Dingli, David

Abstract Measurable residual disease (MRD) assessment has become central to risk-adapted treatment strategies in multiple myeloma, yet the prognostic value of MRD negativity following autologous stem cell transplantation (ASCT) across individual high-risk cytogenetic abnormalities (HRCAs) remains unclear. We analyzed 351 newly diagnosed patients who achieved MRD negativity (sensitivity 2.4×10 − 6 ) at Day 100 following ASCT and had baseline cytogenetic data available. Median follow-up was 50.4 months. Standard-risk cytogenetics were present in 46% (n = 162), while 34% (n = 118) had one HRCA and 20% (n = 71) had ≥ 2 HRCAs. Despite uniform MRD negativity, several HRCAs continued to confer inferior progression-free survival (PFS). Compared with the standard-risk group (4-year PFS 84%), patients with del(17p), 1q21+, t(4;14), or MAF translocations [t(14;16)/t(14;20)] had significantly lower 4-year PFS rates: 56% (HR 2.89; p = 0.0001), 60% (HR 2.46; p = 0.0001), 43% (HR 3.50; p = 0.0001), and 58% (HR 2.51; p = 0.01), respectively. Isolated del(17p) and 1q21 + also conferred inferior PFS. The 4-year PFS was 65% for patients with one HRCA (HR 2.31; p = 0.0004) and 55% for those with ≥ 2 HRCAs (HR 2.75; p = 0.0001). In this large MRD-negative post-ASCT cohort, several HRCAs, including isolated HRCAs, remained clinically meaningful drivers of inferior PFS, highlighting that early MRD negativity does not uniformly mitigate the impact of high-risk biology.

Abstract Castleman disease (CD) is a heterogeneous group of lymphoproliferative disorders anatomically classified by distribution (unicentric CD [UCD], oligocentric CD [oligoCD], or multicentric CD [MCD]). Human herpes virus 8–negative MCD is called idiopathic MCD (iMCD), which includes clinical subtypes with varying phenotypes and responses: TAFRO (thrombocytopenia, anasarca, fever, renal dysfunction and/or reticulin fibrosis, and organomegaly), IPL (idiopathic plasmacytic lymphadenopathy), and not otherwise specified. OligoCD has recently emerged as an intermediate form between UCD and MCD, with unclear clinical behavior, and IPL has not been validated in a Western cohort. We retrospectively analyzed 217 patients with CD evaluated at our institution between January 2004 and August 2024. Survival probabilities were compared using log-rank tests. Overall, 57% had UCD, 20% had oligoCD, and 23% had iMCD. Patients with oligoCD and iMCD more frequently exhibited systemic symptoms than those with UCD. Patients with oligoCD and iMCD had significantly shorter event-free survival (EFS) of 8.9 and 2.3 years, respectively, than those with UCD (not reached; P< .001 and P< .02). Among iMCD subtypes, iMCD-IPL demonstrated a longer EFS than iMCD-TAFRO (P = .02), with no deaths during the follow-up periods. The results validate oligoCD and iMCD-IPL as new subtypes in this Western cohort. The survival outcome in oligoCD was intermediate between UCD and iMCD, with only a subset of patients with oligoCD requiring systemic therapy. iMCD-IPL had a favorable survival outcome in this US cohort, similar to what has been reported in non-Western countries. Tailoring treatment strategies to disease subtypes and vigilant monitoring of oligoCD for progression may improve survival outcomes in CD.

ABSTRACT Introduction Although covalent Bruton's tyrosine kinase inhibitors (cBTKis) have transformed treatment of chronic lymphocytic leukemia and small lymphocytic leukemia (CLL/SLL), cBTKi‐related cardiotoxicity is a known side effect. This real‐world study evaluated incident cardiovascular adverse events (CVAE), healthcare resource utilization (HCRU), and costs among patients with CLL/SLL receiving cBTKis. Methods Adult patients with CLL/SLL who initiated ibrutinib or acalabrutinib treatment (index date) between 2020 and 2023 were identified using US claims data and followed up to 36 months post‐index. Incident CVAEs (not present pre‐index) were assessed during cBTKi treatment and patients were stratified by CVAE status. HCRU and costs were evaluated per 1000 patient‐months (PPPM). Results Overall, 2069 patients were identified (mean age of 73.7 ± 9.1 years, 40.4% female) with a mean treatment‐specific observation period of 11.4 ± 9.5 months. At least one incident CVAE was observed in 442 (21.4%) patients. The incidence rate was 21.6 PPPM for hypertension, 8.9 PPPM for atrial fibrillation, 8.6 PPPM for ventricular arrhythmias, and 8.3 PPPM for atrial flutter. Patients with incident CVAEs had significantly more total medical service days PPPM (4334 vs. 3138, p < 0.001), primarily driven by increased inpatient (690 vs. 230), outpatient (2798 vs. 2425), other visit (662 vs. 375), and ER days (184 vs. 109) than those without CVAEs. Total healthcare costs (PPPM) were substantially higher for patients with incident CVAEs ($20,250,560 vs. $17,413,460, p < 0.001) mainly due to higher inpatient ($3,417,948 vs. $915,839, p < 0.001), outpatient ($2,415,060 vs. $1,769,628, p < 0.01), and ER costs ($186,820 vs. $87,585, p < 0.001). Conclusions The observed class‐effect of high CVAEs with cBTKis underscores the unmet need for safer, more selective agents for CLL/SLL treatment. The HCRU and economic burden remain high for CLL/SLL, especially among patients experiencing CVAEs during cBTKi treatment. These findings emphasize the importance of optimizing clinical management to reduce CVAE risk and downstream impacts on HCRU and costs.

Abstract Background: The phase II and III GRIFFIN and PERSEUS studies evaluated DVRd vs. VRd in NDMM pts that were transplant eligible (TE). These studies included consolidation (cons) and dual agent maintenance (maint) with dara and len (DR). Little is known about the efficacy of DVRd in RW practice including frequency of bor use, use of cons, use of DR maint, and subsequent treatment after progression (PD) on DVRd. We aim to evaluate the RW efficacy of NDMM pts treated with DVRd across the tri-site Mayo Clinic Comprehensive Cancer (MCCC). Methods: We retrospectively analyzed the medical records of pts treated with DVRd between June 2018 and June 2024 at the MCCC. Outcomes were estimated using the Kaplan-Meier method. Results: 464 pts were included; 278 pts were male, and the median (m) age of MM diagnosis was 64 years (yr). 114 pts had ISS III, 205 pts had R-ISS III, 266 pts had high risk (HR) FISH, 80 pts had extramedullary disease, 165 pts had ultra HR disease (dz) (as per 2025 IMS/IMWG consensus), and 47 pts had renal insufficiency (RI) with creatinine &gt;2 mg/dL. Starting len dose was 25mg in 356 pts, 15 mg in 40 pts and ≤10mg in 65 pts. 399 pts received bor 1x per week and 63 2x per week, 91 pts received 1-2 cycles of a different regimen prior to DVRd due to hospitalization (n=23), RI (n=38), poor performance status (n=6), other (n=34). 315 (67.9%) pts underwent autologous transplant (ASCT). The m number of induction cycles was 5; 4 for pts who underwent ASCT and 6 for pts who did not. The best ORR to induction for pts who underwent ASCT was 98% with 247 (79%) achieving ≥VGPR, and 82 (26%) achieving minimal residual disease negativity (MRD-) to at least 10-5. The best ORR for pts who did not undergo ASCT was 87%. For those who underwent ASCT, (96% with melphalan 200mg/m2), the ORR at day 100 was 97% with 56% achieving MRD-. At 1-yr post ASCT, 30% (93/312) were MRD-. 42 pts (13%) received post ASCT cons with DVRd for a m of 2 cycles. 281 pts received post ASCT maint including 107 (38%) len, 53 (19%) bor-len, 91 (32%) dara-len, 14 (5%) dara, 16 (6%) other. 61(13%) pts had change in treatment, due to change to second line therapy (35; 55%), discontinuation (d/c) of len (11; 17%), d/c of dara (3; 5%), d/c of bor (15; 23%), d/c of dex (0; 0%). The m follow-up time for all pts was 26 months (mo) (17-39). The m PFS of pts who underwent ASCT was not reached (NR), and was 57 mo (52-NA) for pts who did not undergo ASCT. For pts who underwent ASCT, the PFS at 24mo for pts who did not have HR FISH was 93% (88-99%) compared to 80% (73-88%) for pts with HR FISH (p=0.12) and 77% (68-87%) for pts with ultra-HR dz (p=0.013).The PFS at 24mo of pts with RI who underwent ASCT was 81% (66-98%) compared to 86% (82-92%) for those without RI, p=0.57. The PFS at 24mo of pts with RI who did not undergo ASCT was 53% (28-100%) compared to 64% (55-75%) for those without RI, p=0.42. The ORR and MRD- rate for pts who received once-weekly bor was 94% and 24%, compared to 94% and 27% for pts who received 2x weekly bor (p=0.85, p=0.93). For pts who underwent ASCT, the PFS at 24mo for pts who received len maint was 91% vs. 83% for pts who receive dual agent maint (DR or VR) (p=0.25), although pts who got dual agent maint were more likely to have HR FISH than pts who received len maint (p&lt;0.001). The PFS at 24mo for pts that received post-ASCT cons was 91% compared to 85% for those that did not (p=0.53); pts who got post-ASCT cons were more likely to have HR FISH (p=0.07). For pts that underwent ASCT, the 3 yr PFS rate is 85% and the 3 yrs OS rate is 96%. For pts that did not undergo ASCT the 3 yrs PFS rate is 60% and the 3 yr OS rate is 85%. 55 pts had functional HR (FHR) MM (relapse within 18 mo) and m PFS for FHR pts who underwent ASCT was 15 mo (11-NA), while m PFS was NR for pts without FHR MM (p&lt;0.001). 79 pts relapsed after 1st line DVRd. The most common 2nd line therapies (tx) were dara-carfilzomib (K)-D, dara-pomalidomide(P)-D, KPD, and other. The m follow-up time from 2nd line tx was 10 mo, the best ORR to 2nd line tx was 76%, and the m PFS with 2nd line tx was 18 mo (7-NA). Conclusion: In this RW analysis, the efficacy and survival outcomes of NDMM pts treated with DVRd was comparable to that reported in the PERSEUS and GRIFFIN trials, although MRD- rates appear lower. DR maint and post-ASCT cons use was not common and was used more frequently in pts with HR FISH. Pts can be effectively salvaged following PD on front-line DVRd with available tx.

Abstract Background: VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a hemato-inflammatory syndrome due to somatic mutations in UBA1 gene. Recently, DNA methyltransferase inhibitors (specifically, 5-azacitidine) and allogeneic hematopoietic stem cell transplantation (alloHSCT) have shown success in eradication of UBA1 clones and clinical remission in some patients. This study aims to provide a comparative efficacy analysis between DNA methyltransferase inhibitors (hypomethylating agents/HMA) versus alloHSCT in VEXAS syndrome patients. Methods: This is a multi-center, retrospective cohort study. UBA1 mutations were detected either through next generation sequencing [NGS, limit of detection (LOD) 2% variant allele fraction (VAF)] or quantitative droplet digital polymerase chain reaction testing (ddPCR, LOD 0.5% VAF). Outcomes of interest included overall survival (OS), glucocorticoid (GC) discontinuation/reduction in dose (prednisone &lt; 10 mg/day), and complete molecular remission (CMR, defined as an undetectable UBA1 mutation). OS was calculated from the time of diagnosis to death or last follow up. Cumulative incidence of reduction in GC dose was calculated using competing risk analysis after accounting for death. Results: Between years 2020-2024, a total of thirty-nine male patients (median age 67, range 45-82 years) with VEXAS syndrome, necessity for therapy (GC-refractory inflammation and/or progressive marrow failure/myeloid neoplasm) and confirmed UBA1 pathogenic mutation were included. Of these, 18 (46%) received HMA therapy (5-azacitidine 72% and Decitabine 28%) with a median of 4 (range 1-36) cycles. and 21 (54%) underwent alloHSCT (MSD=4, MUD=12, MMUD=2, and haploidentical=3), all received reduced intensity conditioning (Flu/Mel =11, Flu/Bu=5, Flu/Cy/TBI=2, and TBF=3) and 91% received post-transplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis (only 2 patients in alloHSCT group received prior HMA without benefit). Baseline characteristics were well-balanced between HMA and alloHSCT groups; age at treatment (median 70 vs 65 years, p=0.2), and UBA1 M41V subtype (25% vs 40%, p=0.3), cytogenetic and non-UBA1 mutation abnormalities (p=0.4), prior lines of therapy (median 4 in both, p=0.5), time from diagnosis to therapy (median 7 vs 13 months, p=0.15), indication for therapy (p=0.12), Charlson CI scores (median 4 in both, p=0.4) and HCI-CI scores (median 4 in both, p=0.7). At a median follow-up of 45 (range 7-57) months, 11 (28%) deaths (alloHSCT=3 and HMA=8) were documented. Causes of death included infections (n=6), cardiac disease (n=2), poor graft function (n=2) and pulmonary GVHD (n=1). Compared to HMA therapy, alloHSCT group demonstrated higher rates of GC discontinuation (52% vs 6%, p&lt;0.01) and CMR (evaluable= 22, 100% vs 50%, p&lt;0.01). In the HMA group, 50% (n=9) discontinued therapy after a median of 4 months due to infectious complications or lack of benefit. In the alloHSCT group, 3 (14%) patients developed grade 2 acute GVHD (1-skin, 2-gut, no grade 3-4 acute GVHD) and 4 (19%) experienced moderate to severe chronic GvHD (2-lung, 2-mucocutaneous). In multivariable analysis (MVA) adjusted for age and HCT-CI, alloHSCT was identified as the strongest favorable predictor for OS (HR 0.18 95% CI 0.04-0.8) with similar results when analysis was restricted to transplant-eligible patients &lt; 75 years of age (HR 0.1, 95% CI 0.03-0.6). In a 6-month post-treatment landmark analysis (n=31 evaluable), patients who underwent alloHSCT (n=17) exhibited numerically superior GC discontiuation rate (29% vs 14%, p=0.049) and subsequent OS compared to HMA (2-years OS: 84% vs. 61%, median not reached vs 25 months, 95% CI: 0.06–1.7). In a post-treatment competing risk [GC dose reduction (death)] analysis alloHSCT was associated with superior 2-, and 3-year rates of 57% (10%), and 76% (10%), compared to HMA 22% (24%), and 31% (42%) [p&lt;0.01 (0.04)]. AlloHSCT was also associated with higher rate of CMR (evaluable= 21, alloHSCT N=16 and HMA N=5, 100% vs 60%, p=0.01). At the last follow up, none of the patients who achieved CMR had re-emergence of the UBA1 clone (despite early mixed chimerism). Conclusions: This study represents the largest comparative analysis of alloHSCT versus HMA therapy in VEXAS syndrome, and confirms superiority of alloHSCT in achieving molecular remission, GC discontinuation/dose reduction, and overall survival. Prospective clinical trial confirmation is warranted.

Abstract Background: Disease relapse is a major cause of mortality post allogeneic hematopoietic stem cell transplantion (alloHCT) in patients with myeloid neoplasms (MN). Cytogenetic risk classification is a key prognostic factor in predicting relapse post-transplant. Next generation sequencing (NGS) offers added prognostic insight by identifying relapse-associated mutations. We assessed the impact of mutation type and burden on post-alloHCT relapse risk and relapse-free survival (RFS) in MN patients with non-adverse-risk cytogenetics. Methods: We retrospectively reviewed patients who underwent alloHCT at Mayo Clinic Rochester between 01/01/2018 - 10/01/2023. Eligible patients had MN with non-adverse-risk cytogenetics [Acute myeloid leukemia (AML) with non-adverse-risk cytogenetics per ELN 2022, myelodysplastic syndrome (MDS) with non-high/very high-risk cytogenetics per IPSS-R criteria, and myeloproliferative neoplasms (MPN) (excluding myelofibrosis), chronic myelomonocytic leukemia (CMML), or MDS/MPN overlap with non-complex and non-monosomal karyotypes]. The primary endpoint was 3-year cumulative incidence of relapse (CIR) post-alloHCT, analyzed via competing risk models. RFS was estimated via Kaplan-Meier method. Prognostic mutations were identified using univariate (UVA) and multivariate (MVA) Cox models. A decision tree was used to define mutation-based relapse risk groups. Results: Of 585 patients, 215 (37%) met inclusion criteria; 133 (62%) were male. Median age at diagnosis was 61 years (IQR 53-65.5). Diagnoses included AML (125, 58.1%), MDS (55, 25.6%), CMML (17, 7.9%), MDS/MPN (11, 5.1%), and MPN (7, 3.3%). Median follow-up post-alloHCT was 3.2 years (IQR 1.9-5.2). Donor sources were mostly matched unrelated donors (120; 55.8%), followed by matched related donors (72; 33.5%), haploidentical donors (15; 7%), mismatched unrelated donors (6; 2.8%), and cord blood transplants (2; 0.9%). Most patients reduced intensity/non-myeloablative conditioning (144, 67%), while others received myeloablative (71, 33%). Mutation frequencies were as follows: ASXL1 58 (27.0%), RUNX1 45 (20.9%), FLT3 41 (19.1%), SRSF2 41 (19.1%), DNMT3A 39 (18.1%), STAG2 22 (10.2%), SF3B1 18 (8.4%),BCOR 18 (8.4%), WT1 16 (7.4%), U2AF1 13 (6.0%), ZRSR2 10 (4.7%), TP53 6 (2.8%), EZH2 3 (1.4%). In UVA, mutations in FLT3 (HR 2.15, p=0.018), SF3B1 (SF3B1 HR 3.08, p=0.002), PTPN11(HR 2.93, p=0.032), and WT1 (HR 2.29, p=0.069) were associated with increased risk of 3-year CIR. However, only FLT3 (HR 1.98, p=0.042) and SF3B1 (HR 4.0, p&lt;0.001) retained significance in MVA. SF3B1 correlated with inferior 3-year RFS in UVA (HR 1.99, p=0.034) but not in MVA. Mutations in ASXL1, BCOR, EZH2, RUNX1, SRSF2, STAG2, ZRSR2, U2AF1, and TP53 had no significant impact on CIR or RFS. Harboring ≥2 or ≥3 mutations did not impact CIR or RFS. A decision tree model based on SF3B1, FLT3, DNMT3A, and WT1 mutations stratified patients into 3 risk groups. The high-risk group (n=32; 15%) had 50% 3-year relapse incidence (RI) and included patients with SF3B1 mutations or SF3B1-wildtype (WT) with concurrent FLT3 and DNMT3A mutations. The intermediate-risk group (n=36; 17%) included SF3B1-WT patients with either FLT3 mutations and DNMT3A WT (21% RI), or SF3B-1-WT and FLT3-WT patients with WT1 mutations (33% RI). The low-risk group (n=147; 67%) lacked all 4 mutations and had the lowest 3-year RI of 14%. The 3-year CIR significantly differed across these 3 risk groups (51.9%, 27.3%, and 15.8% in high, intermediate, and low-risk groups respectively; p&lt;0.001). The 3-year RFS was significantly inferior in the high-risk group (35.55%, p=0.001), but similar among intermediate and low-risk groups (67.11% and 63.4%, respectively). Conclusion: In non-adverse risk cytogenetic MN, SF3B1 and FLT3 mutations predicted relapse post-alloHCT. Notably, mutations that were traditionally associated with adverse-risk AML per ELN 2022 (e.g, ASXL1, TP53) were not associated with relapse in this cohort. The discrepancy may reflect exclusion of patients with high-risk cytogenetics, as the prognostic impact of these mutations may depend on co-cytogenetic anomalies. In non-adverse-risk cytogenetics MN, we identified 3 groups of patients based on the presence or absence of SF3B1, FLT3, DNMT3A, and WT1 mutations. Those with mutated SF3B1 or concurrent FLT3/DNMT3A mutations experienced the highest risk of relapse post-alloHCT, translating into inferior RFS. Our findings need to be verified in a larger data registry.

Abstract Introduction: Multiple myeloma (MM) predominantly affects older adults who vary widely in physiological status and treatment outcomes. Comprehensive Geriatric Assessment (CGA) is considered the gold standard for frailty assessment in older cancer patients (pts), but clinical useis limited. Current frailty tools for MM include only select GCA domains, rely on trial datasets, and do not incorporate pt-reported outcomes (PROs). Since their development, treatment strategies have evolved with the use of anti-CD38 MAbs and quadruplets in older pts. The impact of geriatric impairments on treatment tolerance in the era of modern therapy remains unclear and changes in geriatric domains during treatment are not well characterized. Aim: This prospective study evaluates the association between pt-reported CGA and treatment outcomes in older MM pts.Methods: We included MM pts ≥60 years initiating a new treatment at Mayo Clinic from March 2023-June 2024. Pts completed the CARG GCA (Hurria et al 2005) electronically prior to and after 4 treatment cycles. We collected data on toxicity using CTCAE and PRO-CTCAE and quality of life using the PROMIS10-GH SF.Results: Ninety pts were enrolled. Median age was 72 (range: 63-86), 42% female, and &gt;90% non-Hispanic white. Over half (59%) were newly diagnosed with 41% and 56% receiving quadruplets and triplets, respectively. Among newly diagnosed pts, 34% had early stem cell transplant. Baseline median self- and physician- reported KPS were 80% and 90%, respectively, with high correlation (r=0.657). The median number of meds per pt was 9 (range:0-30), 39% had ≥3 comorbidities, 21% reported ≥1 fall in the past 6 months, and 40% reported ≥1 IADL limitation. On the Hospital Anxiety and Depression Scale, 3% and 7% had anxiety and depression, respectively. On the Blessed Orientation-Memory-Concentration test, 19% had mild cognitive impairment, and 1% had severe cognitive impairment. While only 19% had grade (G) ≥3 non-hematologic toxicity by CTCAE, 71% had ≥1 treatment delay, dose reduction, or discontinuation, and 39% had ≥1 ED visit or unplanned hospitalization within the first 4 cycles. This suggests physician grading of non-hem toxicities may inadequately capture toxicity burden from MM therapy. Notably, the rate of G≥3 toxicity by PRO-CTCAE was 49%, highlighting the discrepancy between physician- and pt-reported symptom burden. CGA domains significantly associated with G≥3 non-hem toxicity were: age (74 v 71.5, p=0.032), ≥3 comorbidities (65% v 33%, p=0.015), anxiety (18% v 0%, p=0.006), ≥1 IADL limitation (65% v 33%, p=0.018), physician KPS ≤80 (53% v 27%, p=0.042), limitations in vigorous activities (100% v 78%, p=0.023) and limitations in climbing several flights of stairs (88% v 56%, p&lt;0.001). Predictors of PRO-CTCAE G≥3 toxicity were ≥1 falls (30% v 11%, p=0.030), ≥3 comorbidities (52% v 26%, p=0.011), polypharmacy (≥9 meds) (67% v 43%, p=0.023), and physician KPS ≤80 (43% v 22%, p=0.030). CGA domains associated with ≥1 treatment adjustments were polypharmacy (62% v 33%, p=0.017) and unintentional weight loss (35% v 12%, p=0.028). Polypharmacy was the only domain associated with healthcare utilization (68% v 45%, p = 0.040), which may reflect underlying multimorbidity and greater pain burden. On multivariable logistic regression, any level of limitation in climbing several flights of stairs (OR: 6.0, 95% CI 1.2-30.3; p= 0.030) and older age (OR: 1.1, 95% CI 1.0-1.1; p=0.032) were independently associated with G≥3 non-hem toxicity, reflecting impaired functional status and reduced physiologic reserve, while ≥3 comorbidities only trended toward significance (OR:1.9, 95% CI 1.1-3.9, p=0.051).Compared to baseline, there were no significant changes in CGA domains or PROMIS10 scores after 4 cycles. While there was no significant difference in the proportion of pts reporting limitations in IADLs or physical function, we observed heterogeneity among individual pts, with changes in all 3 directions (improvement, stability, and decline). Conclusions: Geriatric impairments are prevalent in older pts with MM; pt-reported impairments are significantly associated with G≥3 non-hem toxicities, need for treatment modifications, and increased healthcare utilization, even in the era of novel therapies. Physical functional trajectories during treatment are variable among individual pts, underscoring the need for personalized treatment strategies and reassessment of geriatric domains throughout treatment.

Abstract Background The advent of T-cell redirecting bispecific antibodies (BsAb) therapies has led to deeper and durable responses in patients with RRMM. We sought to identify adverse prognostic factors for patients treated with BsAbs. We also explored whether the extent of the non-involved free light chain (niFLC) suppression could serve as a potential marker of T-cell engager activity, given the binding of BsAbs to both clonal and non-clonal plasma cells and the short half-life of serum FLCs. Methods We conducted a retrospective analysis of RRMM patients treated with BsAbs between 2022 and 2025 at Mayo Clinic. Baseline lymphocyte counts and ferritin levels were collected and analyzed both as continuous and dichotomized variables. niFLC was considered undetectable if it was below the quantification limit, while the magnitude of niFLC suppression was defined as the absolute difference between niFLC levels and the lower normal range threshold at the time of best response. In addition to standard statistical methods, interaction models were used to explore the potential effect modification of niFLC dynamics. Results A total of 158 patients were included (teclistamab, 73%; talquetamab, 15%; elranatamab, 12%). The median follow-up is 12 months (range 0 to 28 months). Median age is 71(range 65 to 77); 52% (n=85) were triple-class refractory (refractory to an IMiD, a PI, and CD38-antibody) and 37% (n=60) were penta-refractory. CAR-T therapy was previously administered in 28% (n = 46) patients, and 70% had undergone an autologous stem cell transplant. One or more high risk cytogenetic features including del(17p), gain(1q), amp(1q), del(1p), t(4;14), and t(14;16) were present in 57% (n = 90) of patients. Extramedullary disease was noted at the time of BsAb therapy in 44% of patients. Utilizing IMWG response criteria, 68% (n=107) achieved ≥partial response, and 64% (n=101) had ≥ very good partial response (VGPR) as best response following BsAb treatment. The median time to best response was 1.6 months (range 0.7 to 4.4). On multivariable analyses, baseline immunoparesis (HR 1.96; 95% CI, 1.08–3.58; p = 0.0274) and elevated ferritin levels (≥ 337 ng/mL) (HR 1.96; 95% CI, 1.24–3.09; p = 0.0041) were independent predictors of inferior progression-free survival (PFS). Lower baseline absolute lymphocyte count, analyzed as a continuous variable, was significantly associated with shorter PFS in the univariable analysis (HR 0.66; 95% CI, 0.44–0.98; p = 0.04), but not in the multivariable model (HR 0.75; 95% CI, 0.5–1.13; p = 0.166). Detectable niFLC at the time of best response was also significantly associated with inferior PFS (HR 1.80; 95% CI, 1.14–2.84; p = 0.0114). However, the magnitude of niFLC suppression did not show a statistically significant impact on PFS. The median PFS was 5 months in patients with high ferritin levels (≥ 337 ng/mL) and 21 months in those with lower ferritin (p = &lt; 0.005). Similarly, PFS was 8 months in those with immunoparesis and not reached in those without baseline immunoparesis (p = 0.008). At the time of best response, detectable niFLC was associated with a trend toward shorter PFS (5 vs. 13 months), although the difference was not significant (p = 0.06). Logistic regression analysis supported these findings, with higher ferritin levels (OR 2.28; 95% CI: 1.09–4.96; p = 0.032) and the presence of baseline immunoparesis (OR 2.60; 95% CI: 1.18–6; p = 0.02) being significantly associated with higher likelihood of progression or death. Patients with deep reduction in niFLC achieved a VGPR or better. In contrast, those with detectable or higher-than-normal niFLC levels did worse in terms of response. Notably, niFLC became undetectable in 72% of patients with ≥VGPR (73/101), compared to 52% of those who did not achieve this level of response (30/57). Conclusion Among RRMM patients treated with BsAbs, baseline immunoparesis and elevated ferritin levels emerged as independent predictors of worse PFS. While failure to induce a deep reduction in niFLC at the time of best response suggests a tumor extrinsic mechanism of resistance, and it is also linked to inferior outcomes.