Phase 3 Evaluation of Lenalidomide and Daratumumab SC Versus Lenalidomide and Dexamethasone in Frail, Newly Diagnosed Multiple Myeloma Patients Ineligible for High-Dose Therapy
- Trial ID
- 2024-514088-25-00
- Protocol
- 2018_16
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3 study is to compare the **efficacy** of daratumumab subcutaneous injection combined with lenalidomide (R-Dara SC) versus lenalidomide and dexamethasone (Rd) in terms of progression-free survival (PFS) in frail subjects with newly diagnosed **Multiple Myeloma** who are ineligible for high-dose chemotherapy and autologous stem cell transplant. This comparison is clinically relevant as it aims to determine a more effective treatment regimen for this specific patient population, potentially improving their disease management and quality of life.
Secondary objectives include evaluating:
- Time-to-treatment failure
- Time-to-next treatment
- PFS2 time
- Overall survival
- Complete remission (CR)
- Very good partial response (VGPR) or better
- Overall response (CR + VGPR + partial response [PR])
- Occurrence of grade 3 or more side effects
- Safety and tolerability of Daratumumab SC when administered in combination with lenalidomide
- Treatment effects on patient-reported outcomes and health economic/resource utilization
- Minimal residual disease (MRD) negative rate at 12 months
- Event-free survival
These secondary objectives aim to provide a comprehensive assessment of the treatment's impact on disease progression, patient quality of life, and safety profile, which are crucial for optimizing therapeutic strategies in this patient group.
Participants
The clinical trial focuses on evaluating the efficacy of daratumumab SC injection in combination with lenalidomide in patients with **Multiple Myeloma**. The study population includes both male and female participants who are at least 65 years of age. Participants are required to have newly diagnosed multiple myeloma and must not be candidates for high-dose chemotherapy or autologous stem cell transplant. The trial does not involve a vulnerable population. Participants must have a documented frailty score of 2 or higher and meet specific clinical laboratory criteria prior to the first drug intake. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is a **randomized**, open-label, active-controlled, parallel-group, multicenter study designed to evaluate the efficacy of **daratumumab** subcutaneous injection combined with **lenalidomide** (R-Dara SC) compared to lenalidomide and **dexamethasone** (Rd) in frail subjects with newly diagnosed **multiple myeloma** who are ineligible for high-dose chemotherapy and autologous stem cell transplant. The primary objective is to assess progression-free survival (PFS) in this population. The trial is expected to enroll approximately 294 subjects, with 98 participants in the control arm and 196 in the experimental arm. The study commenced on October 7, 2019, with an estimated completion date of July 20, 2026.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, documented multiple myeloma, and frailty score. The inclusion visit will involve baseline assessments and randomization. Follow-up visits will occur regularly to monitor treatment response, safety, and adverse events. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and collecting data on overall survival and quality of life. The expected duration of participant involvement is up to 84 weeks, depending on individual response and progression.
Participants may be withdrawn from the study early due to reasons such as disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is the duration from randomization to either disease progression or death, as determined by the 2016 International Myeloma Working Group (IMWG) criteria. Secondary endpoints include time-to-treatment failure, time to next treatment, and overall survival. Safety evaluations will include monitoring adverse events, changes in vital signs, and laboratory test results. Quality of life will be assessed using standardized questionnaires at specified intervals throughout the study.
Treatment
The clinical trial involves the administration of three primary treatments, each with distinct pharmaceutical characteristics and administration protocols. **Dexamethasone** is utilized in the study as an **oral solution**. The active substance, dexamethasone, is of chemical origin. Participants receive a maximum daily dose of 20 mg, with the treatment period extending up to 8 weeks. The oral route of administration is employed to facilitate ease of use and compliance monitoring.
**Daratumumab**, marketed as **DARZALEX 1800 mg solution for injection**, is administered via **subcutaneous injection**. This protein-based therapeutic is provided by Janssen-Cilag International NV. The maximum daily dose is set at 1800 mg, with a treatment duration of up to 84 weeks. The subcutaneous route is selected to optimize the pharmacokinetic profile and patient adherence.
**Lenalidomide**, available as **Revlimid 25 mg hard capsules**, is another key component of the trial. This chemical-origin medication is administered orally, with a maximum daily dose of 25 mg. The treatment period for lenalidomide is also up to 84 weeks. The oral capsule form is chosen to ensure consistent dosing and patient compliance.
In this study, the combination of lenalidomide and daratumumab (R-Dara SC) is compared against the combination of lenalidomide and dexamethasone (Rd) in frail subjects with previously untreated multiple myeloma. The primary objective is to evaluate the efficacy in terms of progression-free survival (PFS) in participants who are ineligible for high-dose therapy and autologous stem cell transplant. Compliance monitoring is conducted throughout the trial to ensure adherence to the dosing schedules and to assess the safety and efficacy of the treatments.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **Progression-Free Survival (PFS)** time. PFS is defined as the duration from the date of randomization to either the occurrence of progressive disease or death, whichever occurs first. Disease progression will be determined according to the 2016 International Myeloma Working Group (IMWG) criteria. Secondary endpoints include time-to-treatment failure, time to next treatment, PFS2 time, overall survival (OS) time, complete response (CR), very good partial response (VGPR) or better, overall response, and minimal residual disease (MRD) negativity at 12 months.
Additional assessments will include the collection of adverse events (AEs) of grade 3 or higher, evaluation of safety data by type, frequency, severity, and relation to study drug, as well as changes in vital signs, physical examinations, and incidence of treatment-emergent adverse events (TEAEs). Quality of life will be evaluated using the EORTC C30, MY20, and EQ-5D questionnaires, which will be filled out every 3 months during the first year and every 6 months thereafter until the end of treatment. Event-Free Survival (EFS) will also be measured, defined as the time from randomization to discontinuation of therapy for any reason, including death, progression, or toxicity.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subject must be at least 65 years of age
- Subject must have documented multiple myeloma satisfying the CRAB riteria and measurable disease defined as: 1-Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma 2-Measurable disease as defined by any of the following: - IgG myeloma: Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL; or - IgA, IgM, IgD, or IgE multiple myeloma: serum M-protein level ≥0.5 g/dL ; or - Light chain multiple myeloma: Serum immunoglobulin free light chain ≥ 10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio (only measurable with freelite® by Binding site); or - Urine M-protein level ≥200 mg/24 hours
- Newly diagnosed and not considered candidate for high-dose chemotherapy with SCT
- Subject must have a Frailty Score ≥ 2
- Subject must have within 5 days prior to first drug intake (C1D1) pretreatment clinical laboratory values meeting the following criteria during the Screening Phase: a) hemoglobin ≥7.5 g/dL (≥4.65 mmol/L; prior red blood cell [RBC] transfusion or recombinant human erythropoietin use is permitted); b) absolute neutrophil count ≥1.0 x 109/L (granulocyte colony stimulating factor [GCSF] use is permitted); c) platelet count ≥70 x 109/L for subjects in whom <50% of bone marrow nucleated cells are plasma cells; otherwise platelet count >50 × 109/L (transfusions are not permitted to achieve this minimum platelet count). d) aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN); e) alanine aminotransferase (ALT) ≤2.5 x ULN; f) total bilirubin ≤2.0 x ULN, except in subjects with congenital bilirubinemia, such as Gilbert syndrome (direct bilirubin ≤2.0 x ULN); g) creatinine clearance≥30mL/min(for lenalidomide dose adjustment for subjects with creatinine clearance 30-60 mL/min). Creatinine clearance may be calculated using the Cockcroft-Gault formula h) corrected serum calcium ≤14 mg/dL (≤3.5 mmol/L)
- Measurable ISS with β2-microglobulin and albumin values for randomization
- A man who is sexually active with a woman of childbearing potential must agree to use a latex or synthetic condom, even if they had a successful vasectomy. All men must also not donate sperm during the study, for 4 weeks after the last dose of lenalidomid, and for 4 months after the last dose of daratumumab. Women participating in this study must be postmenopausal
- Each subject must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF
- Subjects affiliated with an appropriate social security system
Exclusion Criteria
- Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, or smoldering multiple myeloma.
- Subject has a diagnosis of Waldenström's disease, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions.
- Subject has prior or current systemic therapy or SCT for multiple myeloma, with the exception of an emergency use of a short course of corticosteroids before treatment.
- Subject has a history of malignancy within 5 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 5 years).
- Subject has had radiation therapy within 14 days of randomization.
- Subject has had plasmapheresis within 28 days of randomization.
- Subject is exhibiting clinical signs of meningeal involvement of multiple myeloma.
- Subject has known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume [FEV] in 1 second <60% of predicted normal), persistent asthma, or a history of asthma within the last 2 years (intermittent asthma is allowed). Subjects with known or suspected COPD or asthma must have a FEV1 test during screening.
- Subject is known to be seropositive for history of human immunodeficiency virus (HIV)
- Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
- (Known to be) seropositive for hepatitis C.
- Subject has any concurrent medical or psychiatric condition or disease (eg, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study.
- Subject has clinically significant cardiac disease, including: myocardial infarction within 1 year before randomization, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 4 Grade ≥ 2) or clinically significant ECG abnormalities screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) >470 msec
- Subject has known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or Investigator's Brochure).
- Subject has plasma cell leukemia (according to World Health Organization [WHO] criterion: ≥20% of cells in the peripheral blood with an absolute plasma cell count of more than 2 × 109/L) or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
- Subject is known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder). Subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. Subject is taking any prohibited medications as per Section 8.3.
- Subject has had major surgery within 2 weeks before randomization or has not fully recovered from surgery.
- Subject has received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before randomization or is currently enrolled in an interventional investigational study.
- Refusal to consent or protected by legal regime ( guardianship, trusteeship)
- Subject has contraindications to required prophylaxis for deep vein thrombosis and pulmonary embolism
- Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 07 Oct 2019 | 20 |
 France | Not Recruiting | 07 Oct 2019 | 274 |
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 |
|---|---|---|---|---|---|---|
DEXAMETHASONE | Test | — | ORAL | 20 | 8 | SUB07017MIG |
DARZALEX 1800 mg solution for injection | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 1800 | 84 | PRD8157846 |
Revlimid 25 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 25 | 84 | PRD9264271 |