Daratumumab-bortezomib-dexamethasone (Dara-VCd) vs Bortezomib-Thalidomide-Dexamethasone (VTd), Then Maintenance With Ixazomib (IXA) or IXA-Dara

NCT03896737 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: EMN18
• Study Type: interventional
• Target: 401
• Locations: 3 countries
• Sites: 3

Brief Summary

This protocol is a phase II multicenter, randomized, open label study designed to assess the efficacy and safety of daratumumab combined with bortezomib, cyclophosphamide and dexamethasone (Dara-VCd) versus the association of bortezomib, thalidomide and dexamethasone (VTd) as pre transplant induction and post transplant consolidation, followed by maintenance with ixazomib alone or in combination with daratumumab, in newly diagnosed multiple myeloma (MM) patients eligible for autologous stem cell transplantation. Patients enrolled in the Dara-VCd arm will receive: 4 cycles of daratumumab-bortezomib-cyclophosphamide-dexamethasone induction, followed by transplantation and 2 cycles of daratumumab-bortezomib-cyclophosphamide-dexamethasone consolidation. The choice of cyclophosphamide in combination with bortezomib and dexamethasone is suggested by the better safety profile of cyclophosphamide, in comparison with thalidomide and the efficacy of the alkylator agent, when combined with bortezomib. Once-weekly bortezomib seems to be equally effective and better tolerated than the standard twice weekly schedule. The outcomes and response rate did not appear to be affected by the bortezomib dosing schedule. Patients enrolled in the VTd arm will receive: 4 cycles of bortezomib-thalidomide-dexamethasone induction, followed by autologous transplantation and 2 cycles of bortezomib-thalidomide dexamethasone as consolidation. The VTd drug association is the current standard first line induction therapy for multiple myeloma patients who are eligible to stem cell transplantation. At the end of consolidation phase patients with at least a partial response (≥ PR) will be rerandomized (assigned by chance) to one of 2 treatment groups to receive maintenance treatment with ixazomib alone or in combination with daratumumab. Patients will receive treatment until any sign of progression or intolerance, up to 24 months.

Conditions

Multiple Myeloma

Keywords

diagnosis; elderly; autologous stem cell transplantation

Outcome Measures

Primary Outcomes (2)

• Progression free survival (PFS)

  PFS in part 1 and part 2 of the study will be measured from the date of first or second randomization to the date of first observation of disease progression or death to any cause as an event. Subjects who withdraw from the study will be considered censored at the time of the last complete disease assessment. Subjects who complete the study, have no progressed, and are still alive at the cut-off date of final analysis will be censored at the cut-off date. All subjects who were lost to followup prior to the end of the study have no progressed, and are still alive will also be censored at the time of last contact.

  5 years

• MRD negativity

  MRD evaluation by clonotypic analysis of Immunoglobulin heavy chain (IgH) Variable-Diversity-Junctional (VDJ) gene rearrangement will be performed on bone marrow (BM) samples obtained by the end of induction and consolidation and thereafter every 6 mm after the first maintenance treatment dose. The Clonal Sequencing (ClonoSEQTM) assay (Adaptive Biotechnologies, Seattle) will be used at sensitivity thresholds of 10-3 (1 cancer cell per 1,000 nucleated cells), 10-4 and \>/= 10-5. The rate of MRD negativity in each of the treatment arms of study protocol is determined as the proportion of patients with MRD negativity (\>/=10-5 sensitivity level) at any established treatment point. Patients who withdraw from the study or are lost to Follow-up (FU) will be considered censored a t the time of the last MRD assessment. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment.

  5 years

Secondary Outcomes (7)

• Overall response rate (ORR)

  5 years

• Progression free survival 2 (PFS2)

  5 years

• Duration of response (DoR)

  5 years

• Overall survival (OS):

  5 years

• Time to the next anti-myeloma therapy (TNT)

  5 years

Study Arms (2)

Dara-VCd

EXPERIMENTAL

treatment period includes administration of four 28-day cycles of induction with Dara- VCd; then patients will undergo transplant and finally they will receive two 28-day cycles of Dara-VCd consolidation treatment. The response will be assessed after each cycle. Patients in the first randomization will be stratified according to FISH (standard/missing vs high risk,defined as del17, t 4;14, t 14;16) and ISS (I vs II and III). TREATMENT SCHEMA - INDUCTION Daratumumab: 16 mg/Kg given by IV infusion on days 1, 8, 15, 22, on cycles 1-2 and on days 1, 15 on cycles 3-4. Bortezomib: 1.3 mg/m2 given SC injection on days 1, 8,15, 22; Cyclophosphamide: 300 mg/ m2 given orally or IV infusion on days 1, 8, 15, 22; Dexamethasone: 40 mg given orally or by IV infusion on days 1, 8, 15,22 Repeat for four 4-week induction cycles.

Drug: Daratumumab plus Velcade Cyclophosphamide Dexamethasone

VTd

ACTIVE COMPARATOR

treatment period includes administration of four 28-day cycles of induction with VTd; then patients will undergo transplant and finally they will receive two 28-day cycles of VTd consolidation treatment. TREATMENT SCHEMA INDUCTION ARM VTd: Bortezomib: 1.3 mg/m2 given by SC injection on days 1, 4, 8, 11 of 28-day cycle; Thalidomide: 100 mg given orally on days 1-28. Dexamethasone: 20 mg given orally or by IV injection on days 1, 2, 3, 4, 8, 9, 10 and 11 of every 28-day cycle. Repeat for four 4-week induction cycles.

Drug: Velcade Thalidomide Dexamethasone

Interventions

Daratumumab plus Velcade Cyclophosphamide Dexamethasone DRUG

To compare Dara-VCd versus VTd as pre transplant induction and post transplant consolidation, both followed by a maintenance phase with Ixazomib alone or in combination with Daratumumab, in newly diagnosed Multiple Myeloma (MM) young patients eligible for autologous stem cell transplantation.

Dara-VCd

Velcade Thalidomide Dexamethasone DRUG

To compare Dara-VCd versus VTd as pre transplant induction and post transplant consolidation, both followed by a maintenance phase with Ixazomib alone or in combination with Daratumumab, in newly diagnosed Multiple Myeloma (MM) young patients eligible for autologous stem cell transplantation.

VTd

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient at least 18 years of age and ≤ 65 years.
• Patient eligible for autologous stem cell transplantation (ASCT).
• Left Ventricular Ejection Fraction (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:
• Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma
• Measurable disease as defined by at least one of the following:
• serum M-protein level ≥1 g/dL or urine M-protein level ≥200 mg/24 hours; or
• Light chain multiple myeloma: 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:
• 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 (CLcr)\<40 mL per minute (measured or estimated by validated equations) or serum creatinine \>177 μmol/L (\>2 mg/dL)
• Anaemia: haemoglobin value of \>20 g/L below the lower limit of normal, or haemoglobin value \<100 g/L
• 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

You may not qualify if:

• Patient with a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, smoldering MM or Plasma Cell Leukemia (PCL). 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 end-organ damage or amyloidosis. Plasma cell leukemia is defined as presence of circulating plasmacells (PCs) \>2×109/L in peripheral blood or a peripheral blood plasmacytosis \>20%
• Patient with a diagnosis of Waldenström's disease, or other conditions in which immunoglobulin M (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) 4.0.
• Patient is exhibiting clinical signs of meningeal involvement of multiple myeloma.
• Clinical active infectious hepatitis type A, B, C or HIV.
• Subject has known chronic obstructive pulmonary disease (COPD) (defined as a Forced Expiratory Volume In 1 second (FEV1) \<60% of predicted normal), persistent asthma, or a history of asthma within the last 2 years. 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.

Sponsors & Collaborators

• Stichting European Myeloma Network: lead
• EMN Trial Office S.r.l. Impresa Sociale: collaborator

Study Sites (3)

University Hospital Ostrava

Ostrava, 708 52, Czechia

Location

General Hospital of Athens "Alexandra"

Athens, 115 28, Greece

Location

A.O.U. Maggiore della Carità di Novara

Novara, 28100, Italy

Location

MeSH Terms

Conditions

Multiple Myeloma; Disease

Interventions

daratumumab

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Model Details: Dara-VCD versus VTd

Study Record Dates

• First Submitted: March 28, 2019
• First Posted: April 1, 2019
• Study Start: April 16, 2019
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): February 1, 2028
• Last Updated: August 11, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1); CZ (1); GR (1)