cevostamab (RG6160) / Roche - LARVOL DELTA

PLYCOM: A Study Evaluating the Safety and Efficacy of Multiple Treatments in Participants With Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=200 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Mar 2030 ➔ May 2027 | Trial primary completion date: Mar 2030 ➔ May 2027

Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

A Study Evaluating the Pharmacokinetics, Safety, and Efficacy of Cevostamab in Chinese Participants With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=20 | Not yet recruiting | Sponsor: Hoffmann-La Roche

New P1 trial • Hematological Malignancies • Multiple Myeloma • Oncology

SEQUENTIAL BCMA CAR-T CELL THERAPY IS SAFE AND EFFICACIOUS IN REFRACTORY MULTIPLE MYELOMA IN A REAL-WORLD SETTING (EBMT 2025) - "Remarkably, all patients with long-term remissions to ide-cel (≥ 1 year) obtained durable responses to cilta-cel and were still in remission at last follow up whereas short-lived responses to ide-cel seem to predict lower DOR to cilta-cel.Patients relapsing after cilta-cel had unfavorable prognosis and did not durably respond to salvage therapies including cevostamab, talquetamab and Pom-PACE.Extended follow-up and detailed treatment data including two more patients will be presented at the meeting. Notwithstanding potential logistical challenges and financial toxicity, our data indicates that sequential BCMA-CART therapy using commercially available products is safe and elicits durable responses in a sizable number of patients, especially in those who durably responded to first the first CART product. Responses to cilta-cel as second CART product seem comparable to those published in a recent real-word analysis (Sidana et al., Blood 2024)."

CAR T-Cell Therapy • Clinical • IO biomarker • Real-world • Real-world evidence • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Oncology

SEQUENTIAL BCMA CAR-T CELL THERAPY IS SAFE AND EFFICACIOUS IN REFRACTORY MULTIPLE MYELOMA IN A REAL-WORLD SETTING (EBMT 2025) - "Remarkably, all patients with long-term remissions to ide-cel (≥ 1 year) obtained durable responses to cilta-cel and were still in remission at last follow up whereas short-lived responses to ide-cel seem to predict lower DOR to cilta-cel.Patients relapsing after cilta-cel had unfavorable prognosis and did not durably respond to salvage therapies including cevostamab, talquetamab and Pom-PACE.Extended follow-up and detailed treatment data including two more patients will be presented at the meeting. Notwithstanding potential logistical challenges and financial toxicity, our data indicates that sequential BCMA-CART therapy using commercially available products is safe and elicits durable responses in a sizable number of patients, especially in those who durably responded to first the first CART product. Responses to cilta-cel as second CART product seem comparable to those published in a recent real-word analysis (Sidana et al., Blood 2024)."

CAR T-Cell Therapy • Clinical • IO biomarker • Real-world • Real-world evidence • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Oncology

GO39775: Dose-Escalation Study of Cevostamab in Participants With Relapsed or Refractory Multiple Myeloma (R/R MM) (clinicaltrials.gov) - P1 | N=420 | Active, not recruiting | Sponsor: Genentech, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Hematological Malignancies • Multiple Myeloma • Oncology

PLYCOM: A Study Evaluating the Safety and Efficacy of Multiple Treatments in Participants With Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=200 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Dec 2026 ➔ Mar 2030 | Trial primary completion date: Mar 2026 ➔ Mar 2030

Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

EU/3/21/2424 - orphan designation for treatment of multiple myeloma (European Medicines Agency) - "This medicine was designated as an orphan medicine for the treatment of multiple myeloma in the European Union on 13 April 2021."

Orphan drug • Multiple Myeloma

Orphan Drug Designations and Approvals (FDA) - Generic Name: cevostamab, Date Designated: 02/03/2021, Orphan Designation: Treatment of multiple myeloma, Orphan Designation Status: Designated

Orphan drug • Multiple Myeloma

A Study to Evaluate the Safety, Pharmacokinetics, and Activity of XmAb24306 in Combination With Cevostamab in Participants With Relapsed/Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=90 | Active, not recruiting | Sponsor: Genentech, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Hematological Malignancies • Multiple Myeloma • Oncology

A Study to Evaluate the Safety, Pharmacokinetics, and Activity of XmAb24306 in Combination With Cevostamab in Participants With Relapsed/Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=90 | Recruiting | Sponsor: Genentech, Inc. | Trial completion date: Jan 2027 ➔ Sep 2026 | Trial primary completion date: Aug 2026 ➔ Mar 2026

Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Tocilizumab Prophylaxis for Patients with Relapsed or Refractory Multiple Myeloma Treated with Teclistamab, Elranatamab or Talquetamab (ASH 2024) - "J Clin Oncol 2023) and the investigational bispecific antibody cevostamab (Trudel et al...A single repeat dose of tocilizumab was given for ICANS and additional dexamethasone was given to 3 patients for ICANS...Conclusions : Our findings build on previous evidence that tocilizumab may be effective as a preventative, rather than reactive, measure for patients treated with a bispecific antibody for RRMM. Larger randomized studies are needed to confirm and expand on our results."

Clinical • Cerebral Hemorrhage • CNS Disorders • Epilepsy • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Multiple Myeloma • Neutropenia • Oncology • Pneumonia • Respiratory Diseases

CAMMA 1: A Study Evaluating the Safety, Pharmacokinetics, and Activity of Cevostamab in Participants With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=126 | Active, not recruiting | Sponsor: Genentech, Inc. | Recruiting ➔ Active, not recruiting | N=184 ➔ 126

Enrollment change • Enrollment closed • Monotherapy • Hematological Malignancies • Multiple Myeloma • Oncology

A Multi-Institution Phase 2, Single-Arm, Non-Inferiority Study of Limited-Duration Teclistamab for Relapsed and Refractory Multiple Myeloma (LimiTec) (ASH 2024) - P2 | "Sustained off-drug responses have been observed in patients who discontinued teclistamab for reasons other than progression and have also been reported with cevostamab, an anti-FcRH5xCD3 bispecific antibody under investigation as a limited-duration regimen (17 cycles) in MM (Lesokhin et al, ASH 2022). Conclusions : This multi-institution, single-arm, phase 2 study is exploring whether limited-duration teclistamab is non-inferior to continuously administered therapy in patients who have received 6 to 9 months of teclistamab and have achieved at least a very good partial response. Accrual started in July 2023 and is ongoing."

Clinical • Head-to-Head • IO biomarker • P2 data • Hematological Malignancies • Infectious Disease • Leukemia • Lymphoma • Multiple Myeloma • Oncology

Comprehensive Review of Bispecific Antibody Constructs In Multiple Myeloma: Affinities, Dosing Strategies and Future Perspectives. (PubMed, Clin Lymphoma Myeloma Leuk) - "Teclistamab, elranatamab (both BCMA × CD3), and talquetamab (GPRC5D × CD3) are approved for treating MM patients who have received at least 3 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody...As linvoseltamab, alnuctamab, and ABBV-383 (all BCMA × CD3), as well as forimtamig (GPRC5D × CD3) and cevostamab (FcRH5 × CD3) progress through late-stage clinical development, emerging trispecific antibodies are now available that target either 2 different MM-associated antigens or provide additional co-stimulatory signals to prevent T-cell exhaustion. Despite this plethora of therapeutic options, resistance to bsAbs is an inevitability, and the optimal positioning of these drugs within the current MM treatment landscape remains to be determined. In this review, we examine the available data on all clinically accessible bsAbs, evaluating their potential, current limitations, and..."

Journal • Review • Hematological Malignancies • Multiple Myeloma • Oncology

Remote Patient Monitoring for Early Detection of Cytokine Release Syndrome in Myeloma Patients: A Comparative Study between Standard Care and Remote Monitoring (ASH 2024) - "Material and Methods : This monocentric academic study included patients with RRMM treated with a bsAb (teclistamab, talquetamab, cevostamab). These findings offer opportunities for safe and controlled RPM use in an outpatient setting after bsAb administration. In addition, our observations endorse further investigation into the RPM system, particularly on the added value of more comprehensive measurements to the temperature only assessment for early CRS detection."

Clinical • Cytokine release syndrome • Hematological Malignancies • Inflammation • Multiple Myeloma • Oncology

Epigenetic Modifications As a Mechanism of Resistance to BCMA-Directed Immunotherapies in Multiple Myeloma: Insights from Multi-Omic Profiling (ASH 2024) - "It benefits haplotype phasing, resolving complex repetitive regions and large complex SVs.MethodsWe analyzed pre- and post-treatment samples and PBMCs from three RRMM patients resistant to different BCMA-directed therapies (BCMA CART, elranatamab, and belantamab mafodotin)...In patient one, BCMA methylation increased by 53%, rising from 36% in the pre-CART to 89% in the post-CART sample (and 89% as well at a later relapse post-cevostamab)...The efficacy of demethylating agents to overcome drug resistance needs further investigation. Methylation marks can trace a cancer cell´s memory, reflecting its development and treatment history."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • CRBN • SDC1

Biomarker Correlates and Clinical Activity of Cevostamab in Patients (pts) with Triple-Class Refractory Multiple Myeloma (MM) Who Have Received ≥1 Prior B-Cell Maturation Antigen (BCMA)-Targeted Bispecific Antibody (BsAb): Results from the Phase I/II CAMMA 2 Study (ASH 2024) - P1/2 | "Clinical responses were less frequent in the prior BsAb group than in the prior ADC and CAR-T groups, which could be explained by the higher number of prior lines of therapy and T-cell exhaustion due to multiple prior exposures to BsAbs. Notably, the high frequency of CD8+ T-cell subsets expressing inhibitory immune checkpoints in the prior BsAb group suggests a level of T-cell dysfunction that could prevent effective T-cell activation."

Biomarker • Clinical • IO biomarker • P1/2 data • Anemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Oncology • Pneumonia • Respiratory Diseases • Thrombocytopenia • CD8 • IFNG • IL6 • PD-1 • TIGIT

Cevostamab in Patients with Heavily Pretreated Relapsed/Refractory Multiple Myeloma (RRMM): Updated Results from an Ongoing Phase I Study Demonstrate Clinically Meaningful Activity and Manageable Safety and Inform the Doses and Regimen for Combination Studies (ASH 2024) - P1 | "Pts with CRS were managed with tocilizumab (47.4%), steroids (21.1%), or both agents (10.5%). C1 TS dosing provides effective CRS mitigation. Cevostamab combination studies may use the 0.3/1.2/3.6mg TS regimen and the Q3W 160mg TD (or similar TD exposure)."

Clinical • P1 data • Anemia • Cough • Fatigue • Hematological Disorders • Hematological Malignancies • Hemophagocytic lymphohistiocytosis • Immunology • Infectious Disease • Inflammation • Multiple Myeloma • Neutropenia • Oncology • Rare Diseases • Respiratory Diseases • Septic Shock

Novel PD-L1 Blocking Peptide with Mitochondrial Targeting Sequence: A Strategy to Counteract Resistance in T-Cell Immunotherapy for Myeloma (ASH 2024) - "We hypothesize that combining PP-k with T-cell-engagers will significantly enhance MM cell killing and overcome resistance.Objectives : We evaluated PP-k alone and together with teclistamab (approved BCMAxCD3 antibody) and cevostamab (FcRH5xCD3 antibody) in preclinical models of myeloma, including in vitro assays and an organ culture model where myeloma cells colonize the bone microenvironment. In the immune-suppressive tumor : bone co-cultures, PP-k significantly enhances T-cell activation when combined with bispecific antibodies. Ongoing studies with patient-derived cells and immunocompetent mouse models are investigating PP-k's efficacy, mechanism of action, and potential for future clinical trials."

Hematological Malignancies • Multiple Myeloma • Oncology • CALR • CD8 • GZMB • IL2RA

Quantitative Pharmacology for Dose and Regimen Determination of Cevostamab Monotherapy in Relapsed/Refractory Multiple Myeloma (ASH 2024) - P1 | "A comprehensive in silico evaluation based on QSP simulations indicated that the 0.3/1.2/3.6mg triple-step priming regimen prior to the target dose falls within the region of lowest post-dose peak IL-6 concentrations suggesting lowered CRS risk for cevostamab. The clinical data, along with the E-R and PopPK-TGI analyses, demonstrate that increasing cevostamab exposure is associated with higher response rates (overall response rate and VGPR+ rate), with the attainment of plateau at the 160mg Q3W dose, implying diminishing gains at doses beyond 160mg Q3W.Conclusions : The model-guided clinical dose escalation/expansion data together with the quantitative pharmacology strategies and insights support that the 0.3/1.2/3.6mg triple-step priming regimen and the Q3W 160mg target dose provides a favorable benefit-risk for the R/R MM population."

Monotherapy • Hematological Malignancies • Multiple Myeloma • Oncology • IL6

CAMMA 2: A Study Evaluating the Efficacy and Safety of Cevostamab in Prior B Cell Maturation Antigen (BCMA)-Exposed Participants With Relapsed/Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=90 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting

Enrollment closed • Hematological Malignancies • Multiple Myeloma • Oncology

Next-Generation Novel Therapies in Multiple Myeloma (ICBMT 2024) - "A wealth of therapeutic options have been approved for the treatment of newly diagnosed (ND) and relapsed/refractory (RR) multiple myeloma (MM) over the past two decades, with proteasome inhibitors (bortezomib, carfilzomib, ixazomib), immunomodulatory drugs (IMiDs; thalidomide, lenalidomide, pomalidomide), and monoclonal antibodies (mAbs; including the CD38 mAbs daratumumab and isatuximab, as well as the SLAMF7-targeting mAb elotuzumab) currently forming the backbone of treatment approaches in each setting. Additional targeted therapies have further enhanced the armamentarium, including, previously, the histone deacetylase inhibitor panobinostat, and, more recently, the nuclear export inhibitor selinexor 1 and the peptide–drug conjugate (PDC) melflufen. 2,3 Furthermore, novel immune-based treatment options such as the antibody–drug conjugate (ADC) belantamab mafodotin, the BCMA-targeting CAR T-cell therapies idecabta-gene vicleucel (ide-cel) and ciltacabtagene autoleucel..."

Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • CRBN • IRF4 • SLAMF7

MODULE 4: Bispecific Antibodies for the Treatment of MM (ASH 2024) - "This program is supported by educational grants from GSK, Janssen Biotech Inc, administered by Janssen Scientific Affairs LLC and Karyopharm Therapeutics.Available efficacy and safety findings leading to the FDA approvals of the BCMA-directed bispecific antibodies teclistamab and elranatamab for R/R MM; optimal incorporation into management algorithms Efficacy and safety documented with investigational anti-BCMA bispecific antibodies for pretreated MM, such as linvoseltamab and alnuctamab Available efficacy and safety findings with non-BCMA-targeted bispecific antibodies for MM, such as talquetamab and cevostamab Recent FDA approval and optimal incorporation of talquetamab into disease management Spectrum, incidence and severity of CRS and other toxicities with various BCMA- and non-BCMA-directed bispecific antibodies; optimal mitigation and management strategies Rationale for and early-phase data with bispecific antibodies in combination with other systemic therapies,..."

Hematological Malignancies • Multiple Myeloma • Oncology

CAMMA 1: A Study Evaluating the Safety, Pharmacokinetics, and Activity of Cevostamab in Participants With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=184 | Recruiting | Sponsor: Genentech, Inc. | Trial completion date: Jul 2025 ➔ Jan 2026 | Trial primary completion date: Sep 2024 ➔ Jan 2026

Monotherapy • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Sequencing of Bispecific Antibodies in Relapsed Refractory Multiple Myeloma (IMW 2024) - "To date, 3 BsAB have been approved for RRMM, two of which – Teclistamab (tec) and elranatamab (elra) target BCMA, while talquetamab (talq) targets the GPRC5D protein...The most utilized first BsAb was tec (56%), followed by elra (19%), AMG 701 (13%), talq (6%), and cevostamab (cevo) (6%)... Treatment of RRMM remains challenging given the limited options and poor outcomes seen in this population. Our results support the sequential use of BsAbs with an ORR of 38% to second BsAb with an average duration of treatment of 232 days for those remaining on their second BsAb at time of analysis. Despite the clinical benefit observed, infectious complications remain a significant risk of this strategy, requiring close and frequent monitoring."

Febrile Neutropenia • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Novel Coronavirus Disease • Oncology • Pneumonia • Respiratory Diseases • Respiratory Syncytial Virus Infections