Citations

Abstract Background and Significance: Waldenström's Macroglobulinemia (WM) is an indolent B cell disorder characterized by proliferation of clonal lymphoplasmacytic lymphocytes in the bone marrow, lymph nodes, as well as liver and spleen, and secreting a monoclonal IgM Protein. WM is a rare disorder with about 1,700 cases diagnosed in the U.S. each year. There have been significant advances in the management of patients with WM in the last decade, with Bruton's tyrosine kinase (BTK) inhibitors (ibrutinib and zanubrutinib) emerging as a major treatment advancement in this disease. Currently, both BTK inhibitors are approved for the treatment of WM patients with newly diagnosed as well as relapsed/refractory (R/R) disease. BTK inhibitors are effective for the therapy of WM, especially among patients with MYD88 mutation, although the response rates are lower in patients with CXCR4 mutations. In addition, these drugs can cause cardiac side effects such as atrial and ventricular arrhythmias as well as an increased risk of bleeding/bruising. Thus, these drugs can be difficult to use in patients who are older and have cardiac comorbidities. BCL-2 overexpression is well described in a number of B cell malignancies, including WM, leading to inhibition of apoptosis of malignant cells. BCL-2 inhibition with venetoclax has been tested in patients with R/R WM and showed excellent activity with an overall response rate (ORR) of 85% and very good partial response (VGPR) rate of 19%. The therapy was overall well tolerated with no evidence of cardiac toxicity. Given the excellent activity and tolerability of Venetoclax in WM, we are conducting a national cooperative group randomized phase 2 trial comparing ibrutinib+rituximab (IR) vs. venetoclax+rituximab (VR) in patients with newly diagnosed WM. Our hypothesis is that with this trial, we have the potential to develop a more effective therapy targeting BCL-2 for patients with untreated WM, that does not have cardiac or hemostatic toxicity. In addition, we are testing use of a fixed duration therapy with these regimens. Study design and methods: The ongoing clinical trial () is being conducted through the Southwest Oncology Group (SWOG) and is enrolling at multiple SWOG, ECOG, and ALLIANCE centers throughout the US. Major inclusion criteria include 1) newly diagnosed WM confirmed by biopsy and measurable disease (≥0.5 g/dl IgM type paraprotein), 2) meeting WM-related clinical criteria to initiate therapy (cytopenias, B symptoms, bulky lymphadenopathy, neuropathy, hyperviscosity) 3) adequate blood counts (ANC >1000, HGB ≥7.5, PLT ≥50,000), 4) eGFR ≥30 ml/min, 5) adequate liver function tests (total bilirubin ≤1.5 x ULN and AST, ALT and alkaline phosphatase ≤3 x ULN), 6) Zubrod performance status ≤2, 7)prior treatment with single-agent R allowed as long as >6 months prior to registration. Once enrolled the patients will be randomized 1:1 to IR vs. VR. I will be started at 420 mg daily at start of therapy while V will be given at 400mg daily during cycle 1 week 1 and then increased to 800 mg daily from cycle 1 day 8 onwards. R will be given weekly x 4 in cycles 2 and 5. Dose adjustments for both I and V can be done depending on toxicity. Therapy will be given for 2 years and then the patients will be observed off treatment. Patients with disease progression during these 2 years of therapy can cross-over to the other arm. The primary endpoint of the study is rate of VGPR or better. With 41 eligible participants per arm (total N=82), this design has 80% power to reject the null hypothesis of a 25% VGPR rate, given the alternative of a 50% VGPR rate, with a one-sided alpha of 10%. To account for an anticipated 10% ineligibility rate, approximately 46 participants will be accrued per arm (92 total). Current enrollment stands at 15 patients. The secondary end points include ORR, complete response rate, major response rate, progression free and overall survival rates.

Abstract Isatuximab is an immunoglobulin G1κ monoclonal antibody that binds with high affinity to CD38 expressed on plasma cells. Anti-CD38 antibodies have shown efficacy as monotherapy and in combination in a variety of settings for patients with multiple myeloma and light chain (AL) amyloidosis. This multicenter, cooperative group phase 2 trial was designed to evaluate hematologic response, organ response, and safety of isatuximab monotherapy for the treatment of relapsed AL amyloidosis. Isatuximab at 20 mg/kg was administered IV weekly during the first 28-day cycle, and then every other week during cycles 2 to 24. Forty-three patients were registered, with 35 patients being evaluable for response. The overall hematologic response rate was 77.1%, with 57% of patients achieving a very good partial response (VGPR) or better. The median time to partial response (PR) or better was 1.1 months. Renal response occurred in 50% (7/14) of patients with renal involvement, and cardiac response occurred in 57% (8/14) of patients who were evaluable utilizing N-terminal pro b-type natriuretic peptide (NT-proBNP) with cardiac involvement. The most common treatment-related grade ≥3 adverse events included lymphopenia (n = 3, 8.5%) and infection (n = 2, 6%). Isatuximab demonstrated substantial efficacy in previously treated patients with AL amyloidosis, and was associated with a good safety profile. This trial was registered at www.clinicaltrials.gov as #NCT03499808.

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)

Background and significance: Light chain (AL) amyloidosis is a plasma cell malignancy characterized by the production of amyloidgenic clonal light chains that deposit in various tissues. The addition of daratumumab to bortezomib, cyclophosphamide and dexamethasone (Dara-VCD) has improved the depth of hematologic and organ responses and is an approved induction therapy in newly diagnosed AL amyloid patients (DOI: 10.1056/NEJMoa2028631). However, this approach has not yet demonstrated an overall survival (OS) benefit and follow up remains short. With strict adherence to eligibility criteria, in particular severity of cardiac involvement, autologous stem cell transplantation (ASCT) as consolidative therapy is safe with transplant related mortality on par with multiple myeloma. This approach generates deep and sustained responses, but it is unclear if it offers an additional survival benefit following Dara-VCD induction. The only randomized trial evaluating the role of ASCT in AL amyloid is outdated (DOI: 10.1056/NEJMoa070484) and no randomized data exist to inform the optimal use of ASCT in the era of Dara-VCD induction. Furthermore, multi-organ involvement in AL amyloid drives morbidity and mortality thus the impact of any consolidative therapy on cardiac and renal involvement in addition to overall survival but must be defined. Finally, the approval of Dara-VCD therapy was based on complete hematologic response rates but there is increasing data demonstrating that achieving minimal residual disease (MRD) negativity by either bone marrow next generation flow cytometry (DOI: 10.1002/ajh.26562) or peripheral blood mass spectrometry (DOI: 10.1038/s41408-020-0291-8) generates improved organ response, hematologic progression free survival, and possibly OS. Methods: This randomized phase 3 SWOG led intergroup trial (S2213; NCT06022939) is being conducted within the United States and will accrue a total of 143 participants per arm. The primary endpoint will compare MOD-PFS (major organ deterioration progression free survival: defined as time from randomization to death, cardiac/renal progression, or hematologic progression) between participants receiving an ASCT with those receiving 3 cycles of Dara-VCD consolidation following 3 cycles of uniform Dara-VCD induction. Following the assigned consolidation, all patients will receive 18 months of daratumumab maintenance therapy. A median MOD-PFS of 31 months is anticipated in the non-ASCT arm. This study has 90% power and a two-sided significance level of 0.05 to detect a hazard ratio of 0.62 corresponding to a MOD-PFS of 50 months in the ASCT arm. Important additional endpoints include OS, hematologic PFS, cardiac and renal responses, MRD negativity both by peripheral blood mass spectrometry and bone marrow next generation flow cytometry, delayed utilization of ASCT, and quality of life. Key inclusion criteria include non-severe cardiac AL amyloid (NT-proBNP <5000; TnT < 0.06; NYHA I or II, EF ≥ 40%), CrCl ≥30 mL/min, serum dFLC > 2 mg/dL, and supine systolic BP ≥ 90 mmHg. Importantly, patients are permitted to have up to one full cycle or 28 days of any plasma cell directed therapy prior to enrollment. This trial was activated on 12/1/2023 with the first patient enrolled 07/01/2024. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819; and in part by Janssen Pharmaceuticals Inc. of Johnson & Johnson (now J&J Innovative Medicine).

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.

TPS7575 Background: Light chain (AL) amyloidosis is a plasma cell malignancy characterized by the production of amyloidgenic clonal light chains that deposit in various tissues. The addition of daratumumab to bortezomib, cyclophosphamide and dexamethasone (Dara-VCD) has improved depth of hematologic and organ responses. However, this approach has not yet demonstrated an overall survival (OS) benefit with short follow-up. Autologous stem cell transplant (ASCT) consolidation remains safe and is associated with deep and durable hematologic responses with an 83% 2-year progression free survival (PFS) and up to 72% of patients achieving a VGPR or better, comparable to Dara-VCD (79%). In multiple myeloma, ASCT improved PFS even in patients who are MRD negative at the end of standard induction therapy. It is thus reasonable to consider that ASCT might provide similar benefits in AL patients. No randomized data exist to inform the optimal use of ASCT in the era of Dara-VCD. Methods: This randomized phase 3 SWOG led intergroup trial will accrue a total of 143 participants per arm and compare MOD-PFS (major organ deterioration progression free survival: defined as time from randomization to death, cardiac/renal progression, or hematologic progression) between participants receiving an ASCT with those receiving Dara-VCD consolidation following uniform Dara-VCD induction. A median MOD-PFS of 31 months is anticipated in the non-ASCT arm. This study has 90% power and a two-sided significance level of 0.05 to detect a hazard ratio of 0.62 corresponding to a MOD-PFS of 50 months in the ASCT arm. Important additional endpoints include OS, hematological PFS, cardiac and renal responses and progression, MRD negativity both by peripheral blood mass spectrometry and bone marrow next generation flow cytometry, delayed utilization of ASCT, and quality of life. This trial was activated on 12/1/2023. Funding: NIH/NCI/NCTN grants and in part by Janssen Pharmaceuticals. Clinical trial information: NCT06022939 . [Table: see text]

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 Background The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. Methods We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. Results Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P = .002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32–36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44–46% for BC, for carriers with two first-degree relatives diagnosed with BC. Conclusions These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.

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.