Phase III Evaluation of Elotuzumab with Carfilzomib, Lenalidomide, and Dexamethasone in Newly Diagnosed Multiple Myeloma Post-Autologous Stem Cell Transplant
- Trial ID
- 2024-515783-31-00
- Protocol
- DSMM_XVII
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase III study is to compare the rate of patients achieving a Very Good Partial Response (**VGPR**) or better, according to the International Myeloma Working Group (**IMWG**) criteria, who are also Minimal Residual Disease (**MRD**) negative, as assessed by flow cytometry, following two different induction regimens: quadruple therapy (Elotuzumab, Carfilzomib, Lenalidomide, and Dexamethasone - E-KRd) versus triple therapy (Carfilzomib, Lenalidomide, and Dexamethasone - KRd) in patients with newly diagnosed **Multiple Myeloma**. Additionally, the study aims to determine progression-free survival (**PFS**) following maintenance treatment. This is clinically relevant as achieving MRD negativity is associated with improved outcomes in multiple myeloma, and comparing these regimens could inform optimal treatment strategies.
Secondary objectives include:
- Assessing the long-term efficacy, quality of life (**QoL**), and safety of the treatment regimens.
- Evaluating the impact of MRD negativity, regardless of IMWG response, on disease-free survival (**DFS**) and overall survival (**OS**).
Participants
The clinical trial involves participants diagnosed with **newly diagnosed multiple myeloma**. The study population includes both male and female subjects, aged between 18 and 70 years. Participants are required to be in generally good health, as indicated by an **ECOG Performance Status** of 2 or less and a left ventricular ejection fraction of at least 50%. The trial does not specify the total number of participants, as the sponsor has not provided this information. Selection criteria include eligibility for autologous stem cell transplantation and the absence of prior systemic therapy for multiple myeloma, except for specific pre-treatments like dexamethasone. Participants must have measurable disease parameters and meet specific laboratory test result thresholds. Lifestyle considerations include adherence to a pregnancy prevention plan for females of childbearing potential and specific precautions for male subjects regarding potential teratogenic risks. The trial includes a vulnerable population, and all participants must have the legal capacity to consent to study participation.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **elotuzumab** in combination with **carfilzomib**, **lenalidomide**, and **dexamethasone** (E-KRd) compared to the combination of carfilzomib, lenalidomide, and dexamethasone (KRd) in patients with newly diagnosed **multiple myeloma**. This is a Phase III, randomized, double-blind, controlled trial. The trial aims to assess the rate of patients achieving a very good partial response (VGPR) or better, as well as minimal residual disease (MRD) negativity, following induction treatment. The trial also seeks to determine progression-free survival (PFS) during maintenance therapy.
The trial is expected to last until August 2027, with recruitment having started in August 2018. Participants will be involved in the study for a maximum treatment period of 48 weeks, depending on the treatment arm they are assigned to. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The screening visit will ensure that participants meet the inclusion criteria, such as being between 18 and 70 years old, having newly diagnosed multiple myeloma, and being eligible for autologous stem cell transplantation.
Participants will be randomly assigned to one of the treatment arms and will receive either the quadruple regimen (E-KRd) or the triple regimen (KRd). The study is double-blind, meaning neither the participants nor the investigators will know which treatment the participants are receiving. Follow-up visits will occur regularly to monitor the participants' health, treatment adherence, and any adverse events. The end-of-study visit will evaluate the primary and secondary endpoints, including VGPR rates, PFS, overall survival (OS), and quality of life (QoL).
Participant involvement may be terminated early if they experience unacceptable adverse events, withdraw consent, or if the investigator deems it necessary for the participant's safety. The trial will adhere to strict ethical guidelines, ensuring that all participants provide informed consent and are aware of the potential risks and benefits of the study. The trial's primary endpoints include the rate of VGPR or better response and MRD negativity following induction treatment, while secondary endpoints encompass overall response rates, PFS, OS, and QoL assessments.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Dexamethasone** is provided in tablet form for **oral use**. The maximum daily dose is 40 mg, with a total maximum dose of 1600 mg over a treatment period of up to 10 days. This medication is of chemical origin and is not a pediatric formulation.
**Lenalidomide** is administered in hard capsule form, also for **oral use**. The trial includes various dosages: 5 mg, 10 mg, 15 mg, and 25 mg capsules. The maximum daily dose ranges from 5 mg to 25 mg, depending on the specific formulation, with a total maximum dose ranging from 1050 mg to 21900 mg over a treatment period of up to 48 days. Lenalidomide is classified as an immunomodulating agent and is of chemical origin.
**Elotuzumab** is provided as a powder for solution for infusion, intended for **intravenous use**. The maximum daily dose is 20 mg/kg, with a total maximum dose of 1200 mg/kg over a treatment period of up to 48 days. Elotuzumab is a monoclonal IgG1 antibody and is not a pediatric formulation. It is manufactured by Bristol-Myers Squibb International Corporation.
**Dexamethasone dihydrogen phosphate disodium Ph. Eur.** is administered as a solution for injection via **intravenous use**. The maximum daily dose is 8 mg, with a total maximum dose of 192 mg over a treatment period of up to 10 days. This formulation is of chemical origin and is not intended for pediatric use.
**Carfilzomib**, marketed as Kyprolis, is provided as a powder for solution for infusion for **intravenous use**. The maximum daily dose is 36 mg/m², with a total maximum dose of 360 mg/m² over a treatment period of up to 10 days. Carfilzomib is of chemical origin and is classified as an immunomodulating agent.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The study aims to evaluate the efficacy and safety of these experimental medications in the treatment of newly diagnosed multiple myeloma.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the rate of patients achieving a Very Good Partial Response (VGPR) or better, according to the International Myeloma Working Group (IMWG) criteria, and being **Minimal Residual Disease (MRD)** negative as assessed by flow cytometry following six cycles of induction treatment. Additionally, the 3-year progression-free survival (PFS) rate will be calculated from randomization during the maintenance phase.
Secondary endpoints encompass a range of measures, including the objective response rate (ORR) following induction and consolidation treatment with Elotuzumab, Carfilzomib, Lenalidomide, and Dexamethasone (E-KRd) versus Carfilzomib, Lenalidomide, and Dexamethasone (KRd), as well as ORR at the end of the study treatment program. Progression-free survival (PFS) and overall survival (OS) will be evaluated, with specific attention to cytogenetic abnormalities and MRD negativity rates assessed by flow cytometry. Disease-free survival (DFS) for patients achieving MRD negativity and quality of life (QoL) will also be measured using the EORTC-QLQ C30 and EORTC multiple myeloma module QLQ-MY20. The type, incidence, relatedness, and severity of adverse events will be recorded according to NCI CTCAE version 4.03, along with the occurrence of laboratory abnormalities.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Adult patients of age ≥ 18 and ≤ 70 years at the time of signing the informed consent form
- Eligible for autologous stem cell transplantation (ASCT)
- Patient must not have been previously treated with any prior systemic therapy for the treatment of multiple myeloma (only dexamethasone at a cumulative dose of 320 mg; plasmapheresis/dialysis without concomitant chemotherapy, local irradiation of bone lesions; and surgical intervention permitted as pretreatment)
- Newly diagnosed multiple myeloma according to the IMWG updated criteria42: Clonal bone marrow plasma cells ≥ 10% or extramedullary plasmacytoma or biopsy proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events: Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: - Hypercalcaemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the upper limit of normal or > 2.75 mmol/L (> 11 mg/dL) - Renal insufficiency: creatinine clearance < 40 mL per min or serum creatinine > 177 μmol/L (> 2 mg/dL) - Anaemia: haemoglobin value of >2 g/dL below the lower limit of normal, or a haemoglobin value < 10 g/dL - Bone lesions: one or more osteolytic lesions on skeletal radiography, computed tomography (CT), or PET-CT Any one or more of the following markers of malignancy: - Clonal bone marrow plasma cell percentage ≥ 60% - Involved: uninvolved serum free light chain ratio ≥ 100, provided the absolute level of the involved light chain is at least 100 mg/L - One or more focal lesions of at least 5mm or greater in size on MRI studies
- Measurable disease parameters as follows: Serum monoclonal paraprotein (M-component) level ≥ 1 g/dL and/or urine Mprotein level ≥ 200 mg/24 hours or In case of IgA myeloma: Serum monoclonal paraprotein level ≥0.5 g/dL and/or urine M-protein level ≥ 200 mg/24 hours or For patients with no detectable M-component: Serum FLC assay: Involved FLC level ≥10 mg/dL (≥ 100 mg/L) provided serum FLC ratio is abnormal
- ECOG Performance Status ≤ 2
- Echocardiography with left ventricular ejection fraction (LVEF) ≥ 50%
- Laboratory test results within these ranges: White blood cell count (WBC) 2 x 109 /L Absolute neutrophil (ANC) count ≥ 1.0 x 109 /L Platelet count ≥ 75 x 109 /L Haemoglobin > 8 g/dL Calculated creatinine clearance (estimation of the glomerular filtration rate [GFR]; according to MDRD, see Appendix 19.5) ≥ 30 mL/minute Total bilirubin ≤ 1.5 x upper limit of normal (ULN) AST and ALT ≤ 2.5 x ULN Corrected serum calcium level < 3.5 mmol/L (< 14 mg/dL)
- Patient’s legal capacity to consent to study participation
- Patients capable to understand the purposes and risks of the study, who are willing and able to participate in the study and from whom written and dated informed consent to participate in the study has been obtained.
- All females Must acknowledge to have understood the hazards lenalidomide can cause to an unborn fetus and the necessary precautions associated with the use of lenalidomide. The investigator must ensure that a FCBP: - Complies with the conditions of the pregnancy prevention plan, including confirmation that she has an adequate level of understanding. - Acknowledges the aforementioned requirements.
- Male subjects must ▪ Understand the potential teratogenic risk if engaged in sexual activity with a pregnant female or a FCBP. Understand the potential teratogenic risk if the subject donates semen or sperm. Practice complete abstinence (true abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence [e.g. calendar, ovulation, symptothermal or post-ovulation methods] and withdrawal are not acceptable methods of contraception.) or agree to use a condom during sexual contact with a pregnant female or a FCBP while taking lenalidomide, carfilzomib and elotuzumab, during any dose interruptions and for 28 days after the last dose of lenalidomide and for 90 days after last dose of carfilzomib if allocated in Arm B without administration of elotuzumab, or for a total of 180 days after last application of elotuzumab, if allocated in Arm A with application of elotuzumab, even if he has undergone a successful vasectomy. Notify the investigator immediately, if pregnancy or a positive pregnancy test does occur in the partner of a male subject while taking lenalidomide, carfilzomib, and/or elotuzumab. Not donate semen or sperm while receiving lenalidomide, during dose interruptions and for at least 28 days after the last dose of lenalidomide and for at least 90 days after the last dose of carfilzomib. Receive counseling about pregnancy precautions and the potential risks of fetal exposure to lenalidomide at a minimum of every 28 days during induction and consolidation phase. In maintenance phase counseling must be conducted with each lenalidomide prescription issued by the investigator.
- All subjects must Not donate blood while taking lenalidomide, during dose interruptions and for at least 28 days after the last dose of lenalidomide. Agree never to give lenalidomide to another person. Agree to return all unused lenalidomide capsules to the investigator (with exception of prescribed lenalidomide capsules) During induction and consolidation phase, be aware that no more than a 28-day lenalidomide supply may be dispensed with each cycle of lenalidomide. During maintenance therapy, be aware that for females of childbearing potential no more than a 28-day lenalidomide supply may be prescribed with each cycle of lenalidomide, for all others no more than a 12 week lenalidomide supply may be prescribed.
Exclusion Criteria
- POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
- Waldenström’s macroglobulinemia or IgM myeloma
- Plasma cell leukemia (> 2.0 x 109 /L circulating plasma cells by standard differential blood count)
- Pregnant, breast-feeding females, FCBPs and males who are unwilling to comply with the lenalidomide Pregnancy Prevention Risk Management Plan (see Appendix E).
- Patients with high cardiovascular risk, including but not limited to history of myocardial infarction or coronary stenting in the past 6 months; NYHA Class III or IV heart failure, uncontrolled angina, uncontrolled hypertension, severe uncontrolled arrhythmias
- Prior cerebral vascular accident (CVA) with persistent neurological deficit
- Active infection
- Known HIV-seropositivity, active or chronic hepatitis A, B, C or D-infection (including patients who are tested anti-HBC positive and/or HBsAg positive) –serological testing for hepatitis A; B; C, D required. However, testing for hepatitis D only required in case of patients who tested positive for acute or chronic hepatitis B.
- Any other severe concomitant disease or disorder, including the presence of laboratory abnormalities, which places the subject at unacceptable risk or which could influence patient’s ability to participate in the study and his/her safety during the study or interfere with interpretation of study results.
- Greater or equal to Grade 2 peripheral neuropathy on clinical examination within 14 days before enrolment
- Major surgery within 4 weeks prior to randomization
- Any systemic anti-myeloma therapy except a cumulative dose of 320 mg of dexamethasone
- Any prior or concurrent malignancy other than multiple myeloma. Exceptions include patients who have been disease-free for at least five years before study entry or patients with adequately treated and completely resected basal cell or squamous cell skin cancer, in situ cervical, breast or prostate cancer
- Known hypersensitivity to carfilzomib, lenalidomide, and elotuzumab or to any of the excipients of carfilzomib, lenalidomide, and elotuzumab or to any other component of any study drug formulation
- Participation in any other clinical trial or treatment with any experimental drug or other experimental therapy within 28 days before enrolment to the study or during study participation until the end of treatment visit
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 28 Aug 2018 | 82 |
 Germany | Not Recruiting | 28 Aug 2018 | 492 |
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 | CAPSULE, HARD | ORAL USE | 25 | 10 | PRD10089707 |
Empliciti 400 mg powder for concentrate for solution for infusion. | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 20 | 48 | PRD4073310 |
LENALIDOMIDE | Test | — | ORAL USE | 5 | 48 | SUB25389 |
Elotuzumab | Test | POWDER FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 20 | 48 | PRD957143 |
DEXAMETHASONE | Test | — | ORAL USE | 40 | 10 | SUB07017MIG |
Elotuzumab | Test | POWDER FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 20 | 48 | PRD3424159 |
DEXAMETHASONE DIHYDROGEN PHOSPHATE DISODIUM PH. EUR. | Test | — | INTRAVENOUS USE | 8 | 10 | SUB176825 |
Kyprolis 60 mg powder for solution for infusion | Test | POWDER FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 36 | 10 | PRD3374183 |
LENALIDOMIDE | Test | — | ORAL USE | 15 | 48 | SUB25389 |
LENALIDOMIDE | Test | — | ORAL USE | 10 | 48 | SUB25389 |