Randomized, Multicenter, Open-Label Study Comparing Bortezomib-Melphalan-Prednisone With/Without Daratumumab vs. Lenalidomide-Dexamethasone With/Without Daratumumab in ASCT-Ineligible Multiple Myeloma Patients
- Trial ID
- 2024-512049-17-00
- Protocol
- Real MM
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **progression-free survival (PFS)** of two treatment regimens, bortezomib-melphalan-prednisone (VMP) versus lenalidomide-dexamethasone (Rd), with or without the addition of daratumumab (Dara-VMP, Dara-Rd) in a real-life, unselected patient population. This is clinically relevant as it aims to determine the most effective treatment strategy for patients with multiple myeloma who are ineligible for autologous stem cell transplantation, potentially improving patient outcomes and guiding treatment decisions.
Secondary objectives include: - Comparing the overall response rate (ORR) between the VMP and Rd arms with or without daratumumab. - Determining the minimal residual disease (MRD) negativity rate by next-generation flow (NGF) at various time points. - Comparing the duration of response (DOR), overall survival (OS), progression-free survival 2 (PFS2), time to next therapy (TNT), and time to progression (TTP) between the treatment arms. - Evaluating safety in terms of incidence of hematologic and non-hematologic adverse events. - Comparing the rate of treatment discontinuation and dose reductions or death due to toxicity. - Validating the frailty score in a real-life population using geriatric assessment. - Comparing the quality of life (QoL) and health-related costs between the treatment arms. - Evaluating the risk of infectious complications. - Determining the correlation between MRD negativity and various survival metrics. - Assessing differences in response and outcomes in subgroups with different prognostic factors.
Participants
The clinical trial involves a study population of **newly diagnosed multiple myeloma** patients who are either aged 65 years or older or are ineligible for autologous stem cell transplant. The trial includes both male and female participants, and the population is considered vulnerable. The sponsor has not provided the total number of participants. Participants were selected based on their diagnosis and eligibility criteria, which include specific health conditions and the ability to undergo standard treatments. Lifestyle considerations such as diet and physical activity are not specified. The trial aims to compare the progression-free survival of different treatment regimens in a real-life, unselected patient population.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, multicenter study aimed at comparing two standard treatment regimens for patients with **multiple myeloma** who are ineligible for autologous stem cell transplantation. The trial involves the administration of bortezomib-melphalan-prednisone (VMP) with or without daratumumab (Dara-VMP) versus lenalidomide-dexamethasone (Rd) with or without daratumumab (Dara-Rd). The primary objective is to evaluate progression-free survival (PFS) among these treatment groups. The trial is expected to run from its recruitment start date in May 2018 to its estimated end date in May 2028, encompassing a total duration of approximately 10 years.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, medical history, and specific laboratory parameters. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, assess disease progression, and manage any adverse events. These visits will occur at specified intervals throughout the treatment period, with additional visits scheduled for comprehensive assessments at 6, 12, 24, 36, 48, and 60 months. The end-of-study visit will conclude the participant's involvement, during which final evaluations will be conducted.
The expected length of participant involvement in the trial is contingent upon individual response to treatment and disease progression, with the maximum treatment period varying by regimen. Conditions that may lead to early termination from the study include withdrawal of consent, significant adverse events, or disease progression that necessitates alternative therapeutic interventions. Participants who withdraw or are lost to follow-up will be censored at the time of their last complete disease assessment. The trial's design ensures rigorous monitoring and data collection to achieve its primary and secondary endpoints, including overall survival, minimal residual disease negativity, and quality of life assessments.
Treatment
The clinical trial involves several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Revlimid** is administered in the form of hard capsules, available in dosages of 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg. The active substance in Revlimid is **lenalidomide**, a chemical compound classified as an immunomodulatory agent. The maximum daily dose is 25 mg, with a total maximum dose of 24,150 mg over a treatment period of 46 weeks. The route of administration is oral.
**DARZALEX** is provided as a solution for injection and a concentrate for solution for infusion, with the active substance being **daratumumab**, a monoclonal antibody. The solution for injection is available at a concentration of 1800 mg, administered subcutaneously, with a maximum daily dose of 1800 mg and a total maximum dose of 140,400 mg over 70 weeks. The concentrate for infusion is administered intravenously, with a dosage of 16 mg/kg, and a total maximum dose of 1248 mg/kg over the same period.
**Prednisone Teva** is administered as 5 mg tablets, with **prednisone** as the active substance, a chemical corticosteroid. The maximum daily dose is 60 mg/m², with a total maximum dose of 2160 mg/m² over 54 weeks. The administration route is oral.
**SOLDESAM** is provided as oral drops, with **dexamethasone sodium phosphate** as the active substance, also a chemical corticosteroid. The maximum daily dose is 40 mg, with a total maximum dose of 7360 mg over 46 weeks, administered orally.
**VELCADE** is available as a powder for solution for injection, with **bortezomib** as the active substance, a chemical proteasome inhibitor. The maximum daily dose is 1.3 mg/m², with a total maximum dose of 67.6 mg/m² over 54 weeks, administered subcutaneously.
**ALKERAN** is administered as 2 mg film-coated tablets, with **melphalan** as the active substance, a chemical alkylating agent. The maximum daily dose is 9 mg/m², with a total maximum dose of 324 mg/m² over 54 weeks, administered orally.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial compares the efficacy of these treatments in patients with multiple myeloma, specifically those ineligible for autologous stem cell transplantation. The study evaluates the progression-free survival of patients receiving these treatments, with or without the addition of daratumumab.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **progression-free survival (PFS)**, which will be measured from the date of randomization to the date of first observation of disease progression (PD) or death from any cause. Subjects who withdraw from the study will be censored at the time of the last complete disease assessment, and those who complete the study without progression and are alive at the cut-off date of final analysis will be censored at that date.
Secondary endpoints include the rate of minimal residual disease (MRD) negativity at various timepoints, overall response rate (ORR), duration of response (DOR), second progression-free survival (PFS2), overall survival (OS), time to next treatment (TNT), and time to progression (TTP). MRD negativity will be assessed using Next Generation Flow with a sensitivity level of ≥10^-5 at 6, 12, 24, 36, 48, and 60 months. ORR will include complete and partial responses as per the International Response Criteria. DOR is defined as the time between the first documentation of response and PD. PFS2 is the time from randomization to objective tumor progression on next-line treatment or death. OS is the time between randomization and death, with subjects censored at the time of death or withdrawal. TNT and TTP will be measured from randomization to the date of next anti-myeloma therapy or first observation of PD, respectively.
Additional assessments include safety evaluation through the incidence, severity, and type of adverse events (AEs) according to NCI-CTCAE v. 4.0, and quality of life (QoL) through Health-Related QoL questionnaires such as EORTC-QLQ-C30, QLQ-MY20, and EQ-5D-5L. These questionnaires will be collected every 3 months for the first year and every 6 months thereafter. Health-related costs will also be reported through self-reported questionnaires regarding various healthcare services. Infectious risk complications will be evaluated in terms of incidence, severity, type of infection, and their impact on PFS.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients has given voluntary written informed consent before the performance of any study related procedure
- Patients with newly diagnosed symptomatic multiple myeloma (NDMM) based on standard IMWG (International Myeloma Working Group) criteria:
- Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following CRAB features and myeloma-defining events:
- 1.1) Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically
- 1.1.1) Hypercalcemia: serum calcium >0.25 mmol/L (>1mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11mg/dL)
- 1.1.2) Renal insufficiency: creatinine clearance (CLcr)<40 mL per minute (measured or estimated by validated equations) or serum creatinine > 177 µmol/L (>2mg/dL)
- 1.1.3) Anemia: hemoglobin value of >20g/L below the lower limit of normal, or a hemoglobin value <100g/L
- 1.1.4) Bone lesions: one or more osteolytic lesion 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
- 1.2) Any one or more of the following biomarkers of malignancy:
- 1.2.1) 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)
- 1.2.2) 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)
- 1.2.3) >1 focal lesion detected by MRI (magnetic resonance imaging) studies (each focal lesion must be 5 mm or more in size
- According to physician’s opinion, patients can undergo either one of the two standard treatments and procedures
- Females of childbearing potential (FBCP) must use an effective contraceptive method for 28 days before the study treatment, during the treatment and for at least 3 months after the last dose of study drugs
- Male subjects must use an effective barrier method if sexually active with FCBP during treatment and for at least 6 months after the last dose of study drug
- Patients should be ineligible for ASCT, defined as: - ≥ 65 years old; - younger than 65 years but who reject the transplant procedure or with abnormal cardiac, pulmonary, hepatic and renal function defined as: • LVEF (left ventricular ejection fraction) < 40%; • FEV1 (forced expiratory volume-1 second) < 40%; • Bilirubin > 1.5 UNL, AST/ALT >2.5 UNL; • Creatinine clearance < 60 mL/min.
Exclusion Criteria
- Hypersensitivity to any active substance or to any of the excipients (lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, boron, mannitol, nitrogen, crospovidone, colloidal anhydrous silica, hypromellose, titanium dioxide, macrogol, talc, sodium starch glycolate, sodium benzoate, propylene glycol, sodium dihydrogen phosphate, hydroxypropyl beta cyclodextrin, sodium saccharin, sodium EDTA, sodium hydroxide, L-histidine, L-histidine hydrochloride monohydrate, L-methionine, polysorbate 20, sorbitol (E420), recombinant human hyaluronidase (rHuPH20))
- Hereditary intolerance to fructose
- Pregnant and lactating women
- FBCP that do not follow the Pregnancy Prevention Plan requirements
- Acute diffuse infiltrative pulmonary and pericardial disease
- Acute viral infections (e.g. herpes simplex or ocular herpes simplex, herpes zoster, varicella)
- Systemic mycotic or bacterial infections, unless specific anti-infectious therapy is ongoing
- Peptic ulcer
- Psychosis
- Administration of prophylactic vaccine from 8 to 2 weeks before starting treatment
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Recruiting | 01 May 2018 | 450 |
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 |
|---|---|---|---|---|---|---|
Revlimid 20 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 25 | 46 | PRD9264267 |
Revlimid 15 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 25 | 46 | PRD9264282 |
VELCADE 3.5 mg powder for solution for injection | Test | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 1.3 | 54 | PRD3349073 |
Revlimid 10 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 25 | 46 | PRD9264283 |
DARZALEX 20 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 16 | 70 | PRD4091122 |
Revlimid 2.5 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 25 | 46 | PRD9264285 |
ALKERAN 2 mg Compresse rivestite con film | Test | COMPRESSE RIVESTITE CON FILM | ORAL USE | 9 | 54 | PRD981238 |
Revlimid 25 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 25 | 46 | PRD9264271 |
DARZALEX 20 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 16 | 70 | PRD6808129 |
Revlimid 5 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 25 | 46 | PRD9264284 |