Fonseca, Rafaël

AbstractPatients with multiple myeloma (MM) have a lower efficacy from COVID‐19 vaccination and a high rate of mortality from COVID‐19 in hospitalized patients. However, the overall rate and severity of COVID‐19 infection in all settings (including non‐hospitalized patients) and the independent impact of plasma cell‐directed therapies on outcomes needs further study. We reviewed the medical records of 9225 patients with MM or AL amyloidosis (AL) seen at Mayo Clinic Rochester, Arizona, and Florida between 12/01/2019 and 8/31/2021 and identified 187 patients with a COVID‐19 infection (n = 174 MM, n = 13 AL). The infection rate in our cohort was relatively low at 2% but one‐fourth of the COVID‐19 infections were severe. Nineteen (10%) patients required intensive care unit (ICU) admission and 5 (3%) patients required mechanical ventilation. The mortality rate among hospitalized patients with COVID‐19 was 22% (16/72 patients). Among patients that were fully vaccinated at the time of infection (n = 12), two (17%) developed severe COVID‐19 infection, without any COVID‐related death. On multivariable analysis, treatment with CD38 antibody within 6 months of COVID‐19 infection [Risk ratio (RR) 3.6 (95% CI: 1.2, 10.5), p = .02], cardiac [RR 4.1 (95% CI: 1.3, 12.4), p = .014] or pulmonary comorbidities [RR 3.6 (95% CI 1.1, 11.6); p = .029] were independent predictors for ICU admission. Cardiac comorbidity [RR 2.6 (95% CI: 1.1, 6.5), p = .038] was an independent predictor of mortality whereas MM/AL in remission was associated with lower mortality [RR 0.4 (95% CI: 0.2–0.8); p = .008].

PURPOSE: Financial hardship (FH) in cancer care is a growing challenge for patients, their caregivers, and health care providers with impact on morbidity and mortality. In this study, we report on a standardized approach to describe the prevalence and predictors for FH as part of routine clinical workflow. We also report on the association of FH with survival in our cancer patient population. METHODS: This study includes patients who completed a FH screen at least once between 2018 and 2020. Demographics, disease state, and mortality data were extracted from the medical records. Multivariable logistic regression models were used to examine association of sociodemographic and disease variables with FH. By using propensity score weighting to account for differences in demographic and clinical factors between patients with and without FH, we then fit Cox proportional hazards models to examine the relationship between FH and survival. RESULTS: The study cohort included 31,154 patients. FH was reported by 14% (n = 4,250) of the patients. A significantly higher likelihood of having FH ( P < .001 for all) was reported by racial/ethnic minority patients; those who were unemployed/disabled, single, or divorced; patients from disadvantaged neighborhoods; and those who were self-pay or had government insurance. Older age, being retired, and living farther from the cancer center were associated with significantly less likelihood of endorsing FH. Patients who endorsed FH had a lower survival (hazard ratio for mortality 1.46). CONCLUSION: Our study identified key groups more likely to report FH in a relatively affluent population at a large cancer center and showed an adverse association between FH and survival. Further research is needed to develop clinical care pathways for patients at high risk for worse financial and clinical outcomes.

Abstract Minimal residual disease (MRD) assays allow response assessment in patients with multiple myeloma (MM), and negativity is associated with improved survival outcomes. The role of highly sensitive next generation sequencing (NGS) MRD in combination with functional imaging remains to be validated. We performed a retrospective analysis on MM patients who underwent frontline autologous stem cell transplant (ASCT). Patients were evaluated at day 100 post-ASCT with NGS MRD and positron emission tomography (PET-CT). Patients with ≥ 2 MRD measurements were included in a secondary analysis for sequential measurements. 186 patients were included in the analysis. At day 100, 45 (24.2%) patients achieved MRD negativity at a sensitivity threshold of 10− 6. MRD negativity was the most predictive factor for longer time to next treatment (TTNT). Negativity rates did not differ according to MM subtype, R-ISS Stage nor cytogenetic risk. PET-CT and MRD positivity had poor agreement. Patients with sustained MRD negativity had longer TTNT, regardless of baseline risk characteristics. Our results show that the “real world” ability to measure deeper and sustainable responses distinguishes a subpopulation of patients with better outcomes. Achieving MRD negativity was the strongest prognostic marker and could help guide therapy-related decisions and serve as a response marker for clinical trials.

Two Letters to Blood address the risks of COVID-19 in populations with precursors of hematological disease. In the first article, Miller and colleagues report on whether clonal hematopoiesis of intermediate potential (CHIP) is associated with adverse outcomes with COVID-19, finding no association between CHIP and 28-day mortality while providing data indirectly linking IL-6 signaling and patient outcomes. In the second article, Ho and colleagues investigate the outcomes of patients with monoclonal gammopathy of undetermined significance (MGUS) with COVID-19, reporting that one-fourth had a severe infection and that on multivariable analysis, adverse outcomes are more likely if immunoparesis is present.

TPS8068 Background: Elranatamab (PF-06863135) is a humanized bispecific antibody that targets both B cell maturation antigen (BCMA) on multiple myeloma (MM) cells and CD3 on T cells resulting in T cell- mediated cytotoxicity. In preclinical studies, elranatamab has demonstrated anti-myeloma activity and delayed disease progression. In the ongoing phase 1 MagnetisMM-1 study, elranatamab has demonstrated clinical efficacy and a manageable safety profile in patients with relapsed/refractory MM (Bahlis et al, J Clin Oncol 2021). Elranatamab maximum tolerated dose has not yet been reached. Subcutaneous (SC) elranatamab at the recommended dose of 76 mg QW on a 28-d cycle with a 2 step-up priming dose regimen administered during the first week is currently being evaluated in a phase 2 study, MagnetisMM-3 (Lesokhin et al, Blood, 2021). Methods: MagnetisMM-9 (start date: Oct 2021; estimated completion date: Apr 2025) is an open-label, multicenter, non-randomized phase 1/2 study evaluating an alternative priming regimen to further mitigate cytokine release syndrome (CRS) incidence and severity and to evaluate SC elranatamab Q2W and Q4W dosing regimens in patients with relapsed/refractory MM. In part 1 of the study, patients will receive premedications and 2 step-up priming doses on cycle 1 D1 (4 mg) and D4 (20 mg), followed by elranatamab 76 mg QW for 6 cycles, and a dose Q2W thereafter if partial response or better is achieved and maintained. In part 2, higher doses of elranatamab ( > 76 mg) at increased intervals between doses will be evaluated. The primary endpoint is grade ≥2 CRS rate during cycle 1. Secondary endpoints include dose-limiting toxicities (part 2 only), objective response rate, duration of response, progression-free survival, overall survival, minimal residual disease negativity rate, safety, and pharmacokinetics. Eligible patients should be ≥18 years of age with a MM diagnosis and measurable disease according to IMWG criteria, refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody, relapsed/refractory to their last treatment regimen, and have an ECOG performance status ≤1. Key exclusion criteria are smoldering MM, active plasma cell leukemia, amyloidosis, POEMS syndrome, stem cell transplant within 12 weeks of enrollment, active, uncontrolled bacterial, fungal, or viral infections, or any other active malignancy within 3 years prior to enrollment (except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ), or previous treatment with an anti-BCMA bispecific antibody. The study is open at centers in the USA, UK, Japan, and Taiwan. Clinical trial information: NCT05014412.

8022 Background: Bone marrow (BM) assessment of minimal residual disease (MRD) is being considered as a surrogate endpoint in clinical trials and is prognostic for survival in multiple myeloma (MM). Timing of BM assessment is variable across Chimeric Antigen Receptor T cell (CART) therapy trials and differs from standard of care practice. BM myeloma cell clearance can be detected by month 1 post CART, even before serum immunofixation becomes negative. BM is still hypocellular at month 1, thus prognostic value of MRD negative (MRDneg) at this timepoint is unclear. We examined impact of Day 30 MRD status in patients (pts) who received CART at Mayo Clinic. Methods: Medical records were reviewed retrospectively for MM pts who received CART between 8/2016 and 6/2021. PFS and OS were plotted by Kaplan-Meier method. Results: Sixty MM pts received CART and had BM biopsy at month 1. Median age was 62 yrs, 53% were male, and 78% were BM MRDneg by flow cytometry. Baseline demographics were similar between MRDneg and MRD+ (Table). Overall, 85% (40/47) who were month 1 BM MRDneg had i/u FLC<normal. Patients who achieved CR/sCR had higher rates of BM MRDneg (100% vs 61%, p<0.001) and i/u FLC< normal (89% vs 58%, p<0.001). At month 1, 24/60 (40%) pts had hypocellular BM. Serial BM samples at month 3 (n=35), 6 (n=28) and 12 (n=23) showed MRDneg rate of 93% (25/27), 56% (9/16) 58% (7/12), respectively.. Rate of hypocellularity was 54% (19/35), 32% (9/28) and 30% (7/23), respectively. Among the MRDneg/hypocellular pts at month 1, hypocellular BM was seen in 8/11 (73%) pts at month 3 and 2/4 (50%) pts at month 6 and 12. Compared to MRD+, pts who had BM MRDneg at months1 had longer PFS (Table). PFS was not statistically significantly different between pts who had BM MRDneg and were either hypocellular or not. MRDneg pts with i/u FLC<normal at months1 had better median PFS compared to those who did not. (MRD+:2.9 months (1.2-NR). MRDneg/FLC>normal: 4.9 months (2.3-NR). vs MRDneg/FLC<normal:17.9 months (11.8-NR), p<0.0001). Conclusions: Hypocellular BM is common in the 3 months post CART. Regardless of BM cellularity, BM MRDneg at month 1 correlates with deep response and prolonged PFS. Majority of BM MRDneg pts at month 1 also had FLC<normal. BM MRDneg status and FLC normalization were associated with longer survival. Our data support the continued evaluation of BM early post CART infusion as a prognostic tool. [Table: see text]

AbstractAltered energy metabolism and changes in glycolytic and oxidative phosphorylation pathways are hallmarks of all cancer cells. The expression of select genes associated with the production of various enzymes and proteins involved in glycolysis and oxidative phosphorylation were assessed in the clonal plasma cells derived from patients with newly diagnosed multiple myeloma (NDMM) enrolled in the Multiple Myeloma Research Foundation (MMRF) CoMMpass data set. A scoring system consisting of assigning a point for every gene where their fragments per kilobase of transcript per million (FPKM) was above the median yielded a minimum of 0 and a maximum of 12 for the set of genes in the glycolytic and oxidative phosphorylation pathways to create a total energy metabolism molecular signature (EMMS) score. This EMMS score was independently associated with worse progression free survival (PFS) and overall survival (OS) outcomes of patients with NDMM. A higher EMMS score was more likely to be present in clonal plasma cells derived from Multiple myeloma (MM) patients than those from patients with monoclonal gammopathy of undetermined significance (MGUS). This was functionally confirmed by the clonal plasma cells from MM patients having a higher rate of mitochondrial and glycolysis‐derived ATP formation than clonal plasma cells from MGUS patients. Thus, this study provides evidence for the effect of energy metabolism within clonal plasma cells on pathogenesis and outcomes of patients with MM. Exploiting the energy‐producing metabolic pathways within clonal plasma cells for diagnostic and therapeutic purposes in MM should be explored in the future.

Abstract Background: Fc receptor-homolog 5 (FcRH5) is a type I membrane protein that is expressed exclusively in the B-cell lineage, and at a higher level on myeloma cells than on normal B cells. Cevostamab is a FcRH5xCD3 bispecific antibody (BsAb) that facilitates T cell-directed killing of myeloma cells. Initial data from the dose-escalation phase of the ongoing Phase I study (NCT03275103) of cevostamab monotherapy in patients (pts) with heavily pre-treated RRMM demonstrated promising activity and manageable safety, along with near ubiquitous FcRH5 expression on myeloma cells (Cohen et al. ASH 2020; Sumiyoshi et al. EHA 2021). We present updated safety and efficacy data from a larger cohort of pts, including results comparing Cycle (C) 1 single step-up (SS) and double step-up (DS) dosing for the mitigation of cytokine release syndrome (CRS). Methods: Participants have RRMM for which no established therapy is available or appropriate. Cevostamab (intravenous infusion) is administered in 21-day cycles. In the SS cohorts, the step dose (0.05-3.6mg) is given on C1 Day (D) 1 and the target dose (0.15-198mg) on C1D8. In the DS cohorts, the step doses are given on C1D1 (0.3-1.2mg) and C1D8 (3.6mg), and the target dose (60-160mg) on C1D15. In both regimens, the target dose is given on D1 of subsequent cycles. Cevostamab is continued for a total of 17 cycles, unless progressive disease or unacceptable toxicity occurs. CRS is reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: At data cut-off (18 May 2021), 160 pts had been enrolled (median age: 64 years, range: 33-82 years; male: 58.1%); 21.3% of pts had extramedullary disease. Median number of prior lines of therapy was 6 (range: 2-18). Most pts (85.0%) were triple-class refractory (PI, IMiD, anti-CD38 antibody). 28 pts (17.5%) had received ≥1 prior CAR-T, 13 pts (8.1%) ≥1 prior BsAb, 27 pts (16.9%) ≥1 prior antibody-drug conjugate (ADC), and 54 pts (33.8%) ≥1 prior anti-BCMA targeting agent. Median follow-up in exposed pts was 6.1 months. Almost all had ≥1 adverse event (Table). The most common was CRS (128/160 pts [80.0%]; Grade [Gr] 1: 42.5%; Gr 2: 36.3%; Gr 3: 1.3%). Immune effector cell-associated neurotoxicity syndrome (ICANS) associated with CRS was observed in 21 pts (13.1%) and in 34/211 (16.1%) CRS events (Gr 1: 8.5%; Gr 2: 6.2%; Gr 3: 1.4%). Most CRS events occurred in C1 (87.2%), arose within 24 hours of cevostamab administration (70.5%), and resolved within 48 hours of onset (83.4%). In the pts with CRS, tocilizumab was used for CRS management in 43.8% and steroids in 25.8% (both agents: 18.0%). In SS dose-escalation (68 pts), 3.6mg was chosen as the most effective C1D1 SS dose for limiting CRS in C1, with no target dose-dependent increase in the rate or severity of CRS observed after the C1D8 administration. Likewise, in DS dose-escalation (30 pts), 0.3/3.6mg was identified as the preferred C1D1/C1D8 DS dose for limiting CRS in C1. Notably, the overall rate of CRS was lower in the pts who received the 0.3/3.6mg/target DS regimen than in those who received the 3.6mg/target SS regimen (77.3% [34/44] vs 88.2% [75/85], respectively). The rate of ICANS associated with CRS was also lower in the 0.3/3.6mg/target DS cohort than in the 3.6mg/target SS cohort (4.5% [2/44] vs 21.2% [18/85], respectively). At data cut-off, 158/160 pts were efficacy evaluable. In dose-escalation, responses were observed at the 20-198mg target dose levels, and data suggested a target dose-dependent increase in clinical efficacy. Median time to response was 29 days (range: 20-179 days). Two dose-expansion cohorts were opened: ORR was higher at the 160mg dose level (54.5%, 24/44 pts) than at the 90mg dose level (36.7%, 22/60). At target dose levels &gt;90mg, ORRs in pts with prior exposure to CAR-Ts, BsAbs, ADCs, and anti-BCMA targeting agents were 44.4% (4/9 pts), 33.3% (3/9), 50.0% (7/14), and 36.4% (8/22) respectively. Median follow-up among all responders (n=61) was 8.1 months; estimated median duration of response was 15.6 months (95% CI: 6.4, 21.6). Conclusions: Cevostamab monotherapy continues to show clinically meaningful activity in a large cohort of pts with heavily pre-treated RRMM, with a target dose-dependent increase in ORR, but no increase in CRS rate. Responses appear durable, and are observed in pts with prior exposure to CAR-Ts, BsAbs, and ADCs. Compared with SS dosing, DS dosing at the 0.3/3.6mg level appears to be associated with a trend for an improved C1 safety profile. Figure 1 Figure 1. Disclosures Trudel: Amgen: Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Roche: Consultancy; Genentech: Research Funding; Pfizer: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Sanofi: Honoraria. Cohen: BMS/Celgene: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Oncopeptides: Consultancy; Novartis: Research Funding; Genentech/Roche: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy; Takeda: Consultancy. Krishnan: MAGENTA: Consultancy; BMS: Consultancy, Current equity holder in publicly-traded company, Speakers Bureau; JANSSEN: Consultancy, Research Funding; City of Hope Cancer Center: Current Employment; REGENERON: Consultancy; SANOFI: Consultancy; GSK: Consultancy; Amgen: Speakers Bureau. Fonseca: Kite: Consultancy; Juno: Consultancy; Merck: Consultancy; Sanofi: Consultancy; Pharmacyclics: Consultancy; Novartis: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aduro: Consultancy; Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees; Patent: Prognosticaton of myeloma via FISH: Patents & Royalties; AbbVie: Consultancy; GSK: Consultancy; Scientific Advisory Board: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Amgen: Consultancy; Mayo Clinic in Arizona: Current Employment; Celgene: Consultancy; BMS: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Spencer: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Berdeja: Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy; Abbvie, Acetylon, Amgen: Research Funding; EMD Sorono, Genentech: Research Funding; Celularity, CRISPR Therapeutics: Research Funding; GSK, Ichnos Sciences, Incyte: Research Funding; Lilly, Novartis: Research Funding; Poseida, Sanofi, Teva: Research Funding. Lesokhin: Serametrix, Inc: Patents & Royalties; Behringer Ingelheim: Honoraria; Genetech: Research Funding; Iteos: Consultancy; Janssen: Honoraria, Research Funding; pfizer: Consultancy, Research Funding; bristol myers squibb: Research Funding; Trillium Therapeutics: Consultancy. Forsberg: University of Colorado: Current Employment; Karyopharm, Sanofi, Genentech: Research Funding. Costa: Karyopharm: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rodriguez-Otero: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Regeneron: Honoraria; Clínica Universidad de Navarra: Current Employment. Kaedbey: Takeda, Sanofi: Honoraria; Celgene/BMS, Janssen: Honoraria; Royal Victoria Hospital Lakeshore Hospital: Ended employment in the past 24 months; Jewish General Hospital - McGill University: Current Employment. Richter: Janssen, Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive biotechnologies: Speakers Bureau; BMS, Karyopharm, Antengene: Membership on an entity's Board of Directors or advisory committees; Tisch Cancer Institute: Icahn School of Medicine at Mount Sinai: Current Employment. Mateos: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Bluebird bio: Honoraria; GSK: Honoraria; Oncopeptides: Honoraria. Thomas: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Acerta Pharma: Research Funding; X4 Pharma: Research Funding; Ascentage Pharma: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding. Wong: Genentech: Current Employment; CTMX, UBX, BMRN: Current equity holder in publicly-traded company. Li: Genentech/Roche: Current Employment, Current equity holder in publicly-traded company. Choeurng: Genentech: Current Employment, Current equity holder in publicly-traded company. Vaze: Roche/Genentech: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Samineni: Genentech: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Sumiyoshi: Genentech: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Cooper: Genentech: Current Employment; Roche: Current holder of individual stocks in a privately-held company. Harrison: Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene/ Juno/ BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusa: Consultancy, Honoraria, Speakers Bureau; Terumo BCT: Consultancy, Honoraria. OffLabel Disclosure: Cevostamab is a FcRH5xCD3 bispecific antibody that facilitates T cell-directed killing of myeloma cells. Cevostamab is an investigational agent.

Abstract Introduction: Despite recent treatment (tx) advances that have improved overall survival (OS), multiple myeloma (MM) remains a mostly incurable malignancy. Txs become less effective with each successive line of therapy (LOT). The rapidly evolving tx landscape has raised questions about the optimal tx sequence; recent trial data may be useful to develop and test hypotheses about tx sequencing. However, real-world (RW) data have shown that while most patients (pts) with newly diagnosed MM (NDMM) receive first-line (1L) tx, attrition rates are high in later LOT, with up to 50% of transplant ineligible (TIE) pts receiving no tx beyond 1L. As many pts will not have an opportunity to be salvaged with later LOT, achieving the longest possible progression-free survival (PFS) upfront is critical. In the MAIA trial, daratumumab (DARA), lenalidomide, and dexamethasone (D-Rd) demonstrated significant PFS (hazard ratio [HR]=0.53, P&lt;0.0001) and OS (HR=0.68, P=0.0013) benefit vs Rd. In a subgroup of pts ≥65 years old in the SWOG S0777 study, bortezomib, lenalidomide, and dexamethasone (VRd) had no significant OS benefit vs Rd. In the absence of head-to-head studies comparing different tx sequences, clinical trial data can be used to explore different scenarios. Published models suggest that delaying DARA until later LOT is a viable tx strategy. Limitations of these models include basing conclusions on tx sequences other than those recommended in clinical guidelines, not accounting for the attrition rates from 1L to subsequent LOT and relying on inappropriate clinical inputs for second-line (2L) tx and beyond. While addressing those limitations, we examined different clinical scenarios to explore the clinical value of using DARA first vs saving it until a later LOT. Methods: We examined 3 potential clinical tx sequences using a lifetime three-health state clinical simulation to estimate survival outcomes in pts with TIE NDMM. The 3 health states were: 1L (time on tx + any subsequent tx-free interval), 2L (time on 2L + any subsequent LOT), and death. Tx sequences were reflective of clinical guidelines: D-Rd in 1L followed by pomalidomide (POM)- or carfilzomib (CAR)-based regimens in 2L and VRd or Rd in 1L followed by DARA-based regimens in 2L (Figure). Pt characteristics were assumed to be similar to those of pts in MAIA. Time spent in the 1L health state with D-Rd and Rd was based on time to next tx or death (TTNT) curves derived from MAIA; TTNT curves with VRd were derived by applying PFS HRs estimated in the PEGASUS study. The attrition rate for the base case analysis (58.8%) was based on MAIA data. Although similar to published studies, it includes pts who were lost to follow-up and may be an overestimate. A sensitivity analysis evaluated a more conservative estimate (27.2%) excluding censored pts. Attrition rates were assumed to be the same across tx arms. Time spent in the 2L health state with DARA-based and POM- or CAR-based regimens was based on RW OS curves derived from the nationwide EHR-derived deidentified Flatiron Health database. RW data were used as pts in published 2L trials are younger than in MAIA and many have had prior ASCT. We evaluated median OS and 5- and 10-year survival rates. Results: Using D-Rd in 1L improved median OS by 2.5 or 3.5 years compared with delaying DARA-based regimens until 2L after VRd or Rd, respectively (Table). The probability of being alive at 5 and 10 years was higher with D-Rd than with VRd or Rd as initial therapy (Table). Changes in attrition rates impacted the expected median OS, but the absolute difference in median OS was maintained, with an incremental OS benefit consistently &gt;2 years. Conclusions: Unlike previous attempts to examine outcomes with different tx sequences, we incorporated clinically representative sequences for pts with NDMM, included attrition rates, and explored their impact on OS with different tx sequences. Our approach shows that achieving the longest possible PFS in 1L drives OS outcomes. Saving agents until later LOT does not take into account that many pts do not reach 2L, as evidenced by published data on attrition rates in MM. Our findings show that in pts with TIE NDMM, starting with D-Rd may provide up to 3.5 years of additional OS gain with the currently available 2L tx. This gain could increase with new 2L agents currently in development, reinforcing the importance of using the best agents first, to increase the probability of pts benefitting from tx currently in development. Figure 1 Figure 1. Disclosures Fonseca: Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees; Scientific Advisory Board: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy; Janssen: Consultancy; GSK: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aduro: Consultancy; Patent: Prognosticaton of myeloma via FISH: Patents & Royalties; AbbVie: Consultancy; Mayo Clinic in Arizona: Current Employment; BMS: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Juno: Consultancy; Takeda: Consultancy; Merck: Consultancy. Hashim: Johnson and Johnson: Current Employment. Nair: Janssen Research & Development: Current Employment. He: Janssen: Current Employment, Current equity holder in publicly-traded company. Ammann: Janssen: Current Employment, Current equity holder in publicly-traded company. Lam: Janssen: Current Employment, Current equity holder in publicly-traded company. Wildgust: Janssen: Current Employment, Current equity holder in publicly-traded company. Kumar: Beigene: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Amgen: Consultancy, Research Funding; Antengene: Consultancy, Honoraria; Roche-Genentech: Consultancy, Research Funding; Tenebio: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Bluebird Bio: Consultancy; BMS: Consultancy, Research Funding; Carsgen: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.