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

P2, N=50, Not yet recruiting, Australasian Myeloma Research Consortium

P3, N=284, Not yet recruiting, Qilu Pharmaceutical Co., Ltd.

Isatuximab and therapeutics directed against each of the other six new HCL targets are currently in clinical use to treat other disorders. Consequently, leveraging the JunD-RhoH axis has identified a battery of therapies that could be repurposed as new means of treating relapsed or refractory HCL.

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

P2, N=20, Recruiting, Eastern Cooperative Oncology Group | Trial completion date: Oct 2024 --> Jun 2027 | Trial primary completion date: Oct 2024 --> Jun 2027

P2, N=75, Recruiting, Canadian Myeloma Research Group | Not yet recruiting --> Recruiting

P=N/A, N=50, Recruiting, Pack Health | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Oct 2024 --> Aug 2025

P3, N=171, Not yet recruiting, Takeda

P3, N=120, Recruiting, HI-Bio, A Biogen Company | Not yet recruiting --> Recruiting

Background and Significance : Lenalidomide (LEN) maintenance after autologous stem cell transplant (ASCT) therapy extends disease control in multiple myeloma (McCarthy PL, et al...EHA 2024 abstr 958).The IBEX trial, described herein, is a Phase II trial designed to evaluate the combination of IBER and subcutaneous DARA (IBER+DARA(SC)) as maintenance therapy in myeloma pts who remain MRD(+) following ASCT.Study Design and Methods : The primary objective is to assess the efficacy of post-ASCT IBER+DARA(SC) maintenance as reflected by capacity to induce MRD(-) responses using the commercially available ClonoSEQ assay with a 10-5 sensitivity...Subcutaneous DARA is weekly for cycles 1-2, every other week for cycles 3-6, then monthly thereafter, following the DARA schedule currently being used in the S1803 trial. Patients will be treated for up to 2 years on this study (26 cycles of therapy).This study is registered with ClinicalTrials.gov : ID NCT06107738

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

P3, N=395, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Jan 2027 --> Jan 2026

P2, N=40, Recruiting, Goethe University | Not yet recruiting --> Recruiting

P1, N=15, Not yet recruiting, Roswell Park Cancer Institute | Initiation date: Nov 2024 --> Feb 2025

P1/2, N=272, Completed, Takeda | Active, not recruiting --> Completed

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

The instantaneous change in serum M-protein level was found to be associated with PFS in the final joint model. Using model simulations, we retrospectively supported the Isa 10 mg/kg weekly for 4 weeks, then biweekly (QW/Q2W) dosing regimen of the ICARIA-MM phase III pivotal study, and validated it using the same phase III pivotal study data.

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.

P2, N=20, Recruiting, University of Alabama at Birmingham | Trial primary completion date: Jan 2025 --> Jan 2026

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.

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.

P2, N=96, Recruiting, Mayo Clinic | Trial completion date: Nov 2024 --> Dec 2026 | Trial primary completion date: Nov 2024 --> Dec 2026

P2, N=60, Not yet recruiting, Keymed Biosciences Co.Ltd | Phase classification: P1/2 --> P2 | N=36 --> 60

P3, N=120, Not yet recruiting, HI-Bio, A Biogen Company

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.

Background The only FDA-approved therapy for systemic light chain (AL) amyloidosis is daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (i.e., Dara-CyBorD)...At the time of the MRD test, 30 (58.8%) patients were on active surveillance, 10 (19.6%) were on daratumumab and 9 (17.6%) on venetoclax...In patients with relapsed AL, MRD negativity is correlated with a better hematological response and could potentially play a role in clinical trial design. The impact of gender on MRD status remains an important area for further study.

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.

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 received Isa (10 mg/kg IV) in the Isa-VRd arm and bortezomib (1.3 mg/m2 SC), lenalidomide (25 mg PO), and dexamethasone (20 mg IV/PO) in both arms. More pts had positive-to-negative conversions with Isa-VRd vs VRd, with conversion events increasing over the maintenance period. These data support the benefit of Isa in addition to VRd as initiation therapy, as well as the addition of Isa to Rd during maintenance in transplant-ineligible pts with NDMM.

P1, N=290, Active, not recruiting, Janssen Research & Development, LLC | Trial primary completion date: Sep 2024 --> Aug 2025

P1/2, N=252, Active, not recruiting, Genmab | Recruiting --> Active, not recruiting

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