Evaluation of Minimal Residual Disease-Based Strategy with Teclistamab Post-Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone in Newly Diagnosed Multiple Myeloma
- Trial ID
- 2023-508310-41-00
- Protocol
- RC23_0267
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the efficacy of a **minimal residual disease** (MRD)-based strategy in patients with newly diagnosed **multiple myeloma**. Specifically, for Cohort A, the aim is to determine the rate of sustained MRD negativity at a sensitivity of 10^-5 following induction therapy. For Cohort B, the objective is to assess the rate of conversion from positive MRD to negative MRD at the same sensitivity level. These outcomes are clinically relevant as they provide insights into the depth of response and potential long-term remission in multiple myeloma patients.
Secondary objectives include:
- Assessing the safety and tolerability of Tec-Len in Cohort A and Tec-Tal in Cohort B post-induction.
- For Cohort A, determining the rate of sustained MRD negativity at a sensitivity of 10^-6.
- For Cohort B, evaluating the rate of conversion from positive MRD to negative MRD at sensitivities of 10^-6 and 10^-5.
- Determining overall survival (OS), progression-free survival (PFS), duration of response (DOR), and time to response (TTR) according to IMWG criteria (2016).
- Evaluating complete response (CR) or better, very good partial response (VGPR) or better, and overall response rate (ORR).
- Identifying biological prognostic factors influencing outcomes and response.
- Assessing quality of life (QoL).
Participants
The clinical trial involves participants diagnosed with **multiple myeloma**, a condition characterized by the presence of monoclonal plasma cells in the bone marrow and measurable disease. The study population includes both male and female subjects, aged between 18 and 65 years, who are newly diagnosed and eligible for high-dose therapy and autologous stem cell transplantation. Participants are required to have a Karnofsky performance status score of at least 50% and meet specific clinical laboratory criteria. The trial does not include a vulnerable population. Participants must adhere to lifestyle restrictions specified in the protocol, including contraceptive measures for both male and female subjects to prevent pregnancy during and after the study period. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed to evaluate a **minimal residual disease**-based strategy in patients with newly diagnosed **multiple myeloma**. This is a Phase 2, randomized, double-blind, controlled trial. The trial aims to assess the efficacy of a T-cell redirector following treatment with a combination of **daratumumab**, **bortezomib**, **lenalidomide**, and **dexamethasone**. The trial is expected to commence on April 20, 2024, and conclude by June 20, 2030, with an estimated duration of 6 years for participant involvement.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including age, documented multiple myeloma, and measurable disease. The trial will include follow-up visits at regular intervals to monitor the participants' health status and response to treatment. The primary endpoint is the sustained MRD negativity at one year, while secondary endpoints include the presence and severity of treatment-emergent adverse events, overall survival, progression-free survival, and other response criteria.
The study will involve multiple cohorts, with Cohort A focusing on patients who achieve MRD negativity after induction therapy, and Cohort B on those who remain MRD positive. Participants will be required to adhere to specific lifestyle restrictions and contraceptive measures throughout the study and for a period after the last dose of study treatments. Conditions that may lead to early termination from the study include withdrawal of consent, non-compliance with study procedures, or adverse events that compromise participant safety.
Treatment
The clinical trial involves the administration of several experimental and non-experimental treatments. **VELCADE** (bortezomib) is provided as a 3.5 mg powder for solution for injection. It is administered subcutaneously with a maximum daily dose of 1.3 mg/m² and a total dose not exceeding 31.2 mg/m² over a treatment period of up to 6 months. **DARZALEX** (daratumumab) is another experimental treatment, available as an 1800 mg solution for injection, administered subcutaneously with a maximum daily dose of 1800 mg and a total dose of 28800 mg over 6 months.
**JNJ-64407564** (talquetamab) is administered as a solution for injection subcutaneously, with a maximum daily dose of 0.8 mg/kg and a total dose of 21.27 mg/kg over a period of 104 weeks. **Teclistamab** is also administered subcutaneously as a solution for injection, with a maximum daily dose of 3 mg/kg and a total dose of 76.86 mg/kg over 104 weeks.
**DEXAMETHASONE** is used in two forms: as dexamethasone acetate, administered orally and intravenously, with a maximum daily dose of 16 mg and a total dose of 48 mg over 1 month, and as dexamethasone sodium phosphate, administered intravenously, with a maximum daily dose of 40 mg and a total dose of 1440 mg over 6 months. **PREDNISONE** (prednisolone) is administered orally and intravenously, with a maximum daily dose of 60 mg and a total dose of 420 mg over 3 months.
**LENALIDOMIDE** is provided in capsule form for oral use, with a maximum daily dose of 25 mg and a total dose of 3150 mg over 6 months. **MONTELUKAST** (montelukast sodium) is administered orally, with a maximum daily dose of 10 mg and a total dose of 160 mg over 6 months.
Non-experimental treatments include **PARACETAMOL** (buclizine hydrochloride, paracetamol, codeine phosphate), administered orally and intravenously, with a maximum daily dose of 1000 mg and a total dose of 29000 mg over 26 months. **ANTIHISTAMINES** for systemic use are also included, administered orally and intravenously, with a maximum daily dose of 50 mg and a total dose of 1450 mg over 26 months.
Participant compliance is monitored through regular assessments and adherence checks to ensure accurate dosing and administration. The trial aims to evaluate the efficacy and safety of these treatments in patients with newly diagnosed multiple myeloma, focusing on minimal residual disease-based strategies.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the evaluation of **Minimal Residual Disease (MRD)** status in patients with newly diagnosed multiple myeloma. The primary endpoints include the rate of sustained MRD negativity in Cohort A and the conversion rate from positive to negative MRD status in Cohort B, both assessed at one year (Cycle 13 Day 1) after completion of 12 cycles of maintenance therapy. MRD status will be determined using Next-Generation Sequencing (NGS) with a threshold of <10^-5 for MRD negativity.
Secondary endpoints will include the presence and severity of treatment-emergent adverse events (TEAEs) as defined by NCI CTCAE Version 5.0, excluding cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which will be assessed based on ASTCT guidelines. Additional secondary endpoints involve the conversion to MRD negativity by three months (Cycle 4 Day 1) for Cohort B, overall survival (OS), progression-free survival (PFS), duration of response (DOR), time to response (TTR), overall response rate (ORR) as defined by the IMWG response criteria, and changes in quality of life scores using EQ-5D-5L and EORTC QC30 over specified timepoints.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female patients must be at least 18 years of age at the time of consent younger than 66 years.
- A male patient must agree not to donate sperm for the purpose of reproduction during the study and for a period of 6 months after receiving the last dose of study. Male patients should consider preservation of sperm prior to study treatment as anti cancer treatments may impair fertility.
- Documented multiple myeloma satisfying the CRAB criteria and measurable disease as defined by: a. Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma AND any one or more of the following myeloma defining events: i. Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than ULN or >2.75 mmol/L (>11 mg/dL) ii. Renal insufficiency: creatinine clearance <40 mL/min (as calculated by the Cockcroft-Gault, see Appendix 6) or serum creatinine >177 μmol/L (>2 mg/dL) iii. Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin <10 g/dL (Hemoglobin measurement performed as part of standard of care within 42 days before enrollment is acceptable for screening for CRAB criteria; but must be performed within 28 days before enrollment for other eligibility requirements) iv. Bone lesions: one or more osteolytic lesions on skeletal radiography, CT or PET-CT (PET-CT=18F-fluorodeoxyglucose positron emission tomography with computed tomography. If bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement). v. Clonal bone marrow plasma cell percentage ≥60% (Clonality should be established by showing κ/λ-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used). vi. Involved: uninvolved serum free light chain ratio ≥100 (These values are based on the serum Freelite assay [The Binding Site Group, Birmingham, UK]. The involved free light chain must be ≥100 mg/L.) vii. >1 focal lesion on MRI studies (Each focal lesion must be 5 mm or more in size.) b. Measurable disease at Screening as defined by any of the following: i. Serum M-protein level ≥0.5 g/dL; or ii. Urine M-protein level ≥200 mg/24 hours; or iii. Serum Ig FLC ≥10 mg/dL and abnormal serum Ig kappa lambda FLC ratio. Source: Rajkumar 2014
- Newly diagnosed patients eligible for high dose therapy and autologous SCT.
- Have a Karnofsky performance status score ≥50% (ECOG performance status ECOG score ≤2; Appendix 5
- Have clinical laboratory values meeting the following criteria. Hematology : Hemoglobin ≥8 g/dL (≥5 mmol/L; without prior RBC transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted). Platelets : ≥75×109/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). ANC : ≥1.0×109/L (before the first dose of treatment, 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 and ALT ≤2.5×ULN . Total bilirubin ≤2.0×ULN; except in participants with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤1.5×ULN is required). eGFR ≥30 mL/min based on Cockroft-Gault Formula calculation (Appendix 6) or creatinine clearance measured by a 24-hour urine collection. Serum calcium corrected for albumin ≤14 mg/dL (≤3.5 mmol/L) or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L; see Appendix 7)
- A female patient of childbearing potential must have a negative serum pregnancy test within 10 to 14 days prior to the start of study treatment and again either a serum or urine pregnancy test within 24 hours of the start of study treatment and must agree to further serum or urine pregnancy tests during the study and for a period of 6 months after the last dose of study treatments.
- A female patient must be (as defined in Appendix 1): a. Not of childbearing potential, or b. Of childbearing potential and 1) Practicing 2 reliable methods of contraception simultaneously including one highly effective method of contraception and one other effective method of contraception (see Appendix 1) starting 4 weeks prior to dosing, throughout the study including during dose interruptions and for period of 6 months after the last dose of study treatments. For patients who are of childbearing potential, see Section 6.8.3.3 for details regarding concomitant use of estrogen containing products and lenalidomide.
- 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 a period of 6 months after the last dose of other study treatments. Female patients should consider preservation of eggs prior to study treatment as anti-cancer treatments may impair fertility.
- A male patient must wear a condom (with spermicidal foam/gel/film/cream/suppository) when engaging in any activity that allows for passage of ejaculate to another person during the study and for a period of 6 months after the last dose of study treatments. If the male patient’s partner is a female of childbearing potential, she must also be practicing a highly effective method of contraception (see Appendix 1). 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.
- Voluntary written informed consent must be given before performance of any study related procedure not part of normal medical care, with the understanding that the patient may withdraw consent at any time without prejudice to future medical care.
- Willing and able to adhere to the lifestyle restrictions specified in this protocol.
- Affiliation with French social security system or beneficiary from such system.
Exclusion Criteria
- Medical Conditions 1. Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the NCI CTCAE Version 5.0.
- COPD with a 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.
- Moderate or severe persistent asthma within the past 2 years (see Appendix 8 [for severity of Asthma]), 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.
- CNS involvement or clinical signs of meningeal involvement of multiple myeloma. If either is suspected, negative whole brain MRI and lumbar cytology are required.
- Plasma cell leukemia, Waldenström's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes), or primary light chain amyloidosis.
- Any ongoing myelodysplastic syndrome or B cell malignancy (other than multiple myeloma).
- Any history of malignancy, other than multiple myeloma, which is considered at high risk of recurrence requiring systemic therapy.
- Active malignancies (ie, progressing or requiring treatment change in the last 24 months) other than multiple myeloma. The only allowed exceptions are malignancies treated within the last 24 months that are considered cured: a. Non-muscle invasive bladder cancer (solitary Ta-PUNLMP or low grade, <3 cm, no CIS). b. Non-melanoma skin cancers treated with curative therapy or localized melanoma treated with curative surgical resection alone c. Noninvasive cervical cancer d. Localized prostate cancer (M0, N0) with a Gleason Score ≤7a, treated locally only (radical prostatectomy/radiation therapy/focal treatment) e. Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, or history of localized breast cancer (antihormonal therapy is permitted) f. Other malignancy that is considered cured with minimal risk of recurrence in consultation with the Sponsor NOTE: In the event of any questions, consult the Sponsor prior to enrolling a patient.
- Stroke, transient ischemic attack, or seizure within 6 months prior to signing ICF.
- Presence of the following cardiac conditions: a. New York Heart Association stage III or IV congestive heart failure (Appendix 10) b. Myocardial infarction or coronary artery bypass graft ≤6 months prior to enrollment c. History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration d. Uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities e. History of severe non-ischemic cardiomyopathy
- 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: a. Acute diffuse infiltrative pulmonary disease a. Evidence of active systemic viral, fungal, or bacterial infection, requiring systemic antimicrobial therapy b. History of autoimmune disease with the exception of vitiligo, type I diabetes, and prior autoimmune thyroiditis that is currently euthyroid based on clinical symptoms and laboratory testing. c. Disabling psychiatric conditions (eg, alcohol or drug abuse), severe dementia, or altered mental status. d. 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 (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. e. History of noncompliance with recommended medical treatments
- Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any study drug (daratumumab, bortezomib, lenalidomide, dexamethasone, teclistamab or talquetamab) or its excipients (refer to the appropriate IBs and SmPCs) or analogues and study–required co-medication.
- Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs.
- Prior/Concomitant Therapy 14. Prior or current systemic therapy or SCT 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.
- Received a strong CYP3A4 inducer within 5 half-lives prior to the first dose of study treatment (Flockhart 2016: http://medicine.iupui.edu/flockhart/).
- Plasmapheresis within 28 days prior to the first dose of study treatment.
- 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.
- Taken any disallowed therapies as noted in Section 6.8, Concomitant Therapy before the planned first dose of study intervention.
- Received a live, attenuated vaccine within 4 weeks before the first dose of study drug. Non-live or replicating vaccines authorized for emergency use (eg, COVID-19) are allowed.
- Diagnostic Assessments 20. HIV infection (positive, history, treatment for HIV).
- 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 see Section 8.4.4.1 for further required assessments.
- Active hepatitis C infection as measured by positive 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 undetectable HCV-RNA 12 weeks following the completion of therapy, the patient is eligible for the study.
- Other non-inclusions 23. Patients unable to complete baseline NGS evaluation at Screening.
- Patient is pregnant, a nursing mother, or planning to become pregnant while enrolled in this study or within 6 months after the last dose of study treatment.
- Patient plans to father a child while enrolled in this study or within 6 months after the last dose of study treatment, whichever is later.
- Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the patient (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
- Person under guardianship, trusteeship or deprived of freedom by a judicial or administrative decision.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 20 Apr 2024 | 103 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
DARZALEX 1800 mg solution for injection | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 1800 | 6 | PRD8157846 |
MONTELUKAST | Other | PHF00082MIG | ORAL USE | 10 | 6 | SCP1139557 |
teclistamab | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 3 | 104 | PRD9936206 |
DEXAMETHASONE | Other | PHF00245MIG | ORAL AND IV | 16 | 1 | SCP10332310 |
DEXAMETHASONE SODIUM PHOSPHATE | Test | — | INTRAVENOUS USE | 40 | 6 | SUB01615MIG |
PARACETAMOL | Other | PHF00082MIG | ORAL AND IV | 1000 | 26 | SCP1081917 |
DEXAMETHASONE | Test | — | ORAL USE | 40 | 6 | SUB07017MIG |
VELCADE 3.5 mg powder for solution for injection | Test | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 1.3 | 6 | PRD703624 |
JNJ-64407564 | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 0.8 | 104 | PRD10381752 |
LENALIDOMIDE | Test | — | ORAL USE | 25 | 6 | SUB25389 |