A Phase 2 interventional study of Daratumumab (Intravenously) with VRd (Bortezomib, Lenalidomide, and Dexamethasone) in Newly Diagnosed Multiple Myeloma (NDMM), sponsored by Tata Memorial Centre. Recruiting at 2 sites in India. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-10-23.
Sponsored by Tata Memorial Centre · Phase 2, Interventional, and Treatment
The goal of this clinical trial is to evaluate whether a modified (less frequent) dosing schedule of daratumumab, when added to standard VRd therapy, can be an effective induction regimen for treating newly diagnosed multiple myeloma (NDMM).
The main questions it aims to answer are:
Treatment regimen Daratumumab (Dara), Bortezomib, Lenalidomide, and Dexamethasone will be given together for four cycles of induction therapy
Duration of each cycle will be 28 days
Response Assessment
2a. Primary Objective
The primary objective is to determine if the addition of a modified (less frequent) daratumumab schedule to VRd will increase MRD negativity at end of four cycles of induction (compared to historical data with VRd alone)
2b. Secondary Objective(s)
To evaluate time to engraftment post-ASCT
2c. Exploratory objective
To measure immune cell subsets
3. Intervention
Patients will receive 4 cycles of Dara-VRd induction, with daratumumab administered as follows: Day 1, 15 , 29 , 50 , 71 , and 92 . Each 28-day cycle also includes weekly bortezomib (1.3 mg/m² SC/IV), lenalidomide (15-25 mg OD on days 1-21), and dexamethasone (40 mg weekly).
Following induction, transplant-eligible patients will proceed to autologous stem cell transplant (ASCT), while transplant-ineligible patients will continue VRd to a total of 9-12 cycles, followed by maintenance.
4. Sample size - 52 patients
5. Duration of study - 4 years
6. Statistical Analytical Plan
A. Analysis for MRD negativity, response, safety and PFS
Data will be tabulated in Microsoft-Excel sheet, and analyzed using SPSS v23.0. Data will be analyzed descriptively. MRD negativity rate and 95% CIs will be calculated using the Clopper-Pearson method. PFS will be analyzed using the Kaplan-Meier method. PFS will be defined as the time from the date of initiation of induction therapy to the date of disease progression or death due to any cause, whichever occurs first. Safety analyses will be performed in all patients who had received at least one dose of study treatment (safety population). Association between MRD and exploratory subgroups (standard vs high risk cytogenetics) will be assessed using Fisher's exact test. Summary statistics will be provided for clinical and demographic characteristics and for adverse events.
B. Pharmacokinetic analysis
Pharmacokinetic model: The pharmacokinetic analysis will utilize a previously validated two-compartment model to characterize daratumumab behavior in the body, incorporating both linear clearance, which accounts for nonspecific IgG clearance, and Michaelis-Menten elimination, which captures saturable target-mediated clearance mechanisms. This model will account for interindividual variability (IIV) in clearance and volume of distribution. The concentration-time data collected according to the pharmacokinetic sampling plan will be fitted to this model. The population pharmacokinetic analysis will be performed using a nonlinear mixed-effect model approach with Pumas software (Version 2.5.1; MD, USA).
Covariates: The covariates with biological/physiological importance will be tested in a stepwise fashion. Covariate effects will be assessed for statistical significance using asymptotic 95% confidence intervals (CIs). Model-predicted PK exposure metrics will be generated for subgroup analyses based on relevant covariates.
Model evaluation: Goodness-of-fit plots will be evaluated with visual inspection of the following diagnostic scatter plots- population predicted concentrations (PRED) versus observed concentrations (DV), individual predicted concentrations (IPRED) versus DV and time after dosing versus weighted residuals (WRES). The nonparametric bootstrap resampling technique will be adopted to validate the reliability and stability of the final model. The stability and performance of the final model will be assessed using a visual predictive check (VPC).
Exposure-response evaluation: In terms of efficacy, responders will be defined as patients achieving MRD negativity. Safety evaluations will focus on grade ≥3 treatment-emergent AEs (TEAEs). Relationships between daratumumab exposure measures (AUC / maximum concentration (C max) and maximum trough concentration (C trough-max) and MRD negativity / AEs will be explored using exposure quartiles.
C. Immune-cell subset analysis
Continuous data will be presented as mean/median/SD and categorical data as frequencies and proportions. The quantitative differences between the continuous variables such as immune cell subsets in MM patients against categorical parameters such as cytogenetics, and MRD status, will be evaluated using the Mann-Whitney-U test. The association of immune cell parameters with negative or positive MRD will be evaluated using the odds ratio (OR). A two-sided P value less than 0.05 will be considered statistically significant.
272 studies on the registry are indexed under Neoplasm, Residual; 124 are open to participants now.
This study's planned enrollment of 52 is close to the median of 50 across 173 interventional studies indexed under Neoplasm, Residual.
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Exclusion Criteria
Four cycles of induction Each cycle - 28 days Components of induction regimen 1. Less frequent daratumumab schedule as per Daratumumab: 16 mg/kg IV (Day1, Day 15, Day 29, Day 50, Day 71, Day 92) 2. Bortezomib: 1.3 mg/m² SC or IV, weekly 3. Lenalidomide: 15-25 mg orally, daily for 21 of 28 days 4. Dexamethasone: 40 mg weekly, orally or IV
Drug: Daratumumab (Intravenously) with VRd (Bortezomib, Lenalidomide, and Dexamethasone)
This arm includes newly diagnosed multiple myeloma (NDMM) patients who meet all inclusion and exclusion criteria. Patients will be administered 4 cycles of Dara-VRd induction. Each cycle will be of 28 days month. In each Dara-VRd cycle, Daratumumab will be administered at a dose of 16 mg/kg intravenously (Day1, Day 15, Day 29, Day 50, Day 71, Day 92), Bortezomib will be given weekly at a dose of 1.3 mg/m2 subcutaneous or intravenous, Lenalidomide will be given at a dose of 15-25 mg OD (21 days out of 28 days), and Dexamethasone 40mg once weekly - oral or intravenous.
Post-induction MRD negativity rate
Proportion of participants achieving measurable (minimal) residual disease (MRD) negativity at the end of four cycles of induction therapy with daratumumab, bortezomib, lenalidomide, and dexamethasone (Dara-VRd). MRD negativity will be assessed
Time frame: At the end of Cycle 4 (each induction cycle is 28 days; MRD assessed within 2 weeks after completion of Cycle 4 [approximately Days 113-127]
Overall Response Rate (ORR) and ≥Complete Response (≥CR) Rate After Four Cycles of Induction
ORR (defined as the proportions of subjects who achieved PR or better) and ≥CR (as per the IMWG criteria) After 4 cycles post-induction
Time frame: At the end of Cycle 4 (each induction cycle is 28 days; response assessed between Days 107 and 112).
Overall Response Rate (ORR) and ≥Complete Response (≥CR) Rate Day 100 (±15 days) post-transplant
ORR (defined as the proportions of subjects who achieved PR or better) and ≥CR (as per the IMWG criteria) at day100 (± 15 days) post-transplant
Time frame: Day 100 (±15 days) following autologous hematopoietic stem cell transplant
Progression-Free Survival (PFS)
Progression-free survival (PFS), defined as the time from treatment initiation to documented disease progression or death from any cause, whichever occurs first.
Time frame: From treatment initiation through 2 years of follow-up.
Incidence of Grade ≥3 Adverse Events
Incidence of treatment-emergent Grade 3 or higher adverse events, as assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 5.0.
Time frame: Up to 4 weeks after the last dose of study treatment.
Minimal residual disease (MRD)Negativity at Day 100 (±15 Days) Post-Autologous Stem Cell Transplantation (ASCT)
Proportion of participants who achieve measurable (minimal) residual disease (MRD) negativity at Day 100 (±15 days) following autologous stem cell Transplantation (ASCT), as assessed using the protocol-specified validated MRD assay
Time frame: Day 100 (±15 days) following autologous stem cell transplantation (ASCT).
Sustained MRD negativity
Sustained MRD negativity (1-year apart) in patients who do not undergo ASCT
Time frame: 1 year apart (non-ASCT pts)
pharmacokinetics (pK) of daratumumab
To evaluate pharmacokinetics (pK) of daratumumab The Pharmacokinetic study will be carried out during the 1st, 3rd and 6th dose of daratumumab. Its time points are 1st dose (day 1): Pre-dose, end of infusion (EOI), EOI + 2 h, EOI + 5 h, and EOI + 24 h; any time during days 4 and 8; before the second pre-dose (day 15). 3rd dose (day 29): Pre-dose, end of infusion (EOI), EOI + 24 h; any time during days 36 and 43. 6th dose (day 92): Pre-dose, end of infusion (EOI), EOI + 24 h; any time during days 99 and 106.
Time frame: From Day 1 (first daratumumab dose) through Day 106 (completion of PK sampling after the sixth daratumumab dose).
Stem-cell yield after mobilization
Proportion of participants who achieve a stem cell collection yield of ≥5 × 10⁶ CD34+ cells/kg body weight following mobilization with granulocyte colony-stimulating factor (G-CSF) and plerixafor.
Time frame: During stem-cell mobilization and collection, up to 6 months after completion of four cycles of induction therapy and prior to ASCT.
Time to Engraftment Following Autologous Stem Cell Transplantation (ASCT)
Time from autologous stem cell transplantation (ASCT) to hematopoietic engraftment, defined as the first day of achieving an absolute neutrophil count (ANC) ≥0.5 × 10⁹/L and a platelet count ≥20 × 10⁹/L without platelet transfusion support, according to institutional criteria.
Time frame: From the date of autologous stem cell transplantation (ASCT) until hematopoietic engraftment, assessed up to approx day 30 days after ASCT.
Plan to share: No — The information in the study records will be kept confidential. The study participant's personal information will not be shared with any other parties unless explicit written consent is provided. No reference will be made in oral or written reports which could link study participant to the study. The clinical charts will be housed in the medical records department at ACTREC TMC. Data will be stored securely for a period of five years and will be made available only to persons conducting the study and to the regulatory authorities. Result of the study will not be communicated to the participant unless deemed necessary.
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