Darzalex (daratumumab)

P=N/A, N=100, Recruiting, Peking University People's Hospital

We showed the efficacy of daratumumab in combination with targeted therapies for the treatment of pulmonary MM.

P2, N=385, Completed, Bristol-Myers Squibb | Active, not recruiting --> Completed

P1/2, N=101, Active, not recruiting, University of Chicago | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025

Complement-dependent cytotoxicity (CDC) is a primary mechanism-of-action of monoclonal antibody (mAb) immunotherapies used to treat haematological cancers, including rituximab and daratumumab. It is possible that any increase in C1q post-exercise may have been masked by the increase and subsequent interaction with CRP, which utilises C1q to facilitate muscular repair. This is the first study to investigate whether exercise can increase circulating C1q and improve mAb-mediated CDC and our findings show that downhill running exercise does not increase circulating C1q nor improve CDC in vitro.

In the preclinical setting, MT-0169 effectively lysed primary MM cells from newly diagnosed and heavily pretreated MM patients, including those refractory to daratumumab, with minimal toxicity against nonmalignant hematopoietic cells. Finally, MT-0169 showed efficient in vivo anti-MM activity in various mouse xenograft models, including one in which MM cells are grown in a humanized bone marrow-like niche. These findings support clinical investigation of MT-0169 in relapsed/refractory MM patients, including those refractory to CD38-targeting immunotherapies.

P3, N=520, Not yet recruiting, GlaxoSmithKline

We report results from the part 1, dose-finding component of the COMMANDER trial, testing the ability of Iber + daratumumab (dara) + dexamethasone (Iber-Dd) and Iber-Dd + carfilzomib (Iber-DKd) to upgrade response in MRD positive patients (pts) after AHCT. Conclusions Iber-Dd and Iber-DKd are safe combinations, able to significantly and rapidly reduce disease burden and lead to MRD negativity after modern induction therapy and AHCT in NDMM. This study is ongoing, complete safety and efficacy results from part 1 and updated results from part 2 will be presented.

Background: Ciltacabtagene autoleucel (cilta-cel) demonstrated superior progression-free survival (PFS) and overall survival compared to standard of care (SOC; pomalidomide, bortezomib, and dexamethasone or daratumumab, pomalidomide, and dexamethasone) in patients with lenalidomide-refractory multiple myeloma (MM) after 1-3 prior lines of therapy (LOTs) in the phase 3 CARTITUDE-4 trial. The increase in the TTNT and sustained benefits in PROs, along with prolonged survival, support cilta-cel as a new SOC treatment for MM patients who are refractory to lenalidomide and have received 1-3 prior LOTs. Importantly, with ~3 years of follow-up, a single infusion of cilta-cel provided patients with a longer delay in worsening of MM related symptoms, functional impacts, and GHS/QoL. The totality of clinical and patient-reported evidence demonstrates the significant benefit of cilta-cel.

B-cell maturation antigen (BCMA)-targeting bispecific T-cell engagers (BiTEs), Teclistimab and Elranatamab have shown rapid and durable responses in RRMM with a lower incidence and severity of cytokine release syndrome (CRS) compared to chimeric antigen receptor T-cell therapies...CRS occurred within 24 hours of the first priming dose, lasted two days, and resolved with IV fluids, tocilizumab, and dexamethasone without recurrence... In this case series of heavily pre-treated Daratumumab relapsed/ refractory AL amyloidosis patients with advanced cardiac involvement, Elranatamab elicited rapid and deep hematological responses with all patients achieving a hematological complete response with deep suppression of iFLC within two weeks of treatment initiation, including MRD negative disease and cardiac responses in all tested patients after 3-5 cycles. Elranatamab was well-tolerated with no added toxicity and acceptable safety profile. These data support Elranatamab’s use in relapsed/refractory AL amyloidosis and prospective studies using BCMA-targeting BiTEs in this high-risk, high-need population.

Pts were assigned 1:1 to cilta-cel or SoC (pomalidomide, bortezomib, and dexamethasone [PVd]/daratumumab, pomalidomide, and dexamethasone [DPd]). At 33.6-mo median follow-up in CARTITUDE-4, cilta-cel vs SoC significantly increased overall MRD-negativity rates >3-fold in the ITT set, with pts achieving MRD negativity rapidly post cilta-cel. The prognostic value of MRD-negative ≥CR at mo 12 was shown, as median PFS was >3 years in pts with MRD-negative ≥CR at mo 12, regardless of tx. These data further underscore the benefit of cilta-cel, which led to significant >3-fold increases vs SoC in rates of MRD-negative ≥CR at any time and at mo 12, and sustained MRD negativity.

The presence of both high CTC and HRCA identifies a group of patients with an overall dismal outcome. The addition of daratumumab to VRd induction/consolidation and R maintenance improves outcome in NDMM patients with high-risk disease defined by high CTC, leading to higher rates of deep and sustained MRD-neg and better PFS.

D-VRd resulted in significantly higher rates of overall and sustained MRD negativity at both 10–5 and 10–6 sensitivity thresholds versus VRd at all timepoints in TIE and transplant-deferred patients with NDMM. This deeper response translated into significant improvements in overall PFS in the D-VRd group. Of patients who achieved MRD-negativity (10–5) with D-VRd, >80% were alive and progression-free at 54 months.

Tal-DP exhibits a deep, long-term impact on efficacy through complementary mechanisms of action and may be especially beneficial in pts with prior BsAb exposure, who typically have unfavorable BL immune profiles. Ongoing analyses of tec-DP from MajesTEC-2 (NCT04722146) will be presented.

P=N/A, N=50, Recruiting, Peking University People's Hospital | Not yet recruiting --> Recruiting

P2, N=29, Active, not recruiting, French Innovative Leukemia Organisation | Trial completion date: Jun 2026 --> Dec 2025

P1, N=17, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jun 2024 --> Jun 2026 | Trial primary completion date: Jun 2024 --> Jun 2026

P1, N=34, Active, not recruiting, AbbVie | Recruiting --> Active, not recruiting | N=360 --> 34 | Trial completion date: Aug 2026 --> Dec 2025 | Trial primary completion date: Aug 2026 --> Feb 2024

Despite application of several new drugs, such as daratumumab, bortezomib/lenalidomide/dexamethasone, in combination with hematopoietic stem cell transplantation, overall prognosis remains poor and the pathological mechanism of MM is still unknown. The present findings suggested that miR-1343-3p may regulate ATG7 and autophagy by directly targeting the 3'UTR of ATG7. To the best of our knowledge, there are no direct data showing the roles of miR-1343-3p in development of MM; however, miR-1343-3p may be considered a potential target for MM treatment.

P1, N=184, Recruiting, Genentech, Inc. | Trial completion date: Jul 2025 --> Jan 2026 | Trial primary completion date: Sep 2024 --> Jan 2026

However, plasma cells were largely unchanged, and NK-cells expressing CD38 - the daratumumab target antigen - increased in blood. Future research should consider the optimal timings of exercise during daratumumab treatment in myeloma to avert exacerbation of daratumumab-mediated NK-cell lysis.

P2, N=39, Not yet recruiting, UNC Lineberger Comprehensive Cancer Center | Initiation date: Sep 2024 --> Dec 2024

P2, N=30, Recruiting, Janssen Research & Development, LLC | Trial completion date: Apr 2028 --> Feb 2027

P2; Trial completion date: Aug 2026 --> May 2026 | Trial primary completion date: Aug 2024 --> May 2024

P2, N=50, Active, not recruiting, University of Arkansas | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Oct 2024 --> Oct 2025

P3, N=706, Completed, Janssen Research & Development, LLC | Active, not recruiting --> Completed

This study investigates the effectiveness of CD38-targeting monoclonal antibodies (mAbs), daratumumab and isatuximab, in impairing crucial cellular processes and survival pathways in pBL malignant cells. The study also revealed a correlation between CD38 and MYC expression levels in pBL patient samples, suggesting CD38 involvement in key oncogenic processes. The study emphasises the therapeutic potential of CD38-targeting mAbs, particularly isatuximab, in pBL.

P=N/A, N=50, Not yet recruiting, Peking University People's Hospital

Post-treatment 18F-FDG PET (Daratumumab Bortezomib Thalidomide Dexamethasone) revealed a completely reduced signal of bone lesions, suggesting a complete response, which was substantiated both clinically and biologically, with the concurrent disappearance of telangiectasia and the monoclonal component, and the normalization of the EPO level. In future, additional data will be required to confirm the added value of 18F-FDG PET with TEMPI. Nevertheless, 18F-FDG PET can be a preferred tool for the extension workup and therapeutic evaluation of TEMPI syndrome.

P2, N=401, Active, not recruiting, Stichting European Myeloma Network | Trial completion date: Feb 2025 --> Feb 2026 | Trial primary completion date: May 2024 --> Jun 2025

Iber-Dd and Iber-DKd are safe combinations and able to eliminate MRD persistent after modern induction therapy and ASCT in NDMM. This study is ongoing, complete safety and efficacy results from part 1 and updated results from part 2 will be presented at the meeting.

P3, N=440, Not yet recruiting, Juno Therapeutics, Inc., a Bristol-Myers Squibb Company

P2, N=52, Active, not recruiting, Academic and Community Cancer Research United | Recruiting --> Active, not recruiting

Notably, our findings showed that daratumumab-induced NK fratricide was restricted to CD38-CD38 crosslinking and was not related to ADCC via CD16a-CD38 crosslinking. This study is the first in the literature to show the successful engineering of a tetravalent immune cell engager composed of tandem VHH units, which achieves high affinity and anticancer activity without mediating fratricide.

P2, N=30, Recruiting, Janssen Research & Development, LLC | Not yet recruiting --> Recruiting

P1/2, N=300, Recruiting, Karyopharm Therapeutics Inc | Active, not recruiting --> Recruiting

P3, N=395, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Oct 2028 --> Jan 2027

P1, N=15, Active, not recruiting, AIDS Malignancy Consortium | Recruiting --> Active, not recruiting

P2, N=11, Active, not recruiting, Mayo Clinic | Trial completion date: Feb 2026 --> Oct 2027

IRF-4 demonstrates high MFI on PCs, and it is not expressed on other leukocytes. In MM patients with MRD, daratumumab treatment does not affect IRF-4 expression. IRF-4 is a promising marker for PC identification in MRD assessment of MM patients undergoing anti-CD38 therapy.

Patients were treated either with carfilzomib, lenalidomide, and dexamethasone plus autologous stem cell transplant (KRd-ASCT, NCT01816971) or with daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd, NCT03500445). In addition to the prognostic significance of MS(-) at any level, the depth of MS negativity is associated with longer PFS. LC-MS(-) and/or 10-6 MRD(-) patients experience long term disease control. The potential of LC-MS to enhance the prognostic potential of MRD at 10-6 for predicting longer disease control is currently under evaluation in a larger sample set.

In cohort A (NDMM), treatment consists of daratumumab 1800 mg SC (typical schedule), weekly bortezomib 1.3 mg/m2 SC, lenalidomide 25 mg PO days 1-21 and weekly dexamethasone 40 mg PO/IV (DaraVRd) every 28 days for 6 cycles followed by assessment of MRD by next-generation sequencing (clonoSEQ). Quadruplet induction results in deep responses allowing an opportunity to defer ASCT based on individual treatment response in NDMM. This study provides the initial feasibility of utilization of post induction MRD in guiding next steps in treatment. This approach is being further explored in the larger ongoing, randomized phase II MASTER-2 clinical trial to see if comparable clinical outcomes are possible without ASCT in those achieving deep response to induction therapy.