Last updated on July 2019

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


Brief description of study

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.

Detailed Study Description

INDUCTION AND CONSOLIDATION REGIMEN:

Arm Dara-VCd:

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 subcutaneous (SC) injection on days 1, 8,15, 22; Cyclophosphamide: 300 mg/ m2 given orally or by 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. After induction all patients will be given Cyclophosphamide at the dose of 3 g/m2, followed by Granulocyte Colony-Stimulating Factor (G-CSF) for stem cell collection. Cyclophosphamide will start 4-6 weeks after start of the fourth cycle of therapy.

Stem cell collection will be performed as soon as CD34+ cells are present in peripheral blood, which is usually between 9-14 days after first day of Cyclophosphamide. Stem cells will be harvested at a minimum of 4 x 106 CD34+ cells/kg and cryopreserved. In case insufficient stem cells are collected the procedure may be repeated or alternatively bone marrow stem cell collection may be performed or Plerixafor may be used.

4-6 weeks after cyclophosphamide patients will be treated with High Dose Melphalan followed by autologous stem cell reinfusion according to the schedule below:

  • Melphalan 200 mg/ m day - 2 i.v. rapid infusion
  • Stem cell infusion Minimum of 2 x 10^6CD34+cells/kg day 0 90-120 days after Melphalan administration consolidation treatment will be administered: Daratumumab: 16 mg/Kg given by IV infusion on days 1, 15; Bortezomib: 1.3 mg/m2 given by SC injection on days 1, 8, 15, 22; Cyclophosphamide: 300 mg/ m2 given orally or by 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 2 4-week consolidation cycles.

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 4 4-week induction cycles. After induction all patients will be given Cyclophosphamide at the dose of 3 g/m2, followed by G-CSF for stem cell collection. Cyclophosphamide will start 4-6 weeks after start of the fourth cycle of therapy.

Stem cell collection will be performed as soon as cluster of differentiation 34 (CD34)+ cells are present in peripheral blood, which is usually between 9-14 days after first day of Cyclophosphamide. Stem cells will be harvested at a minimum of 4 x 106 CD34+ cells/kg and cryopreserved. In case insufficient stem cells are collected the procedure may be repeated by using also Plerixafor or alternatively bone marrow stem cell collection may be performed.

4-6 weeks after cyclophosphamide patients will be treated with High Dose Melphalan followed by autologous stem cell reinfusion according to the schedule below:

  • Melphalan 200 mg/ m day -2 i.v. rapid infusion
  • Stem cell infusion Minimum of 2 x 10^6CD34+cells/kg day 0 90-120 days after Melphalan administration consolidation treatment will be administered: 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 2 4-week consolidation cycles.

MAINTENANCE TREATMENT:

All patients in PR after consolidation will be randomized to receive:

Arm I Ixazomib 3 mg on days 1, 8, 15 of cycle 1-4, followed by ixazomib 4 mg on days 1, 8, 15 cycles from cycle 5*.

Repeat each cycle every 28 days. Patients will receive treatment until any sign of progression or intolerance, up to 24 months.

Arm II Ixazomib 3 mg on days 1, 8, 15 of cycle 1-4, followed by ixazomib 4 mg on days 1, 8, 15 cycles from cycle 5*.

Daratumumab 16 mg/kg on day 1. Repeat each cycle every 28 days. Patients will receive treatment until any sign of progression or intolerance, up to 24 months.

*The dose escalation is admitted only in case there have been no non-hematologic Adverse Events (AEs) Grade 2 related to study drug and no dose interruptions related to study drug toxicities.

Patients in the first randomization will be stratified according to fluorescent in situ hybridization (FISH) (standard/missing vs high risk, defined as del17, t 4;14, t 14;16) and International Staging System (ISS) (I vs II and III) Patients randomized to maintenance treatment will be stratified according to induction treatment and Minimal Residual Disease (MRD) status by nerve growth factor (NGF) (positive and not evaluable vs negative).

STATISTICAL DESIGN A total of 400 patients will be needed, in according to the study design, to provide a power of at least 85% to the statistical analysis with a two sided alpha error of 0.05 (see study protocol for details).

The statistical analysis will be performed in according to the intention to treat principle and will include summary of descriptive statistics (arithmetic mean and standard deviation, minimum and maximum, median with the interquartile range as appropriate) for continuous variables, absolute frequencies and percentages will be reported for qualitative variables. 95% Confidence intervals will be provided for variables subjected to statistical inference.

Proportions will be compared between treatment groups by use of the chi-square test or Fisher's exact test.

Kaplan-Meier method will be used for survival analyses to estimate and compare survival outcomes.

The log-rank test will be adopted to compare survival curves. Multivariable analysis, using semi parametric Cox proportional hazard regression model, will be performed to assess factors significantly affecting the progression free survival.

The safety analysis will include all patients randomized who will receive at least one dose of study treatment and the toxicity will be compared between treatment groups with chi-squared test.

All tests will be considered significant with p values less than 0.05.

Clinical Study Identifier: NCT03896737

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