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Disease response and progression assessment in multiple myeloma (MM) is based on various measurements of monoclonal protein (serum and urine protein electrophoresis, serum free light chain (FLC, and or quantitative immunoglobulins). Currently, the IMWG consensus response criteria require two sequential assessments of any one marker made at any time before confirmation of disease progression and the institution of any new therapy. However, this can be cumbersome in clinical trials. Herein, we hypothesized that if two markers meet the progression criteria simultaneously, a repeat of either will not be necessary for confirmation. We retrospectively studied all sequential patients with myeloma enrolled in clinical trials at Mayo Clinic. We identified 583 episodes of confirmed progression in our study. Among the 583 progression episodes, nearly 70% (sensitivity of the simultaneous criteria) met the two simultaneous variable criteria at the first testing, indicating progression. Conversely, among 413 patients who met progression criteria by two simultaneous values, 98% (specificity of the simultaneous criteria) of patients subsequently had confirmed progression by sequential values. In summary, for patients with two disease burden markers meeting the simultaneous progression criteria, sequential assessment either one for confirmation may not be necessary to determine disease progression.

e19531 Background: Effective treatment and elimination of clonal plasma cells (PC) in multiple myeloma (MM) are typically associated with recovery of polyclonal (normal) plasma cells (PPC). Studies suggest that robust PPC recovery is associated with better outcomes. However, it is unclear if this remains valid in the context of monoclonal antibodies, such as Daratumumab, that selectively target plasma cells, and in turn, may adversely impact PPC recovery. Methods: We identified patients with MM who underwent MRD testing using Euroflow method at 6-12 months after treatment initiation. Eight patients had disease progression prior to MRD testing and were excluded from further analysis. PPC was quantitated by the proportion of total events acquired during flow examination. Patients were considered MRD-negative if they had <1 clonal PCs in 10 5 cells, as detected in the marrow. We first examined the impact of initial therapy (Daratumumab vs. non-Daratumumab based regimens) and MRD status on PPC recovery. Subsequently, we analyzed impact of PPC recovery on patient outcomes in terms of progression-free survival (PFS) and overall survival (OS). Results: We identified 572 patients who had MRD testing by flow at a median of 9 months (range 6-12) after treatment initiation. The median age was 63 years, 58% were male. Daratumumab was part of initial therapy in 17% of patients; the most common induction therapies were PI-IMiD triplets (73%), and dara-PI-IMiD quads (15%). In our cohort, 74% of patients were MRD-negative. In our practice, only samples with no monotypic PCs identified on initial low-sensitivity flow proceed to MRD testing, hence, the proportion of MRD-negative patients appears higher in our study than previously reported. Median PPC was 0.02% and was similar between MRD-negative and -positive patients. We found the median PPC was significantly low in patients who received Daratumumab compared to the non-Daratumumab treated cohort (0.011% vs. 0.023%; p<0.01). There was a trend towards lower PFS and OS among the lowest PPC quartile group compared to the upper 3 quartiles, although this was not significant (p=0.07 for PFS and OS, Wilcoxon). This trend was more evident among patients who did not receive Daratumumab. Conclusions: Our study demonstrates negative impact of anti-CD38 therapy with Daratumumab on recovery of PPCs after initial treatment, consistent with the persistent hypogammaglobulinemia seen in clinical practice among these patients. However, unlike the observation with the non-Daratumumab treated cohort, the low proportion of PPCs does not significantly impact patient outcomes among patients who received Daratumumab.

e19545 Background: Cytogenetic abnormalities (CA) at diagnosis are important prognostic factors in multiple myeloma (MM), but there is limited information on how these abnormalities evolve at first relapse and their significance. Methods: This retrospective study included patients aged ≥18 years, with a confirmed diagnosis of MM who experienced at least one disease relapse and had fluorescence in situ hybridization analysis within six months of both diagnosis and relapse. Data on CA and clinical outcomes were collected. High-risk (HR) secondary CA were defined as the presence of deletion of chromosome 17p (del17p) or gain or amplification of chromosome 1q. The primary objective was to evaluate changes in HR secondary CA at first relapse, while the secondary objective was to assess the impact of the cytogenetic changes on overall survival (OS) from diagnosis. Based on the presence or absence of HR secondary CA, patients who were tested for HR secondary CA at both time points were classified into four groups: 1) persistent absence of HR secondary CA, 2) emergence of HR secondary CA at relapse, 3) persistent presence of HR secondary CA, and 4) loss of HR secondary CA at relapse. Results: A total of 233 patients diagnosed between 2004 and 2023 were included. HR secondary CA were tested in 98.7% (n= 230) of patients at diagnosis, with 24.8% (n=57) testing positive. At first relapse, testing for HR secondary CA was performed in 97.4% (n=227) of patients, of whom 23.8% (n=54) tested positive. Del17p was evaluated in 98.3% (n=229) of patients at baseline and 95.7% (n=223) at relapse, with positivity increasing from 10.9% (n=25) to 15.3% (n=34). Gain or amplification of chromosome 1q was evaluated in 49.4% (n=115) at baseline and 25.5% (n=60) at relapse, with positivity rate rising from 28.7% (n=33) to 38.3% (n=23). There were no differences in overall response rate or very-good-partial-response-or-better rates to the initial therapy at diagnosis between the groups. (Table) Emergence/persistence of HR CA were associated with lower OS from diagnosis. Conclusions: Emergence of HR secondary CA at first relapse in MM has prognostic significance. These findings highlight the importance of serial cytogenetic testing for risk stratification. Response rate to initial line of therapy and overall survival from diagnosis among patients tested for HR secondary CA both at diagnosis and first relapse (n=224). Outcome Persistent absence of HR secondary CA(n=142) Emergence of HR secondary CA at relapse (n=25) Persistent presence of HR secondary CA (n=27) Loss of HR secondary CA at relapse(n=30) p-value Overall response rate a 75% (106) 76% (19) 63% (17) 67% (20) 0.5 b Very-good-partial response or better response rate 43% (61) 36% (9) 44% (12) 40% (12) >0.9 b Median (95% CI) OS from diagnosis in years 11.3 (9.7-13.4) 7.5 (5.1-12.1) 6.1 (4.2-9.4) 10.1 (6.5-14.1) <0.0001 c a Partial response or better; b Chi-square test; c Log-rank test.

e19503 Background: The uptake of BCMA directed ADCs in MM has been hindered by ocular toxicity. Belantamab mafodotin (BM) and MEDI2228 (MEDI) are BCMA directed monoclonal antibodies conjugated to the microtubule inhibitor, monomethyl auristatin F and the alkylator, pyrrolobenzodiazepine, respectively. Differences in the ADCs payload, antibody specificity and linker stability influence ocular toxicity. We investigated the patterns of ocular toxicity and tolerability of BCMA directed ADC therapy. Methods: Retrospective study of MM patients who commenced treatment with a commercial or investigational BCMA directed ADC at the Mayo Clinic between 2019-22. Results: 111 patients were included, the median age was 69 and median follow up 40 months. The median number of prior treatments was 6, 87% of patients were triple class refractory, 50% penta class refractory, 14% had prior BCMA directed therapy and 24% had extraosseous disease. Treatments included BM (n=56, 50%), BM in combination with other MM therapy (n=12, 11%) and MEDI (n=43, 39%). The overall response rate was 30% for BM and 44% for MEDI. The median OS and PFS for BM was 8 and 2 months, the median OS and PFS for MEDI was 11 and 5 months. The median number of ADC cycles was 2.5. Ocular toxicity is summarized in the table 1. Keratopathy was more common with BM (p=0.004). Only 4 MEDI patients developed keratopathy, all grade 1 and associated with dry eyes and/or photophobia. In contrast, 60% of BM patients developed keratopathy (13% grade 3-4 keratopathy). The median time to keratopathy onset was 1 month with BM, and 2.8 with MEDI. The median time until keratopathy was 4.6 months for BM. Loss of best-corrected visual acuity (VA) was significantly more common with BM (p<0.001). The median time to any decline in VA was 1.5 months for BM and 2.3 for MEDI. The median time until VA returned to baseline was 2.4 months for BM and 2.3 for MEDI. The frequency of dose delays for ocular toxicity was comparable between ADCs, as was the number of dose reductions (16% BM vs. 12% MEDI, p=0.5). The most common reasons for treatment discontinuation were progression or death (BM=69%, MEDI=44%) and ocular toxicity (BM=18%, MEDI=30%). Conclusions: Treatment interruptions, dose reductions and drug discontinuation are common with BCMA directed ADC therapy. Further research to optimize the administration schedule of these agents is warranted. BM and MEDI produce distinct patterns of ocular side effects, namely keratopathy and reduced VA with the former, and photophobia and dry eyes with the latter. BM N = 68 MEDI N = 43 p-value 2 Prophylactic steroid eye drops 4 (6%) 28 (68%) <0.001 Prophylactic lubricant eye drops 42 (63%) 33 (80%) 0.051 Max grade keratopathy 0.004 1-2 29 (47%) 4 (19%) 3-4 8 (13%) 0 (0%) VA equal or worse than 20/40 26 (68%) 6 (20%) <0.001 Days of ADC treatment 59 (33, 167) 68 (41, 105) 0.9 Dose delay for ocular toxicity 19 (28%) 8 (19%) 0.2 n (%); Median (IQR); 2 Chisq test; Wilcoxon rank sum.

7541 Background: Multiple myeloma (MM) is characterized by recurrent cytogenetic abnormalities, including translocations involving the immunoglobulin heavy chain locus on chromosome 14 and trisomies, which are considered primary and clonal. Throughout disease progression, MM cells may acquire additional abnormalities, which include chromosome 1 abnormalities (gain or amplification of 1q or deletion of 1p) and chromosome 17 abnormalities (del 17p or monosomy 17p). All these factors are considered high-risk markers that predict below-average outcomes. While outcomes related to 1q have been documented, their relationship with other abnormalities and clinical characteristics is less clearly defined. Methods: We created a cohort of newly diagnosed MM (NDMM) patients from April 1996 to December 2023 for whom FISH testing was performed using a panel that included 1q findings. Data on clinical and laboratory characteristics, other FISH abnormalities, and survival outcomes were collected from existing databases and the electronic medical record (EMR). Results: The cohort included 875 patients, with a median age of 65. Of these patients, 60% were male and 91% identified as white. A 1q abnormality was observed in 443 patients (51%); 87% exhibited a gain of 1q, while 13% showed amplification of 1q. Among those tested, other abnormalities included del13 (58%), t(11;14) (25%), t(4;14) (17%), t(14;16) (6%), del 17p (13%), and trisomies (51%). The distribution of abnormalities concerning the presence of 1q is presented in the table. Patients with 1q abnormalities were more likely to present with additional high-risk cytogenetic abnormalities. The median overall survival (OS) for those with a 1q abnormality was 73 months, compared to 105 months for those without it. Among these, patients with 1q amplification tended to have worse outcomes than those with a 1q gain, though this observation did not reach statistical significance. Conclusions: Abnormalities of chromosome 1, including 1q gain and amplification, can be seen in nearly 50% of patients with NDMM who are tested. 1q abnormalities are associated with other high-risk cytogenetic abnormalities. Measures of disease burden are higher among those with a 1q abnormality. Interestingly, we observed a higher proportion of patients with lambda light chain and those with IgA among those with a 1q abnormality. The presence of a 1q abnormality was associated with inferior survival, with a trend towards worse outcomes among those with 1q amplification compared to 1q gain. Clinical characteristics and cytogenetic associations of multiple myeloma patients with and without 1q abnormalities. 1q abnormality present 1q abnormality absent P del13 78% 39% <0.01 t(4;14) 25% 8% <0.01 t(11;14) 22% 27% NS t(14;16) 15% 3% <0.01 Trisomies 48% 53% NS 17p del 24% 12% <0.01 Lambda light chain 45% 26% <0.01 IgA 32% 16% <0.01 Hemoglobin 10.3 g/dL 11.2 g/dL <0.01

ABSTRACT Background Paroxysmal nocturnal haemoglobinuria (PNH) is an ultra‐rare, acquired non‐malignant haematological disorder characterised by thrombosis risk, serious complications and debilitating symptoms in untreated patients. Objective This anchored indirect treatment comparison (ITC) evaluated efficacy data between proximal complement 3 inhibitor (C3i) pegcetacoplan and factor B inhibitor, iptacopan, in patients with PNH previously treated with complement 5 inhibitors (C5i; eculizumab, ravulizumab). Methods Respective pivotal studies provided patient‐level trial data for pegcetacoplan (16‐week PEGASUS [NCT03500549]) and published data for iptacopan (24‐week APPLY PNH [NCT04558918]). Differences in study design, duration and statistical methods between PEGASUS and APPLY PNH necessitated the comparative analyses to be conducted on secondary measures based on haemoglobin (Hb) levels, absolute reticulocyte count (ARC), lactate dehydrogenase (LDH) levels, and patient‐reported outcomes on the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT‐Fatigue) scale scores. The availability of a common reference C5i treatment group in both PEGASUS and APPLY PNH studies allowed anchored ITC (Bucher method). Simulated treatment comparison (STC) assessed the robustness of the main analysis. Results Overall, baseline characteristics of the populations in the PEGASUS and APPLY PNH studies were broadly comparable. Anchored ITC showed comparable outcomes (mean difference, [95% CI]) on change‐from‐baseline to end of study for pegcetacoplan versus C5i, and iptacopan versus C5i, respectively, across endpoints: Hb level ( − 0.49 g/dL [ − 1.78, 0.80]); ARC ( – 34.41 × 10 9 /L [ − 90.02, 21.21]); LDH level ( − 115.16 U/L [ − 244.40, 14.01]); FACIT‐Fatigue score (3.57 [ − 5.60, 12.73]). Finally, the STC produced results consistent with the main Bucher analyses across all clinical endpoints and patient‐reported fatigue, providing similar point estimates and confidence intervals. Conclusion This anchored ITC, based on data from pivotal trials, did not indicate significant differences in clinical or patient‐reported outcomes between pegcetacoplan and iptacopan in PNH treatment. The findings suggest that PNH treatment decisions should also consider individualised disease‐ and patient‐related factors. Trial Registration: ClinicalTrials.gov identifier: NCT03500549.

PURPOSE Cytokine release syndrome (CRS) of any grade occurs in 56%-80% of bispecific antibodies (BsAbs) used in multiple myeloma (MM). Risk mitigation strategies are required to expedite escalation of care if toxicities develop. The rarity of grade 3 or 4 CRS compels protocolized outpatient management of BsAbs as outpatient practice may avoid hospital admissions and costly resource utilization without compromising safety. MATERIALS AND METHODS Patients with MM who received BsAb step-up dosing (SUD) from August 23, 2023, to March 29, 2024, were enrolled. Baseline demographics, patient outcomes, and CRS management were reviewed to assess the safety of outpatient practice. Resource utilization was also analyzed. RESULTS In this study, 34 patients received outpatient SUD of BsAbs (teclistamab n = 17, talequetamab n = 17) with 16 remaining outpatient throughout the entire SUD period. CRS occurred in seven patients who did not require hospitalization, demonstrating the safety of outpatient management of BsAb toxicity, regardless of low-grade CRS. CRS was observed in 24 patients (maximum grade 2) and immune effector cell–associated neurotoxicity syndrome in four patients (maximum grade 3). All patients with CRS received steroids, including 12 patients at home when instructed. Tocilizumab was given to 13 patients, accounting for 18 doses. If all doses of BsAbs and tocilizumab were given outpatient, the medication margin would be $115,004 in US dollars (USD). CONCLUSION An outpatient-based practice for BsAb administration demonstrated safety and cost savings. The description of our practice and results of this study provide valuable insights into the safety, feasibility, and resource stewardship of outpatient management of BsAbs. Future research should attempt to predict and stratify CRS risk to deliver a tailored supportive strategy and continued increase of outpatient management.

ABSTRACTThe optimal conditioning schedule and CD34+ cell dose for autologous stem cell transplantation (ASCT) for AL amyloidosis is unknown. Patients (n = 1704) who underwent ASCT for AL amyloidosis between 2003 and 2020 in 9 centers were included. Data on melphalan conditioning dose, number of conditioning days, whether a rest day between conditioning and stem cell infusion was given or not, and infused CD34+ cell dose were collected. Full‐dose melphalan (≥ 180 mg/m2) was administered in 63.7% of the patients, and 80.4% had melphalan split into 2‐day conditioning. A rest day (day −1) between the conditioning regimen and stem cell infusion was provided in 52.5% of patients. The median infused CD34+ cell count was 4.7 × 106/kg. An infused CD34+ cell count ≥ 4.5 × 106/kg was associated with a shorter time to neutrophil and platelet engraftment. In a nominal regression analysis, full‐dose melphalan, 1‐day melphalan conditioning, and omitting a rest day between conditioning and stem cell infusion were independent predictors of post‐ASCT higher deep hematological response. The median follow‐up was 8.6 years, and 38% of patients died. Independent predictors of superior overall survival in multivariate Cox regression analysis included full‐dose melphalan, having no rest day, and infused CD34+ cells ≥ 4.5 × 106/kg. Independent predictors of higher day‐100 transplant‐related mortality (TRM) in nominal logistic regression analysis included poorer performance status, NT‐proBNP/BNP ≥ 1800/400 pg/mL, serum albumin < 2.5 g/dL, CD34+ cells < 4.5 × 106/kg, and not having a rest day. In conclusion, 1 day of melphalan conditioning and administration of CD34+ cells ≥ 4.5 × 106/kg are recommended for ASCT in AL amyloidosis.