A Phase 2 Randomized Study of Carfilzomib, Lenalidomide, and Dexamethasone Versus Lenalidomide and Dexamethasone in High-Risk Smoldering Multiple Myeloma

The primary objective of this study is to assess the **minimal residual disease (MRD)** negativity rate by next-generation flow (NGF) after 9 cycles for all eligible intention-to-treat (ITT) patients receiving carfilzomib, lenalidomide, and dexamethasone (KRd) versus lenalidomide and dexamethasone (Rd) in patients with high-risk smoldering multiple myeloma (SMM). Evaluating MRD negativity is clinically relevant as it serves as a prognostic marker for long-term outcomes in multiple myeloma, potentially guiding treatment decisions and improving patient management.

Secondary objectives include:

• Assessing MRD (NGF) negativity rate after 4 cycles of induction treatment and after completion of maintenance treatment.
• Evaluating the correlation of MRD (NGF) negativity rate with progression-free survival (PFS), progression-free survival-2 (PFS2), duration of response (DOR), and overall survival (OS).
• Determining overall response rate (ORR) after 4 and 9 cycles of induction treatment and after maintenance.
• Evaluating the toxicity and safety of the combination therapy, including the type, frequency, and severity of adverse events (AEs) and their relationship to the study drug, as well as serious adverse events (SAEs).
• Assessing disease heterogeneity in relation to clinical outcomes through molecular profiling on bone marrow samples.

The clinical trial involves participants diagnosed with **Smoldering Multiple Myeloma** or **Multiple Myeloma**. The study population includes both male and female subjects, aged over 18 years, with a **WHO/ECOG performance status** of 2 or less, indicating a relatively stable general health status. Participants were selected based on specific criteria, including a confirmed diagnosis of high-risk Smoldering Multiple Myeloma according to the Mayo Clinic and/or PETHEMA criteria, and the ability to provide informed consent. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants are required to have normal organ and marrow function and a calculated creatinine clearance of at least 50 ml/min. Lifestyle considerations include the requirement for all men and premenopausal women to use adequate contraception during and after therapy, adhering to the Lenalidomide Pregnancy Prevention Plan. Females of childbearing potential must have a negative pregnancy test prior to and at the start of lenalidomide treatment. The trial includes a vulnerable population, although specific details about this group are not disclosed.

The clinical trial is designed to evaluate the efficacy of a combination therapy involving **carfilzomib**, **lenalidomide**, and **dexamethasone** compared to **lenalidomide** and **dexamethasone** alone in patients with high-risk **smoldering multiple myeloma**. This is a randomized, controlled, double-blind, Phase II study. The trial aims to assess the minimal residual disease (MRD) negativity rate after nine cycles of treatment using next-generation flow cytometry (NGF) as the primary endpoint. Secondary endpoints include overall response rate, progression-free survival, and overall survival, among others. The trial is expected to run from January 2019 to January 2029, with participant involvement lasting up to 924 days, depending on the treatment arm and response.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as confirmed diagnosis of high-risk smoldering multiple myeloma, age over 18 years, and adequate organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety, with assessments including laboratory tests, imaging, and clinical evaluations. The end-of-study visit will occur after the completion of the treatment cycles or upon early termination.

Early termination from the study may occur if participants experience unacceptable toxicity, disease progression, or withdrawal of consent. Participants are required to adhere to the study protocol, including the use of adequate contraception during and after therapy, as per the Lenalidomide Pregnancy Prevention Plan. The trial's design ensures rigorous monitoring of safety and efficacy, with data collected contributing to the understanding of treatment outcomes in this patient population.

The clinical trial involves the administration of **Kyprolis** (carfilzomib), a **powder for solution for infusion**. This experimental medication is provided in a dosage form of 60 mg and is administered via **intravenous use**. The maximum daily dose is 56 mg/m², with a total maximum dose of 1476 mg/m² over a treatment period of 252 days. The product is re-packaged and re-labelled for the trial, and it is of chemical origin. Participant compliance is monitored through scheduled infusions.

**Revlimid** (lenalidomide) is used in multiple formulations within the study, including 5 mg, 10 mg, 15 mg, and 25 mg **hard capsules**. This medication is administered **orally**. The maximum daily dose for lenalidomide is 25 mg, with a total maximum dose of 9765 mg over a treatment period of 924 days. The capsules are re-packaged and re-labelled for the trial, and they are of chemical origin. Participant compliance is monitored through pill counts and patient diaries.

**Fortecortin** (dexamethasone) is provided in 2 mg **tablets** and is administered **orally**. The maximum daily dose is 20 mg, with a total maximum dose of 240 mg over a treatment period of 252 days. This product is of chemical origin and is not re-packaged or re-labelled for the trial. Compliance is monitored through pill counts and patient diaries.

**Dexamethason-ratiopharm** is another formulation of dexamethasone used in the study, available in 4 mg and 8 mg **tablets**. These are also administered **orally**. The maximum daily dose is 20 mg, with a total maximum dose of 240 mg over a treatment period of 252 days. This product is of chemical origin and is not re-packaged or re-labelled for the trial. Compliance is monitored through pill counts and patient diaries.

All medications used in the trial are of chemical origin and have been authorized for use in the European Union. The trial aims to assess the efficacy of these treatments in patients with high-risk smoldering multiple myeloma, with a focus on achieving minimal residual disease (MRD) negativity. The study involves rigorous monitoring of participant compliance and adherence to dosing schedules to ensure the integrity of the trial results.

The efficacy of the clinical trial will be assessed primarily through the **MRD (Minimal Residual Disease) negativity rate** by next-generation flow cytometry (NGF) after 9 cycles for all eligible intention-to-treat (ITT) patients. Patients achieving MRD negativity after cycle 9 will be considered successful, while all other eligible randomized ITT patients, including those who discontinue the protocol before cycle 9, will be considered failures. Secondary efficacy endpoints include the MRD negativity rate evaluated by NGF after cycle 4 and after completion of maintenance, correlation of MRD negativity rate with progression-free survival (PFS), overall response rate (ORR) after 9 cycles of induction treatment, PFS, progression-free survival-2 (PFS2), duration of response (DOR), overall survival (OS), and the correlation of MRD negativity rate with PFS, PFS2, DOR, and OS.

Additional assessments will include the toxicity of the combination therapy (carfilzomib, lenalidomide, and dexamethasone), safety profiles including the type, frequency, and severity of adverse events (AEs), serious adverse events (SAEs), and the relationship of AEs to the study drug. Disease heterogeneity in relation to clinical outcomes will also be evaluated through molecular profiling on bone marrow samples. The efficacy parameters will be measured and collected at specified timepoints, including after cycle 4, cycle 9, and upon completion of maintenance therapy, using validated laboratory tests and patient-reported outcomes where applicable.