A Phase 2 Study to Evaluate Safety and Efficacy of Teclistamab- and Talquetamab-based Combination Regimens in Participants with Newly Diagnosed Transplant Eligible Multiple Myeloma

Phase 2

Recruiting

• Conditions: Newly Diagnosed Multiple Myeloma in patients eligible for stem cell transplantation

• Registration Number: 2024-517382-17-00
• Lead Sponsor: Universitaetsklinikum Heidelberg AöR

Brief Summary

To evaluate the safety and tolerability of teclistamab- and talquetamabbased combination regimens over the entire treatment phase for each arm, in participants with ND-TEMM.

Detailed Description

Not available

Study Timeline

• Study First Posted: 2024-09-11
• Last Update Posted: 2025-04-16

Recruitment & Eligibility

• Status: Ongoing, recruiting
• Sex: Not specified
• Target Recruitment: 130

Inclusion Criteria

18 to 70 years of age, inclusive

Must sign an ICF indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.

Participants in Arms A, A1, B, D, E, E1, F, F1 must also satisfy all of the following criteria to be enrolled in the study: 1A. Documented multiple myeloma as defined by the criteria below: a. Multiple myeloma diagnosis according to the IMWG diagnostic criteria b. Measurable disease at screening as defined by any of the following: 1. Serum M-protein level ≥1.0 g/dL or 2. Urine M-protein level ≥200 mg/24 hours or 3. Serum immunoglobulin free light chain level ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio 2A. Newly diagnosed participants for whom HDT and ASCT is part of the intended treatment plan.

Participants Arms C, C1; C2 must also satisfy all of the following criteria 1B. diagnosed multiple myeloma according to IMWG criteria, see note

2B. Must have received 4 to 6 cycles of 3 or 4 drug-induction therapy that includes a proteasome inhibitor and/or an IMiD with or without anti-CD38 monoclonal antibody and a single or tandem ASCT. Post-ASCT consolidation is permitted for up to 2 cycles as long as the total number of induction plus consolidation cycles does not exceed 7.

3B. Must have received only one line of therapy and achieved at least a PR as per IMWG 2016 response criteria based on the investigator's assessment. Participants with plasmacytomas at the time of diagnosis must meet IMWG 2016 response criteria for ≥PR based on repeat imaging utilizing the same modality.

4B. Must have received HDT and ASCT within 12 months of the start of induction therapy and be within 6 months of the last ASCT. (7 months for participants who received consolidation at the time of enrollment).

Have an ECOG performance status score of 0 to 2 at screening

Have clinical laboratory values meeting the following criteria during the Screening Phase. Hematology: Hemoglobin>=7.5 g/dL (>=4.65 mmol/L; without prior RBC transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted) Platelets: >=75×10E9/L in participants in whom <50% of bone marrow nucleated cells are plasma cells and >=50×10E9/L in participants in whom ≥50% of bone marrow nucleated cells are plasma cells (without transfusion support or thrombopoietin receptor agonist within 7 days before the laboratory test) Absolute neutrophil count: >=1.0×109/L (prior growth factor support is permitted but must be without support for 7 days for G-CSF or GM-CSF and for 14 days for pegylated-G-CSF) Chemistry AST, ALT: ≤2.5×ULN eGFR: ≥30 mL/min based on Cockcroft-Gault formula or a 24-hour urine collection Total bilirubin: ≤2.0×ULN; (isolated total bilirubin ≥ 1.5 x ULN with conjugated [direct] bilirubin <1.5xULN is allowed for those participants with known congenital nonhemolytic hyperbilirubinemia such as Gilbert's syndrome). Serum calcium corrected for albumin: ≤14 mg/dL (≤3.5 mmol/L) or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L)

A female participant of childbearing potential must have a negative highly sensitive serum pregnancy test at screening, and within 24 hours before start of study treatment, and must agree to further pregnancy tests during the study.

A participant must be either a. Not of childbearing potential, or b. Of childbearing potential and practicing 2 effective methods of contraception from the time of signing ICF until 6 months after the last dose of study treatment. Contraception must begin 4 weeks prior to dosing of lenalidomide.

A female participant must agree not to donate eggs (ova, oocytes) or freeze for future use, for the purposes of assisted reproduction during the study and for a period of 6 months after receiving the last dose of study treatment.

A male participant must wear a condom when engaging in any activity that allows for passage of ejaculate to another person during the study and for a minimum of 100 days after receiving the last dose of study treatment.

A male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 100 days after receiving the last dose of study treatment.

Must be willing and able to adhere to the lifestyle restrictions specified in this protocol, including adherence to the global PPP or local PPP program for lenalidomide.

Exclusion Criteria

1.a. Ongoing myelodysplastic syndrome or B-cell malignancy (other than MM)

Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any study drug/excipients.

Pregnant, breastfeeding, or planning pregnancy while enrolled in this study or within 6 months after the last dose of any study treatment.

Plans to father a child while enrolled in this study or within 100 days after the last dose of any study treatment.

significant traumatic injury or major surgery within 2 weeks prior to the start of study treatment, or will not have fully recovered from surgery, or has major surgery planned during the study or within 2 weeks after the last dose of study treatment.

Received an investigational drug, used an invasive investigational medical device within 4 weeks or 5 half-lives of the respective drug/IMP before enrollment or is enrolled in an interventional study.

Have gastrointestinal disease that may significantly alter the absorption of oral drugs

Received a live, attenuated vaccine within 4 weeks before the first dose of study treatment.

Be unable or unwilling to undergo antithrombotic prophylactic treatment.

Arms A, A1, B. D, E, E1, F and F1 1. Prior or current systemic therapy or stem cell transplant for plasma cell dyscrasia, with the exc. of emergency use of a short course (equiv. of dexamethasone 40 mg/day for a max. 4 days) of corticosteroids before treatment.

Radiotherapy within 14 days or focal radiation within 7 days of enrollment. Radiotherapy on measurable soft-tissue plasmacytoma(s) is not permitted even in the setting of palliation for symptomatic management.

b. History of malignancy (other than MM), considered high risk of recurrence requiring systemic therapy.

Plasmapheresis within 28 days of enrollment.

Plasma cell leukemia, smoldering MM, Waldenström's macroglobulinemia, POEMS syndrome, or primary light chain amyloidosis.

Arms B, F, and F1 only: Peripheral neuropathy or neuropathic pain Grade 2 or higher

Arms B, F, and F1 only: received a strong CYP3A4 inducer within 5 half-lives prior to enrollment

Arms C, C1 and C2 1. Received any prior BCMA-directed therapy (Arms C and C1 only) or GPRC5D-directed therapy (Arm C2 only).

Any previous therapy with an immune cell redirecting agent or gene modified adoptive cell therapy (eg, CAR T cells, NK cells).

Discontinued treatment due to any AE related to lenalidomide as determined by the investigator.

Radiotherapy within 14-day or focal radiation within 7 days of enrollment.

Progressed on MM therapy any time prior to screening.

Received a cumulative dose of corticosteroids equivalent to ≥40 mg dexamethasone within the 14 day period before the start of study treatment.

c. Active malignancy other than MM. Exceptions (details see protocol): - Non-muscle invasive bladder cancer - Non- melanoma skin cancer after curative therapy or localized melanoma after curative surgical resection alone - Non-invasive cervical cancer - Breast cancer: adequately treated lobular carcinoma in situ, or history of localized breast cancer - Localized prostate cancer, treated locally only

Plasma cell leukemia, smoldering MM, Waldenström's macroglobulinemia, POEMS syndrome, or primary light chain amyloidosis.

Intolerant to starting dose of lenalidomide.

CNS involvement or clinical signs of meningeal involvement of MM.

Stroke, transient ischemic attack or seizure within 6 months prior C1D1.

History of allogeneic stem cell transplant or organ transplantations requiring immunosuppressive therapy.

Any of the following - Positive HIV, Hep B, active Hep C (details see protocol) - COPD with a FEV1 <50% of predicted normal. Moderate/severe persistent asthma within the past 2 years or uncontrolled asthma.

Concurrent medical or psychiatric condition or disease that is likely to interfere with study procedures, or that in the investigator's opinion would constitute a hazard for participants, such as: a. Acute diffuse infiltrative pulmonary disease b. Evidence of active systemic viral, fungal or bacterial infection, requiring systemic antimicrobial therapy c. History of autoimmune disease, exc. vitiligo, type I diabetes, prior autoimmune thyroid disease currently euthyroid d. Disabling psychiatric conditions, severe dementia, or altered mental status e. History of noncompliance

Following cardiac conditions: a. New York Heart Association stage III or IV congestive heart failure b. Myocardial infarction, unstable angina, or coronary artery bypass graft ≤6 months prior enrollment c. History of clinically significant ventricular arrhythmia or unexplained syncope d. Uncontrolled cardiac arrhythmia or clinically significant abnormal ECG.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Incidence and severity of AEs and SAEs		Incidence and severity of AEs and SAEs

Secondary Outcome Measures

Name	Time	Method
To evaluate MRD negativity rates, conversion, and sustainability: Post-induction, post-ASCT, post-maintenance, and best overall - MRD negative CR Sustained MRD negative CR (duration ≥12 months) after 18 cycles of maintenance treatment MRD negative CR conversion and deepening during maintenance		To evaluate MRD negativity rates, conversion, and sustainability: Post-induction, post-ASCT, post-maintenance, and best overall - MRD negative CR Sustained MRD negative CR (duration ≥12 months) after 18 cycles of maintenance treatment MRD negative CR conversion and deepening during maintenance
To evaluate the efficacy of Teclistamab and Talquetamab based combination regimes as induction and posttransplant maintenance treatments, and teclistamab in combination with talquetamab as replacement for ASCT following induction. Post-induction, post-ASCT (Arms A, A1, B, E, E1 and, if applicable, F and F1), postmaintenance (Arms A, A1, B, E, E1 and, ifapplicable, F and F1), post-Tec-Tal (Arm D), and best overall: - ORR (at least a PR or better) - CR or better - VGPR or better DOR PFS		To evaluate the efficacy of Teclistamab and Talquetamab based combination regimes as induction and posttransplant maintenance treatments, and teclistamab in combination with talquetamab as replacement for ASCT following induction. Post-induction, post-ASCT (Arms A, A1, B, E, E1 and, if applicable, F and F1), postmaintenance (Arms A, A1, B, E, E1 and, ifapplicable, F and F1), post-Tec-Tal (Arm D), and best overall: - ORR (at least a PR or better) - CR or better - VGPR or better DOR PFS
To assess feasibility of successful transplantation (all arms except ArmD): Stem cell yield and days to engraftment (all arms except Arm D)		To assess feasibility of successful transplantation (all arms except ArmD): Stem cell yield and days to engraftment (all arms except Arm D)
To characterize the PK of teclistamab and talquetamab in participants with multiple myeloma before and after an ASCT or during Tec-Tal treatment, and to characterize the PK of daratumumab after an ASCT: PK parameters using population PK approach		To characterize the PK of teclistamab and talquetamab in participants with multiple myeloma before and after an ASCT or during Tec-Tal treatment, and to characterize the PK of daratumumab after an ASCT: PK parameters using population PK approach
To assess the immunogenicity of teclistamab, talquetamab and daratumumab: Measure presence of ADAs		To assess the immunogenicity of teclistamab, talquetamab and daratumumab: Measure presence of ADAs
evaluation of this end points: MRD negativity rates, conversion, and sustainability: Post-induction, post-ASCT, post-maintenance, and best overall Sustained MRD negative CR: ≥12 months and after 18 cycles of maintenance treatment. Sustained MRD negative CR - ORR (at least a PR or better) - CR or better - VGPR or better Post-induction, post-ASCT, post-maintenance (assessments 3-monthly), and best overall:		evaluation of this end points: MRD negativity rates, conversion, and sustainability: Post-induction, post-ASCT, post-maintenance, and best overall Sustained MRD negative CR: ≥12 months and after 18 cycles of maintenance treatment. Sustained MRD negative CR - ORR (at least a PR or better) - CR or better - VGPR or better Post-induction, post-ASCT, post-maintenance (assessments 3-monthly), and best overall:
of evaluation of this end points (continued) DOR: 3-monthly response assessment PFS: 3-monthly response assessment PK analysis: over the		of evaluation of this end points (continued) DOR: 3-monthly response assessment PFS: 3-monthly response assessment PK analysis: over the

Trial Locations

Locations (11)

Medical Center - University Of Freiburg; 🇩🇪 Freiburg Im Breisgau, Germany

Universitaetsklinikum Schleswig-Holstein AöR; 🇩🇪 Kiel, Germany

Asklepios Kliniken Hamburg GmbH; 🇩🇪 Hamburg, Germany

Charite Universitaetsmedizin Berlin KöR; 🇩🇪 Berlin, Germany

Klinikum Chemnitz gGmbH; 🇩🇪 Chemnitz, Germany

Universitaetsklinikum Wuerzburg AöR; 🇩🇪 Wuerzburg, Germany

Klinikum rechts der Isar der TU Muenchen AöR; 🇩🇪 Munich, Germany

Universitaetsklinikum Heidelberg AöR; 🇩🇪 Heidelberg, Germany

Universitaetsklinikum Carl Gustav Carus Dresden an der Technischen Universitaet Dresden AöR; 🇩🇪 Dresden, Germany

University Medical Center Hamburg-Eppendorf; 🇩🇪 Hamburg, Germany

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Medical Center - University Of Freiburg

🇩🇪Freiburg Im Breisgau, Germany

Monika Engelhardt

Site contact

+4976127032460

monika.engelhardt@uniklinik-freiburg.de