Phase II Study of Daratumumab with Bortezomib-Cyclophosphamide-Dexamethasone vs. Bortezomib-Thalidomide-Dexamethasone in Transplant-Eligible Multiple Myeloma Patients
- Trial ID
- 2024-511781-37-00
- Protocol
- EMN18
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **progression-free survival (PFS)** at 36 months from the first randomization and 24 months from the second randomization in young patients newly diagnosed with multiple myeloma (MM) who are eligible for autologous stem cell transplantation. This is clinically relevant as PFS is a critical endpoint in assessing the efficacy of treatment regimens in delaying disease progression in MM, thereby potentially improving patient outcomes.
Secondary objectives include:
- Determining the overall response rate (ORR).
- Determining the very good partial response (VGPR) rate.
- Determining the complete response (CR) rate.
- Determining the second progression-free survival (PFS2).
- Assessing the safety profile of the treatment regimens.
- Determining the duration of response (DoR).
- Evaluating overall survival (OS).
- Determining the time to progression (TTP).
- Determining the time to next therapy (TNT).
- Assessing minimal residual disease (MRD) negativity rate by next-generation flow cytometry (NGF) and imaging negativity by PET/CT after induction, consolidation, and during maintenance.
- Evaluating the role of MRD on OS.
- Determining the prognostic role of different sensitivity levels of MRD.
- Determining the duration of MRD negativity.
- Assessing the conversion rate of MRD negativity to positivity and vice versa.
- Evaluating whether tumor response and outcome may change in subgroups with different prognoses according to current and new prognostic factors, as evaluated by next-generation sequencing (NGS).
- Determining the impact of maintenance treatment on MRD.
- Defining prognosis factors, as assessed by NGS.
- Evaluating quality of life (QoL).
Participants
The clinical trial involves a study population of **young patients affected by multiple myeloma** who are eligible for autologous stem cell transplantation. The trial includes both male and female participants, aged between 18 and 65 years. Participants are required to have a documented diagnosis of multiple myeloma with measurable disease and must meet specific laboratory and health criteria, such as an ECOG performance status score of 0, 1, or 2, or a Karnofsky performance status of at least 60%. The trial population was selected based on their eligibility for autologous stem cell transplantation and their ability to comply with the protocol requirements. Participants must adhere to specific lifestyle considerations, including the use of reliable contraception methods for both men and women of childbearing potential. The sponsor has not provided the total number of participants involved in the study.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, phase II study to evaluate the efficacy of two treatment regimens in young patients newly diagnosed with **multiple myeloma**. The trial compares the combination of daratumumab with bortezomib, cyclophosphamide, and dexamethasone (Dara-VCd) against bortezomib, thalidomide, and dexamethasone (VTd) as pre-transplant induction and post-transplant consolidation therapies. Both regimens are followed by a maintenance phase with ixazomib alone or in combination with daratumumab. The primary objectives include determining progression-free survival (PFS) at 36 months from the first randomization and minimal residual disease (MRD) negativity rate after consolidation and during maintenance, assessed by next-generation sequencing (NGS).
The trial is expected to last until April 16, 2031, with recruitment having started on April 16, 2019. Participants will be involved in the study for a maximum treatment period of 24 to 36 months, depending on the treatment phase. 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. Participants are required to meet specific inclusion criteria, such as being between 18 and 65 years of age, having a documented diagnosis of multiple myeloma, and being eligible for autologous stem cell transplantation (ASCT). Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent.
Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit involves detailed assessments to confirm eligibility, including laboratory tests and imaging studies. Follow-up visits occur at regular intervals to evaluate treatment efficacy and safety, with specific assessments for MRD negativity using NGS. The end-of-study visit includes a final evaluation of treatment outcomes and any long-term effects. Participants are expected to adhere to the study protocol, including the use of reliable contraception for those of childbearing potential, to minimize risks and ensure the integrity of the trial data.
Treatment
The clinical trial involves several experimental medications, each with specific administration protocols. **SOLDESAM 0.2%** is an oral drop solution containing **dexamethasone sodium phosphate**. It is administered orally with a maximum daily dose of 40 mg and a total dose of 960 mg over a treatment period of 24 months. Compliance is monitored through regular assessments.
**Endoxan Baxter 200 mg** is a powder for solution for injection containing **cyclophosphamide monohydrate**. It is administered intravenously with a maximum daily dose of 300 mg/m² and a total dose of 7200 mg/m² over 24 months. The administration schedule is determined by the investigator, and participant compliance is monitored through infusion records.
**DEXAMETHASONE/ROSEMONT 2 mg/5 ml** is an oral solution containing **dexamethasone**. It is administered orally with a maximum daily dose of 40 mg and a total dose of 960 mg over 24 months. Compliance is assessed through patient diaries and regular follow-ups.
**SOLDESAM 8 mg/2 ml** is a solution for injection containing **dexamethasone sodium phosphate**. It is administered intravenously with a maximum daily dose of 40 mg and a total dose of 960 mg over 24 months. Administration is monitored through infusion logs.
**DARZALEX 1800 mg** is a solution for injection containing **daratumumab**. It is administered subcutaneously with a maximum daily dose of 1800 mg and a total dose of 72000 mg over 36 months. Compliance is monitored through injection records and patient follow-ups.
**VELCADE 3.5 mg** is a powder for solution for injection containing **bortezomib**. It is administered subcutaneously with a maximum daily dose of 3 mg/m² and a total dose of 72 mg/m² over 24 months. Administration is tracked through injection logs.
**Endoxan®** is a coated tablet containing **cyclophosphamide monohydrate**. It is administered orally with a maximum daily dose of 300 mg/m² and a total dose of 7200 mg/m² over 24 months. Compliance is monitored through pill counts and patient diaries.
**Endoxan 500 mg** is a powder for injection/infusion containing **cyclophosphamide monohydrate**. It is administered intravenously with a maximum daily dose of 300 mg/m² and a total dose of 7200 mg/m² over 24 months. Administration is tracked through infusion records.
**Dexamethasone Krka 40 mg** and **20 mg** tablets contain **dexamethasone**. They are administered orally with a maximum daily dose of 40 mg and a total dose of 960 mg over 24 months. Compliance is assessed through patient diaries and regular follow-ups.
**Endoxan 50 mg** is a coated tablet containing **cyclophosphamide**. It is administered orally with a maximum daily dose of 300 mg/m² and a total dose of 7200 mg/m² over 24 months. Compliance is monitored through pill counts and patient diaries.
**Thalidomide BMS 50 mg** is a hard capsule containing **thalidomide**. It is administered orally with a maximum daily dose of 100 mg and a total dose of 16800 mg over 24 months. Compliance is assessed through patient diaries and regular follow-ups.
**Endoxan Baxter 50 mg** is a coated tablet containing **cyclophosphamide monohydrate**. It is administered orally with a maximum daily dose of 300 mg/m² and a total dose of 7200 mg/m² over 24 months. Compliance is monitored through pill counts and patient diaries.
**IXAZOMIB CITRATE** is administered as a suspension for injection with a maximum daily dose of 4 mg and a total dose of 180 mg over 24 months. It is administered orally, and compliance is monitored through patient diaries and regular follow-ups.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Progression Free Survival (PFS)** and **Minimal Residual Disease (MRD) negativity**. PFS will be measured from the date of first or second randomization to the date of first observation of disease progression or death from any cause. The efficacy of the treatment regimens will be compared at specified time points: 3 years from the first randomization and 2 years from the second randomization. MRD negativity will be evaluated using clonotypic analysis of immunoglobulin heavy chain (IgH) VDJ gene rearrangement on bone marrow samples, utilizing the ClonoSEQ TM assay at sensitivity thresholds of 10^-3, 10^-4, and ≥10^-5.
Secondary endpoints include Overall Response Rate (ORR), Progression Free Survival 2 (PFS2), Duration of Response (DoR), Overall Survival (OS), Time to Progression (TTP), Time to the Next Anti-Myeloma Therapy (TNT), and MRD by Next Generation Flow (NGF) and PET/CT. ORR will be assessed using the International Response Criteria, including categories such as stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD). PFS2 will measure the time from first randomization to second disease progression or death. DoR will be the time between first documentation of response and PD. OS is defined as the time from first randomization to death. TTP will be measured from randomization to first observation of PD or death due to PD. TNT will be measured from first randomization to the date of next anti-myeloma therapy. MRD by NGF and PET/CT will assess immunophenotypic CR and PET/CT negativity according to IMWG criteria.
Additionally, the trial will define prognostic factors using Next Generation Sequencing (NGS) to characterize the genomic profile of the multiple myeloma clone(s) at diagnosis and first progression. This analysis will help identify prognostic factors related to disease progression and stratify patients based on evolution patterns for potential clinical correlations.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient at least 18 years of age and ≤ 65 years.
- Patient eligible for ASCT.
- LVEF ≥ 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available.
- Newly diagnosed multiple myeloma patient.
- Patient has given voluntary written informed consent before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
- Patient with documented multiple myeloma and measurable disease as defined by: 1) Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma. 2) Measurable disease as defined by at least one of the following: 2.1) serum M-protein level ≥1 g/dL or urine M-protein level ≥200 mg/24 hours; or 2.2) Light chain multiple myeloma: involved serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio.
- Evidence of end organ damage/presence of biomarkers of malignancies, specifically: 1) 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). 2) Renal insufficiency: creatinine clearance <40 mL per minute (measured or estimated by validated equations) or serum creatinine >177 μmol/L (>2 mg/dL). 3) Anaemia: haemoglobin value of >20 g/L below the lower limit of normal, or haemoglobin value <100 g/L. 4) Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT. If bone marrow has <10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement.
- Any one or more of the following biomarkers of malignancy: 1) Clonal bone marrow plasma cell percentage ≥ 60% (clonality should be established by showing κ/λ-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used). 2) Involved/uninvolved serum free light chain ratio ≥100 (values based on the serum Freelite assay. The involved free light chain must be ≥100 mg/L). 3) or >1 focal lesion on MRI studies (each focal lesion must be 5 mm or more in size)
- Patient is, in the investigator(s) opinion willing and able to comply with the protocol requirements.
- Women of childbearing potential must commit to either abstain continuously from heterosexual intercourse or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, hormonal patches, vaginal rings or implants] or partner’s vasectomy through a medical assessment of success of the procedure, according to local procedure) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin prior to dosing and for at least 4 weeks before starting thalidomide through 90 days after the last dose of study drugs and 6 months after the last dose of cyclophosphamide. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy.
- Male patient agrees to use an acceptable method for contraception (i.e., condom or abstinence) during study drug therapy (including dose interruption) and for 90 days after the last dose of study drugs and 6 months after the last dose of cyclophosphamide.
- Patient with an ECOG performance status score of 0, 1, or 2 or Karnofsky performance status ≥ 60%.
- Pretreatment clinical laboratory values within 30 days of enrolment: - Platelet count ≥75 x 10^9 /L; - Absolute neutrophil count (ANC) ≥ 1 x 10^9 /L (G-CSF use is permitted); - Corrected serum calcium <14 mg/dL (<3.5 mmol/L); - Aspartate transaminase (AST) ≤ 2.5 x the upper limit of normal (ULN); - Alanine transaminase (ALT) ≤ 2.5 x the ULN; - Total bilirubin ≤ 1.5 x the ULN; - Calculated or measured creatinine clearance ≥ 30 mL/minute
- Patient has a life-expectancy >3 months.
Exclusion Criteria
- Patient with a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, plasma cell leukemia or smoldering multiple myeloma. Monoclonal gammopathy of undetermined significance is defined by presence of serum M-protein <3 g/dL; clonal bone marrow plasma cells <10%, and absence of end-organ damage; or amyloidosis that can be attributed to the plasma cell proliferative disorder. Smoldering multiple myeloma is defined as serum monoclonal protein ≥ 30 g/L or urinary monoclonal protein ≥ 500 mg per 24 h and/or clonal bone marrow plasma cell 10-60% with absence of related organ or tissue impairment or endorgan damage or amyloidosis. Plasma cell leukemia is defined as the presence of circulating plasmacells (PCs) >2×10^9 /L in peripheral blood or a peripheral blood plasmacytosis >20%.
- Patient with a diagnosis of Waldenström’s disease, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions.
- Patient has prior or current systemic therapy or SCT for multiple myeloma, with the exception of an emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment.
- Patient has peripheral neuropathy of grade 2 or higher as defined by National Cancer Institute Common Toxicity Criteria (NCI CTC) 5.0.
- Patient is exhibiting clinical signs of meningeal involvement of multiple myeloma.
- Known to be: - seropositive for human immunodeficiency virus (HIV) - seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR. - seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).
- Subject has known chronic obstructive pulmonary disease (COPD), persistent asthma, or a history of asthma within the last 2 years with a forced expiratory volume in 1 second [FEV1] <60%. Subjects with known or suspected COPD or asthma must have a FEV1 test during screening.
- Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.
- Known allergy to any of the study medications, their analogues, or excipients in the various formulations.
- Contraindication to any of the required concomitant drugs or supportive treatments.
- Pregnant or lactating females.
- Acute active infection requiring antibiotics or infiltrative pulmonary disease.
- Serious medical condition, laboratory abnormality or psychiatric illness that prevented the subject from the enrolment or place the subject at unacceptable risk, including acute diffuse infiltrative pericardial and pulmonary disease.
- Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs.
- Invasive malignancy within the past 5 years.
- Major surgery within 14 days before enrollment.
- Radiotherapy within 14 days before enrollment.
- Live vaccine 30 days before start of treatment and 90 days after the end of study treatment
- Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment.
- Participation in other clinical trials with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial.
- Patients that have previously been treated with ixazomib, or participated in a study with ixazomib whether treated with ixazomib or not.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 16 Apr 2019 | 72 |
 Greece | Not Recruiting | 16 Apr 2019 | 69 |
 Italy | Not Recruiting | 16 Apr 2019 | 260 |
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 Krka 40 mg tablety | Test | TABLETY | ORAL USE | 40 | 24 | PRD4331972 |
Endoxan Baxter 50 mg Compresse rivestite | Test | COMPRESSE RIVESTITE | ORAL USE | 300 | 24 | PRD350117 |
Endoxan 50 mg obalené tablety | Test | OBALENÉ TABLETY | ORAL USE | 300 | 24 | PRD352334 |
SOLDESAM 8 mg/2 ml soluzione iniettabile | Test | SOLUZIONE INIETTABILE | INTRAVENOUS USE | 40 | 24 | PRD354313 |
DARZALEX 1800 mg solution for injection | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 1800 | 36 | PRD8157846 |
Dexamethasone Krka 20 mg tablety | Test | TABLETY | ORAL USE | 40 | 24 | PRD4331971 |
SOLDESAM 0,2% gocce orali, soluzione | Test | GOCCE ORALI, SOLUZIONE | ORAL USE | 40 | 24 | PRD362173 |
Thalidomide BMS 50 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 100 | 24 | PRD9254326 |
Endoxan 500 mg prášek pro injekční/infuzní roztok | Test | PRÁŠEK PRO INJEKČNÍ/INFUZNÍ ROZTOK | INTRAVENOUS USE | 300 | 24 | PRD347605 |
Endoxan Baxter 500 mg Polvere per soluzione iniettabile | Test | POLVERE PER SOLUZIONE INIETTABILE | INTRAVENOUS USE | 300 | 24 | PRD350119 |