Phase II Multicenter Study of Carfilzomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma Patients ≤70 Years
- Trial ID
- 2024-516908-42-00
- Sponsor
- Fundacion PETHEMA
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase II multicenter study is to evaluate the rate of patients achieving an **immunophenotypic response**, specifically a complete response (CR) with minimal residual disease (MRD)-negative status, using multiparametric flow cytometry on day +100 following high-dose therapy and autologous peripheral blood stem cell transplantation. This is clinically relevant as achieving MRD-negative status is associated with improved long-term outcomes in patients with smoldering multiple myeloma at high risk of progression to symptomatic myeloma.
Secondary objectives include:
- Evaluating the rate of patients in immunophenotypic response after consolidation and at 3 and 5 years post-transplant.
- Assessing efficacy in terms of response rates, including stringent complete response (sCR), CR, very good partial response (VGPR), and partial response (PR) after various treatment phases: induction, transplantation, consolidation, and maintenance.
- Evaluating time to progression (TTP) to symptomatic disease.
- Assessing progression-free survival (PFS).
- Evaluating overall survival (OS).
- Assessing the safety profile during different phases of the study: induction, high-dose melphalan followed by autologous transplantation, consolidation, and maintenance.
Participants
The clinical trial involves participants diagnosed with **smoldering multiple myeloma** at high risk of progression to symptomatic myeloma. The study population includes both male and female subjects aged between 18 and 70 years. Participants are required to have a good general health status, as indicated by an ECOG performance status of less than 2. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection criteria emphasize the ability to fulfill all clinical trial requirements and the capacity to attend scheduled visits. Participants must have been diagnosed with high-risk smoldering multiple myeloma within the last five years, with specific clinical markers such as a high percentage of clonal plasma cells in the bone marrow or the presence of monoclonal proteins. Lifestyle considerations, such as diet or physical activity, are not detailed in the trial information. The trial includes a vulnerable population, and women of childbearing potential must adhere to strict contraceptive measures and regular pregnancy testing throughout the study duration.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of a combination therapy involving **dexamethasone**, **pomalidomide**, and **daratumumab** in patients with **smoldering multiple myeloma** at high risk of progression to symptomatic myeloma. This is a phase II, multicenter study with a randomized, double-blind, controlled design. The trial is expected to span from May 28, 2015, to June 30, 2027, with the primary objective of assessing the rate of patients achieving immunophenotypic complete response with minimal residual disease-negative status on day +100 post high-dose therapy and autologous stem cell transplant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18-70 years), diagnosis of high-risk smoldering multiple myeloma, and ability to comply with study requirements. Following the screening, participants will enter the induction phase, followed by high-dose therapy and autologous stem cell transplantation, consolidation, and maintenance phases. Follow-up visits will be scheduled to monitor response rates, time to progression, progression-free survival, and overall survival, as well as to assess the safety profile of the treatment regimen. The end-of-study visit will conclude the participant's involvement, which is anticipated to last up to 85 days, depending on individual response and treatment tolerability.
Participants may be withdrawn from the study early if they experience unacceptable toxicity, withdraw consent, or if the investigator deems it in the participant's best interest. The trial will adhere to rigorous ethical standards, ensuring that participants are fully informed and consent voluntarily. The study aims to provide valuable insights into the potential benefits of this therapeutic approach for patients with high-risk smoldering multiple myeloma.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Dexamethasone** is utilized in this study as a **glucocorticoid** in the form of a tablet. The maximum daily dose is 40 mg, with a total maximum dose of 13,600 mg over a treatment period of 85 days. The route of administration is oral, and participant compliance is monitored throughout the trial.
**Pomalidomide** is administered in various dosages, including 1 mg, 2 mg, 3 mg, and 4 mg hard capsules, under the brand name Imnovid. Each dosage form is taken orally, with a maximum daily dose of 4 mg and a total maximum dose of 7,140 mg over the 85-day treatment period. The capsules are manufactured by Bristol-Myers Squibb Pharma EEIG, and the active substance is of chemical origin. Compliance with the dosing schedule is closely monitored to ensure adherence to the protocol.
**Daratumumab** is provided as an injection with a maximum daily dose of 1,800 mg and a total maximum dose of 171,000 mg over the course of the study. The administration route is subcutaneous, and the active substance is a protein of other origin. The treatment period for daratumumab is also 85 days, and participant adherence to the dosing regimen is tracked to maintain the integrity of the trial data.
In addition to the experimental medications, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, as deemed necessary by the study protocol. The dosing schedules and administration routes are designed to optimize therapeutic outcomes while ensuring participant safety and compliance. Monitoring of participant adherence to the treatment regimen is conducted through regular assessments and documentation.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the evaluation of **immunophenotypic complete remission** (CR) using flow cytometry. The primary endpoint is the achievement of CR on day +100 following induction treatment and high-dose therapy with autologous stem cell transplantation (HDT-ASCT). Secondary endpoints include the assessment of CR after consolidation and maintenance phases, as well as at 3 and 5 years post-HDT-ASCT. Additional efficacy parameters include response rates such as stringent complete response (sCR), very good partial response (VGPR), and overall response rate (ORR) after various treatment phases, including induction, HDT-ASCT, consolidation, maintenance, and rescue therapy.
The trial will also measure time to progression (TTP) to symptomatic disease, progression-free survival (PFS), and overall survival (OS). These parameters will be collected and analyzed at specified timepoints throughout the study duration. The safety profile will be evaluated after each treatment phase to ensure comprehensive monitoring of patient outcomes. The use of multiparametric flow cytometry (MFC) is a critical tool in assessing minimal residual disease (MRD)-negative status, which is integral to determining the efficacy of the treatment regimen in patients with high-risk smoldering multiple myeloma.
Inclusion and Exclusion Criteria
Inclusion Criteria
- The patient must, in the investigator’s opinion, be able to fulfill all of the clinical trial requirements.
- The patient must voluntarily sign the informed consent document before any study procedures that are not part of standard clinical care are carried out. The patient must be made aware that they can withdraw from the study at any time without this affecting their future medical care.
- The patient must be aged between 18 and 70 years, and eligible to receive high-dose therapy and autologous peripheral blood stem cell transplant.
- The patient must have been diagnosed with SMM with high risk of progression to symptomatic MM, or ultra-high risk of progression to symptomatic disease in the five years prior to inclusion in the study. It should be emphasized that we are referring to a diagnosis of high-risk SMM during this time period, not to monoclonal gammopathy, or intermediate or low-risk smoldering myeloma. In other words: o SMM with high risk of progression to symptomatic disease: 1. ≥ 10% BM clonal PC and presence of a monoclonal protein, IgG >3 g/dl or IgA >2 g/dl or Bence Jones proteinuria of >1 g/24h and absence of lytic lesions, hypercalcemia, renal failure (creatinine < 2 mg/dl) and anemia (hemoglobin > 10 g/dl, or not 2 g/dl below the lower limit of normal.) 2. ≥ 10% BM clonal PC or IgG >3 g/dl or IgA >2 g/dl, or Bence Jones proteinuria > 1 g/24 h (but not both at the same time), always in the absence of lytic lesions, hypercalcemia, renal failure and anemia. These patients can be included in the study if they fulfill the following additional criteria: - Presence of a percentage of phenotypically abnormal PC in the in plasma cell compartment of the BM (aPC/PC) ≥ 95% and immunoparesis, defined as a reduction in the concentration of 1 or 2 immunoglobulins (lgs) by more the 25%, compared with the normal values of the corresponding lg. o SMM with ultra-high risk of progression to symptomatic disease: 1. Appearance of more than 1 focal lesion on MRI (ideally whole-body MRI) 2. Clonal PC in BM ≥ 60%. 3. Ratio of involved /uninvolved sFLC greater than 100 together with involved free light chain levels great than 100 mg/L.
- The patient must present an ECOG performance status of < 2.
- The patient must be able to attend scheduled visits.
- Women with gestational capacity must have a negative pregnancy test (serum or urine) which will be taken in the 14 days prior to initiation of treatment with the study drug. Sexually active women must also agree to use two methods of contraception [hormonal contraceptives (oral, injectable, or implants)], tubal ligation, intrauterine device, barrier methods with spermicide, or her partner has had a vasectomy) while receiving the study drug. Women with gestational capacity must agree to have a pregnancy test every 4 weeks (urine or serum) while receiving the study drug (or every 14 days if they have irregular menstrual cycles), and 4 weeks after receiving the last dose of the study drug.
Exclusion Criteria
- Any physical or mental health condition that prevents the patient from signing or understanding the informed consent document.
- The patient has received prior treatment for SMM.
- The patient is pregnant or breastfeeding.
- The patient has lytic lesions, anemia, renal failure or hypercalcemia.
- Any of the following abnormal laboratory values: o Absolute neutrophil count (ANC) < 1,000/mm3. o Platelet count < 75,000/mm3. o Serum GOT or GPT > 3 times the upper limit of normal. o Total serum bilirubin > 2 times the upper limit of normal.
- History of neoplasms other than multiple myeloma (except in the case of basal cell skin cancers, squamous cell cancers or carcinoma in situ of the cervix or breast unless the patient has been disease-free for >5 years.
- The patient has undergone major surgery in the 4 weeks prior to inclusion in the study.
- The patient has active HIV, hepatitis B or hepatitis C infection.
- The patient has received an investigational drug of any type in the 4 weeks prior to inclusion in the study.
- The patient has experienced unstable angina or myocardial infarction in the 6 months prior to recruitment, class III or IV cardiac failure (according to the New York Heart Association criteria) uncontrolled angina, a history of acute coronary artery syndrome, uncontrolled ventricular arrhythmias, sick sinus syndrome or electrocardiographic evidence of acute ischemia or grade 3 conduction system abnormalities, unless the patient has a pacemaker.
- Uncontrolled hypertension or diabetes.
- Significant neuropathy (grades 3-4, or grade 2 with pain), in the 14 days prior to recruitment.
- Known history of allergies to captisol (a derivative of cyclodextrin that is used to dissolve carfilzomib).
- The patient presents a contraindication that prevents the administration of the concomitant or adjunctive treatments, including hydration intolerance due to pre-existing pulmonary or cardiac impairment.
- LVEF < 40
- Pulmonary hypertension.
- Presence of an acute active infection that requires treatment (systemic antibiotics, antivirals, or antifungal agents), in the 14 days prior to recruitment.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 28 May 2015 | 90 |
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 | 40 | 85 | SUB07017MIG |
Imnovid 2 mg hard capsules | Test | HARD CAPSULES | ORAL | 4 | 85 | PRD9260805 |
Imnovid 1 mg hard capsules | Test | HARD CAPSULES | ORAL | 4 | 85 | PRD9260804 |
DARATUMUMAB | Test | — | SUBCUTANEOUS | 1800 | 85 | SUB175772 |
Imnovid 3 mg hard capsules | Test | HARD CAPSULES | ORAL | 4 | 85 | PRD9260806 |
Imnovid 4 mg hard capsules | Test | HARD CAPSULES | ORAL | 4 | 85 | PRD9260808 |