GMMG-HD10 / DSMM-XX / 64007957MMY2003, MajesTEC-5

Study Overview
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Brief Summary
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A Phase 2 Study to Evaluate Safety and Efficacy of Teclistamab in Combination with Daratumumab, Lenalidomide, and Dexamethasone with or without Bortezomib as Induction Therapy and Teclistamab in Combination with Daratumumab and Lenalidomide as Maintenance Therapy in Participants with Newly Diagnosed Transplant Eligible Multiple Myeloma. OBJECTIVES: The primary objective is to evaluate the safety and tolerability of Tec-DRd and Tec-DVRd as induction therapy and Tec-DR as post-transplant maintenance therapy in participants with ND-TEMM. The key secondary objective is to evaluate the efficacy of Tec-DRd and Tec-DVRd as induction therapy and Tec-DR as post-transplant maintenance therapy.

Detailed Description
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OVERALL DESIGN: 70 participants will be enrolled with approximately 10 participants in Arm A, 10 participants in Arm C, 40 participants in Arm A1 and Arm B (20 each Arm), and optionally 10 further participants in Arm C1 Arms A, A1 and B will receive Induction Therapy of 6 cycles (28-days each): Treatment: Tec-DRd (Arm A, A1) or Tec-DVRd (Arm B) followed by HDT and a single ASCT according to local SoC treatment. Thereafter a Maintenance Therapy of maximum 18 cycles with Tec-DR is performed. In Arm C and C1 participants will enter the study for maintenance treatment of 18 cycles with Tec-DR, after induction, HDT and ASCT according to local SoC (outside of the study). Participants will receive maintenance treatment with Tec-DR for a maximum of 18 cycles or until confirmed progressive disease, death, intolerable toxicity, loss to follow-up, or consent withdrawal, whichever comes first. An optional end of treatment is possible for patients who have 12 months sustained MRD negativity. Periodic safety evaluations will be conducted to ensure that treatment is safe and tolerable. Upon treatment discontinuation, an EOT Visit will be conducted. Thereafter, the participant will continue in the Follow-up Phase until death, withdrawal of consent, loss to follow-up, or end of the study, whichever occurs first.

Official Title
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A Phase 2 Study to Evaluate Safety and Efficacy of Teclistamab in Combination With Daratumumab, Lenalidomide, and Dexamethasone With or Without Bortezomib as Induction Therapy and Teclistamab in Combination With Daratumumab and Lenalidomide as Maintenance Therapy in Participants With Newly Diagnosed Transplant Eligible Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Teclistamab (Tec)
* Drug: Daratumumab
* Drug: Dexamethasone
* Drug: Lenalidomide
* Drug: Bortezomib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - 18 years of age to 70 years of age, inclusive Have an ECOG performance status score of 0 to 2 at screening Have clinical laboratory values meeting prespecified criteria during the Screening Phase. Participants in Arm A, A1 and Arm B must also satisfy all of the following criteria to be enrolled in the study: 1. Documented multiple myeloma requiring treatment as defined by the criteria below: Multiple myeloma diagnosis according to the IMWG diagnostic criteria Measurable disease at screening as defined by any of the following: Serum M-protein level ≥1.0 g/dL or Urine M-protein level ≥200 mg/24 hours or Serum immunoglobulin free light chain level ≥10 mg/dL and abnormal serum free light chain ratio 2. Newly diagnosed participants for whom HDT and ASCT is part of the intended treatment plan. Participants Arm C and C1 must also satisfy all of the following criteria: Newly diagnosed multiple myeloma according to IMWG criteria. 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 6. 3 Must have received only one line of therapy and achieved at least a PR as per IMWG 2016 without evidence of progression at the time of enrollment. 4. 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. Exclusion Criteria: - CNS involvement or clinical signs of meningeal involvement of multiple myeloma. Stroke or seizure within 6 months prior study start Cycle1 Day1. History of transplantations requiring immunosuppressive therapy. Seropositive for HIV, HEP B, Active Hep C infection (details see protocol). COPD with a FEV1 <50% of predicted normal. Moderate /severe persistent asthma within the past 2 years or any uncontrolled asthma. Exclude if FEV1 <50% of predicted normal. Concurrent medical or psychiatric condition or disease that is likely to interfere with study procedures, or that in the investigators opinion would constitute a hazard for participants. Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any study drug/excipients. Pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 6 months after the last dose of any study treatment regimen. Plans to father a child while enrolled in this study or within 3 months after the last dose of any component of the study treatment regimen. Arm A, A1 and B - Prior or current systemic therapy or stem cell transplant for any plasma cell dyscrasia, with the exception of emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment. - Arm B only: Peripheral neuropathy or neuropathic pain Grade 2 or higher as defined by the NCI-CTCAE Version 5. Due to a potential interaction with bortezomib, received a strong CYP3A4 inducer within 5 half-lives prior to enrollment Arm C and C1 - Discontinued treatment due to any AE related to lenalidomide as determined by the investigator. - Progressed on multiple myeloma therapy at any time prior to screening. Received a cumulative dose of corticosteroids equivalent to ≥40 mg of dexamethasone within the 14 day period before the start of study treatment administration. Intolerant to the starting dose of lenalidomide (10 mg). For further details on inclusion/exclusion criteria please refer to the study protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Induction Treatment of Arm A, A1 and B contains 6 cycles of Tec-DRd [Arm A, A1] or Tec-DVRd [Arm B]) Enrollment will be staggered with Arm A opening first and the opening of Arm B dependent on safety results from Arm A. Induction therapy is followed by HDT and a single ASCT according to local SoC. After ASCT, participants will receive maintenance treatment with Tec-DR. Arm C and C1 participants will enter the study at Maintenance Treatment with Tec-DR after induction, HDT, and ASCT according to local SoC (outside of the study). Arm A, A1, B and C, C1 will receive maintenance treatment for a maximum of 18 cycles or until confirmed progressive disease, death, intolerable toxicity, loss to follow-up, or consent withdrawal, whichever comes first. An optional end of treatment is possible for those patients who have sustained MRD negativity of 12 months. Periodic safety evaluations will be conducted to ensure that treatment is safe and tolerable.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A Tec-DRd Induction and Tec-DR Maintenance<br>Arm A participants will receive teclistamab as subcutaneous (SC) injection in combination with daratumumab SC, lenalidomide and dexamethasone in 6 cycles of induction therapy, followed by teclistamab SC injection in combination with daratumumab SC and lenalidomide in maximum 18 cycles of maintenance therapy. | Drug: Teclistamab (Tec)<br>* Subcutaneous administration of Teclistamab<br>* Other names: JNJ-64007957;Drug: Daratumumab<br>* Subcutaneous administration of Daratumumab<br>Drug: Dexamethasone<br>* administered i.v. or orally<br>Drug: Lenalidomide<br>* Administration oral<br>|
| Experimental: Arm B Tec-DVRd Induction and Tec-DR Maintenance<br>Arm B participants will receive teclistamab as subcutaneous (SC) injection in combination with daratumumab SC, lenalidomide, dexamethasone and bortezomib in 6 cycles of induction therapy, followed by teclistamab SC injection in combination with daratumumab SC and lenalidomide in maximum 18 cycles of maintenance therapy. | Drug: Teclistamab (Tec)<br>* Subcutaneous administration of Teclistamab<br>* Other names: JNJ-64007957;Drug: Daratumumab<br>* Subcutaneous administration of Daratumumab<br>Drug: Dexamethasone<br>* administered i.v. or orally<br>Drug: Lenalidomide<br>* Administration oral<br>Drug: Bortezomib<br>* Subcutaneous administration<br>|
| Experimental: Arm C Tec-DR Maintenance<br>Arm C participants will receive maximum 18 cycles of teclistamab SC injection in combination with daratumumab SC and lenalidomide as maintenance therapy. | Drug: Teclistamab (Tec)<br>* Subcutaneous administration of Teclistamab<br>* Other names: JNJ-64007957;Drug: Daratumumab<br>* Subcutaneous administration of Daratumumab<br>Drug: Lenalidomide<br>* Administration oral<br>|
| Experimental: Arm A1 Tec-DRd Induction and Tec-DR Maintenance<br>Arm A participants will receive teclistamab as subcutaneous (SC) injection in combination with daratumumab SC, lenalidomide and dexamethasone in 6 cycles of induction therapy, followed by teclistamab SC injection in combination with daratumumab SC and lenalidomide in maximum 18 cycles of maintenance therapy. | Drug: Teclistamab (Tec)<br>* Subcutaneous administration of Teclistamab<br>* Other names: JNJ-64007957;Drug: Daratumumab<br>* Subcutaneous administration of Daratumumab<br>Drug: Dexamethasone<br>* administered i.v. or orally<br>Drug: Lenalidomide<br>* Administration oral<br>|
| Experimental: Arm C1 Tec-DR Maintenance<br>Arm C participants will receive maximum 18 cycles of teclistamab SC injection in combination with daratumumab SC and lenalidomide as maintenance therapy. | Drug: Teclistamab (Tec)<br>* Subcutaneous administration of Teclistamab<br>* Other names: JNJ-64007957;Drug: Daratumumab<br>* Subcutaneous administration of Daratumumab<br>Drug: Lenalidomide<br>* Administration oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| number of incidence and severity of adverse events [safety and tolerability] |  | through study completion, up to 28 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MRD negativity rate | MRD negativity rate measured by Flow Cytometry | after 6 cycles (each cycle is 28 days) induction therapy (app.month 6), after High Dose Therapy (app. month 10), after 18 cycles (each cycle is 28 days) of maintenance therapy (app. month 28) | 
| Response on therapy [efficacy] | Response on therapy according to IMWG: Overall Response Rate (ORR) (at least a PR or better) Complete Response (CR) or better Very Good Partial Response (VGPR) or better Duration of Response (DoR) | after each cycle (each cycle is 28 days) induction ( app. at month 1,2,...,6), after High Dose therapy (app. month 10), after each cycle (each cycle is 28 days) of maintenance (app. at month 11,12, ...28), during FU every 3 months (app. up to 3-4 years) | 
| Progression Free Survival [efficacy] |  | From randomization to the date of disease progression to death (app. up to 3-4 years) | 
| Serum concentration of teclistamab and daratumumab [pharmacokinetics] |  | through study completion, up to 28 months | 
| Presence of ADAs to teclistamab and daratumumab [immunogenicity] |  | through study completion, up to 28 months | 
| Stem cell yield | feasibility of successful transplantation | after High Dose Therapy (after app. 10 months) | 
| days to engraftment | feasibility of successful transplantation | after High Dose Therapy (after app. 10 months) |