%, 97%). Renal response occurred in 50% (7/14) of patients with renal involvement with a median time to response of 18.5 months. Cardiac response occurred in 56% (14/25) of patients with cardiac involvement with a median time to response of 16.6 months. Conclusions: Isatuximab monotherapy resulted in high rates of hematologic response in relapsed AL amyloidosis which translated into organ responses. Treatment appears safe and was well tolerated. Support: NIH/NCI/NCTN grant awards U10CA180888, U10CA180819, CA180820, and CA180821; and in part by Sanofi-Aventis (Sanofi US)

Multiple myeloma (MM) is an incurable cancer of plasma cells with nearly 70% of all new diagnoses occurring in adults aged ≥ 65 years. For older adults, medical comorbidities and functional deficits become increasingly more prevalent with increased age and can impact disease outcomes and survival. There are unmet medical needs in this vulnerable patient population who are not eligible for autologous stem cell transplantation to optimize the frontline therapy for better survival and less toxicity. This randomized phase 3 clinical trial is designed to focus on real world patient population to identify an optimal frontline three drug regimen in frail or a subset of intermediate fit newly diagnosed MM patients. Diagnostic criteria and response criteria will be based on IMWG guidelines. Participants must have a calculated myeloma frailty index (Myeloma Frailty Score Calculator (http://www.myelomafrailtyscorecalculator.net/) categorized as frail or intermediate fit (regardless of age) within 28 days prior to registration (NCT05561387). The two most commonly used induction/maintenance regimens in this patient population will be compared, including RVd-Lite (lenalidomide (R), bortezomib (V), and dexamethasone (dex) followed by R maintenance) and DRd (Daratumumab, lenalidomide, and dex followed by R or R-daratumumab maintenance). The study will include three cohorts: (1) RVd-Lite induction followed by Rev maintenance (2) DRd induction followed by Rev maintenance (3) DRd induction followed by D-R maintenance. Induction phases will be 9 cycles in total of 28 days each, followed by maintenance for cycle 10 and beyond in all cohorts until disease progression: V 1.3 mg/m2 on days 1, 8, 15, 22, R 15 mg days 1-21, dex 20 mg days 1, 8, 15, 22 for induction phase and R 10 mg days 1-21 for maintenance phase in cohort 1 (VRd-Lite); SubQ Dara 1800 mg (on days 1, 8, 15, 22 for C1-2, on days 1, 15 for C3-6, on day 1 for C7-9), R 15 mg day 1-21, dex 20 mg days 1, 8, 15, 22 for induction phase and R 10 mg days 1-21 for maintenance in cohort 2 (DRd-R); SubQ Dara 1800 mg (on days 1, 8, 15, 22 for C1-2, on days 1, 15 for C3-6, on day 1 for C7-9), R 15 mg day 1-21, dex 20 mg days 1, 8, 15, 22 for induction phase and Dara 1800mg on day 1 and R 10mg days 1-21 for maintenance in cohort 3 (DRd-DR). The dual primary objectives are (A) to compare progression free survival (PFS) between cohorts 1 (VRd-Lite) and 2 (DRd-R); (B) to compare overall survival (OS) between cohorts 1 (VRd-Lite) and 3 (DRd-DR). Quality of life objectives are to compare patient reported global health status between treatment arms at the end of induction therapy using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire. A total of 459 eligible patients will be enrolled in this randomized three cohort trial. It is hypothesized that Cohort 1 will have a median PFS of 2.667 years and a median OS of 5 years. With 153 eligible participants per cohort accrued over 5 years, and an additional follow-up period of 3 years, this trial has 80% power to detect an increase in the median PFS in Cohort 2 from 2.667 years to 4 years, and 83.4% power to detect an increase in the median OS in Cohort 3 from 5 years to 8.5 years, each with a one-sided type I error rate of 2%. This trial will be conducted among the NCI cooperative groups SWOG, ALLIANCE, and ECOG/ACRIN and incorporate substantial involvement from NCORP and VA member sites. This study is anticipated to provide practice changing data for this transplant-ineligible real world population to achieve deeper and longer remissions with less side effects and better quality of life.

Background: Isatuximab (SAR650984) is an IgG1k monoclonal antibody that binds with high affinity to CD38 expressed on plasma cells in AL amyloidosis. It has been shown to be efficacious and well tolerated in relapsed and refractory multiple myeloma as a single agent and in combination. Here we report on the preliminary results of a prospective multi-center, phase II study of isatuximab in previously treated patients with AL amyloidosis (NCT03499808). Methods: Eligibility included age ≥ 18 years, relapsed or refractory systemic AL amyloidosis, ≥ 1 prior line of therapy, measurable disease (defined as a positive monoclonal serum immunofixation electrophoresis (IFE) or urine IFE, a serum free light chain ratio outside of the normal range (0.25-1.65), and a difference in the involved versus the uninvolved serum free light chain of ≥ 4.5 mg/dL), at least one organ involved, not refractory to daratumumab, ECOG performance status 0-2, creatinine clearance ≥25 mL/min as measured by 24-hour urine collection or as estimated by Cockcroft and Gault formula, and NT-proBNP ≤8500 pg/mL. Patients received isatuximab intravenously 20 mg/kg weekly during the first 28 day cycle and every other week during cycles 2 through 24 for a maximum of 24 cycles. The primary objective was hematologic response with secondary objectives of organ response, safety, progression free survival, and overall survival. Results: At data cut-off (July 24, 2020), 43 patients were registered from March 2018 to September 2019 at 14 institutions. Thirty six patients were eligible with 35 patients receiving at least one dose of isatuximab. Of the eligible patients, the median age was 70 (range 40-81). Prior therapies included proteasome inhibitors in 32 patients (89%), high dose therapy followed by autologous stem cell transplant in 17 patients (47%), immunomodulatory therapy in 9 patients (25%), and anti-CD38 monoclonal antibody therapy in 2 patients (6%). Single organ system involvement was seen in 19 patients (53%), ≥ 2 organ systems in 17 patients (47%), 16 patients (44%) had renal involvement, and 24 (67%) had cardiac involvement. For those with cardiac involvement, 7 patients (29%) had cardiac biomarker stage II and 9 patients (38%) had stage III disease using the Revised Mayo Staging (Kumar S et al., J Clin Oncol, 2012). A total of 17 patients remain on therapy. The median duration on treatment for eligible patients is currently 11.8 months (current range, 0.3-22.1). Of the 19 patients who discontinued treatment, the most common reasons included adverse events in 5 patients (26%), disease progression in 4 patients (21%), sub-optimal response in 2 patients (11%), and concerns related to COVID-19 in 2 patients (11%). The current median follow up is 16.3 months. The most common drug-related AEs were infusion related reactions in 18 patients (50%) with the majority (16/18) being grade I or II, anemia in 9 patients (25%) with the majority (8/9) being grade I, and lymphopenia in 8 patients (22%). Patient characteristics and preliminary safety data were previously presented at the International Symposium on Amyloidosis. The overall hematologic response rate was 77%. Hematological complete response (CR) was observed in 1 of 35 evaluable (completing at least 1 dose) patients (3%), very-good-partial response (VGPR) in 19 patients (54%), and partial response (PR) in 7 patients (20%). Conclusions: Isatuximab demonstrates encouraging efficacy in previously treated patients with AL amyloidosis. The administration of isatuximab in these patients is associated with a good safety profile similar to other monoclonal antibodies against CD38. The data will be updated at the meeting. Disclosures Sanchorawala: Prothena: Research Funding; Caelum: Research Funding; Oncopeptide: Research Funding; Janssen: Research Funding; Regeneron: Other: advisory board; Caleum: Other: advisory board; Proclara: Other: advisory board; Abbvie: Other: advisory board; UpToDate: Patents & Royalties; Takeda: Research Funding; Celgene: Research Funding. Kapoor:Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Janssen: Research Funding; Amgen: Research Funding; GlaxoSmithKline: Research Funding; Takeda: Honoraria, Research Funding. Neparidze:GlaxoSmithKline: Research Funding; Janssen: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Diagnostic committee member . Sarosiek:Spectrum: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Usmani:Incyte: Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Array Biopharma: Research Funding; Pharmacyclics: Research Funding; Celgene: Other; Seattle Genetics: Consultancy, Research Funding; GSK: Consultancy, Research Funding; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Abbvie: Consultancy. Orlowski:Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; STATinMED Research: Consultancy; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Isatuximab is FDA approved for relapsed refractory myeloma in combination with pomalidomide and dexamethasone. Isatuximab is not FDA approved for AL amyloidosis.

Abstract Introduction The spectrum and frequency of mutations in newly diagnosed and relapsed MM has been reported and exhibits a pattern which is distinct from other peripheral lymphoid disorders. A number of data sources have suggested that MM is not a single disease, but rather a collection of molecularly diverse entities which present as malignancies of plasma cells with different clinical courses and response to therapy. To test this hypothesis we examined the spectrum of common mutations and their associations with gene expression in etiological subgroups defined by a simplified TC classification based on translocation subgroup and the deregulation of a D group cyclin. Materials and methods We examined a set of gene expression data from 907 newly diagnosed MM patients and classified them according to an updated TC model. An additional set of 482 cases underwent both sequencing by the FoundationOne Heme targeted panel and gene expression profiling. Mutational data were analyzed for significant associations with gene expression data within five primary TC subgroups: D1, D2, CCND (translocated 11q13 or 6p21), MMSET, and MAF. Results Gene expression signatures of GEP70 risk status, chromosomal aberrations [1q+, 1p-, 13q-, 17p-, HRD], proliferation index, NF-kB activation, and BCL2/MCL1 ratio were not distributed evenly across the TC subgroups, consistent with distinct biological differences amongst groups. Having noted differential expression patterns between subgroups, we hypothesized that distinct patterns of mutation may also exist across TC subgroups. Mutations in RB1 and CDKN2C, seen primarily in the D2 and MMSET subgroups, were mutually exclusive yet both associated with increased proliferation and HR status. Thus two paths to extreme proliferation emerge through either ahomozygous deletion of CDKN2C (with low expression of CDKN2C) or an RB1 alteration (with high expression of CDKN2C). Mutations in KRAS, NRAS, and BRAF were not evenly distributed across subgroups and were significantly inversely associated with an NF-kB signature. RRAS2 was also significantly inversely associated with MAPK mutations in the D1 and D2 subgroups, while genes encoding sprouty-related proteins, SPRED1 and SPRED2, were positively associated with MAPK mutations in the CCND-11q13 subgroup. Overall, MAPK mutations were most significantly associated with elevated expression of DKK1, a known Wnt antagonist, and DUSP6, a known inhibitor of the pathway. These gene expression patterns were primarily localized in the D1, D2, and CCND-11q13 subgroups. In contrast, the MMSET and MAF subgroups had a unique patterns of expression not seen in the D1, D2, or CCND subgroups. A gene set enrichment analysis showed that the DNA replication and cell cycle pathways were significantly enriched in the MMSET and MAF subgroups in the presence of MAPK pathway mutations. Within the MMSET subgroup, MAPK mutations were positively associated with GEP70 HR, proliferation index, and membership of the UAMS-PR subtype, while being negatively associated with FGFR3 expression. This result indicates that the reliance on FGFR3 signaling as an oncogenic driver is lost in the presence of a MAPK activating mutation. Conclusions In MM proliferative signals are delivered via the RAS and NF-kB pathways and activation of these two pathways appears to offer mutually exclusive pathways to disease progression since the majority of cases exhibit a reciprocal relationship between these two signaling pathways. The MMSET and MAF subgroups lack a strong association between NF-kB and MAPK signaling pathways, which may indicate that their initiating translocation event and subsequent genetic patterns provide a unique background in which MAPK alterations accelerate progression. As mutational interactions are differential across TC subgroups, we propose a comprehensive approach to MM classification that includes the etiologic designation by simplified TC subgroups and the subsequent use of genetic and biological markers characteristic of acquired features associated with disease progression, such as MAPK or NF-kB activation. Distinct patterns of RNA expression are associated with DNA mutations in myeloma when contextualized by etiologic subgroups. This indicates that the cellular background in which a mutation occurs has a distinct impact on downstream expression patterns-this observation is particularly relevant to the MMSET and MAF subgroups. Disclosures Pawlyn: Celgene: Consultancy, Honoraria, Other: Travel Support; Takeda Oncology: Consultancy. Morgan:Univ of AR for Medical Sciences: Employment; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol Meyers: Consultancy, Honoraria; Janssen: Research Funding.

Key Points Using the largest set of patients with newly diagnosed myeloma, we identified 63 mutated driver genes. We identified oncogenic dependencies, particularly relating to primary translocations, indicating a nonrandom accumulation of genetic hits.

341 Background: Genomes of metastatic pancreatic cancers frequently contain intrachromosomal aberrations indicating DNA repair abnormalities associated with sensitivity to DNA damaging agents such as the platinums. Cisplatin was added to a nab-paclitaxel + gemcitabine regimen, which has been determined to improve survival over gemcitabine alone (NEJM 2013; 369:1691-1703). The objectives are to determine the efficacy and safety of nab-paclitaxel and gemcitabine plus cisplatin in patients with Stage IV pancreatic cancer. Methods: Eligibility criteria included Stage IV adenocarcinoma of the pancreas, no prior chemotherapy for systemic disease, KPS ≥ 70; life expectancy ≥ 12 weeks and measurable disease. Doses are nab-paclitaxel 125 mg/m2 undiluted, gemcitabine 1000 mg/m2 in 500 ml of normal saline (NS), each infused over 30 minutes on days 1 and 8 of a 21 day cycle, along with 3 different dose levels of cisplatin (25, 37.5 or 50 mg/m2) in 500 ml of NS infused over 60 minutes, after the nab-paclitaxel infusion. Pre and post cisplatin hydration was given. The maximum tolerated dose and phase II dose of cisplatin is 25 mg/m2. Results: 25 pts were treated; 24 were evaluable (baseline and ≥ 1 follow up CT scan). The most common drug related grade (gr) 3 - 4 adverse events (AEs), n = 25, were thrombocytopenia 76% (gr 3 = 36%, gr 4 = 40%) with no serious bleeding events, anemia 32% (gr 3 = 32%, gr 4 = 0%), neutropenia 24% (gr 3 = 20%, gr 4 = 4%), infection 20% (gr 3 = 16%, gr 4 = 4%), and diarrhea 16% (gr 3 = 16%, gr 4 = 0%). Peripheral neuropathy ≥ gr 3 was seen in only 1 pt (gr 3 = 4%). Grade 5 AEs were infection (1), cardiac arrest (1), and stroke (1). Median time on therapy was 5.5 months, range (1 – 9.5). By RECIST 1.1 criteria, 2 pts had complete response (8.3%), 15 partial response (62.5%), 4 stable disease (16.7%), and 3 progressive disease (12.5%). Median overall survival to date as of 11/10/16 is 16.5 months. Conclusions: Although a small study, the high response rate and landmark evolving median survival are very encouraging. This regimen is being expanded in patients with stage IV pancreatic cancer, neoadjuvant and adjuvant settings. Clinical trial information: NCT01893801.

Abstract Background: The genomes of metastatic pancreatic cancers contain a myriad of intrachromosomal aberrations indicating a likely high prevalence of DNA repair deficiencies indicating sensitivity to DNA damaging agents such as the platinum’s. Because of this, the drug cisplatin was added to an albumin-bound paclitaxel + gemcitabine regimen, which has already been determined to improve survival over gemcitabine alone in a randomized phase III trial (NEJM 2013; 369:1691-1703). Objectives: To determine the efficacy and safety of albumin-bound paclitaxel and gemcitabine plus cisplatin for patients with advanced pancreatic cancer Methods: Eligibility criteria included Stage IV pancreatic cancer, no prior chemotherapy for systemic disease, KPS ≥ 70; life expectancy ≥ 12 weeks and measurable disease. The doses were albumin-bound paclitaxel 125 mg/m2 undiluted, gemcitabine 1000 mg/m2 in 500 ml of normal saline (NS), each infused over 30 minutes on days 1 and 8 of a 21 day cycle, along with 3 different dose levels of cisplatin (25, 37.5 or 50 mg/m2) in 500 ml of NS infused over 60 minutes, after the nab-paclitaxel infusion. Pre and post cisplatin hydration was given. Results: To date, 10 patients have been entered on study with all patients being evaluable, (baseline and at least one follow up CT scans completed). There have been 2 complete responses (20%), 6 partial responses (PR), (60%), 1 stable disease (10%), and 1 patient with progressive disease (10%), by RECIST 1.1 criteria. An exponential decrease in CA19-9 correlating with the t1/2 of the marker was noted. Response was seen rapidly with PR observed at the first staging evaluation at 9 weeks in 7 of 10 patients. The 8th patient achieved a PR at 18 weeks. Serious adverse events occurred in 4 patients: non-neutropenic sepsis/pneumonia (n = 1), and non-neutropenic bacteremia (n = 1) in the cisplatin 25 mg/m2 cohort; clostridium difficile colitis (n = 1) with cisplatin 37.5 mg/m2; and neutropenic fever/pneumonia (n = 1) with cisplatin 50mg/m2. Discussion: The study has completed phase Ib and will be expanded at the phase II dose of cisplatin 25 mg/m2 for a total of 25 patients. If this favorable response rate is confirmed, this 3 drug regimen could be further developed both for patients with advanced disease as well as in neoadjuvant and adjuvant settings. Supported by grants from the Seena Magowitz Foundation and the SU2C Dream Team Citation Format: Gayle S. Jameson, Erkut Borazanci, Elizabeth Poplin, Michael T. Barrett, John Crowley, Adam Rosenthal, Amy Stoll-D'Astice, Karen L. Ansaldo, Steven Boone, Leticia Lebron, Ramesh K. Ramanathan, Ronald L. Korn, Daniel D. Von Hoff. High complete and partial response rate in a phase Ib pilot trial with cisplatin plus albumin-bound paclitaxel and gemcitabine in patients with advanced pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-003. doi:10.1158/1538-7445.AM2015-LB-003