Cook, Joselle

Abstract Background Multiple myeloma, the second most common hematologic malignancy, has witnessed incremental progress in its management over the past decade underscored by substantial improvement in patient outcomes, although it remains largely incurable. Due to its relapsing-remitting course with current therapies, patients experience considerable burden, particularly with the use of parenteral regimens that are administered on a continuous basis. As such, exploration of newer oral, finite-duration therapeutic options may be of benefit. Selinexor, an oral selective exportin (XPO)-1 inhibitor has an established synergistic activity with other antimyeloma therapies, including immunomodulatory drugs and proteasome inhibitors. In combination with dexamethasone, selinexor is currently approved at 80 mg twice a week dose, and in combination with bortezomib plus dexamethasone, it is approved at 100 mg once weekly dose for patients with relapsed and/or refractory multiple myeloma (RRMM). Herein, we present the results of Arm B of the 2-arm SCOPE trial that examined an all-oral regimen of selinexor, pomalidomide and low-dose dexamethasone (SPd) regimen for RRMM. Methods The SCOPE trial is an investigator-initiated, single arm, phase 2 study that assessed the efficacy and safety of selinexor (S), 60 mg orally (PO) weekly, pomalidomide (P), 4 mg PO, days 1-21 and dexamethasone (d), 40 mg PO, weekly in 28-day cycles given for a fixed duration (total 18 cycles ) in patients who were exposed to up to 2 prior lines of antimyeloma therapy, at least one of which included both a proteasome inhibitor and the immunomodulatory agent, lenalidomide. Olanzapine, along with a 5-HT3 antagonist comprised the mandatory anti-emetic prophylactic regimen. The trial's primary endpoint was overall response rate (ORR), based on confirmed response, and the key secondary endpoints were progression-free survival (PFS), duration of response (DOR), overall survival (OS), and safety of SPd. The International Myeloma Working Group (IMWG) 2016 criteria were used for response assessment in addition to reporting of the minor response. The distribution of PFS and OS was estimated using the Kaplan Meier method. Toxicity was graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 5. Results At the data cutoff date (May 28, 2025), 28 of 29 enrolled patients with RRMM were evaluable. The median age at study entry was 67.5 years (range: 65-72 years). SPd was used as the first salvage regimen in 21% of patients, and the remaining 79% of patients had previously received 2 lines of therapy at study entry. All patients had previously been exposed to a proteasome inhibitor and an immunomodulatory agent, and 32% were dual refractory. Notably, 64% of patients had previously been exposed to the anti-CD38 monoclonal antibody, daratumumab, and 11% of patients were daratumumab-refractory. The median follow-up was 23.9 months (range: 2.9-38.8 months). The patients had received a median of 9 cycles of SPd (range:1-18 cycles), and at data cutoff, 36% of patients had completed all the planned 18 cycles of SPd. The ORR was 61% (95% CI:41-78) and the rate of measurable residual disease (MRD)-negative complete response (CR) was 21%, CR 11%, very good partial response (VGPR) 18%, partial response (PR) 11% as the best response achieved. Additionally, 7% and 25% of patients had attained a minor response (MR) and stable disease (SD), respectively. The median PFS was 24 months [95% CI: 7.1– not-estimable (NE)] months, and the median DOR was not reached (NR). 2-year OS rate was 93%. The toxicity associated discontinuation rate was 7%, and no grade (Gd) 5 events or unexpected toxicities were encountered during treatment. Gd 3 or higher hematologic toxicities occurred in 43% [Gd 3/4 anemia (11%/0%), thrombocytopenia (14%/0%), neutropenia (25%/7%), lymphopenia (4%/4%)]. Gd 3+ non-hematologic toxicities occurred in 46% [Gd 3 /4 (%) infections (21%/0%), fatigue (4%/0%), nausea (7%/0%) and anorexia (0%/7%). No patients experienced Gd 3 or 4 diarrhea, vomiting or weight loss. Additional data will be presented at the meeting. Conclusion Weekly selinexor in combination with pomalidomide and dexamethasone is an effective and safe, all-oral regimen for patients with RRMM who are previously exposed to a proteasome inhibitor and lenalidomide. SPd regimen is currently being examined in an ongoing phase 3 randomized controlled trial.

Abstract Introduction: Suboptimal response to therapy, early disease relapse, and limited long-term survival remain critical challenges in a substantial number of patients with multiple myeloma (MM). While cross-sectional imaging studies are commonly obtained in clinical practice, only limited information is currently incorporated into risk stratification efforts and clinical decision making. Here, we investigate the use of novel image-based biomarkers to identify patients at high risk for adverse outcomes. Methods: We obtained the pretreatment 18F-FDG PET/CT scans of patients with newly diagnosed MM with available clinical and laboratory data seen at Mayo Clinic between 2006 and 2022. In this analysis, we included 637 patients with detectable metabolic tumor volume on their pretreatment scan. The native DICOM images were pre-processed and subjected to automated image segmentation using nnU-Net (nnU-Net v1.0, inference using a pre-trained hematologic malignancies model). Limitations of this automated segmentation approach include heterogeneity introduced by varying image quality, technical variability in PET reconstruction, and potential inclusion of non-neoplastic FDG-avid lesions in segmented regions. PyRadiomics was used to extract quantitative radiomics features for clinical prediction modeling. We evaluated the predictive power of tumor size-, shape-, and texture-related radiomics features for identifying high-risk disease (advanced ISS stage at diagnosis, the presence of high-risk FISH abnormalities, failure to achieve a stringent complete response [sCR] to first-line therapy by IWMG criteria, and early mortality). All radiomics features were quantile-normalized for downstream modeling. Forward and backward feature selection as well as testing for multicollinearity were used to remove redundant features. Results: Median age at diagnosis of the 637 myeloma patients was 64 years (range 22–90), and 387 patients (61%) were male. After a median follow-up of 4.4 years (95% CI 0.2–11.7), median overall survival (OS) was 7.3 years (95% CI 6.3–8.3). Increased total tumor volume (upper tertile vs lower tertiles), measured by the total tumor surface area, was associated with advanced ISS stage (III vs I+II; OR 1.73, 95% CI 1.24–2.42, p=0.001, n=637). Increased tumor density (dichotomized at the median), measured by the median gray level intensity (OR 1.93, 95% CI 1.94–3.12, p=0.007, n=303), and decreased tumor heterogeneity (lower tertile vs upper tertiles), measured by the variability of gray-level intensities (OR 1.88, 95% CI 1.49–3.12, p=0.012, n=303), were associated with the presence of high-risk cytogenetics. Both increased total tumor volume (4.9% increase per tertile, 95% CI 2.2–7.6, p<0.001, n=600) and tumor density (8.9% increase per tertile, 95% CI 4.5–13.3, p<0.001, n=600) were independently associated with more extensive bone marrow involvement at diagnosis. Increased tumor heterogeneity (upper tertiles vs lower tertile), as measured by rapid changes of gray level intensities, was associated with failure to achieve a stringent complete response to first-line therapy (OR 0.50, 95% CI 0.30–0.82, p=0.006, n=351). Increased tumor volume was associated with shorter OS (HR 1.35 per tertile, 95% CI 1.11–1.63, p=0.002, n=301), independent of age, sex, ISS stage, and the presence of high-risk cytogenetics. A simple additive score consisting of tertiles of total tumor volume, ISS stage, and plasma cell labeling index ≥2% identified patients at risk of mortality within 3 years of diagnosis (OR 2.00, 95% CI 1.40–2.85, p<0.001, n=126), with moderate discrimination (AUC=0.71). Sensitivity analysis demonstrated total tumor volume and texture as most predictive of overall survival in a random forest survival model (C-index 0.712, 95% CI 0.649–0.775) and tumor texture as most predictive of response to therapy in a random forest classification model (C-index 0.693, 95% CI 0.607–0.779). Conclusions: Automated image segmentation and radiomics feature extraction from 18F-FDG PET/CT scans produces biomarkers that capture disease stage, burden, and risk in newly diagnosed MM. Total tumor volume and heterogeneity are strongly associated with important disease characteristics and can be used to identify patients at high risk for therapeutic resistance, early mortality, and inferior long-term outcomes.

Abstract Introduction Cila-cel is associated with a 10-15% risk of delayed neurotoxicity (DNT) with rates of cranial nerve palsies (IEC-NP) and parkinsonism (IEC-PKS) seen at a rate of 10% and 1-4% respectively and can occur as early as 3-4 weeks after infusion. We and others have shown that high post-infusion peak absolute lymphocyte count (ALCpeak) of >3x10^9/L is associated with an increased risk of delayed neurotoxicity (Lim et al., ASCO 2025) whilst the risk was negligible (~1%) when ALCpeak fell below that threshold. Since December 2024, we implemented prophylactic administration of dexamethasone (PPX DEX) when ALC was >3x10^9/L (defined as high ALCpeak). Outcome of these patients are described here. Methods Analysis of clinical outcome included 230 pts treated between Feb 2022 and Nov 2024 as a historical cohort and 102 patients treated between Dec 2024 and May 2025 after the introduction of dexamethasone prophylaxis using an oral dose of 10mg twice a day for at least three days in the high ALCpeak cohort. Results No significant differences were seen between the new and historical cohort in pre-lymphodepletion disease burden (bone marrow plasma cell %, involved light chain or M-spike level), and rates of all/high-grade CRS or ICANS, IEC-HS and rates of tocilizumub use. Median follow-up in the new cohort of 102 pts was 3.6 months (95% CI 3.3-4.2). Eleven (10.8%) developed DNT [3 (2.9%) with IEC-PKS, 8 (7.8%) with IEC-NP]. High ALCpeak of >3x10^9/L was observed in 51 (50%) pts. Among pts with high ALCpeak, DNT was observed in 10 (20%) pts [3 (5.9%) with IEC-PKS, 7 (13.7%) with IEC-NP] whereas among 51 pts with ALCpeak <3x10^9/L, DNT was observed in 1 (2%) pt [1 (2%) with IEC-NP]. In the high ALCpeak cohort, 38 (75%) received DEX [6 (12%) for toxicity management, 32 (63%) PPX DEX]. Of the 38 pts treated with DEX, DNT was observed in 6 (16%) pts (2 (5.3%) IEC-PKS, 4 (10.5%) IEC-CNP). We next compared DNT rates between this new cohort of high ALCpeak pts receiving DEX (n=38) against the historical cohort with high ALCpeak (n=98). Estimated 90-day DNT by Kaplan-Meier method was (19.2% vs 20.5%; p=0.53): IEC-PKS (5.8% vs 7.2%; p=0.60) and IEC-NP (11.7% vs 13.3%; p=0.58). In patients with high ALCpeak, the use of DEX did not appear to significantly reduce the risk of DNT compared to historical controls (HR 0.76, 0.33-1.78), IEC-PKS (HR 0.67, 0.14-3.10) or IEC-NP (0.73, 0.24-2.23). We next compared ALC expansion over the first month post CAR-T infusion (area under the curve, AUC). Among the new cohort of 102 patients, no difference was seen in the AUC of pts who received DEX but did not develop DNT vs those who developed DNT (31.0 vs 57.9, p=0.28); No difference in AUC was seen in the new high ALCpeak cohort receiving DEX vs the historical cohort with high ALCpeak (36.0 vs 43.8, p=0.15) Of the eight cases of IEC-NP, 4 received PPX DEX. No noticeable differences were observed in the severity of presentation, laterality of cranial nerve involvement and rates of multiple cranial nerve involvement between these 4 cases who received PPX DEX and the 16 cases from the historical cohort. At the time of database freeze, 3 of the 4 cases had resolved and 1 was improving. Median time to complete symptom resolution was 38 days vs 69 days in the historical cohort. Of the three cases of IEC-PKS, 2 received PPX DEX. Median time to symptom onset for IEC-PKS was 46 days (vs. 24 days in historical cohort). Both cases had severe symptoms non-responsive to first line high-dose methylprednisolone, second line intrathecal chemotherapy and third line high-dose cyclophosphamide. Both pts subsequently died from sepsis 28 and 67 days post-cyclophosphamide. Conclusion While ALCpeak >3x10^9/L predicts risk of DNT in pts treated with cilta-cel, the use of PPX DEX does not appear to significantly reduce ALC expansion and does not appear to significantly reduce the risk of DNT, IEC-PKS or IEC-NP. Other strategies to reduce ALC or alter T cell functions may need to be considered.

Abstract Background: Multiple myeloma patients face complex barriers to diagnosis, care access, support, and navigation. This study analyzes patient-reported experiences to identify structural gaps and cluster patients into meaningful segments based on their needs and perceptions. Methods: We administered a 48-item anonymous survey to adult myeloma patients at the Medical College of Wisconsin and through national platforms, including the International Myeloma Foundation, Leukemia & Lymphoma Society, and Facebook groups. The survey assessed demographics, treatment experiences, delays, perceived personalization, and barriers to care. We used JMP 17 for analysis and Julius.AI for visualization. Rule based segmentation of structured responses was used to identify distinct patient personas. Chi-square tests assessed associations, with p < 0.05 considered significant. The study was IRB-approved. Results : A total of 320 participants responded between April 25 and June 5, 2025; 289 (90.3%) completed the survey in full. The cohort was predominantly older (55.7%, n=170/305 between 60- 75), White (79.3%, n=241/304), female (58.9%, n=179/304), highly educated (89.5%, n=272/304), and suburban (52.5%, n=159/303). Modal insurance types were Medicare (37.8%) or private insurance (30.9%); 11.2% both. Most (69.7%) reported a smooth treatment start; delays were primarily due to insurance/cost (4%). Using rule-based segmentation of structured responses, we identified three distinct patient personas: (1) Empowered but Unsupported (n=56; 17.5%) who indicated no emotional support barriers, less interest in navigators, but frequent reports of unmet needs such as poor communication. (2) Engaged and Informed (n=105; 32.8%): Highly motivated patients who requested personalized care, clinical trial transparency, or insurance navigation and (3) Delayed and Discouraged (n=35; 10.9%) who reported lower support, diagnostic delays, and a strong perception of race-related disparities. Unclassifiable personas (n=124) were due to missing or neutral responses There was no difference in self identified race across the personas (p = 0.08), but 100% of the Delayed/ Discouraged group believed race played a role in care, compared with 44% of the Engaged/Informed and 21.4% of the Empowered/Unsupported (p < 0.001). Minoritized patients (86.7% Black, 100% other minoritized) were more likely to perceive race as a factor (p = 0.0024). Empowered/Unsupported patients were significantly more likely to request better communication (100%) and empathy (53.6%), while Engaged and Informed patients prioritized clinical trial access (61%). None of the Delayed and Discouraged patients made this request (p < 0.0001). Black respondents most frequently expressed the need for greater empathy (53.7%; p = 0.0012). Those <60 (40.2%, n=33) were more likely to express interest in clinical trials (p=0.03), this interest did not vary by race (p=0.36). Interest in patient navigation did not significantly differ by education level (p = 0.3), suggesting that even highly educated patients may struggle with treatment complexity. Most patients felt their care was personalized (71.1% 207/291), with no differences by race (p = 0.55), but perceptions varied by persona with only 39.1% of Engaged/Informed patients felt their treatment was always tailored, vs. 61.8% of Empowered/Unsupported and 88.6% of Delayed/Discouraged (p < 0.0001), contrasting patients' expectations with the actual delivery of care. Conclusion: Patient-reported experiences reveal distinct personas with differing needs, perceptions and expectations of care. While most patients reported smooth treatment transitions and felt their care was personalized, gaps persist particularly among highly engaged patients who report unmet expectations around communication, personalization, and trial access. Perceptions of racial disparities persist, especially among minoritized groups illuminating the unequal experiences of patients within the myeloma care landscape. These findings stress the importance of segmenting care approaches to align with patient identity, complexity, and support needs in multiple myeloma.

Abstract Background Measurable residual disease (MRD) negativity post- autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (MM) is associated with favorable outcomes and may overcome the adverse impact of high-risk cytogenetic abnormalities (HRCAs). However, as the definition of high risk evolves and MRD emerges as a key endpoint, understanding its prognostic value within individual HRCAs is critical for treatment guidance. Methods We retrospectively included patients with NDMM that underwent an ASCT between September 19, 2016, and October 19, 2023, and achieved MRD negativity on Day 100 post ASCT. The MRD testing was conducted using multiparameter flow cytometry with a sensitivity of 2x10. HRCAs were defined as del(17p), 1q21+ gain or amplification (1q21+), t(4;14), t(14;16), t(14;20) and del(1p) and rest were considered standard risk (SRCA). Patients were grouped by the number of HRCAs (0, 1, ≥2). An adaptation of the recently proposed International Myeloma Society (IMS)/International Myeloma Working Group (IMWG) classification for high-risk disease (TP53 mutation unavailable) was also used. Progression-free survival (PFS), measured from stem-cell infusion to progression or death, was estimated using Kaplan–Meier methodology and compared using log-rank test. Results We identified 386 patients with MRD negativity post ASCT, of which 381 had cytogenetic data available for analysis. The median follow-up for the study cohort was 47.3 months (95% CI: 43.2-50). The median age at the time of ASCT was 65.7 (25.4-79.2) years and 58.3% patients were males. A total of 49% (n=189) patients had standard-risk cytogenetics, 31.4 % (n=121) harbored 1 HRCA, 15.3% (n=59) patients had two HRCAs and 3.1% (n=12) had 3 HRCAs. The individual HRCA by their prevalence were: 1q21+ in 35.5%(n=137), del(17p) in 14.3% (n=55), t(4;14) in 10.9% (n=42), t(14;16) in 5.4% (n=21), del(1p) in 4.2% (n=16), and t(14;20) in 1.04% (n=4) of patients. The most common double-hit lesions were1q21+ gain and/or amplification co-occurring with t(4;14) (33.9%, n=20) and del(17p) with 1q21+ (18.6%, n=11). Despite universal MRD negativity at Day 100, several HRCAs remained prognostically significant for PFS. Patients with del(17p) had worse 3-year PFS (71%) than those without (81%) [hazard ratio (HR)=1.85, 95% CI 1.11–3.07, p = 0.0172], though 3-year OS did not significantly differ at data cutoff (80% vs. 92%, p=0.1176). Presence of 1q21+ was associated with an inferior 3-year PFS (73%) compared to those without [84%, HR: 1.96 (95% CI: 1.25–3.06), p=0.0026], while 3-year OS was similar (88% vs. 91%, HR:1.33 p=0.36). Isolated 1q21+ had inferior PFS with comparable OS when compared to SRCA [3-year PFS of 82% vs. 88% respectively (HR:1.97, p=0.0177)]; 3-year OS was 91% vs. 94% (HR:1.38, p=0.44)]. Among 1q21+ patients, those with co-occurring HRCAs had a 3-year PFS of 66% vs. 81% for isolated 1q21+ (HR: 1.47, p=0.21). Patients with t(4;14) had worse 3-year PFS (64%) vs. 82% in non t(4;14) [HR 2.11(95% CI: 1.21-3.67) p=0.0064], and 3-year OS of 82% compared to 91% [HR 2.14 (95% CI: 1.02–4.49), p=0.038]. Isolated t(4;14) showed a 3-year PFS of 59% vs. 87% in standard-risk (p=0.06), and 3-year OS of 90% vs. 93% [HR 3.29, 95% CI 0.95–11.33, p = 0.06]. The presence of t(14;16), t(14;20), and del(1p) did not significantly affect 3-year PFS (all p>0.1), likely due to small subsets. When patients were grouped by the number of HRCAs, PFS declined with increasing cytogenetic complexity. Compared to standard risk, the 3-year PFS was 77% for 1 HRCA vs [HR = 2.11 (95% CI: 1.29–3.46), p = 0.0027], 67% for ≥2 HRCA [HR = 2.64 (95% CI: 1.53–4.57), p = 0.0005]. Maintenance therapy was used in 98% of patients. Patients with HRCAs received a doublet maintenance compared to SRCA (p<0.0001), even in MRD negative disease post ASCT. Conclusion In patients with certain HRCA, achievement of MRD negativity post-ASCT does not overcome the adverse impact of HRCA on PFS. In our cohort, patients with del(17p), t(4;14), or 1q21+ continued to exhibit significantly shorter PFS despite achieving MRD-negative status. These findings underscore the need for ongoing risk-adapted strategies even in patients with MM who attain MRD-negative state. The OS estimates are immature at this time.

Abstract Background Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM), characterized by the presence of more than 5% circulating plasma cells on a peripheral blood smear. Despite advancements in therapy, including novel agents and autologous stem cell transplantation (ASCT), pPCL remains associated with markedly poorer survival outcomes compared to newly diagnosed MM. Although disease progression is common in pPCL, individual courses vary widely upon relapse and thereafter. We aim to describe the natural history of pPCL, focusing on clinical features and survival outcomes at the time of relapse or disease progression. Methods Patients with pPCL who were followed at our institution's cancer center between 2006-2024 were included for retrospective analysis. The electronic health record was reviewed to provide detailed information on patient demographics, disease characteristics, treatment regimens, and clinical outcomes. Time to next treatment (TTNT) and overall survival (OS) analysis were performed using the Kaplan-Meier method. Statistical analyses were performed using the SAS biostatistical software JMP 17.0.1 (SAS Institute Inc). Results We analyzed a cohort of 106 patients with relapsed pPCL after first-line therapy, all of whom received induction with novel agents. To date, 64 patients (60%) have died. Across the entire cohort, median OS is 39 months (mos) (95% CI: 25-68). 59 patients (56%) were diagnosed after 2015. Baseline FISH cytogenetics were available for 100 patients; 57 (57%) had one or more high-risk cytogenetic abnormality. Nearly all patients (96%) had ≥50% clonal plasma cells on initial bone marrow biopsy. While most patients (n = 61; 58%) were planned to undergo upfront ASCT, 20 (33%) experienced disease progression during induction therapy and required a more intensive salvage regimen (often infusional chemotherapy) prior to ASCT. The median TTNT after first-line therapy (TTNT#1) for the entire cohort was 10.4 mos (95% CI: 8–14). The median TTNT after second-line therapy (TTNT#2) for the entire cohort was 5.7 mos (95% CI: 4.3–7.1). Clinical details at first relapse, prompting initiation of second-line therapy, were available for 91 patients. Of these, 26 patients (29%) had symptomatic relapses—due to CRAB features or extramedullary disease—while 65 patients (71%) experienced asymptomatic biochemical progression. Symptomatic relapses were followed by significantly shorter TTNT#2 (3.9 vs. 7.0 mos; p = 0.039) and inferior OS from the start of second-line therapy (7.5 vs. 31.2 mos; p <0.0001) compared to asymptomatic relapses. The median TTNT#2 for patients who relapsed during induction and received salvage ASCT was 6.9 mos (n=20). In contrast, those treated after relapse with non-ASCT regimens (n = 86) fared worse; those receiving novel agent-based combinations, including doublets, triplets, or quadruplets (n=64) had respective median TTNT#2 of 3.3, 6.0, and 3.3 mos. Patients treated with infusional chemotherapy (n = 9) had the poorest outcomes, with a median TTNT#2 of just 1.4 mos. The median TTNT diminished with each subsequent line of therapy: TTNT#3 (n = 73) was 5.8 mos, TTNT#4 (n = 53) was 4.0 mos, and TTNT#5 (n = 35) was 2.6 mos. Patients with pPCL harboring the t(11;14) cytogenetic abnormality who were treated with venetoclax-based regimens (n = 8) during any line of therapy had a longer corresponding median TTNT of 15.0 mos. Additionally, 23 patients received anti-BCMA CAR-T cell therapy as a post-relapse line of therapy. At last follow-up, 15 of these patients (65%) had not relapsed, and after a median 20.7 mos of follow-up, the median TTNT following CAR-T cell therapy had not yet been reached. Patients who received CAR-T after 1-3 prior lines (n=15) had a median TTNT that was not reached; those who had received 4 or more prior lines (n=8) had a median TTNT of 20 mos. ConclusionsDespite the use of novel agent-based combination regimens and ASCT as first-line therapy, most patients with pPCL eventually experience disease progression. Consistent with MM, symptomatic relapse in pPCL is associated with poorer outcomes compared to asymptomatic biochemical progression. Additionally, the duration of response shortens with each successive line of therapy. Notable exceptions include venetoclax-based regimens in patients with t(11;14), and anti-BCMA CAR-T cell therapies: each appear to confer more durable responses than historical treatments in patients with relapsed pPCL.

Abstract Overview: The emergence of effective immune therapies for multiple myeloma has highlighted the importance of understanding the roles of less abundant components within the tumor microenvironment. Single-cell analyses provide snapshots of the functional relationships of individual cells at precise moments in time, as well as insight into the overall cellular composition. By integrating single-cell datasets from multiple studies, we improve our ability to identify trends within rare cell populations, such as macrophages, and explore their clinical implications. We investigate human data here because our prior research of murine models indicated that macrophages expressing C1q, particularly those co-expressing Fcgr4, tend to correlate positively with increased tumor burden. Methods: We combined 56 human bone marrow samples – primarily collected at baseline, post-induction, or post-ASCT – with three publicly available data sets: GSE210079 (post CAR-T bone marrow microenvironment); GSE223060 (single-cell analysis of the MMRF cohort); and GSE271107 (disease progression from healthy donors and MGUS to SMM and NDMM). These data sets were integrated using Seurat to generate robust cellular clusters from over 300,000 cells across 117 samples. We validated our single-cell findings with bulk Affymetrix, whole bone marrow gene expression data (collected at baseline and post-baseline) from the Total Therapy clinical trials (GSE136324). Results: A distinct cluster of C1QA/B/C-expressing macrophages was consistently identified in all single-cell cohorts. These cells co-express FCER1G, CSF1R, and CD68 (markers also expressed in murine C1Q macrophages) and typically cluster adjacent to FCGR3A-expressing monocytes. Within the disease progression cohort, C1Q macrophages were found in all phases of progression: healthy donors, MGUS, SMM, and NDMM. However, C1Q macrophages in progressive disease (SMM and NDMM) have distinct expression features including lower levels of MRC1 and higher levels of APOBEC3A and ISG15 – genes linked to inflammatory responses. Among 11 post-induction samples submitted to lenalidomide maintenance, five with shorter responses displayed elevated expression of APOBEC3A and ISG15 in C1Q-expressing macrophages compared to six samples with longer responses. In a cohort of 22 samples 100 days post-ASCT, seven poor responders showed both an increased frequency of C1Q macrophages and elevated APOBEC3A expression compared to good responders. The MMRF cohort indicated that higher baseline frequencies of C1Q macrophages often preceded rapid disease progression (e.g. MMRF_1720, MMRF_1641). Anecdotal evidence from the CAR-T therapy cohort suggests that expansion of C1Q macrophages could serve as an early warning for tumor recurrence; sample 16 showed retention and expansion of C1Q macrophages 28 days post-CAR-T, that was subsequently followed by increased tumor cell counts at 3 months post-therapy. Analysis of bulk, whole bone marrow gene expression revealed that elevated levels of C1Q genes correlated with poorer outcomes, particularly in post-baseline samples. Multivariate Cox survival analysis revealed that high C1Q expression independently predicted inferior overall survival in post-baseline samples after adjusting for age, ISS stage, high levels of tumor-associated markers (SDC1, JCHAIN, DERL3), and high-risk UAMS7 subtypes (MF, MS, PR). Moreover, post-baseline GEP70 risk scores (from matched bone marrow aspirates) positively correlated with elevated C1Q expression in whole bone marrow samples. Conclusion: Both single-cell and bulk analyses indicate that the persistence of immunosuppressive C1Q macrophages following therapy is associated with inferior clinical outcomes. Although the precise mechanisms are yet to be fully understood, the close proximity of similar macrophages to tumor cells–as observed in other cancers–likely also occurs in myeloma and reflects the crucial relationship between tumor cells and macrophages within the bone marrow. While C1Q macrophages are typically rare in individual samples, analysis of combined cohorts is building evidence of their crucial role in immune cross-talk and therapeutic resistance mechanisms.

Abstract Introduction: While the incidence of multiple myeloma (MM) is 2-3 fold higher in Black compared to white individuals, the impact of racial differences on treatment outcomes remains unclear due to the confounding effect of socioeconomic barriers and disparities in access to effective therapies and clinical trials. In this study, we explored the relationship between race, social deprivation, and outcomes in newly diagnosed MM (NDMM) patients (pts) receiving modern therapies with triplet or quadruplet regimens. Methods: Pts with NDMM diagnosis, who received first line treatment between 2015-2025, and had data available on response and survival outcomes were identified through the ASH Research Collaborative MM Data Hub (a real-world database with pts across 11 U.S. institutions). Data on patient demographics (age, race, ethnicity, sex), disease risk status (ISS/R-ISS stage, FISH cytogenetics), treatment regimens (triplet vs quadruplet, anti CD38 monoclonal antibody-based vs not), and disparity measures were abstracted from electronic medical records. Race and ethnicity were self-reported by pts. Social Deprivation Index (SDI) score was calculated based on ZIP code, where higher scores reflect greater deprivation. Progression free survival (PFS) was defined as time from start of treatment until progression or death. Overall survival (OS) was defined as time from start of treatment until death from any cause. Kaplan-Meier methods were used to compare PFS and OS between groups, and cox regression models with log-rank tests were used to evaluate the influence of various factors on outcomes. Results: A total of 1,743 patients were identified; 1,116 (63.8%) identified as non-Hispanic White (NHW) and 402 (23.3%) as non-Hispanic Black (NHB) [note: 85 pts (4.9%) were Hispanic but not included due to limited numbers]. The median age (years) at the start of treatment (61.8 vs. 65.6) was lower for NHB compared to NHW pts (p<0.001). The proportion of females was greater in NHBthan NHW pts(53.5% vs. 41.1%, p=0.0016). Median SDI scores were significantly higher for NHBcompared to NHW pts (68.4 vs. 39.4; respectively; p<0.001), reflecting significantly higher rates of social deprivation. While NHB ptshad higher rates of advanced stage disease (ISS III 26.9% vs. 20.9%, p=0.009), lower rates of autologous stem cell transplant (ASCT) (56.7% vs. 63.6%, p=0.014), and longer median time from treatment initiation to ASCT (6.5 vs. 5.9 months, p=0.043), the rates of standard risk cytogenetics on FISH (72.3% vs. 77.6%), and utilization of CD38 monoclonal antibody-based regimen (29.9% vs. 27.7%) were similar between the two groups. Best response after treatment initiation was similar between the NHB and NHW pts (p=0.12) with complete response 45.7% vs. 52.6% and very good partial response 37.3% vs 34.7%; respectively. However, time to best response (months) was longer in NHB pts (7.2 vs. 6.5, p=0.005). Median follow-up for OS was 4.2 years (95% CI 3.9-4.4; 182 OS events) and for PFS was 1.3 years (95% CI: 1.1-1.6; 302 PFS events) across the two groups. Unadjusted PFS was similar for NHB vs NHW pts (HR=1.05, 95% CI: 0.81- 1.36; median: 5.0 vs 4.9 years; 3-year PFS: 66% vs. 71%). Similarly, unadjusted OS was not significantly different in NHB vs NHW pts (HR=1.12, 95% CI: 0.79-1.59; 5-year OS: 86.4% vs 85.6%). Higher SDI scores were significantly associated with worse OS (HR=1.07, 95% CI: 1.02-1.12; p=0.0065) but not PFS (HR=0.99, 95% CI: 0.95-1.02; p=0.46). Though not statistically significant, univariate analyses indicated a greater impact of high SDI scores (≥70, 75th percentile across all pts) in NHW (HR=1.45, p=0.068) than in NHB pts (HR=0.78, p=0.35) for OS. Adjusting for age, sex, ISS stage, and SDI, NHB did not appear to have worse OS (HR=0.75, 95% CI: 0.35-1.60; p=0.46) or PFS (HR=1.23, 95% CI: 0.78-1.96; p=0.37) compared to NHW pts. Conclusions: Our study represents a diverse population enriched for pts who received modern day standard of care frontline therapies including triplet and quadruplet regimens with or without ASCT. Based on SDI scores, higher social deprivation levels were seen in NHB compared to NHW pts without a difference in outcomes between the two races. Our analysis supports that higher social deprivation among different races rather than race and ethnicity alone may drive differential outcomes and adjustment for factors like SDI is critical to interpretation of survival outcomes by race.

Abstract Introduction LINVO, a human B-cell maturation antigen (BCMA)xCD3 bispecific antibody, was recently approved for triple-class exposed (TCE) RRMM after ≥3 prior therapies (EU) or ≥4 prior lines of therapy (US), demonstrating high efficacy and a generally manageable safety profile. Combining LINVO with an anti-CD38 mAb, such as DARA or ISA, may provide additional benefit to pts with RRMM. Here we report pooled safety and efficacy results from the LINVO + DARA and LINVO + ISA cohorts during the dose-finding portion of the Phase 1b LINKER-MM2 trial (NCT05137054). Methods Eligible pts were aged ≥18 years with RRMM that progressed after ≥3 lines of therapy (LoTs), or ≥2 LoTs if TCE or double-class refractory (immunomodulatory drug [IMiD] + proteasome inhibitor [PI]). Prior treatment (tx) with DARA or ISA was allowed if previously tolerated and ≥6 months (mos) or ≥3 mos washout, respectively, had elapsed since last exposure. Tx began with LINVO monotherapy (Cycle [C]0; 28-day cycle) consisting of 2 step-up doses (5 mg, 25 mg) and 2 full doses (dose level [DL]1 100 mg; DL1b 150 mg; DL2 200 mg) before standard dosing of DARA or ISA was added at C1. LINVO was given once weekly in C1–3 and once every 2 weeks in C4+. At the end of 2024, dosing once every 4 weeks was implemented after C6 if a very good partial response or better (≥VGPR) was achieved. Dexamethasone premedication was required during the first 2 cycles and then given per label for DARA or ISA. Primary endpoints: dose-limiting toxicities (DLTs) and tx-emergent adverse events (TEAEs). Key secondary endpoints: overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and rate of minimal residual disease (MRD) negativity. The analyses reported here combine the LINVO + DARA and LINVO + ISA cohorts. Results As of May 7, 2025, 42 pts were enrolled. All pts were included in the safety analysis set: DL1 (DARA, n=12; ISA, n=6), DL1b (n=6; n=10), or DL2 (n=8; n=0); 37 were included in the efficacy analysis set: DL1 (DARA, n=11; ISA, n=5), DL1b (n=5; n=9), or DL2 (n=7; n=0). At baseline, all pts had received ≥1 PI (refractory to ≥1 PI: 76%) or ≥1 IMiD (refractory to ≥1 IMiD: 86%), and 21 pts (50%) had received prior DARA or ISA (refractory to DARA or ISA: 33% [DARA, n=4; ISA, n=10]). Median number of prior LoTs was 3 (range 2–8), including 50% of pts with TCE and 21% with triple-class refractory disease. Median age was 68 years (range 42–86); male, 57%; ISS stage III at study entry, 12%; high-risk cytogenetics, 31%; bone marrow plasma cells ≥50%, 31%; and soft tissue plasmacytomas, 33% (extramedullary, 12%). Median follow-up duration was 14.8 mos for DL1 (DARA 21.3; ISA 11.3), 7.6 mos for DL1b (DARA 13.5; ISA 5.2), and 5.9 mos for DL2 (all DARA), with 44%, 50%, and 63% of pts still receiving tx, respectively. The most common TEAEs were anemia (any grade [Gr] 48%; Gr 3/4 26%), neutropenia (41%; 41%), diarrhea (38%; 2%), and thrombocytopenia (38%; 17%). Cytokine release syndrome was reported in 33% of pts (all Gr 1/2 events except 1 Gr 3 event during the step-up period that fully resolved). No pts experienced immune effector cell-associated neurotoxicity syndrome (ICANS). Infections were reported in 32 pts (any Gr 76%; Gr ≥3 40%), and 3 resulted in death (1 tx related: cytomegalovirus [CMV] pneumonia; 2 tx unrelated: C. diff colitis and lower respiratory infection). One DLT was observed at DL1b in the ISA cohort (Gr 3 Epstein–Barr virus pharyngitis) and 1 was observed at DL2 in the DARA cohort (Gr 5 CMV pneumonia). Among efficacy evaluable pts, ORR was 75% at DL1 (12/16; ≥VGPR rate 75%), 93% at DL1b (13/14; ≥VGPR rate 57%), and 86% at DL2 (6/7; ≥VGPR rate 86%). Of 10 MRD-evaluable pts, all were MRD negative (<10−5by clonoSEQ or EuroFlow). The 12-mo DOR rate was 79% (95% confidence interval [CI] 52–92; median DOR not reached) and 12-mo PFS rate was 73% (95% CI 53–86; median PFS not reached). Pharmacokinetic analyses showed LINVO concentrations were not affected by the addition of DARA or ISA. ConclusionsIn pts with heavily pretreated RRMM, half of whom had prior anti-CD38 mAb exposure, the combination of LINVO and DARA or ISA was feasible, inducing a high rate of deep and durable responses, and exhibiting a safety profile similar to that reported for each individual drug. These preliminary data support continued development of LINVO plus an anti-CD38 mAb for the tx of pts with MM.