Darzalex (daratumumab)

P3, N=737, Completed, Janssen Research & Development, LLC | Active, not recruiting --> Completed

P2, N=40, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Mar 2025 | Trial primary completion date: Dec 2024 --> Mar 2025

P1, N=126, Active, not recruiting, Genentech, Inc. | Recruiting --> Active, not recruiting | N=184 --> 126

Median number of prior lines was 4 (range 1-13), 19.4% had received CAR-T previously, and 12.9% had been previously exposed to another TCE.Twenty-three pts (74.2%) were enrolled in clinical trials (7 with teclistamab, Tec, 6 with talquetamab, Tal, and 10 with investigational agents). Twelve of these pts received TCE in combination with daratumumab and/or pomalidomide...MRD- seems to translate into long PFS, regardless of HR disease. Prospective studies on fixed duration treatment with TCE based on baseline risk and treatment response are needed.

In the current ADVANCE study (NCT04268498), patients are randomly assigned to receive 8 cycles of carfilzomib-lenalidomide-dexamethasone with or without daratumumab (i.e. Dara-KRd versus KRd). High-dose melphalan (HDM) followed by autologous stem cell transplant (ASCT) is only offered to patients who remain MRD positive after 8 cycles with all patients transitioning to maintenance lenalidomide...Using MRD testing after completed combination therapy, patients will only be offered HDM-ASCT if they remain MRD-positive after 8 cycles; otherwise, they collected stem cells will be stored (delayed transplant) and transition to maintenance therapy. The aim of this translational effort is to define the underlying biology of sustained MRD negativity in NDMM patients.

P3, N=436, Active, not recruiting, Assistance Publique - Hôpitaux de Paris | Trial primary completion date: Jul 2024 --> Jul 2026

P1/2, N=228, Active, not recruiting, Janssen Research & Development, LLC | Recruiting --> Active, not recruiting

Elotuzumab is an approved monoclonal antibody targeting SLAMF7 on plasma and NK cells that enhances the activity of lenalidomide, pomalidomide, and bortezomib in multiple myeloma (MM)...Prior therapies included: pomalidomide (33%), daratumumab (25%), and isatuximab (4%)...Common grade ≥3 adverse events were neutropenia (33%); infections, any (33%); lung infection (27%); hypophosphatemia (19%); and thrombocytopenia (15%). Elo-PVd is one of the first trials of a quadruplet regimen in relapsed/refractory MM incorporating a monoclonal antibody to show efficacy across diverse prior treatments, including triple class exposed with prior anti-CD38 monoclonal antibody.

P2/3, N=135, Recruiting, Tianjin Medical University General Hospital | N=72 --> 135 | Trial completion date: Oct 2024 --> Dec 2025 | Trial primary completion date: Aug 2024 --> Nov 2025

P1/2, N=22, Recruiting, National Institute of Allergy and Infectious Diseases (NIAID) | Trial completion date: Oct 2025 --> Mar 2027 | Trial primary completion date: Oct 2025 --> Jun 2026

In further investigations of this issue, we show here that the pharmacological inhibition of MYC in various lymphoma and multiple myeloma cell lines, as well as patient-derived primary tumor cells, enhances their susceptibility to NK cell-mediated cytotoxicity induced by conventional antibodies targeting CD20 (rituximab) and CD38 (daratumumab), as well as T cell-mediated cytotoxicity induced by the CD19-targeting bispecific T-cell engager blinatumomab. In conclusion, MYC overexpressing tumor cells mitigated the efficacy of therapeutic antibodies through several non-overlapping mechanisms. Given the challenges associated with direct MYC inhibition due to toxicity, successful modulation of MYC-mediated immune evasion mechanisms may improve the outcome of immunotherapeutic approaches in B-cell malignancies.

To report a case of cytomegalovirus (CMV)-related hemorrhagic retinal vasculitis in a patient with multiple myeloma (MM) on daratumumab, a trial cereblon E3 ligase modulatory drug (CELMoD), dexamethasone, and acyclovir, and discuss clinical implications for CMV prophylaxis. Our patient developed CMV-related hemorrhagic retinal vasculitis despite low-dose acyclovir, which provides limited protection against CMV reactivation in CMV seropositive individuals. This case report therefore offers casuistic support for ophthalmic screening for CMV reactivation or CMV prophylaxis with letermovir in this patient population.

Teclistamab (Tec), a bispecific antibody (BsAb) targeting BCMA, shows promise in refractory MM and, when combined with daratumumab (Tec-Dara), may help eliminate residual disease...Prior therapy exclusions apply, except for limited doses of dexamethasone, bortezomib, cyclophosphamide, lenalidomide, or daratumumab...The study seeks to determine if AHCT can be deferred in patients achieving MRD negativity after Dara-VRd without compromising the chance of reaching and sustaining MRD negativity, and whether post-AHCT Tec-Dara can enhance sustained MRD negativity rates compared to post-AHCT Dara-R in MRD-positive patients. The study is currently open for enrollment at multiple sites in the US.

P1, N=15, Recruiting, City of Hope Medical Center | Not yet recruiting --> Recruiting | Trial completion date: Feb 2027 --> May 2028 | Initiation date: Oct 2024 --> Jan 2025 | Trial primary completion date: Feb 2027 --> May 2028

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

An extension of indication has been recently approved by the FDA and EMA (2024) for the treatment of adult patients with RRMM who have received at least 1 prior line of therapy (LOT), including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), and are refractory to lenalidomide (cilta-cel; CARTITUDE-4); and in patients with RRMM after 2 or more prior LOT, including an IMiD, a PI, and an anti-CD38 monoclonal antibody (ide-cel; KarMMa-3)...Results : After applying the KarMMa-3 inclusion and exclusion criteria to the CARTITUDE-1 and CARTITUDE-4 IPD (excluding patients with only 1 prior LOT or no prior daratumumab), 36 patients and 49 patients were included from the cilta-cel trials, respectively...These results are consistent with previously published comparative results between both CAR-T treatments, and the new OS results highlight the added value of cilta-cel in this patient population. These comparisons provide valuable information to contextualize the efficacy of cilta-cel compared to ide-cel for the treatment of multiple myeloma.

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. 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...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.

Conclusions : 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.

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.

Pts were assigned 1 : 1 to cilta-cel or SoC (pomalidomide, bortezomib, and dexamethasone [PVd]/daratumumab, pomalidomide, and dexamethasone [DPd]). 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. Our MRD data demonstrate higher rates of deep and sustained MRD negativity achieved with cilta-cel vs SoC in tx of len-refractory MM as early as first relapse.

Of patients who achieved MRD-negativity (10–5) with D-VRd, >80% were alive and progression-free at 54 months. These data further support the use of D-VRd as a new standard of care for patients with NDMM that are TIE or for whom transplant is deferred.

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.