Teclistamab-Daratumumab and Talquestamab-Daratumumab in Newly Diagnosed High-risk Multiple Myeloma

Study Overview
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Brief Summary
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The goal of this Phase 2, open-label, multicenter, non-randomized pilot study is to evaluate the efficacy (in terms of MRD negative CR rate after Intensification therapy) and safety of Tec-Dara (Teclistamab+Daratumumab) and Tal-Dara (Talquetamab+Daratumumab) in de novo high-risk multiple myeloma (DNHRMM) patients.

Detailed Description
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A total of 30 transplant eligible or elderly fit patients with high risk multiple myeloma will be enrolled 1. Patients will receive a 4-cycle Dara+VRD (daratumumab, bortezomib, lenalidomide, dexamethasone) INDUCTION therapy. Cycles will be of 28 days (4-week cycles) in duration for daratumumab and for VRD. After the 4-cycle Induction, all patients will receive the 1st INTENSIFICATION treatment which consists of 6 cycles of Tec-Dara. Cycles will be of 28 days (4-week cycles) in duration for daratumumab and for teclistamab. 1st Intsensification, patients will receive a 6-cycle Dara+Teclistamab. 2. At the end of 1st Intensification timepoint treatments depends on MRD status: 2.1) MRD negative patients in CR at the end of Intensification will receive MAINTENANCE therapy with Tec-Dara continuously for 2 years. Cycles will be of 28-days in duration for Tec-Dara. Teclistamab (SC) and daratumumab (SC). 2.2) MRD positive patients or patients who didn't achieve CR despite MRD negativity, will have EARLY RESCUE INTERVENTION (ERI) with Tal-Dara for 6 cycles. MRD and response will be evaluated again after 6 cycles treatment with Tal-Dara. MRD negative patients in CR will receive continuous treatment with Tal-Dara for 2 years. 2.2.1 Early Rescue Intervention with Tal-Dara: Patients who are MRD+ after intensification or who convert from MRD negative into positive or experience a relapse from CR (without fulfilling criteria for disease progression) at any time during Tec-Dara treatment will have ERI with Tal-Dara. Cycles will be of 28 days in duration. 2.2.2. MRD negative patients in CR will receive continuous treatment with Tal-Dara for 2 years. Cycles will be of 28-days of duration for Tal-Dara. 4. SALVAGE therapy: If the patient remains MRD+ or doesn't achieve CR despite MRD negativity after 6 cycles of ERI with Tal-Dara or has disease progression at any time, further treatment will be offered as per the investigation decision outside of the study.

Official Title
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An Open Label, Multicenter, Phase 2, Pilot Study, Evaluating Early Treatment With Bispecific T-cell Redirectors (Teclistamab and Talquetamab) in the Frontline Therapy of Newly Diagnosed High-risk Multiple Myeloma

Conditions
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High-Risk de Novo Multiple Myeloma

Intervention / Treatment
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* Drug: Daratumumab
* Drug: Bortezomib
* Drug: Lenalidomide
* Drug: Teclistamab
* Drug: Talquetamab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient is, in the investigator's opinion, willing and able to comply with the protocol requirements. Patient has given voluntary written informed consent before performance of any study-related procedure nor part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care. Patient is ≥ 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of informed consent. Patient has documented diagnosis of multiple myeloma according to IMWG diagnostic criteria, with at least one of the following high-risk features: High-risk FISH: del(17p), t(4;14), t(14;16) and 1q amplifications. R-ISS 3 Presence of extramedullary disease, defined as presence of paramedullary lesions or extramedullary plasmacytoma. Note: In order to have a representative population with high-risk features, 50% of patients included will have ultra-high risk disease defined as: i) R-ISS 3; ii) Double hit (at least two high-risk cytogenetic abnormalities); iii) One high-risk cytogenetic abnormality + extramedullary disease. Patients eligible for transplant with age ≤ 70 years old (young and transplant-eligible) or patients not eligible for transplant with ECOG-PS modified frailty score of 0-1 (elderly-fit). Patient has an ECOG performance status of 0, 1or 2. Exclusion Criteria: Prior or current systemic therapy or SCT for any plasma cell dyscrasia, with the exception of 1 cycle of antimyeloma treatment or the emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment while waiting for results of genetic analysis. A cycle of therapy may include treatment with proteasome inhibitors, immunomodulatory drugs, alkylators and corticosteroids, and/or anti-CD38 monoclonal antibodies (i.e, bortezomib-thalidomide-dexamethasone, D-VTD, bortezomib-lenalidomide-dexamethasone, or bortezomib-cyclophosphamide-dexamethasone, are valid options). Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the NCI-CTCAE Version 5. Patient has a diagnosis of primary light chain amyloidosis, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), plasma cell leukemia or active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) at the time of screening. Myelodysplastic syndrome or active malignancies (ie, progressing or requiring treatment change in the last 24 months) other than relapsed/refractory multiple myeloma. The only allowed exceptions are malignancies treated within the last 24 months that are considered completely cured: Non-muscle invasive bladder cancer (solitary Ta-papillary urothelial neoplasm of low malignancy or low grade, < 3 cm, no carcinoma in situ). Skin cancer (non-melanoma skin cancers treated with curative therapy or localized melanoma treated with curative surgical resection alone). Noninvasive cervical cancer. Localized prostate cancer (M0, N0) with a Gleason score of ≤ 7a, treated locally only (radical prostatectomy/radiation therapy/focal treatment). Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, localized breast cancer and receiving antihormonal agents. Other malignancy that is considered cured with minimal risk of recurrence. Patient has CNS or exhibits clinical signs of meningeal involvement of multiple myeloma. If either is suspected, negative whole brain MRI and lumbar cytology are required.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Induction VRD-Dara + Intensification Tec-Dara + Maintenance Tec-Dara + ERI Tal-Dara<br>Induction (4 cycles) D-VRD. After Induction, all patients recieve 1st INTENSIFICATION treatment (6 cycles of Tec-Dara). Cycles will be of 28 days (4-week cycles) in duration for daratumumab and for Teclistamab. At the end of 1st Intensification timepoint treatments depends on MRD status: MRD negative patients in CR at the end of Intensification will receive MAINTENANCE therapy with Tec-Dara continuously for 2 years. Crossover: patients who convert MRD positive or relapse from CR any time during Teclistamab maintenance will receive the same treatment as MRD positive individuals (early rescue intervention, ERI). MRD positive patients or patients who didn't achieve CR despite MRD negativity, will have ERI (Tal-Dara 6 cycles). MRD and response will be evaluated again after 6 cycles treatment with Tal-Dara. MRD negative patients in CR will receive continuous treatment with Tal-Dara for 2 years. | Drug: Daratumumab<br>* Daratumumab will be administered by SC injection.<br>Drug: Bortezomib<br>* Bortezomib dose will be calculated using the patient's actual body surface area (BSA) at baseline and will be administered by subcutaneous (SC) injection.<br>Drug: Lenalidomide<br>* Lenalidomide will be administered by oral route.<br>Drug: Teclistamab<br>* Teclistamab will be administered by SC injection.<br>* Other names: JNJ-64007957;Drug: Talquetamab<br>* Talquetamab will be administered by subcutaneous (SC) injection.<br>* Other names: JNJ-64407564;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate efficacy in terms of Measurable Residual Disease (MRD) negative Complete Remission rate by Next Generation Flow Cytometry after Teclistamab plus Daratumumab intensification. | MRD measured by Next Generation Flow Cytometry (NGF, with a sensitivity level of 10-6) after 6 cycles of Tec-Dara therapy. | 22 months approximately | 
| Evaluate efficacy in terms of Measurable Residual Disease (MRD) negative Complete Remission rate by Fluorodeoxyglucose Positron Emission Tomography-Computerized Tomography (FDG PET-CT) scan using the Deauville score, after Tec-Dara intensification. | MRD measured by Fluorodeoxyglucose Positron Emission Tomography-Computerized Tomography (FDG PET-CT) scan. | 22 months approximately | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate MRD negative CR rate after Daratumumab plus bortezomib, lenalidomide and dexamethasone (D-VRD) induction. | MRD measured by Next Generation Flow Cytometry. | 16 months approximately | 
| To evaluate MRD negativity after Teclistamab plus Daratumumab (Tec-Dara) intensification using alternative methods | MRD negative rates measured by Next Generation Sequencing (NGS), and Quantitative Immunoprecipitation Free Light Chain Mass Spectrometry (QIP-FLC-MS) after 6 cycles of Tec-Dara therapy. | 22 months approximately | 
| To evaluate MRD conversion after early rescue intervention with Talqutamab plus Daratumumab (Tal-Dara) | Percentage of patients converting from positive MRD to negative MRD evaluated by NGF, NGS, QIP-MS-FLC and FDG-PET-CT scan. | 4 years approximately | 
| To evaluate MRD conversion after Tec-Dara intensification | Percentage of patients converting from positive MRD after D-VRD induction to negative MRD evaluated by NGF, NGS, QIP-MS-FLC and FDGPET-CT scan after Tec-Dara intensification. | 22 months approximately | 
| To evaluate sustained MRD negativity during maintenance treatment in both Tec-Dara and Tal-Dara treatment arms | Proportion of patients with persistent MRD negative disease at month 6, 12, 18 and 24 of maintenance treatment in both Tec-Dara and TalDara treatment, by NGF, NGS, QIP-MS-FLC and FDG-PET-CT scan and annually thereafter. | 76 months approximately | 
| To assess reappearance of MRD positivity or relapse from CR in patients during the Tec-Dara treatment. | Proportion of patients relapsing from MRD negative CR to MRD positive or who relapse from CR (not fulfilling criteria for disease progression) during any phase of Tec-Dara treatment (intensification or maintenance). | 46 months | 
| To assess Time to PFS | PFS is defined as the time from the date of first dose of study drug to the date of first documented disease progression, as defined in the International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurs first. For subjects who have not progressed and are alive, data will be censored at the last disease evaluation before the start of any subsequent anti-myeloma therapy. PFS is measured in months. | 76 months approximately | 
| To assess Time to EFS | EFS is defined as the time from the date of first dose of study drug to the date of first documentation of an event. Definition of event for EFS calculation is: relapse from CR, conversion from Measurable Residual Disease (MRD) negativity (absence of phenotypically aberrant clonal plasma cells by next generation flow with a sensitivity level of 10-6 using the EuroFlow standard operation procedure and complete metabolic response by PET-CT (Deauville score ≤ 3)) to MRD positivity (presence of phenotypically aberrant clonal plasma cells by next generation flow with a sensitivity level of 10-6 using the EuroFlow standard operation procedure and complete metabolic response by PET-CT (Deauville score ≤ 3)), disease progression or death due to any cause, whichever occurs first. For subjects who have not experience any of these events, data will be censored at the last visit. EFS is measured in months. | 76 months approximately | 
| To assess Time to TNT | TNT is defined as the time between date of first dose of study drug and the first dose of the next treatment received. TNT is measured in months. | 76 months approximately | 
| To assess Time to DoR | DoR is the date of initial documentation of a response (Partial Response or better) to the date of first documented evidence of progressive disease, as defined in the International Myeloma Working Group (IMWG) criteria. Relapse from complete response is not considered as disease progression. For subjects who have not progressed, data will be censored at the last disease evaluation before the start of any subsequent anti-myeloma therapy. DoR is measured in months | 76 months approximately | 
| To assess Time to OS | OS is defined as the time from the date of first dose of study drug to the date of the subject's death. If the subject is alive or the vital status is unknown, then the subject's data will be censored at the date the subject was last known to be alive. OS is measured in months. | 76 months approximately | 
| To assess the safety of the treatment described in the protocol | Incidence of treatment-emergent adverse events | 76 months approximately | 
| Immune profiling and genetic characterization | Analysis of immune subpopulation and genetic markers | 76 months approximately | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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High-Risk de novo Multiple Myeloma, Teclistamab, Talquetamab, Daratumumab