Hassan, Rafla

e19503 Background: The anti-B-cell maturation antigen (BCMA) antibody-drug conjugate (ADC) belantamab mafodotin is approved in the USA and EU for relapsed/refractory multiple myeloma (RRMM). Understanding treatment options and patient outcomes following ADC failure is clinically important. This study describes post-ADC treatment patterns and clinical outcomes in real-world patients with RRMM. Methods: Adult patients with MM who received an ADC and initiated ≥1 subsequent line of therapy (LOT) were included. The index date was the start of the first post-ADC LOT. Data were obtained from chart reviews at International Myeloma Foundation International Myeloma Working Group (IMF IMWG) academic sites, and US electronic health records from largely community sites (COTA and Guardian Research Network [GRN]). Patient characteristics and index regimens were summarized descriptively. Time to next treatment (TTNT) and overall survival (OS) were estimated with the Kaplan-Meier estimator. Results: The IMF IMWG cohort (n=40) had a mean age of 70.8 years, median of 7 prior LOTs and 82.5% were triple-class refractory (TCR). Overall, 85% received ADC monotherapy (70% belantamab mafodotin) and 15% combination therapy. Pre-ADC and not considering corticosteroids, patients were commonly exposed to lenalidomide (R; 100%), bortezomib (V; 92.5%), daratumumab (D) and pomalidomide (P; 90% each). Over a median follow-up of 26 months after index date, 29 unique index post-ADC regimens were reported, frequently selinexor (27.5%) and bispecific antibodies (15%). CAR T-cell therapy was administered to 5%, with 60% re-treated with a pre-ADC drug class (PI/IMiD/anti-CD38) after ADC. Median (95% CI) TTNT and OS were 10.8 (7.0–20.6) and 19.0 (13.4–25.1) months, respectively. The COTA-GRN cohort (n=39) had a mean age of 67.5 years, median of 8 prior LOTs, and 51.3% were TCR. Overall, 56% received ADC monotherapy (belantamab mafodotin) and 44% combination therapy. Pre-ADC and not considering corticosteroids, patients were commonly exposed to D and R (97.4% each), and carfilzomib, V and P (94.9% each). Over a median follow-up of 9.2 months, 32 unique index post-ADC regimens were reported, frequently selinexor (23.1%) and venetoclax (17.9%) based; 0% received CAR Ts and 54% were re-treated with a pre-ADC drug class (PI/IMiD/anti-CD38) after ADC. Median (95% CI) TTNT and OS were 4.9 (2.8–non-estimable [NE]) and 12.0 (4.9–NE) months, respectively. Conclusions: Findings highlight that most patients with heavily pretreated BCMA-ADC exposed MM were re-treated with similar classes. Academic centers used novel therapies (ie, CAR T, bispecific antibodies) more often and their patients had longer survival than those treated at community sites. However, clinical outcomes remained sub-optimal, emphasizing the unmet need for effective, accessible post-ADC treatments.

Introduction: The current definition of plasma cell leukemia (PCL) is based on peripheral blood smear (PBS) demonstrating ≥5% plasma cells. However, PCL cases are enriched in translocation t(11;14), which often has a lympho-plasmacytoid appearance. Detection and quantification of circulating tumor plasma cells (CTC) through peripheral blood flow cytometry (PBF) has emerged as a promising approach for assessing disease burden and prognosis in multiple myeloma (MM) patients. While PBF is more sensitive, the potential threshold values on PBF that correspond with the PBS detection of circulating plasma cells (PBS-PC) remain undetermined. It is important to understand this comparison better to categorize PCL based on PBF. Patients and Methods: This is a retrospective cross-sectional diagnostic accuracy study. We reviewed results of patients diagnosed with plasma cell dyscrasia at the Mayo Clinic from January 2011 to December 2020. The presence of circulating tumor plasma cells (CTC) in encounters was evaluated using peripheral blood flow cytometry (PBF) and peripheral blood smear (PBS) for plasma cells (PBS-PC). PBS-PC was measured as a percentage of plasma cells (PC) in a 100-cell manual differential smear count, and PBF was expressed as the number of plasma cell events per 150,000 peripheral blood mononuclear cells (PBMCs) (Ficoll-isolated peripheral blood mononuclear cells using antibodies to CD38, CD138, CD19, CD45, kappa, lambda, sensitivity (Sn)=6.7x10-5). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PBS with respect to PBF were calculated. For threshold analysis, four groups were defined: A = absent PBS-PC, C = ≥1% and <5%, D = ≥5%. Sensitivity and specificity of detecting PBS-PC (y-axis) for groups A vs. B, B vs. C, and C vs. D were plotted against CTC levels on PBF (x-axis) to determine the best cut-off. Area Under the Curve (AUC) was calculated to determine accuracy. Agreement analysis was done for internal validation and reliability assessment. Results: 6066 test records of CTC were reviewed. Circulating tumor plasma cells (CTC) by peripheral blood flow cytometry (PBF) were reported in 1610 (26.5%) instances, and peripheral blood smear for plasma cells (PBS-PC) in 226 (3.7%) tests. Peripheral blood smear (PBS) demonstrated a sensitivity of 9.3%, specificity of 99.5%, positive predictive value (PPV) of 86.7%, and negative predictive value (NPV) of 75.3% when compared to peripheral blood flow cytometry (PBF). The correlation between PBS-PC% and CTC was weakly positive (Spearman's rho=0.27, p<0.01). The median (Q1, Q3) of circulating tumor plasma cells (CTC) for group A (n=5840) was 0 (0, 0), group B (n=82) was 780 (97.75, 4012.75), group C (n=67) was 1801 (61.50, 8723.50), and group D (n=77) was 20518 (2296, 41349) (p-value <0.001). On post-hoc analysis, all pairs had significant differences in CTCs. To distinguish between A and B, a threshold of 32.5 for CTC demonstrated a sensitivity of 81.8% (AUC=87.8%), and to distinguish B and C, 1125 demonstrated a sensitivity of 59.4% (AUC=63.2%). To distinguish between C and D, 5875 for CTC demonstrated a sensitivity of 68.8% (AUC=74.6%). Agreement Analysis: The Bland-Altman plot demonstrates a slight positive bias between the Clonal Event % and %PBS-PC values (mean of difference = 0.28). The variability of differences increases with higher mean values, indicating a potential proportional bias. All predicted thresholds lie within the limits of agreement (LoA) (upper: 6.13, lower: -5.58) and are therefore reliable. The precision range (upper: 0.35, lower: 0.2) is narrower for the predicted thresholds. The methods should not be compared beyond a circulating tumor plasma cell (CTC) count of 9,195. Conclusion: Detection of circulating tumor plasma cells (CTC) by peripheral blood smear (PBS) is very specific but not sensitive and can be improved by peripheral blood flow cytometry (PBF) detection of CTC. Important clinical cutoffs by morphology (presence and ≥5%) have their counterparts by PBF (32 and 5875 out of 150,000 peripheral blood mononuclear cells (PBMC), respectively). The predicted thresholds are reliable. The study is retrospective and may not be generalizable across all demographics and disease severity. Circulating tumor plasma cell (CTC) values aren't absolute counts and may not be generalizable for low white blood cell (WBC) counts.

Background: Light chain (AL) amyloidosis is a rare and understudied plasma cell disorder. It is caused by abnormal misfolding of monoclonal immunoglobulin light chains, leading to extracellular deposition of amyloid, ultimately resulting in organ dysfunction and death. Since AL amyloidosis is uncommon, therapies are adapted from the more common plasma cell disorders like multiple myeloma. Daratumumab, a monoclonal antibody targeting CD38, was first tested in several prospective and retrospective studies in AL patients with relapsed refractory disease. The ANDROMEDA study (Kastritis E et al, NEJM 2021) established daratumumab in combination with CyBorD (Cyclophosphamide-Bortezomib-Dexamethasone) followed by daratumumab maintenance as the new standard of care compared to CyBorD alone for newly diagnosed patients. Consequently, daratumumab maintenance has become universally offered to all newly diagnosed AL amyloidosis patients. Notably, there was no second randomization before the initiation of maintenance therapy in ANDROMEDA. Hence, a critical question that remains is whether the superior efficacy observed in the investigational arm of the ANDROMEDA trial is solely a result of the addition of daratumumab during the induction phase or if the maintenance phase contributed to the favorable outcomes in the investigational arm. We hypothesize that a shorter duration of maintenance would prove non-inferior to the standard duration of daratumumab maintenance in patients with AL amyloidosis that have responded to Daratumumab-CyBorD induction. To answer this question we are conducting a pragmatic phase 2 randomized trial assessing the optimal duration of daratumumab maintenance in patients with AL amyloidosis who have responded to Daratumumab-CyBorD induction. Study Design, Patients and Methods: We use broadened eligibility criteria consistent with pragmatic trial design. The estimated total enrollment is up to 96 patients. The main eligibility criteria are patients with biopsy-proven AL Amyloidosis who have completed 6 cycles of Dara-CyBorD-based induction treatment and achieved an adequate response to induction (defined as hematological complete response (CR), hematological very good partial response (VGPR), or hematological partial response (PR) with at least one organ response). Patients in whom bortezomib and/or cyclophosphamide were omitted from induction due to toxicity concerns or adverse effects are allowed. The major exclusion criteria are patients who were concomitantly diagnosed with multiple myeloma based on International Myeloma Working Group (IMWG) criteria. This phase II, open-label, multicenter trial (NCT05898646) randomizes patients who have attained an adequate response to 6 cycles of Dara-CyBorD-based induction in a 1:1 ratio, using a dynamic allocation procedure that balances the marginal distributions of the stratification factors (age, cardiac stage, and t(11;14) status). Randomization is to either single-agent daratumumab maintenance of 6 cycles duration (experimental arm) or 18 cycles of daratumumab maintenance (control arm) (cycle = 28 days). Treatment is allowed to be given at a local facility After completing maintenance treatment, patients will follow up every 3 months for up to 36 months from registration. The primary endpoint of the trial is to evaluate the non-inferiority of a shorter (6 cycles) daratumumab maintenance measured by event-free survival (EFS) compared to the standard maintenance of 18 cycles in newly diagnosed AL amyloidosis who receive 6 cycles of daratumumab-CyBorD based induction. EFS in this study is defined as time from registration to any of the following events: hematological progression, organ progression, subsequent anti-plasma cell therapy in the absence of hematological progression but with persistent organ dysfunction or death, whichever occurs first. Secondary endpoints are depth of hematological and organ response, bone marrow measurable residual disease negativity rate, duration of response, quality of life, and survival. By investigating whether a shorter duration of maintenance is non-inferior to the standard duration, we aim to inform clinical practice and potentially reduce the toxicities associated with prolonged maintenance therapy, including hypogammaglobulinemia, recurrent infections, the need for intravenous gammaglobulin replacement, and financial toxicity.

Introduction Multiple myeloma (MM) is considered incurable. Despite improved outcomes with novel agents, including BCMA-targeted chimeric antigen receptor (CAR) T-cell therapies, antibody-drug conjugates (ADCs), and bispecific antibodies, patients with relapsed/refractory MM (RRMM) often have poor prognoses. LINKER-MM1 (NCT03761108) is a global, single-arm, Phase 1/2 study of linvoseltamab, a BCMA×CD3 bispecific antibody, in patients with RRMM who were either triple-class exposed (TCE; previously treated with a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody) during ≥3 prior lines of therapy (LOTs), or triple-class refractory to these therapies. Here, we present comparisons of clinical outcomes from LINKER-MM1 with those of a current, international, real-world (RW) external control arm (ECA; NCT05673967). Methods The ECA was derived from 16 academic sites of the International Myeloma Foundation International Myeloma Working Group (IMWG) (N=203; 309 eligible LOTs) and compared with linvoseltamab (N=105; Phase 2 200 mg cohort). Patients in the ECA initiated ≥1 anti-MM therapy after meeting key LINKER-MM1 eligibility criteria. Weighted random sampling and inverse probability of treatment weighting were used to select 1 LOT per patient and balance the ECA and trial populations on prespecified prognostic factors (Kumar S, et al. IMS 2023). The primary endpoint was objective response rate (ORR; IMWG criteria) determined by an independent central review committee (ICRC) based on myeloma laboratories. An independent data review committee reviewed comparability of cohorts and endpoint assessments prior to conducting comparative analyses. Results Median follow-up was 14.3 months for the linvoseltamab cohort (data cutoff: Jan 6, 2024) and 13.4 months for the ECA. After weighting, 15 prognostic factors were balanced between cohorts. Patients in the ECA received 68 distinct regimens, most commonly CAR T-cell therapies (11.3%) and ADCs (10.3%). After balancing the cohorts, patients in the ECA evaluable for response had ICRC-assessed ORR of 46.3% (40.8% by treating physician assessment), among whom 24.0% had very good partial response or better (≥VGPR). When including patients who died without evaluable response, ECA ICRC-assessed ORR was 44.2%. Linvoseltamab induced significantly higher ICRC-assessed ORR (69.5% vs 46.3%, odds ratio [OR] 2.65 [95% confidence interval (CI) 1.66-3.69]) and rate of ≥VGPR (62.9% vs 24.0%, OR 5.37 [95% CI 3.61-8.49]) compared with ECA regimens. Conclusion Despite current use of novel therapies, there is no well-established RW standard of care (SOC) for patients with TCE RRMM treated at IMWG sites. To our knowledge, this is the first RW ECA study in MM with a high percentage of anti-BCMA therapies and response ascertainment for all patients by ICRC. Linvoseltamab induced significantly higher response rates, including rate of ≥VGPR, compared with current RW SOC therapies, highlighting its potential as a highly effective treatment in patients with TCE RRMM.

Introduction Linvoseltamab is an investigational, BCMA×CD3 bispecific antibody designed for the treatment of RRMM. High objective response rates (ORR) to linvoseltamab 200 mg in the LINKER-MM1 trial (NCT03761108) were demonstrated across high-risk subgroups, including patients aged ≥75 years, patients with high-risk cytogenetics, and patients with penta-class refractory status. The aim of this study was to compare ORR, overall and in key subgroups, between patients in Phase 2 of the LINKER-MM1 trial and patients in an international RW SOC external control arm (ECA). Methods The ECA was derived from a chart review of 16 academic sites across 10 countries that are part of the International Myeloma Foundation (IMF)-International Myeloma Working Group (IMWG) and 2 US electronic health record databases (COTA and Guardian Research Network [GRN]). Included patients initiated ≥1 anti-MM treatment after meeting key eligibility criteria of LINKER-MM1. Weighted random sampling and inverse probability of treatment weighting (IPTW) were used to select 1 line of therapy (LOT) per patient and balance the overall ECA and trial populations on prespecified prognostic factors (Kumar S, et al. IMS 2023). For ORR assessment, LINKER-MM1 and IMF-IMWG used independent central review committees per IMWG criteria, COTA used algorithmic assessment based on IMWG criteria, and GRN used physician-assessed responses. Prior to conducting comparative analyses, an independent committee of epidemiology and oncology experts reviewed the comparability of the cohorts and endpoint assessments, and approved study continuation. ORR among patients in LINKER-MM1 and patients in the ECA was compared overall and across prespecified subgroups (≥10 patients per subgroup), including age, race, cytogenetic risk score, international Staging System (ISS), presence of extramedullary plasmacytoma (EMP), refractory class, bone marrow plasma cell (BMPC) proportion, and number of prior LOTs. Results Median duration of follow-up was 14.3 months (data cut-off: January 6, 2024) for patients receiving linvoseltamab (n=105) and 13.6 months for the ECA (n=307; n=194, n=72, and n=41 from IMF-IMWG, COTA, and GRN, respectively). Following IPTW, 13 prognostic factors with <30% missingness were balanced between cohorts, with an effective sample size in the ECA of 197. After adjustment, ORR was significantly higher in patients who received linvoseltamab compared with patients in the ECA (69.5% vs 45.7%, odds ratio [OR] 2.5 [95% confidence interval (CI) 1.6-4.1]) and in key subgroups with age 65-74 years (76.9% vs 48.3%, OR 3.6 [1.6-8.6]), age ≥75 years (72.4% vs 48.5%, OR 2.8 [1.1-7.4]), Black or African American race (82.4% vs 25.0%, OR 14.0 [3.0-85.4]), White race (68.9% vs 49.7%, OR 2.2 [1.3-4.0]), standard cytogenetic risk (72.3% vs 51.3%, OR 2.5 [1.3-4.8]), ISS stage III (58.8% vs 19.7%, OR 5.8 [1.5-25.2]), absence of EMP (71.6% vs 49.3%, OR 2.6 [1.5-4.6]), triple-class refractory status (68.2% vs 45.7%, OR 2.6 [1.5-4.4]), quadruple-class refractory status (66.7% vs 45.9%, OR 2.4 [1.3-4.3]), 4-5 prior LOTs (65.1% vs 40.4%, OR 2.8 [1.3-6.0]), and >5 prior LOTs (75.7% vs 36.1%, OR 5.5 [2.4-13.6]). Numerically higher (not statistically significant) or similar ORR was observed for patients receiving linvoseltamab compared with patients in the ECA with age <65 years (59.5% vs 46.8%, OR 1.7 [0.79-3.6]), high-risk cytogenetics (65.0% vs 63.1%, OR 1.1 [0.41-2.9]), ISS stage I (73.3% vs 64.6%, OR 1.5 [0.62-3.7]), ISS stage II (67.6% vs 53.5%, OR 1.8 [0.72-4.7]), presence of EMP (58.8% vs 56.9%, OR 1.1 [0.32-3.8]), penta-class refractory status (64.3% vs 48.5%, OR 1.9 [0.78-4.8]), BMPC <50% (77.0% vs 67.2%, OR 1.6 [0.61-4.3]), BMPC ≥50% (41.7% vs 36.0%, OR 1.3 [0.36-4.7]), and ≤3 prior LOTs (68.0% vs 66.4%, OR 1.1 [0.43-2.9]). Separate findings will be presented for IMF-IMWG and COTA/GRN data at the congress. Conclusions Linvoseltamab induced better ORR vs RW SOC treatments overall, and better or similar ORR in the key subgroups assessed, highlighting its therapeutic value across a range of patients with RRMM with heterogeneous risk profiles and levels of disease burden.