EFfIcacy and Tolerability of FIXed duration teclistamab and talquetamab FOR FRAIL patients with newly diagnosed multiple myeloma (2 cohort study) - the EMN 37 FITFIX FOR FRAIL trial
- Trial ID
- 2024-520433-76-00
- Protocol
- EMN37
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the progression-free survival at 18 months in patients with newly diagnosed multiple myeloma treated with teclistamab-daratumumab (Cohort 1) or talquetamab-daratumumab (Cohort 2). This endpoint is clinically relevant for evaluating the durability of disease control in frail patients receiving fixed-duration bispecific antibody therapy combined with daratumumab.
The secondary objectives include:
• To assess the efficacy of fixed duration teclistamab-daratumumab (Cohort 1) or talquetamab-daratumumab (Cohort 2).
• To determine the response rate after re-treatment with teclistamab-daratumumab (Cohort 1) or talquetamab-daratumumab (Cohort 2).
• To assess the safety and tolerability of teclistamab-daratumumab (Cohort 1) or talquetamab-daratumumab (Cohort 2).
Participants
The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population consists of **adults** aged **18 years and older** of **both genders** who have been **newly diagnosed** with **multiple myeloma** and are treatment-naïve. Participants are specifically classified as **frail** according to the Simplified IMWG frailty index, representing a **vulnerable population**. Enrollment requires confirmation of multiple myeloma diagnosis with **measurable disease** as defined by IMWG criteria, including specific thresholds for **M-protein** in serum or abnormal **serum free light chain** levels with an abnormal **immunoglobulin kappa/lambda** ratio. Participants must meet defined clinical laboratory value requirements and demonstrate capacity to provide **informed consent**. Individuals of **childbearing potential** are required to utilize adequate contraceptive methods throughout the study period and for three months following the final dose of study medication.
Plans and Procedures
This is a phase II, multicenter, two-cohort clinical trial evaluating the efficacy and tolerability of fixed-duration combination therapies in frail patients with newly diagnosed multiple myeloma. The trial employs a randomized design with two treatment cohorts: Cohort 1 receives teclistamab in combination with daratumumab, while Cohort 2 receives talquetamab in combination with daratumumab. All investigational medicinal products are administered via subcutaneous injection as a solution for injection. The study includes both authorized and investigational products, with daratumumab being a marketed product and teclistamab and talquetamab being investigational agents. Talquetamab and daratumumab have been designated as orphan drugs for the treatment of multiple myeloma.
The primary objective of this trial is to determine progression-free survival at 18 months in patients treated with either combination regimen. The primary endpoint is defined as the duration from the date of randomization to first documented progressive disease or death, whichever occurs first. Secondary efficacy endpoints include overall progression-free survival, overall survival, minimal residual disease negativity rate at 18 months and over time, minimal residual disease-negative complete response at 18 months and over time, sustained minimal residual disease-negative complete response for at least 12 months, depth of response defined by overall response rate and rates of stringent complete response, complete response, very good partial response, and partial response, time to partial response, time to best response, event-free survival, progression-free survival 2, and time to next treatment. Additional secondary endpoints assess response after re-treatment, including depth of response and minimal residual disease negativity rate following re-initiation of therapy.
Safety endpoints encompass the incidence and severity of adverse events during initial therapy, treatment-free interval, and after restarting therapy. The trial monitors discontinuation rates due to treatment-related toxicity during initial therapy and after restarting therapy, including overall discontinuation rates for each individual agent. Causes of treatment discontinuation are documented throughout the study period. Special attention is given to the incidence, grade, and cause of infections as part of the comprehensive safety assessment.
The trial is designed for adult patients aged 18 years or older who are capable of providing informed consent. Eligible participants must have newly diagnosed, treatment-naïve multiple myeloma with measurable disease according to International Myeloma Working Group criteria, defined as M-protein in serum at least 1 g/dL or serum free light chain at least 10 mg/dL with an abnormal serum immunoglobulin kappa/lambda free light chain ratio. Patients must be classified as frail according to the Simplified International Myeloma Working Group frailty index. Clinical laboratory values must meet specified criteria, and patients of childbearing potential must agree to use adequate or highly effective contraception from the time of signing the informed consent form through 3 months after the last dose of study drug.
The trial is estimated to commence recruitment in November 2025, with an estimated completion date in February 2034, representing an overall trial duration of approximately 8 years. Participant involvement includes an initial screening visit to assess eligibility criteria and confirm the diagnosis of newly diagnosed multiple myeloma. Following enrollment and randomization, participants undergo treatment with the assigned combination therapy according to the fixed-duration protocol. Regular follow-up visits are scheduled to assess disease response, minimal residual disease status, and safety parameters. After completion of the initial fixed-duration treatment phase, patients enter a treatment-free interval during which disease monitoring continues. In the event of disease progression or meeting criteria for re-treatment, participants may be eligible to restart therapy. The end-of-study visit occurs upon completion of all protocol-specified assessments or upon meeting criteria for study termination.
Conditions that may lead to early termination from the study include documented progressive disease that does not meet criteria for re-treatment, unacceptable treatment-related toxicity requiring permanent discontinuation of therapy, withdrawal of informed consent by the participant, pregnancy, or investigator decision based on safety concerns or protocol violations. Participants who discontinue study treatment prematurely may continue to be followed for survival and subsequent therapy data collection unless consent is withdrawn for all study procedures.
Treatment
The clinical trial utilizes several experimental medications administered via subcutaneous injection. **JNJ-64407564** (sponsor product code JNJ-64407564) is a solution for injection containing the active substance **talquetamab**, a protein-based agent. This investigational medicinal product is supplied in two formulations (PRD10381753 and PRD10381752) and has been designated as an **orphan drug** (EU/3/21/2486). The pharmaceutical form is a solution for injection administered via **subcutaneous use**. The maximum treatment period is defined as one day. Dosage is measured in **milligrams**, though specific dose amounts are not provided in the available data.
**Teclistamab** (sponsor product code JNJ-64007957) is another experimental agent used in this trial, formulated as a solution for injection. The active substance is **teclistamab**, also classified as a protein-based compound. Two product formulations are utilized (PRD9936207 and PRD9936206), both administered via **subcutaneous use**. The pharmaceutical form is a solution for injection with dosing measured in milligrams. The maximum treatment period is specified as one day.
**DARZALEX 1800 mg solution for injection** is an **authorized medicinal product** (EU/1/16/1101/004) containing **daratumumab** as the active substance. This product holds marketing authorization (EMEA/H/C/004077) and has orphan drug designation (EU/3/13/1153). The commercial daratumumab subcutaneous 1800 mg solution for injection has been specifically packaged, labeled, and released for use in this clinical trial. The pharmaceutical form is a solution for injection administered via **subcutaneous use**. The active substance daratumumab is a protein-based compound, also known by the synonym HuMax-CD38. The product is classified under **ATC code** L01FC01. Dosing is measured in milligrams with a maximum treatment period of one day.
All investigational medicinal products in this trial are manufactured by Janssen-Cilag International N.V. and are formulated as solutions for injection for subcutaneous administration. The trial design incorporates these agents in two distinct cohorts, with Cohort 1 receiving teclistamab in combination with daratumumab (Tec-Dara) and Cohort 2 receiving talquetamab in combination with daratumumab (Tal-Dara).
Efficacy
Efficacy will be assessed using progression-free survival at 18 months as the primary endpoint, defined as the duration from the date of randomization to first documented progressive disease or death, whichever occurs first. Secondary efficacy endpoints include progression-free survival, overall survival, minimal residual disease negativity rate at 18 months and over time, minimal residual disease-negative complete response at 18 months and over time, sustained minimal residual disease-negative complete response of at least 12 months, depth of response defined by the overall response rate and the rate of stringent complete response, complete response, very good partial response and partial response, time to partial response and time to best response, event-free survival with events defined as progressive disease, death, or treatment discontinuation due to toxicity, progression-free survival 2 from the date of randomization to second progressive disease or death, whichever comes first, and time to next treatment. Additional efficacy parameters after re-treatment include depth of response defined by the overall response rate encompassing stringent complete response, complete response, very good partial response and partial response, as well as minimal residual disease negativity rate after re-treatment.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient is ≥18 years of age and capable of giving informed consent and must sign an informed consent form (ICF), indicating that they understand the purpose of, and procedures required for, the study and is willing to participate in the study
- Newly diagnosed and treatment-naïve patients with a confirmed diagnosis of MM with measurable disease according to IMWG criteria
- Measurable disease defined as M-protein in the serum (≥1 g/dL) or serum free light chain assay ≥10 mg/dL [≥100 mg/L] and abnormal serum immunoglobulin kappa/lambda FLC ratio
- Frail according to the Simplified IMWG frailty index
- Have clinical laboratory values meeting the following criteria (see protocol)
- Patients of childbearing potential must agree to use adequate/highly effective contraception from the time of signing the informed consent form through 3 months after the last dose of study drug
Exclusion Criteria
- Non-secretory MM or measurable disease by urine or plasmacytoma only
- Central nervous system involvement of myeloma or presence of the following heart conditions: a. Severe cardiac dysfunction (NYHA classification III-IV) b. Myocardial infarction, unstable angina, or coronary artery bypass graft ≤6 months prior to eligibility c. History of clinically significant ventricular arrhythmia d. Uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities e. Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) >500 msec f. Screening ECHO or MUGA: left ventricular ejection fraction (LVEF) <35%
- Significant pulmonary dysfunction defined as: a. Acute diffuse infiltrative pulmonary disease. b. COPD with Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal or diffusing capacity of the lungs for carbon monoxide [DLCO] <50%. (Note that FEV1 testing is required for patients suspected of having COPD and patients must be excluded if FEV1<50 of predicted normal). c. Moderate or severe persistent asthma within the past 2 years or currently uncontrolled asthma of any classification. (Note that patients who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study).
- Stroke, transient ischemic attack, or seizure within 6 months of eligibility.
- Evidence of active systemic viral, fungal, or bacterial infections, requiring systemic antimicrobial therapy.
- Any of the following infections: a. Seropositive for Human Immunodeficiency Virus (HIV). b. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). c. Seropositive for hepatitis C (anti-HCV antibody positive or HCV-RNA quantitation positive).
- Exclude for any of the following: a. Any history of malignancy other than MM which is considered at high risk of recurrence requiring treatment or a malignancy that has been treated with chemotherapy currently affecting bone marrow capacity. b. Any active malignancy (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: i. Non-muscle invasive bladder cancer (solitary Ta-PUN-LMP or low grade, <3 cm, no CIS) ii. Non-melanoma skin cancers treated with curative therapy or localized melanoma treated with curative surgical resection alone iii. Non-invasive cervical cancer iv. Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ or history of localized breast cancer (anti-hormonal therapy is permitted) v. Localized prostate cancer (M0, N0) with a Gleason Score ≤7a, treated locally only (RP/RT/focal treatment) vi. Other malignancy that is considered cured with minimal risk of recurrence in consultation with the sponsor’s medical monitor.
- Active autoimmune disease requiring systemic immunosuppressive therapy within 6 months before eligibility. Exception: a. Vitiligo not on systemic therapy b. Controlled Type 1 diabetes c. Prior autoimmune thyroid disease that is currently euthyroid based on clinical symptoms and laboratory testing
- Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any study treatment or its excipients (refer to IB and most recently applicable RSI).
- Extensive radiotherapy within 14 days or focal radiation only within 7 days of eligibility.
- Current or active therapy for multiple myeloma or received a cumulative dose corticosteroids equivalent to >40 mg dexamethasone within the 14 days prior to C1D1.
- Received a live attenuated vaccine ≤4 weeks before eligibility. Non-live vaccines or non-replicating authorized for emergency use (eg, COVID-19) are allowed.
- Received a strong CYP3A4 inducer or use of St. John’s wort ≤5 half-lives prior to dosing.
- Patient had major surgery or significant traumatic injury within 2 weeks prior to eligibility. Kyphoplasty or Vertebroplasty is not considered major surgery.
- Have received an investigational drug (including investigation vaccines) or used an invasive investigational medical device <4 week or 5 PK half-lives, before eligibility or is currently enrolled in an interventional investigational study except if only long-term survival data are collected
- Concurrent medical or psychiatric condition or disease (eg, uncontrolled diabetes, alcohol or drug abuse, severe dementia or altered mental status), that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participation in the study.
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 03 Nov 2025 | 46 |
 The Netherlands | Recruiting | 03 Nov 2025 | — |
 Norway | Not Yet Recruiting | 03 Nov 2025 | 12 |
 Spain | Recruiting | 03 Nov 2025 | 46 |
| Netherlands | — | — | 46 |
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 | 0 | 1 | PRD8157846 |
JNJ-64407564 | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 0 | 1 | PRD10381753 |
JNJ-64407564 | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 0 | 1 | PRD10381752 |
teclistamab | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 0 | 1 | PRD9936206 |
teclistamab | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 0 | 1 | PRD9936207 |