Phase III Randomized Study of Continuous vs. Fixed Duration Daratumumab, Lenalidomide, and Dexamethasone Therapy in Relapsed Multiple Myeloma
- Trial ID
- 2024-511855-16-00
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this multi-center phase III randomized study is to demonstrate the **non-inferiority** in overall survival at 4 years of the combination therapy with Daratumumab, Lenalidomide, and Dexamethasone for the treatment of relapsed multiple myeloma, administered for a fixed duration of 24 months compared to continuous administration until disease progression. This is clinically relevant as it may offer a treatment regimen that balances efficacy with potential reduction in treatment burden and side effects associated with prolonged therapy.
Secondary objectives include:
- Comparing the response rate after salvage therapy and the achievement of minimal residual disease, the overall response rate following salvage therapy, progression-free survival, and serious adverse events.
- Evaluating the impact of treatment strategies on Quality of Life.
- Conducting a cost-effectiveness analysis.
- Performing a budget impact analysis.
Participants
The clinical trial involves a study population comprising **adult patients** aged 18 years and older, including both male and female participants. The trial focuses on individuals diagnosed with **multiple myeloma** (MM) at first relapse, requiring initiation of a first-line salvage therapy. Participants must have measurable disease and have received one prior line of therapy for MM, achieving a response of partial remission or better. The trial does not include a vulnerable population. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2, indicating they are in relatively good health. The selection criteria emphasize the need for effective contraception for participants of childbearing potential and require that any toxicities from previous therapies be resolved or stabilized. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is a multi-center, phase III, randomized study designed to evaluate the **non-inferiority** of a combination therapy involving **daratumumab**, **lenalidomide**, and **dexamethasone** for patients with relapsed multiple myeloma. The trial aims to compare continuous versus fixed-duration therapy, with the primary objective being to assess overall survival at four years. The study is structured as an open-label, randomized, and multicenter trial, with participants being randomly assigned to either the experimental arm, receiving the combination therapy for a fixed duration of 24 months, or the control arm, receiving continuous therapy until disease progression.
The trial is expected to last until July 2027, with participant recruitment having commenced in July 2019. Participants will be involved in the study for a maximum treatment period of 84 weeks. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits every 12 weeks to monitor disease progression and quality of life, and an end-of-study visit to assess final outcomes. The primary endpoint is overall survival at four years, while secondary endpoints include response rate, progression-free survival, incidence of adverse events, and quality of life assessments.
Participants are required to meet specific inclusion criteria, such as being adults aged 18 or older, having documented relapsed multiple myeloma, and having received one prior line of therapy. They must also have measurable disease and an ECOG Performance Status score of 0, 1, or 2. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The trial's design ensures rigorous monitoring and evaluation of the therapeutic efficacy and safety of the treatment regimen, contributing valuable data to the field of onco-hematology.
Treatment
The clinical trial involves the administration of **Daratumumab**, a monoclonal antibody used in the treatment of relapsed multiple myeloma. Daratumumab is administered in two forms: as an intravenous infusion and as a subcutaneous injection. The intravenous form is given at a dosage of 16 mg/kg, with a maximum total dose of 1616 mg/kg over a treatment period of 84 days. The subcutaneous form, marketed as Darzalex 1800 mg solution for injection, is administered at a maximum daily dose of 1800 mg, with a total dose not exceeding 182 grams over the same treatment period. The administration route for the subcutaneous form is via subcutaneous injection.
**Dexamethasone**, used in this trial, is administered both orally and intravenously. The active substance in this formulation is **Betamethasone Sodium Phosphate**, which is chemically derived. The maximum daily dose for Dexamethasone is 40 mg, with a total dose limit of 15 grams over the 84-day treatment period. This medication serves as a standard-of-care therapy in the trial.
**Lenalidomide** is another component of the treatment regimen, administered orally. The maximum daily dose for Lenalidomide is 25 mg, with a total dose not exceeding 48 grams over the course of the trial. This medication is also part of the standard-of-care therapy and is used in combination with Daratumumab and Dexamethasone to evaluate the efficacy of continuous versus fixed-duration therapy in patients with relapsed multiple myeloma.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen. The trial aims to assess the non-inferiority in overall survival at four years of the combination therapy administered for a fixed duration of 24 months compared to continuous administration until disease progression.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the measurement of **overall survival (OS)** at 4 years following randomization and the initiation of salvage therapy. This endpoint is designed to evaluate the non-inferiority of the combination therapy of Daratumumab, Lenalidomide, and Dexamethasone for the treatment of relapsed multiple myeloma. Secondary efficacy endpoints include the response rate according to the International Myeloma Working Group (IMWG) criteria, overall response rate, progression-free survival (PFS), incidence of adverse events, and quality of life (QoL) assessments. The response rate will be determined during or after the study treatment at the time of data cutoff, while the overall response rate will be defined as the proportion of subjects achieving complete response (CR) or partial response (PR) according to the IMWG criteria. PFS will be measured from the date of randomization to either disease progression or death, assessed at 4 years post-randomization.
Quality of life will be evaluated every 12 weeks after randomization until disease progression and at the last follow-up using the EORTC QLQ-C30 and EQ-5D 5L questionnaires. Additionally, the trial will include an analysis of incremental cost-effectiveness ratios (ICERs) and a budget impact analysis based on target and prevalent population estimations. These assessments will provide comprehensive data on the efficacy and economic impact of the treatment regimen. The trial is structured as a multi-center, open-label, randomized phase III study, with the estimated end date set for July 25, 2027.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Adult patients (≥ 18 years old)
- Documented MM in relapse according to standard criteria and requiring initiation of a first line salvage therapy.
- Subject must have measurable disease as defined by any of the following :• IgG myeloma : serum monoclonal paraprotein (M-protein) level ≥ 1.0 g/dL or urine M-protein level ≥ 200 mg/24 hours or • IgA, IgM, IgD, or IgE multiple myeloma : serum M-protein level ≥ 0.5 g/dL or urine M-protein level ≥ 200 mg/24 hours; or • Light chain multiple myeloma : serum immunoglobulin free light chain ≥ 10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio.
- Subject must have received one prior line of therapy for MM
- Subject must have achieved a response (PR or better) to the prior regimen.
- Subject must have an ECOG Performance Status score of 0, 1, or 2.
- For subjects experiencing toxicities resulting from previous therapy (including peripheral neuropathy),the toxicities must have been resolved or stabilized.
- Signed informed consent
- Affiliation to a social security system or equivalent (recipient or assign)
- Effective method of contraception for the duration of treatment and 3 months after the last dose for women of childbearing age and men with a partner of childbearing age :Progestin-only pill associated with inhibition of ovulation, Hormonal methods of contraception, including oral contraceptive pills containing a combination of estrogen + progesterone, vaginal ring, injectables, implants and intrauterine devices (IUDs), non-hormonal IUD, Bilateral tubal occlusion, Vasectomized partner with documented azoospermia 90 days after procedure and who received a medical assessment of surgical success, Intrauterine hormone release system (IUS), Complete abstinence : complete abstinence is defined as the complete avoidance of heterosexual intercourse. Complete abstinence is an acceptable form of contraception for all study drugs and must be used throughout the duration of the study and for the duration of time as specified above. It is not necessary to use any other method of contraception when complete abstinence is elected. Acceptable alternate methods of highly effective contraception must be discussed in the event that the subject chooses to forego complete abstinence
Exclusion Criteria
- Evidence of refractoriness or intolerance to lenalidomide and/or daratumumab (or another anti CD38 monoclonal antibody). If previously treated with a lenalidomide or daratumumab-containing regimen, the subject is excluded if he or she :Discontinued due to any severe adverse event related to prior lenalidomide and/or daratumumab (or another anti CD38 monoclonal antibody) treatment, or If, at any time point, the subject was refractory to any dose of lenalidomide and/or daratumumab (or another anti CD38 monoclonal antibody). Refractoriness to lenalidomide and/or daratumumab (or another anti CD38 monoclonal antibody) is defined either as : Subjects whose disease progressed within 60 days of lenalidomide and/or daratumumab (or another anti CD38 monoclonal antibody) administration; or o Subjects whose disease is nonresponsive while on lenalidomide and/or daratumumab (or another anti CD38 monoclonal antibody). Nonresponsive disease is defined as either failure to achieve at least a minimal response or development of progressive disease while on lenalidomide and/or daratumumab (or another anti CD38 monoclonal antibody).
- Subject has received an allogenic stem cell transplant (regardless of timing).
- Subjects planning to undergo a stem cell transplant prior to progression of disease on this study, ie, these subjects should not be enrolled in order to reduce disease burden prior to transplant
- Subject has a history of malignancy (other than MM) within 3 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator is considered cured with minimal risk of recurrence within 3 years).
- Subject has known MM meningeal involvement.
- Subject has plasma cell leukemia (>2.0 × 109/L circulating plasma cells by standard differential) or Waldenström’s macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) or amyloidosis.
- Subject has any concurrent medical condition or disease (eg, active systemic infection) 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.
- Subject has known uncontrolled chronic obstructive pulmonary disease (COPD)
- Subject has clinically significant cardiac disease
- Subject is known to be seropositive for human immunodeficiency virus (HIV), hepatitis B (included history of previous infection) or hepatitis C.
- Creatinine clearance ≤30 mL/min (MDRD method) (lenalidomide dose adjustment will be considered for subjects with creatinine clearance 30-60 mL/min).
- Hypersensitivity to the active substance or to any of the excipients
- Pregnancy or lactaction women
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 25 Jul 2019 | 477 |
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 |
|---|---|---|---|---|---|---|
LENALIDOMIDE | Test | PHF00006MIG | ORAL USE | 25 | 84 | SCP149173 |
DEXAMETHASONE | Test | PHF00169MIG | ORAL AND IV | 40 | 84 | SCP10332310 |
DARZALEX 1800 mg solution for injection | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 1800 | 84 | PRD8157846 |
DARATUMUMAB | Test | PHF00231MIG | INTRAVENOUS | 16 | 84 | SCP12565263 |