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

Sponsor
PETHEMA Foundation (Other)
Overall Status
Not yet recruiting
CT.gov ID
NCT05849610
Collaborator
Janssen, LP (Industry)
30
Enrollment
10
Locations
1
Arm
74
Anticipated Duration (Months)
3
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

A total of 30 transplant elegible or elderly fit DNHRMM (defined by as any one or more of the following: i) High-risk FISH: del(17p), t(4;14), t(14;16) or 1q amplifications; ii) R-ISS 3; or iii) presence of extramedullary disease, defined as presence of paramedullary lesions or extramedullary plasmacytoma) patients will be enrolled.

  1. Patients will receive a 4-cycle Dara+VRD (daratumumab, boretzomib, lenalidomide, dexamethasone) INDUCTION therapy. Cycles will be of 28 days (4-week cycles) in duration for daratumumab and for VRD.
Induction Cycles 1 and 2:

Daratumumab: Daratumumab (SC) 1800 mg once weekly (days 1, 8, 15 and 22). Bortezomib (SC) 1.3 mg/m2 for a total of 4 doses on days 1, 4, 8 and 11. The bortezomib dose will be calculated using the patient's actual body surface area (BSA) at baseline. Lenalidomide (PO) 25 mg daily during the first 21 days. Dexamethasone (PO) 40 mg once weekly (days 1, 8, 15 and 22). The dose will be 40 mg in patients below the age of 75 years, with the possibility of reducing the dose to 20mg in patients that are 75 years of age and older.

Induction Cycles 3 and 4:

Daratumumab (SC) 1800 mg on days 1 and 15. Bortezomib (SC) 1.3 mg/m2 for a total of 4 doses on days 1, 4, 8 and 11. Lenalidomide (PO) 25 mg daily during the first 21 days. Dexamethasone (PO) 40 mg once weekly (days 1, 8, 15 and 22).

  1. After the 4-cycle Induction, all patients will recieve 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 cycles 1 and 2: Daratumumab (SC) 1800 mg on days 1 and 15. Teclistamab Step-up Dose: 3 mg (≤ 60kg) or 4 mg (> 60kg) on day 2, and 15 mg (≤ 60kg) or 25 mg (> 60kg) on day 4. Teclistamab Treatment Dose: 100 mg (≤ 60kg) or 150 mg (> 60kg) for days 8, 15 and 22 of cycle 1, and 100 mg (≤ 60kg) or 150 mg (> 60kg) for days 1, 8, 15 and 22 of cycle 2.

1st Intensification cycles 3-6: Daratumumab SC 1800 mg on day 1. Teclistamab Treatment Dose: 200 mg (≤ 60kg) or 300 mg (> 60kg) for days 1 and 15.

  1. At the end of 1st Intensification timepoint treatments depends on MRD status:

3.1) 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) 200 mg (≤ 60 kg) or 300 mg (> 60 kg) and daratumumab (SC) 1800 mg both given at day 1 of each cycle.

3.2) 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.

3.2.1 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) any time during Tec-Dara treatment will have ERI with Tal-Dara. Cycles will be of 28 days in duration.

ERI consists of 6 cycles:

  • Cycle1: Talquetamab SC Step-Up Dose 1 / SU1 (0.01 mg/kg) on day 2. Talquetamab SC Step-Up Dose 2 / SU2 (0.06 mg/kg) on day 4. Talquetamab SC Step-Up Dose 3 / SU3 (0.4 mg/kg) on day 8. Daratumumab SC (1800 mg) on day 1. Dexamethasone 20 mg or equivalent on days 2, 4, 8 and 15.

  • Cycles 2 -6: Talquetamab SC Treatment Dose (0.8 mg/kg) on days 1 and 15. Daratumumab SC (1800 mg) on day 1.

3.2.2. 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. Talquestamab (SC) 0.8 mg/kg on days 1 and 15. Daratumumab (SC) 1800 mg on day 1.

  1. 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 investigation decision outside of the study.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
30 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Intervention Model Description:
All patients will receive Induction (Dara+VRD) for 4 cycles. Later on, all patients will receive 1st Intensification treatment (Tec+Dara). At this timepoint, treatment will be assigned depending on MRD status: MRD negative patients will receive maintenance with Tec-Dara 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 (commented below). MRD positive inidividuals will receive early rescue intervention with Tal-Dara for 6 cycles. Depending on MRD status at the end od early intervention: b.i) MRD negative patients will receive 2-year maintenance with Tal-Dara. b.ii) MRD positive patients will receive salvage therapy according to investigator's choice.All patients will receive Induction (Dara+VRD) for 4 cycles. Later on, all patients will receive 1st Intensification treatment (Tec+Dara).At this timepoint, treatment will be assigned depending on MRD status:MRD negative patients will receive maintenance with Tec-Dara 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 (commented below). MRD positive inidividuals will receive early rescue intervention with Tal-Dara for 6 cycles. Depending on MRD status at the end od early intervention: b.i) MRD negative patients will receive 2-year maintenance with Tal-Dara. b.ii) MRD positive patients will receive salvage therapy according to investigator's choice.
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
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
Anticipated Study Start Date :
May 1, 2023
Anticipated Primary Completion Date :
Jan 1, 2025
Anticipated Study Completion Date :
Jul 1, 2029

Arms and Interventions

Arm Intervention/Treatment
Experimental: Induction VRD-Dara + Intensification Tec-Dara + Maintenance Tec-Dara + ERI Tal-Dara

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
Induction Cycles 1 and 2: Daratumumab (SC) 1800 mg once weekly (days 1, 8, 15 and 22). Induction Cycles 3 and 4: Daratumumab (SC) 1800 mg on days 1 and 15. 1st Intsensification cycles 1 and 2: Daratumumab (SC) 1800 mg on days 1 and 15. 1st Intensification cycles 3-6: Daratumumab SC 1800 mg on day 1. MRD negative patients in CR at the end of Intensification receive 2-year maintenance daratumumab (SC) 1800 mg given at day 1 of each cycle. MRD positive patients or patients who didn't achieve CR despite MRD negativity, will have EARLY RESCUE INTERVENTION with Tal-Dara for 6 cycles. Cycle1: Daratumumab SC (1800 mg) on day 1. Cycles 2 -6: Daratumumab SC (1800 mg) on day 1. MRD negative patients in CR will receive continuous treatment with Tal-Dara for 2 years. Daratumumab (SC) 1800 mg on day 1 of each cycle.

Drug: Bortezomib
Patients will receive a 4-cycle Dara+VRD (daratumumab, boretzomib, lenalidomide, dexamethasone) INDUCTION therapy. Cycles will be of 28 days (4-week cycles) in duration for daratumumab and for VRD. Induction Cycles 1 and 2: Bortezomib (SC) 1.3 mg/m2 for a total of 4 doses on days 1, 4, 8 and 11. The bortezomib dose will be calculated using the patient's actual body surface area (BSA) at baseline. Induction Cycles 3 and 4: Bortezomib (SC) 1.3 mg/m2 for a total of 4 doses on days 1, 4, 8 and 11.

Drug: Lenalidomide
Patients will receive a 4-cycle Dara+VRD (daratumumab, boretzomib, lenalidomide, dexamethasone) INDUCTION therapy. Cycles will be of 28 days (4-week cycles) in duration for daratumumab and for VRD. Induction Cycles 1 and 2: Lenalidomide (PO) 25 mg daily during the first 21 days. Induction Cycles 3 and 4: Lenalidomide (PO) 25 mg daily during the first 21 days.

Drug: Dexamethasone
Patients will receive a 4-cycle Dara+VRD (daratumumab, boretzomib, lenalidomide, dexamethasone) INDUCTION therapy. Cycles will be of 28 days (4-week cycles) in duration for daratumumab and for VRD. Induction Cycles 1 and 2: Dexamethasone (PO) 40 mg once weekly (days 1, 8, 15 and 22). The dose will be 40 mg in patients below the age of 75 years, with the possibility of reducing the dose to 20mg in patients that are 75 years of age and older. Induction Cycles 3 and 4: Dexamethasone (PO) 40 mg once weekly (days 1, 8, 15 and 22). At the end of 1st Intensification timepoint treatments depends on MRD status. 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. Cycle 1: Dexamethasone 20 mg or equivalent on days 2, 4, 8 and 15.

Drug: Teclistamab
After the 4-cycle Induction, all patients will recieve 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 cycles 1 and 2: Teclistamab Step-up Dose: 3 mg (≤ 60kg) or 4 mg (> 60kg) on day 2, and 15 mg (≤ 60kg) or 25 mg (> 60kg) on day 4. Teclistamab Treatment Dose: 100 mg (≤ 60kg) or 150 mg (> 60kg) for days 8, 15 and 22 of cycle 1, and 100 mg (≤ 60kg) or 150 mg (> 60kg) for days 1, 8, 15 and 22 of cycle 2. 1st Intensification cycles 3-6: Teclistamab Treatment Dose: 200 mg (≤ 60kg) or 300 mg (> 60kg) for days 1 and 15. 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. Cycles will be of 28-days in duration for Tec-Dara. Teclistamab (SC) 200 mg (≤ 60 kg) or 300 mg (> 60 kg).

Drug: Talquetamab
At the end of 1st Intensification timepoint treatments depends on MRD status. 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. Cycle1: Talquetamab SC Step-Up Dose 1 / SU1 (0.01 mg/kg) on day 2. Talquetamab SC Step-Up Dose 2 / SU2 (0.06 mg/kg) on day 4. Talquetamab SC Step-Up Dose 3 / SU3 (0.4 mg/kg) on day 8. Cycles 2 -6: Talquetamab SC Treatment Dose (0.8 mg/kg) on days 1 and 15. 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. Talquestamab (SC) 0.8 mg/kg on days 1 and 15 of each cycle.

Outcome Measures

Primary Outcome Measures

  1. Evaluate efficacy in terms of Measurable Residual Disease (MRD) negative Complete Remission rate by Next Generation Flow Cytometry after Teclistamab plus Daratumumab intensification. [22 months approximately]

    MRD measured by Next Generation Flow Cytometry (NGF, with sensitivity level of 10-6) after 6 cycles of Tec-Dara therapy. MRD refers to percentage (i.e. 0.001%) of tumour cells among normal healthy hematopoietic cells.

  2. 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. [22 months approximately]

    MRD measured by Fluorodeoxyglucose Positron Emission Tomography-Computerized Tomography (FDG PET-CT) scan using the Deauville score and CR evaluated per International Myeloma Working Group (IMWG) 2016 response criteria after 6 cycles of Tec-Dara therapy. MRD refers to percentage (i.e. 0.001%) of tumour cells among normal healthy hematopoietic cells.

Secondary Outcome Measures

  1. To evaluate MRD negative CR rate after Daratumumab plus bortezomib, lenalidomide and dexamethasone (D-VRD) induction. [16 months approximately]

    MRD measured by Next Generation Flow Cytometry (NGF, with sensitivity level of 10-6) and Fluorodeoxyglucose Positron Emission Tomography-Computerized Tomography (FDG PET-CT) scan using the Deauville score and CR evaluated per International Myeloma Working Group (IMWG) 2016 response criteria after 4 cycles of D-VRD induction. MRD measures to the percentage (i.e. 0.001%) of tumour cells among normal healthy hematopoietic cells. The maximum value is 100% and the minimum, which is determined by the performance of the technique, is 0,00001%. The lower the percentage, the better the outcome.

  2. To evaluate MRD negativity after Teclistamab plus Daratumumab (Tec-Dara) intensification using alternative methods [22 months approximately]

    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. NGS measures the percentage of specific oncologic immunoglobulin rearrangements (i.e. 0.001%) among other healthy immunoglobulin rearrangements of B-cells. The maximum value is 100% and the minimum, which is determined by the performance of the technique, is 0,00001%. The lower the percentage, the better the outcome.

  3. To evaluate MRD conversion after early rescue intervention with Talqutamab plus Daratumumab (Tal-Dara) [4 years approximately]

    Percentage of patients converting from positive MRD to negative MRD evaluated by NGF, NGS, QIP-MS-FLC and FDG-PET-CT scan. MRD measured by Next Generation Flow Cytometry (NGF) refers to the percentage (i.e. 0.001%) of tumour cells among normal healthy hematopoietic cells. The maximum value is 100% and the minimum, which is determined by the performance of the technique, is 0,00001%. The lower the percentage, the better the outcome. Next Generation Sequencing (NGS) measures the percentage of specific oncologic immunoglobulin rearrangements (i.e. 0.001%) among other healthy immunoglobulin rearrangements of B-cells. The maximum value is 100% and the minimum, which is determined by the performance of the technique, is 0,00001%. The lower the percentage, the better the outcome.

  4. To evaluate MRD conversion after Tec-Dara intensification [22 months approximately]

    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. MRD measured by Next Generation Flow Cytometry (NGF) refers to the percentage (i.e. 0.001%) of tumour cells among normal healthy hematopoietic cells. The maximum value is 100% and the minimum, which is determined by the performance of the technique, is 0,00001%. The lower the percentage, the better the outcome. Next Generation Sequencing (NGS) measures the percentage of specific oncologic immunoglobulin rearrangements (i.e. 0.001%) among other healthy immunoglobulin rearrangements of B-cells. The maximum value is 100% and the minimum, which is determined by the performance of the technique, is 0,00001%. The lower the percentage, the better the outcome.

  5. To evaluate sustained MRD negativity during maintenance treatment in both Tec-Dara and Tal-Dara treatment arms [76 months approximately]

    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. MRD measured by Next Generation Flow Cytometry (NGF) refers to the percentage (i.e. 0.001%) of tumour cells among normal healthy hematopoietic cells. The maximum value is 100% and the minimum, which is determined by the performance of the technique, is 0,00001%. The lower the percentage, the better the outcome. Next Generation Sequencing (NGS) measures the percentage of specific oncologic immunoglobulin rearrangements (i.e. 0.001%) among other healthy immunoglobulin rearrangements of B-cells. The maximum value is 100% and the minimum, which is determined by the performance of the technique, is 0,00001%. The lower the percentage, the better the outcome.

  6. To assess reappearance of MRD positivity or relapse from CR in patients during the Tec-Dara treatment. [46 months]

    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).

  7. To assess Time to PFS [76 months approximately]

    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.

  8. To assess Time to EFS [76 months approximately]

    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.

  9. To assess Time to TNT [76 months approximately]

    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.

  10. To assess Time to DoR [76 months approximately]

    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

  11. To assess Time to OS [76 months approximately]

    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.

  12. To assess the safety of the treatment described in the protocol [76 months approximately]

    Incidence of treatment-emergent adverse events

  13. Immune profiling and genetic characterization [76 months approximately]

    Analysis of immune subpopulation and genetic markers

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:

  1. Patient is, in the investigator's opinion, willing and able to comply with the protocol requirements.

  2. 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.

  3. 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.

  4. Patient has documented diagnosis of multiple myeloma according to IMWG diagnostic criteria, with at least one of the following high-risk features:

  5. High-risk FISH: del(17p), t(4;14), t(14;16) and 1q amplifications.

  6. R-ISS 3

  7. 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.

  1. Patient has measurable secretory disease at screening defined as either serum monoclonal protein of ≥ 0.5 g/dl or urine monoclonal (light chain) protein ≥ 200 mg/24
  1. For patients whose disease is only measurable by serum free light chain (FLC), the serum immunoglobulin FLC should be ≥ 10mg/dL (100 mg/L), with an abnormal immunoglobulin kappa lambda serum FLC ratio.

  1. Human immunodeficiency virus-positive patients are eligible if the meet all of the following:

  2. No detectable viral load (ie, < 50 copies/mL) at screening

  3. CD4+ count > 300 cells/mm3 at screening

  4. No acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within 6 months of screening

  5. Receiving HAART. Any changes in HAART due to resistance/progression should occur at least 3 months prior to screening. A change in HAART due to toxicity is allowed up to 4 weeks prior to screening.

Note: HAART that could interfere with study treatment is excluded (consult the sponsor for a review of medications prior to randomization/enrollment).

  1. 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).

  2. Patient has an ECOG performance status of 0, 1or 2.

  3. Patient must have adequate organ function, defined by:

  4. Hemoglobin: ≥ 8 g/dL (≥ 5 mmol/L; without prior RBC transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted).

  5. Platelets: ≥ 75 x 109/L in patients in whom < 50% of bone marrow nucleated cells are plasma cells and ≥ 50×109/L in patients 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).

  6. Absolute Neutrophil Count (ANC): ≥ 1.0 x 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).

  7. ALT and AST: ≤ 2.5 x upper limit normal .

  8. eGFR: ≥ 30 mL/min based on Modified Diet in Renal Disease 4 variable Formula calculation or creatine clearance measured by a 24-hour urine collection.

  9. Total bilirubin: Total bilirubin < 1.5 x upper limit normal (isolated total bilirubin ≥ 1.5 x upper limit normal with conjugated [direct] bilirubin < 1.5 x upper limit normal is allowed for those patients with known Gilbert's syndrome).

  10. Serum calcium corrected for albumin: ≤ 14 mg/dL (≤ 3.5 mmol/L) or free ionized calcium ≤ 6.5 mg/dL (≤ 1.6 mmol/L).

  11. A female patient of childbearing potential must have a negative highly sensitive urine or serum (β human chorionic gonadotropin [β hCG]) pregnancy test at screening and within 24hours prior to the start of study treatment and must agree to further urine or serum pregnancy tests during the study.

  12. A female patient must be:

  13. Not of childbearing potential, or

  14. Of childbearing potential and

  1. Practicing true abstinence; or ii. Have a sole partner who is vasectomized; or iii. Practicing 2 effective methods of contraception (at least 1 highly-effective method of contraception).
NOTE: Nonchildbearing potential is defined as follows (by other than medical reasons):

  • ≥ 45 years of age and has not had menses for > 1 year.

  • Has been amenorrhoeic for > 2 years without history of a hysterectomy and oophorectomy and has a follicle stimulating hormone value in the postmenopausal range upon screening evaluation.

  • Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure.

NOTE: Patient must agree to continue the above throughout the study and for 3 months after the last dose of study treatment.

NOTE: If a female patient becomes of childbearing potential after start of the study the female patient must comply with point (b) as described above. If a patient's reproductive status is questionable, additional evaluation should be considered.

NOTE: An interaction between hormonal contraception and talquetamab or teclistamab has not been formally studied. Therefore, it is unknown whether talquetamab or teclistamab may reduce the efficacy of the contraception method.

  1. A female patient must agree not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction during the study and for 3 months after receiving the last dose of study treatment. A female patient should consider preservation of eggs prior to study treatment as anti-cancer treatments may impair fertility.

  2. A male patient 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 3 months after receiving the last dose of study treatment. If the male patient's partner is a female of childbearing potential, the male patient must use condoms (with or without spermicide) and the female partner of the male patient must also be practicing a highly effective method of contraception as condoms may break or leak.

NOTE: If the male patient is vasectomized, he still must wear a condom (with or without spermicidal foam/gel/film/cream/suppository) but his female partner is not required to use contraception.

  1. A male patient must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 3 months after receiving the last dose of study treatment. Male patients should consider preservation of sperm prior to study treatment as anti-cancer treatments may impair fertility.

  2. Patient must be willing and able to adhere to the lifestyle restrictions specified in this protocol.

  3. All prior treatment-related toxicities (defined by National Cancer Institute - Common Toxicity Criteria for AEs [NCI-CTCAE], Version 5.0 must be ≤ Grade 1 at the time of enrolment except for alopecia.

Exclusion Criteria:

  1. 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).

  2. Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the NCI-CTCAE Version 5.

  3. 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.

  4. 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:

  5. Non-muscle invasive bladder cancer (solitary Ta-papillary urothelial neoplasm of low malignancy or low grade, < 3 cm, no carcinoma in situ).

  6. Skin cancer (non-melanoma skin cancers treated with curative therapy or localized melanoma treated with curative surgical resection alone).

  7. Noninvasive cervical cancer.

  8. Localized prostate cancer (M0, N0) with a Gleason score of ≤ 7a, treated locally only (radical prostatectomy/radiation therapy/focal treatment).

  9. Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, localized breast cancer and receiving antihormonal agents.

  10. Other malignancy that is considered cured with minimal risk of recurrence.

  11. 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.

  12. Patient is pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of study treatment.

  13. Patient plans to father a child while enrolled in this study or within 3 months after the last dose of study treatment.

  14. Patient is simultaneously enrolled in other interventional clinical trial.

  15. Patient has received prior radiotherapy within 2 weeks of start of study therapy. Patients must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-central nervous system (CNS) disease.

  16. Plasmapheresis within 28 days of starting study treatment defined as C1D1 of D-VRD.

  17. Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1 testing is required for patients with known or suspected of having COPD or asthma and patients must be excluded if FEV1 < 50% of predicted normal.

  18. Moderate or severe persistent asthma within the past 24 months (See APPENDIX 20), or uncontrolled asthma of any classification. Note that FEV1 testing is required for patients known or suspected asthma and patients must be excluded if FEV1 < 50% of predicted normal.

  19. Patient has a known immediate or delayed hypersensitivity reaction or idiosyncrasy to other molecular antibodies.

  20. Patient had major surgery or had significant traumatic injury within 2 weeks prior to the start of administration of study treatment, or will not have fully recovered from surgery, or has major surgery planned during the time the patient is expected to be treated in the study or within 2 weeks after administration of the last dose of study treatment.

NOTE: Patients with planned surgical procedures to be conducted under local anesthesia may participate. Kyphoplasty or vertebroplasty are not considered major surgery. If there is a question whether a procedure is considered a major surgery, the investigator must consult with the appropriate sponsor representative and resolve any issues before enrolling a patient in the study.

  1. Prior or concurrent exposure to any of the following, in the specified time frame prior to starting study treatment:

  • Investigational vaccine other than SARS CoV-2 vaccine approved/ in use under emergency approval within 4 weeks.

  • Live, attenuated vaccine within 4 weeks. Killed or inactivated vaccines may be administered, however, the response to such vaccines cannot be predicted.

  • Monoclonal antibody therapy within 21 days (not use for the treatment of multiple myeloma).

  1. Received a strong CYP3A4 inducer within 5 half-lives prior to starting study treatment (Flockhart 2021).

  2. A maximum cumulative dose of corticosteroids of ≥ 140 mg of prednisone or equivalent within 14-day period before the first dose of Tec-Dara or Tal-Dara (does not include pretreatment medications).

  3. Allergy, hypersensitivity, or intolerance to boron or mannitol, corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to the Investigator's Brochure and appropriate package inserts), or sensitivity to mammalian-derived products or lenalidomide.

  4. Presence of the following cardiac conditions:

  5. New York Heart Association stage III or IV congestive heart failure.

  6. Myocardial infarction or coronary artery bypass graft ≤ 6 months prior to starting study treatment.

  7. History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration.

  8. Uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities.

  9. Stroke, transient ischemic attack or seizure within 6 months prior to signing informed consent form (ICF).

  10. Any of the following:

  11. Hepatitis B infection (ie, HBsAg or HBV-DNA positive). In the event the infection status is unclear, quantitative viral levels are necessary to determine the infection status.

  12. Active hepatitis C infection as measured by positive hepatitis C virus-ribonucleic acid (HCV)-RNA testing. Patients with a history of HCV antibody positivity must undergo HCV-RNA testing. If a patient with history of chronic hepatitis C infection (defined as both HCV antibody and HCV-RNA positive) completed antiviral therapy and has udetectable HCV-RNA for at least 12 weeks following the completion of therapy, the patient is eligible for the study.

  13. Concurrent medical or psychiatric condition or disease that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study, such as:

  14. Uncontrolled diabetes

  15. Acute diffuse infiltrative pulmonary disease

  16. Evidence of active systemic viral, fungal, or bacterial infection, requiring systemic antimicrobial therapy.

  17. History of active autoimmune disease. with exception of patients with vitiligo, type I diabetes, and prior autoimmune thyroiditis that is currently euthyroid based on clinical symptoms and laboratory testing.

  18. Disabling psychiatric conditions (e.g., alcohol or drug abuse), severe dementia, or altered mental status.

  19. Any other issue that would impair the ability of the patient to receive or tolerate the planned treatment at the investigational site, to understand informed consent or any condition for which, in the opinion of the investigator, participation would not be in the best interest of the patient (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.

  20. History of non-compliance with recommended medical treatments.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Hospital Germans Trials i Pujol Badalona Spain
2 Hospital Clinic i Provincial de Barcelona Barcelona Spain
3 Hospital Doce de Octubre Madrid Spain 28041
4 Hospital Virgen de la Arrixaca Murcia Spain
5 Clinica Universidad de Navarra Pamplona Spain
6 Hospital Universitario de Salamanca Salamanca Spain
7 H. Universitario Marqués de Valdecilla Santander Spain
8 Complejo Hospitalario Santiago (CHUS) Santiago De Compostela Spain
9 Hospital Vírgen del Rocío Sevilla Spain
10 Hospital Universitari i Politecnic la Fe Valencia Spain

Sponsors and Collaborators

  • PETHEMA Foundation
  • Janssen, LP

Investigators

  • Study Chair: Juan José Lahuerta Palacios, Dr, Hospital Universitario 12 de Octubre
  • Study Chair: Joan Bladé, Dr, Hospital Clinic of Barcelona
  • Study Chair: Mª Victoria Mateos, Dr, Hospital Clínico Universitario de Salamanca
  • Study Chair: Paula Rodríguez Otero, Dr, Clínica Universidad de Navarra
  • Study Chair: Jesús San Miguel, Dr, Clínica Universidad de Navarra

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:
PETHEMA Foundation
ClinicalTrials.gov Identifier:
NCT05849610
Other Study ID Numbers:
  • GEM-TECTAL
First Posted:
May 9, 2023
Last Update Posted:
May 9, 2023
Last Verified:
Apr 1, 2023
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by PETHEMA Foundation
High-Risk de novo Multiple Myeloma
Teclistamab
Talquetamab
Daratumumab
Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Dexamethasone
Lenalidomide
Bortezomib
Daratumumab

Study Results

No Results Posted as of May 9, 2023