CD38-targeted antibody-polymer drug conjugates for enhanced treatment of multiple myeloma.

Safety and efficacy of linvoseltamab (LINVO) combined with anti-CD38 monoclonal antibodies (mAbs) daratumumab (DARA) or isatuximab (ISA) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Initial results from the multicohort, Phase 1b LINKER-MM2 trial

Impact of addition of anti-CD38 monoclonal antibody to first line therapy in newly diagnosed multiple myeloma with high risk cytogenetics: A systematic review and meta-analysis of randomized trials

A clinical overview of infection in patients receiving elranatamab (ELRA) in combination with daratumumab (DARA) and lenalidomide (R) for newly diagnosed multiple myeloma in the MagnetisMM-6 trial

The B2M–LILRB1 axis as a novel myeloid immune checkpoint and therapeutic target in multiple myeloma

Impact of tumor burden on the risk of cytokine release syndrome (CRS) in patients with multiple myeloma treated with elranatamab (ELRA) in combination with daratumumab (DARA) and lenalidomide (R) in the MagnetisMM-6 trial

Cardiac risk factors and cardiac events in patients with newly diagnosed amyloid light chain (AL) amyloidosis from the Phase 2 aquarius study of daratumumab (DARA) plus bortezomib, cyclophosphamide, and dexamethasone (D-VCd)

Longitudinal analysis of MRD negativity and immune dynamics in patients with transplant-ineligible newly diagnosed multiple myeloma treated with iberdomide, daratumumab, and dexamethasone from the CC-220-MM-001 trial

Iberdomide plus daratumumab and dexamethasone (IberDd) in patients with newly diagnosed multiple myeloma by renal function: A subgroup analysis of the CC-220-MM-001 trial

Rationale:Primary heavy and light chain amyloidosis (AHL) is extremely rare globally. This study aimed to report the first clinical treatment of AHL secondary diabetes. We also analyzed fasting blood glucose levels across various treatments. Finally, a reference was provided for treatment and laboratory indicators in AHL with secondary diabetes.Patient concerns:The patient was treated in Department of Hematology in Deyang People’s Hospital. He underwent treatment with daratumumab (DARA) + cyclophosphamide, bortezomib, and dexamethasone (CyBorD), autologous stem cell transplantation and bortezomib for AHL, alongside empagliflozin for blood glucose management. Clinical data and laboratory results were collected during phases of treatment and follow-up.Diagnoses:This patient was a middle-aged man with 2 months of swelling in both lower limbs. Tests, including serum and urine analyses and a kidney biopsy, diagnosed him with AHL (IgA-λ).Interventions:He was diagnosed with diabetes after 4 courses of DARA + CyBorD. Then DARA was discontinued. CyBorD, autologous stem cell transplantation, and bortezomib were continued for AHL, alongside empagliflozin for blood glucose management.Outcomes:Finally, very good partial remission and effective control of blood sugar were obtained.Lessons:Current study presented a case of AHL with secondary diabetes following treatment with DARA + CyBorD. For patients with high fasting blood glucose undergoing targeted therapy or chemotherapy, oral glucose tolerance test and glycosylated hemoglobin tests were necessary for the overall health. The difference between free light chain trend changed earlier than 24-hour urine protein, offering guidance for early AHL treatment and enhancing patient quality of life.

Daratumumab (DARA) is a human monoclonal antibody that specifically targets the CD38 protein, which is predominantly expressed in multiple myeloma (MM) cells. However, DARA also binds to CD38 antigens that are sparsely present in red blood cells, leading to difficulties during pre-transfusion testing. It is essential to address DARA’s interference in pre-transfusion testing before proceeding with transfusions. Three MM patients undergoing DARA treatment in our center experienced interference during pre-transfusion testing. The pretransfusion testing included blood grouping, antibody screening, and cross-matching. DARA interference resulted in pan-positive reactions in antibody screening and identification panels and incompatible cross-matches. This interference can mimic high-incidence alloantibodies or warm autoantibodies. To eliminate the interference of DARA in antibody screening, identification, and compatibility testing, we utilized 0.2 M dithiothreitol (DTT) to remove CD38 from both the reagent and donor red blood cells. However, it is important to note that DTT denatures Kell antigens, so these antigens should be typed before treating red cells with this reagent. Effective communication between clinicians and blood transfusion services is crucial before starting DARA treatment to avoid unnecessary workups and delays in transfusion.

7554 Background: Selinexor is a potent selective inhibitor of nuclear export and exhibits synergistic effects when combined with other myeloma therapies. Preliminary results on the combination of selinexor with carfilzomib (CFZ), daratumumab (DARA), or pomalidomide (POM)-based regimens in patients relapsing on therapy were reported (Biran 2023); overall response rate (ORR) Arm 1 (33%), Arm 2 (29%), and Arm 3 (44%). Herein we present the updated results with longer follow-up of selinexor plus CFZ, POM or DARA in MM patients relapsing on current treatment (NCT04661137). Methods: Patients were enrolled to each arm if their disease was refractory to the specific drug. Patients on Arm 1 were treated with selinexor 80 mg on D1, 8, 15; CFZ 20 mg/m 2 IV on D1, 8, 15; and dexamethasone (DEX) on D1, 8, 15, 22. Arm 2 patients received selinexor 60 mg on D1, 8, 15; POM 4 mg on D1-21; and DEX on D1, 8, 15, 22. Arm 3 patients were treated with selinexor 100 mg on D1, 8, 15, 22; DARA 16 mg/kg IV or 1,800 mg SQ on D1, 8, 15, 22 for C1-2; then D1 and 15 for C3-6; then D1 for ≥C7; and DEX on D1, 8, 15, 22. The primary objective was to investigate the ORR of selinexor plus CFZ, POM, or DARA-based regimens. Results: As of Jan 10, 2025, 28 patients were enrolled. Twenty-four were evaluable for response; 7 withdrew consent in which 5 were due to disease progression. Median age was 68 years (range 52-82), 50% male, 54% White, 96% had prior autologous transplant and 21% had extramedullary disease. Nineteen (79%) patients had high-risk cytogenetics, including 1q21 duplication (n=11), t(4;14) (n=8) and TP53 mutation (n=6). The ORR was 38% (95% CI, 19-59%) (PR, 8 [33%]) and clinical benefit rate (CBR) was 83% (95% CI, 63-95%) (PR, 8 [33%]; MR, 1 [4%]; SD, 11 [46%]). With a median follow-up of 11.0 months, the median PFS was 5.7 months (95% CI, 4.7-NR), and median OS was NR months (95% CI, 15-NR). Median DOR was 3.6 months (IQR, 2.5-5.1) with a median treatment duration of 4.0 months (range 0.3-10.8 mos). Most commonly reported Grade 1-2 TEAEs were electrolyte abnormalities (50%) and fatigue (38%). Most commonly reported grade ≥3 TEAEs were neutropenia (25%) and pneumonia (8%).Three patients experienced treatment-related grade 3 SAEs and recovered. One developed chest pain that required hospitalization. One had parainfluenza A-1 pneumonia requiring a treatment delay. One experienced sepsis and pneumonia which led to hospitalization and interruption of treatment. Conclusions: Selinexor as an add-on to CFZ, POM, or DARA-based regimens, in patients actively progressing on these regimens, is well tolerated and safe. This trial demonstrates that selinexor can restore sensitivity to regimens to which MM patients are actively refractory. Future studies can evaluate these combinations in the setting of chimeric antigen receptor T-cell bridging or in the post-bi-specific T-cell engager setting. Clinical trial information: NCT04661137 .

7504 Background: Elranatamab (ELRA), a BCMA-CD3 bispecific antibody, induced deep and durable responses with a manageable safety profile in patients (pts) with relapsed/refractory multiple myeloma (RRMM). MagnetisMM-6 (NCT05623020) is a phase 3, open-label, randomized study evaluating the efficacy and safety of ELRA in combination with lenalidomide (R) ± daratumumab (DARA) (EDR or ER) vs DARA + R + dexamethasone (DRd) in pts with transplant-ineligible (TI) NDMM. Part 1 of the study evaluates the optimal dose of EDR or ER in pts with RRMM or NDMM to determine the recommended phase 3 dose for part 2. Initial results from part 1 dose level G (DLG) are presented. Methods: In DLG, eligible pts had TI (age ≥65 or age <65 years with comorbidities impacting the possibility of transplant) NDMM, measurable disease, ECOG ≤2, and adequate liver, renal and bone marrow function. Pts received subcutaneous (SC) ELRA with a priming regimen followed by ELRA 76 mg SC every 4 weeks (Q4W) on cycle (C) 1 day (D) 1; DARA 1800 mg SC weekly (D1, D8, D15, D22 in C1-C2), every 2 weeks (D1, D15 in C3-C6), and Q4W (D1 in C7+); and oral R 25 mg daily on D1-D21 in 28-day cycles. Endpoints assessed in DLG include safety and preliminary efficacy. Results: A total of 37 pts were enrolled in DLG; 34 received EDR. The median age was 75.0 years (range, 67-83); 37.8% were male; 86.5% were White, 13.5% Asian. Four patients (10.8%) had R-ISS stage III disease, 9 (24.3%) had ≥50% baseline bone marrow plasma cells, 1 (2.7%) had ECOG=2, none had EMD, and 9 (24.3%) were frail according to the simplified IMWG frailty score. At data cutoff (Dec 23, 2024), the median follow-up was 4.6 months (range, 1.2-6.2); treatment was ongoing in 33 pts. TEAEs were reported in 97.3% (G3/4 94.6%) of pts, hematological TEAEs in 78.4% (G3/4 70.3%), and infections in 64.9% (G3/4 18.9%). The most frequent TEAEs (any grade ≥25% or G3/4 ≥10%) are shown in the Table. CRS occurred in 62.2%, all ≤G2; 1 case of G2 ICANS was reported. There was one G5 candida pneumonia. Overall, 36 out of 37 pts are responders with 2 pending confirmation as of DCO. The confirmed ORR (95% CI) by investigator was 91.9% (78.1-98.3), 81.1% with VGPR or better. In pts enrolled ≥4 months before the DCO (n=23), confirmed ORR was 95.7% (78.1-99.9), all with VGPR or better. Conclusions: In pts with TI NDMM, EDR demonstrated a manageable safety profile consistent with the known toxicities of components. High response rate and early responses were observed. Enrollment in dose level H evaluating the ER combination is ongoing. Updated safety and efficacy data with a longer follow-up will be presented. Clinical trial information: NCT05623020 . TEAEs, % Any grade G3/4 Neutropenia, incl. neutrophil count decreased 70.3 67.6 CRS 62.2 0 Pyrexia 35.1 0 Anemia, incl. hemoglobin decreased 32.4 16.2 Injection site reaction 29.7 0 Nausea 27.0 0 Thrombocytopenia, incl. platelet count decreased 13.5 10.8 Asthenia 16.2 10.8

Abstract B cell maturation antigen (BCMA), and Orphan G protein-coupled receptor, class C group 5-member D (GPRC5D) targeted chimeric antigen receptor (CAR) T cell therapies have been successful as treatment options for refractory/relapse multiple myeloma (RRMM) patients. BCMA/GPRC5D dual-targeting CAR-T to address antigen loss is also being explored. However, CAR-T cell manufacturing and potential toxicities have prevented broad patient access. Natural killer (NK) cells have demonstrated an allogeneic cell therapy modality showing promising antitumor efficacy while exhibiting a more favorable safety profile in clinical testing. We have previously shown the successful engineering of IL15 armored BCMA/GPRC5D dual targeted CAR-NK cell therapy for treating MM (AACR 2023; clinical candidate SNC112). To target MM in a broader and more comprehensive manner, SNC112 were tested in combination with Daratumumab (DARA). To improve antibody-dependent cellular cytotoxicity (ADCC) response, high-affinity variants of CD16 (158V/V polymorphism) peripheral blood donors were selected for manufacturing. To avoid self-inflicted NK-cell-mediated fratricide, the stimulation and expansion protocols were optimized to limit CD38 expression on NK cells without inducing gene editing into scaled manufacturing process. In vitro short-term and serial killing assays were performed against MM cell lines to verify CAR functions and evaluate ADCC responses between different manufacturing protocols. The NK purity and surface markers expression were characterized by flow cytometry. The combinational antitumor efficacy was assessed in vivo in multiple xenograft models using NPG mice. SNC112 induced near 100% in vitro specific cytotoxicity using luciferase-label MM cell lines while non-transduced NK showed no cytotoxicity. SNC112 displayed dual-targeted repetitive tumor-killing potential with a RTCA based serial killing assay using CHOK1-BCMA and/or CHOK1-GPRC5D cells. SNC112 manufactured with optimized protocols showed significantly decrease of CD 38 expression (10% vs 80%), improved freeze/thaw recovery, prolonged in vivo persistence, and enhanced ADCC responses. In a CD38-low expression animal model, a sub-optimal dose of SNC112 combined with DARA displayed synergistic increase in tumor targeting through various tumor associated antigens, whereas SNC112 solo and DARA solo resulted in no significant antitumor activity. In a CD38-high expression animal model, both of SNC112+DARA and Non-transduced NK+DARA combos were able to achieve complete clearance of tumor cells. However, only SNC112+DARA could achieve sustained tumor control against re-challenge tumor cells. Studies presented demonstrate the potential of SNC112+DARA combo as a highly effective multi-antigen targeting and a cost-effective off-the-shelf cell therapy in treating MM. Citation Format: Chao Wang, Tingting Liu, Qin Wang, Yanxue Gong, Fanxiang Gao, Feng Zhou, Zhuoxiao Cao. Off-the-shelf BCMA/GPRC5D dual targeted CAR-NK cell therapy combined with Daratumumab in treating multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6122.

Background: Daratumumab (DARA), lenalidomide (LEN), and dexamethasone (DEX, DRd) are one of standards of care for patients with multiple myeloma (MM); however, the clinical impact of relative dose intensity (RDI) remains unclear. In this retrospective study, the aim was to analyze the relationship between the RDI and clinical outcomes in patients with myeloma treated with DRd. Methods: The numbers of patients with newly diagnosed, relapsed, and/or refractory MM were 40 and 71, respectively. Results: The median patient age was 74 years, and the median RDIs for DARA, LEN, and DEX were 84.0%, 39.4%, and 14.6%, respectively. At a median 26.8 months follow-up interval, the 2-year time to the next treatment (TTNT) of the high RDI of DARA (cutoff, 90%) was greater than that of the low RDI of DARA (77.3% vs. 51.6%, p < 0.001), and the 2-year overall survival (OS) of the low RDI of DEX (cutoff, 15%) was longer than that of the high RDI of DEX (87.7% vs. 61.0%, p = 0.027). Multivariate analysis showed that a high RDI for DARA and low RDI for DEX were associated with longer TTNT and OS (hazard ratio, 0.503, p = 0.044; hazard ratio 0.426, p = 0.022, respectively). The high RDI of DARA and low RDI of DEX reduced the incidence of severe infections (p = 0.040 and 0.049). Conclusion: The high RDI of DARA and low RDI of DEX predicted good clinical outcomes in this study's cohort.

Background In recent years, daratumumab (DARA) has gained widespread use in the treatment of systemic light chain (AL) amyloidosis. In this study, we assessed the efficacy and safety of a DARA treatment strategy based on serum free light chain (sFLC) levels and non-fixed cycles. Methods The study included 123 patients with Al amyloidosis who received DARA at our center between July 2020 and September 2023. All patients received the standard DARA treatment (16 mg/kg weekly for four weeks) during the first course. Subsequent treatments were adjusted based on sFLC levels and the physician’s judgment. Results The results demonstrated an impressive overall hematologic response rate (ORR) of 94.3%, with a hematologic very good partial response (VGPR) and complete response (CR) rate of 84.5%. Median time to best hematologic response was 1 months. Cardiac and renal response rates were 39.3% and 60.3%, respectively. Thirty patients experienced grade 1/2 infusion-related reactions after the first infusion. The rate of grade 3/4 adverse events was 21%. The most common adverse events of grade 3 or 4 were pulmonary infection (6.5%), neutropenia and lymphocytopenia (5.7%), elevated transaminases (1.6%), acute kidney injury (1.6%). After a median follow-up of 13 months (range 1-38), The 1-year OS and PFS estimates were 96.5% and 84.4%, respectively. Conclusion These findings indicate that the sFLC levels based and non-fixed cycle DARA strategy is an efficacious and safe treatment strategy in both newly diagnosed and relapsed/refractory AL amyloidosis.

Phase 3 Randomized Study of Daratumumab Monotherapy Versus Active Monitoring in Patients with High-Risk Smoldering Multiple Myeloma: Primary Results of the Aquila Study

Characteristics, Treatment Patterns, and Outcomes of Patients with Multiple Myeloma Retreated with Daratumumab in Real-World Clinical Practice in the USA

Daratumumab with Dose-Adjusted EPOCH Is Feasible in Newly Diagnosed Plasmablastic Lymphoma: AIDS Malignancy Consortium 105

Real-World Clinical Outcomes of Daratumumab-Based Regimens in Chinese Patients with Multiple Myeloma By Cytogenetic Risk: A Subgroup Analysis of the MMY4032 Study