Phase III Randomized Trial of Bortezomib, Melphalan, Prednisone, Lenalidomide, Dexamethasone, Carfilzomib, and Daratumumab in Elderly Patients with Newly Diagnosed Multiple Myeloma
- Trial ID
- 2024-516905-22-00
- Sponsor
- Fundacion PETHEMA
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the efficacy in terms of **immunophenotypic complete response** at 18 months between the standard treatment regimen in Spain for patients with newly diagnosed **multiple myeloma** who are ineligible for bone marrow transplant (VMP followed by Rd) and the experimental KRd treatment (carfilzomib, lenalidomide, dexamethasone, alone or in combination with daratumumab) as induction therapy. This comparison is clinically relevant as it aims to determine the most effective induction therapy for a specific patient population, potentially improving treatment outcomes for older adults with newly diagnosed multiple myeloma.
Secondary objectives include:
- Comparing **Progression-Free Survival (PFS)** from the date of first randomization to progression and/or death between the experimental treatment arm and the control arm at various stages of therapy, and comparing PFS2, Time to Progression (TTP), and Overall Survival (OS) to conventional response categories.
- Correlating the elimination kinetics of **minimal residual disease (MRD)** with PFS at different stages of therapy to evaluate the optimal surrogate response marker for PFS.
- Assessing MRD using next-generation flow cytometry to compare the efficacy of different treatment regimens and investigate the capacity of consolidation and maintenance therapies to reduce MRD levels and preserve response.
- Correlating immunophenotypic response with standard response and classical survival assessment criteria, including stringent complete response (CR), CR, very good partial response (VGPR), partial response (PR), PFS2, and OS.
- Evaluating the evolution of quality of life using specific questionnaires at various time points during and after therapy.
- Evaluating safety in each treatment arm and phase of treatment.
Participants
The clinical trial involves a study population of **patients** with newly diagnosed **multiple myeloma** who are ineligible for bone marrow transplant. The participants are aged between 65 and 80 years, inclusive, and include both male and female subjects. The trial population is selected based on their good general health status, as assessed by the Geriatric Assessment in Hematology scale, with a score of 42 or less. Participants must have a measurable disease and a life expectancy greater than three months. They are required to have adequate organ function and a functional status of 2 or less as defined by the Eastern Cooperative Oncology Group. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of different treatment regimens in patients with newly diagnosed **multiple myeloma**. The trial will compare the standard treatment regimen of bortezomib, melphalan, and prednisone (VMP) followed by lenalidomide and dexamethasone (Rd) against an experimental regimen of carfilzomib, lenalidomide, and dexamethasone (KRd), with or without daratumumab. The study will involve 18 cycles of induction therapy, followed by consolidation and maintenance phases. The trial is expected to run until December 31, 2031, with recruitment having started on October 22, 2018.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, health status, and disease characteristics. The primary endpoint is the immunophenotypic complete response after 18 cycles, evaluated using next-generation flow cytometry. Secondary endpoints include progression-free survival, overall survival, and quality of life assessments. Follow-up visits will occur midway through induction (after 9 cycles), at the end of induction (18 cycles), post-consolidation, and annually during maintenance therapy for at least five years. The end-of-study visit will conclude the participant's involvement, assessing long-term outcomes and any adverse effects.
The expected length of participant involvement is approximately 22 months for the induction and consolidation phases, with additional time for maintenance therapy. Conditions that may lead to early termination from the study include significant adverse effects, disease progression, or withdrawal of consent. Participants must adhere to protocol requirements, including medication adherence and follow-up visit attendance, to remain in the study. The trial aims to provide comprehensive data on the efficacy and safety of the treatment regimens, contributing to improved therapeutic strategies for older adults with multiple myeloma.
Treatment
The clinical trial involves the administration of several **experimental medications** and standard treatments for patients with newly diagnosed **multiple myeloma**. **Dexamethasone** is administered in the form of a tablet, with a maximum daily dose of 40 mg and a total dose of 3520 mg over a treatment period of 22 days. The route of administration is oral.
**Lenalidomide** is provided in hard capsule form, with varying dosages depending on the treatment phase. The maximum daily dose ranges from 5 mg to 25 mg, with a total dose ranging from 6930 mg to 22680 mg. The treatment period can extend up to 108 days, and the administration route is oral.
**Daratumumab** is administered as an injection, with a maximum daily dose of 1800 mg and a total dose of 88200 mg over a 42-day treatment period. The route of administration is subcutaneous.
**Carfilzomib** is provided as a lyophilized powder for solution for injection, with a maximum daily dose of 56 mg/m² and a total dose of 2936 mg/m² over an 18-day treatment period. The administration route is intravenous.
**Melphalan** is administered in tablet form, with a maximum daily dose of 9 mg/m² and a total dose of 324 mg/m² over a 9-day treatment period. The route of administration is oral, and it is classified as a cytotoxic, alkylating agent.
**Prednisone** is provided in tablet form, with a maximum daily dose of 60 mg/m² and a total dose of 2160 mg/m² over a 9-day treatment period. The administration route is oral, and it is classified as a corticosteroid.
**Bortezomib**, marketed as Velcade, is administered as a powder for solution for injection, with a maximum daily dose of 1.3 mg/m² and a total dose of 52 mg/m² over a 9-day treatment period. The route of administration is subcutaneous.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to compare the efficacy of these treatments in achieving an immunophenotypic complete response at 18 months.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the measurement of **immunophenotypic complete response** (MRD negative by cytometry) after 18 cycles of induction therapy. This evaluation will be conducted using next-generation flow cytometry, as developed by the EuroFlow Consortium, in accordance with response guidelines proposed by the International Myeloma Working Group (IMWG). The primary endpoint will focus on the difference in immunophenotypic complete response between each experimental arm and the control group.
Secondary endpoints will include the probability of Progression-Free Survival (PFS) from the date of randomization until progression or death, assessed at various stages: midway through induction (9 cycles), at the end of induction (18 cycles), post-consolidation, and annually during maintenance. Additional secondary endpoints will evaluate the kinetics of MRD elimination at specified timepoints, including 9 cycles, 18 cycles, post-consolidation, and annually during maintenance therapy for at least five years. The study will also assess differences in standard response categories (stringent CR, CR, VGPR, PR), time to second disease progression (SLP2), and overall survival (OS).
Quality of life will be measured using the EQ-5D/5L, QLQ-C30, and MY20 questionnaires, with assessments conducted at initiation, months 6, 12, and 18 during induction therapy, after consolidation, and every 6 months during maintenance. Treatment-related adverse effects will be counted and proportioned for each treatment arm and phase.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients with newly diagnosed multiple myeloma that need to initiate treatment in accordance with that published in 2014 by the IMWG
- Aged between 65 and 80 years old, inclusive.
- Patient in good overall health, assessed by the health status scale (Geriatric Assessment in Hematology GHA scale, appendix 11). (0-94 points GAH scale) [2]. Patients with a score of ≤42 will be included.
- Signed informed consent
- Patients must have measurable disease, defined as: a. For secretory multiple myeloma, measurable disease is defined as the presence of quantifiable M-protein ≥0.5 g/dl, or excretion of free light chains in urine 200 mg/24h or greater. b. For oligo-secretory or non-secretory multiple myeloma, the level of involved plasma free light chains must be ≥10 mg/dl (≥100 mg/L, with an abnormal ratio of free light chains).
- Functional status ≤2 as defined by Eastern Cooperative Oncology Group (ECOG) (see appendix 6).
- Life expectancy greater than 3 months.
- Adequate organ function: a. Platelet count ≥ 50,000/mm3, hemoglobin ≥ 8 g/dl and absolute neutrophil count ≥ 1,000/mm3. The lowest values will be permitted only if they are due to BM infiltration. b. Aspartate transaminase (AST) and alanine aminotransferase ≤ 2.5 times above the upper limit of normal. c. Total bilirubin: ≤ 2 time above the upper limit of normal. d. Serum creatinine ≤ 2 mg/dl. e. Calcium ≤14mg/dl or corrected plasma calcium ≤14mg/dl in patients whose albumin levels are out of range (see appendix 9).
- In their judgement, the investigator feels that the patient is able to comply with all of the protocol requirements.
- Left ventricle ejection fraction ≥ 40%.
- Male patients that receive lenalidomide must agree to use condoms each time they have sexual relations with a pregnant woman or a woman able to become pregnant during the time they are taking the study drug, even if said male patients have undergone a successful vasectomy. If not, they must agree to practice total abstinence (if this is part of the patient’s choice of or normal lifestyle). This commitment must be maintained including during periods when administration of the investigational drug is interrupted and for at least 30 days after treatment has ended. In addition, male patients that receive treatment with lenalidomide must agree not to donate semen or sperm during treatment with the study drug, including during periods of dose interruptions, for at least 90 days after the end of treatment. NOTE: Keeping in mind the age of patients that will be included in this clinical trial (between 65 and 80, inclusive), there is no possibility that women of childbearing potential will be participating. For this reason the pregnancy prevention program (appendix 12) has been modified as a result.
Exclusion Criteria
- Patients older than 81 or younger than 65.
- Patients who are not in good general health according to the GAH scale (appendix 11) (>43 points on the GAH scale).
- Patients who have previously received anti-myeloma treatment, with the exception of steroid pulses in the event of emergency, administration of bisphosphonates or analgesic radiotherapy, or due to the presence of plasmacytomas that caused an emergency.
- Male patients who do not commit to using a condom during sexual relations with pregnant women or women of childbearing potential, even if said male patients have undergone as successful vasectomy. If not, the must agree to practice total abstinence (if this is part of the patient’s choice of or normal lifestyle).
- Left ventricle ejection fraction ≥ 40%.
- Previous medical history of disease other than multiple myeloma (except basal or squamous cell carcinoma, cervical or breast carcinoma in situ, unless the patient has been disease-free for ≥ 5 years.
- Other relevant diseases or adverse medical conditions: a. Myocardial infarction in the 6 months prior to enrolment in the trial. b. Functional class III-IV s per the NYHA, heart failure, uncontrolled angina, uncontrolled ventricular arrhythmia or acute ischemia detected by electrocardiogram or conduction system anomalies. c. History of significant neurological or psychiatric diseases. d. Active infection. e. Significant non-malignant liver disease (for example cirrhosis, active chronic hepatitis). f. Uncontrolled arterial hypertension. g. Any serious medical condition or psychiatric disorder that might interfere with the patient's understanding of the informed consent form.
- Positive for Human Immunodeficiency Virus (HIV) or hepatitis B surface antigen, or active hepatitis C virus infection.
- Limitation in the patient’s capacity to comply with the treatment or follow-up protocol.
- Uncontrolled endocrine disease (for example diabetes mellitus, hypo- or hyperthyroidism). These diseases have required relevant changes in medication in the last month or have required hospitalization of the patient in the last 3 months.
- Patients with ≥ Grade 2 peripheral neuropathy in the 14 days prior to inclusion in the study.
- Known hypersensitivity to any of the study drugs or their excipients.
- Patients treated with any other study drug in the 30 days prior to inclusion.
- Patients with diffuse infiltrative lung disease and/or pericardial effusion.
- Patients that are unable or unwilling to undergo anti-thrombotic therapy.
- Patients with severe chronic obstructive pulmonary disease (CPOD) or asthma with forced expiratory volume in the first minute (VEF1) less than 50%.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 22 Oct 2018 | 462 |
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 | Other | — | ORAL | 40 | 22 | SUB07017MIG |
LENALIDOMIDE | Test | — | ORAL | 10 | 108 | SUB25389 |
DARATUMUMAB | Test | — | SUBCUTANEOUS | 1800 | 42 | SUB175772 |
CARFILZOMIB | Test | — | INTRAVENOUS | 56 | 18 | SUB32911 |
LENALIDOMIDE | Test | — | ORAL | 25 | 22 | SUB25389 |
MELPHALAN | Other | — | ORAL | 9 | 9 | SUB08728MIG |
LENALIDOMIDE | Test | — | ORAL | 5 | 108 | SUB25389 |
PREDNISONE | Other | — | ORAL | 60 | 9 | SUB10020MIG |
VELCADE 3.5 mg powder for solution for injection | Test | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS | 1.3 | 9 | PRD3349073 |
LENALIDOMIDE | Test | — | ORAL | 15 | 22 | SUB25389 |