Phase III Randomized Trial of Carfilzomib, Lenalidomide, and Dexamethasone Versus Lenalidomide and Dexamethasone in Newly Diagnosed Multiple Myeloma Patients Ineligible for ASCT

The primary objective of this randomized Phase III trial is to evaluate the **efficacy** of adding Carfilzomib to the Lenalidomide-Dexamethasone regimen in newly diagnosed multiple myeloma patients who are not eligible for autologous stem cell transplantation. This is assessed by determining the rate of minimal residual disease (MRD) negativity after two years of treatment. Additionally, the study aims to determine the progression-free survival (PFS) of both treatment arms. These objectives are clinically relevant as they address the potential for improved treatment outcomes and prolonged disease control in this patient population.

Secondary objectives include:

• Determining the incidence of dose reduction and drug discontinuation in both treatment arms.
• Evaluating the benefit of cardiovascular baseline assessment and monitoring to mitigate major cardiovascular adverse events, prolong treatment duration, and improve efficacy.
• Assessing the safety of both treatment arms.
• Determining the response rate, progression-free survival 2 (PFS2), time to progression (TTP), duration of response (DOR), overall survival (OS), and time to next therapy (TNT) of both treatment arms.
• Evaluating the benefits of both treatment arms.
• Investigating the correlation between MRD negativity and PFS, PFS2, TTP, TNT, and OS.
• Determining the difference in response and outcome in subgroups with different prognostic factors.

The clinical trial involves **patients with newly diagnosed multiple myeloma** who are either aged 65 years or older or are not eligible for autologous stem cell transplantation (ASCT). The study population includes both male and female participants, with an emphasis on those who are considered vulnerable. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants were selected based on their diagnosis of symptomatic multiple myeloma, as defined by standard CRAB criteria or specific biomarkers of malignancy. The trial includes individuals who are fit or have an intermediate frailty score according to the International Myeloma Working Group (IMWG). Participants must have a left ventricular ejection fraction of at least 40%, controlled blood pressure, and meet specific laboratory value criteria. Lifestyle considerations such as compliance with a Pregnancy Prevention Plan for females of childbearing potential and the use of contraception for both genders are required. The trial population is expected to adhere to hospital visits and procedures as per protocol.

The clinical trial is designed to evaluate the efficacy of adding **carfilzomib** to the **lenalidomide** and **dexamethasone** regimen in patients with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplantation. This is a randomized, phase III trial with a double-blind, controlled design. The trial is expected to last until May 2025, with recruitment having started in May 2019. Participants will be randomly assigned to receive either the experimental regimen of carfilzomib, lenalidomide, and dexamethasone (KRd) or the standard regimen of lenalidomide and dexamethasone (Rd).

The study involves several key visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, cardiac function, and disease status. Following randomization, participants will undergo regular follow-up visits to monitor treatment response and adverse events. These visits will include assessments of minimal residual disease (MRD) at one and two years, as well as evaluations of progression-free survival (PFS) and other secondary endpoints. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

Participant involvement is expected to last up to 60 months, depending on individual response and disease progression. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study procedures. The primary endpoint is the rate of MRD negativity at two years, while secondary endpoints include response rates, overall survival (OS), and quality of life assessments. The trial aims to provide insights into the potential benefits of the KRd regimen in improving outcomes for this patient population.

The clinical trial involves the administration of several **experimental medications**. The primary experimental medication is **Revlimid**, which contains the active substance **lenalidomide**. Revlimid is available in various dosages, including 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg, all in the form of hard capsules. The medication is administered orally, with a maximum daily dose of 25 mg and a total maximum dose of 24,675 mg over a treatment period of 47 weeks. The pharmaceutical form is consistent across all dosages, ensuring uniformity in administration. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

Another experimental medication used in the trial is **Kyprolis**, which contains the active substance **carfilzomib**. Kyprolis is provided as a 60 mg powder for solution for infusion. The route of administration is intravenous, with a maximum daily dose of 56 mg/m² and a total maximum dose of 7,244 mg/m² over a treatment period of 60 weeks. The infusion is prepared and administered under controlled conditions to ensure precise dosing and participant safety.

The trial also includes the use of **SOLDESAM**, which contains the active substance **dexamethasone sodium phosphate**. SOLDESAM is available as a 0.2% oral drops solution. The maximum daily dose is 40 mg, with a total maximum dose of 7,520 mg over a treatment period of 47 weeks. The oral drops are administered according to a specific dosing schedule, and participant compliance is monitored to ensure accurate dosing.

In addition to the experimental medications, the trial employs a standard-of-care therapy, which includes the combination of lenalidomide and dexamethasone. This combination serves as a comparator treatment to evaluate the efficacy of the addition of carfilzomib in the experimental arm. The trial design ensures that all participants receive a consistent and scientifically validated treatment regimen, with regular monitoring to assess treatment outcomes and participant adherence.

The efficacy of the clinical trial will be assessed primarily through the evaluation of **minimal residual disease (MRD)** negativity and progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (MM) who are not eligible for autologous stem cell transplantation. MRD negativity will be determined from bone marrow samples collected after 1 and 2 years of treatment in patients who achieve at least a very good partial response (VGPR) during the first year. The rate of MRD negativity is defined as the proportion of patients with MRD negativity at 2 years of treatment. For patients who withdraw or are lost to follow-up before two years, the best MRD assessment will be considered.

PFS will be measured from the date of randomization to the date of first observation of disease progression or death from any cause. Subjects who withdraw from the study will be censored at the time of the last complete disease assessment. Secondary endpoints include response rate, PFS2, time to progression (TTP), duration of response (DOR), overall survival (OS), time to next treatment (TNT), toxicity, and quality of life as defined by EOCTC QLQ-C30 and QLQ-MY20. The trial will also assess the incidence of dose reduction and drug discontinuation, the benefit of cardiovascular baseline assessment, and the impact of MRD negativity on various outcomes. The trial is a randomized Phase III study comparing the efficacy of Carfilzomib in combination with Lenalidomide and Dexamethasone (KRd) versus Lenalidomide and Dexamethasone (Rd) alone.