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A Phase 3, Prospective, Randomized Clinical Study of VELCADE-Thalidomide-Dexamethasone (VTD) Versus Thalidomide-Dexamethasone (TD) for Previously Untreated Multiple Myeloma (MM) Patients Who Are Candidates to Receive Double Autologous Transplantation

Phase 3
18 Years
65 Years
Open (Enrolling)
Multiple Myeloma

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Trial Information

A Phase 3, Prospective, Randomized Clinical Study of VELCADE-Thalidomide-Dexamethasone (VTD) Versus Thalidomide-Dexamethasone (TD) for Previously Untreated Multiple Myeloma (MM) Patients Who Are Candidates to Receive Double Autologous Transplantation

This prospective phase 3 trial is aimed at evaluating whether, in comparison with standard
TD, addition of Velcade to TD increases rate of CR and nCR from 15% to 30%, respectively.
For this purpose, symptomatic patients aged 18-65 years with previously untreated MM and
quantifiable M-protein in serum or urine are randomized (1:1) to receive induction therapy
comprising three 3-week cycles of Velcade 1.3 mg/sqm, days 1, 4, 8, 11, thalidomide 100 mg,
days 1-14, cycle 1, then 200 mg daily, and dexamethasone 40 mg, days 1, 2, 4, 5, 8, 9, 11,
12, or thalidomide and dexamethasone (same schedule and dosage as in VTD). Randomization to
VTD or TD is stratified according to International Staging System disease stage at
diagnosis. Following induction therapy, patients in both arms receive cyclophosphamide (4
g/sqm, day 0 and granulocyte colony-stimulating factor, 10 μcg/kg/day, from day +2) to
collect autologous peripheral blood stem cells (minimum threshold CD34+ cells: 4 x 10^6/kg)
and two subsequent courses of stem cell-supported high dose melphalan (200 mg/sqm), 3 to 6
months apart. Upon neutrophil (≥1 x 10^9/L) and platelet (≥75 x 10^9/L) recovery following
the first autotransplantation, patients receive thalidomide (100 mg daily) and dexamethasone
(40 mg, days 1-4 every 4 weeks) as bridge therapy until the day before the second

Patients initially randomized to receive VTD or TD induction therapy are planned to receive
two 5-week cycles of VTD (Velcade 1.3 mg/sqm, days 1, 8, 15, 22; thalidomide 100 mg daily;
dexamethasone 40 mg, days 1, 2, 8, 9, 15, 16, 22, 23) or TD (thalidomide 100 mg daily;
dexamethasone 40 mg, days 1-4 and 20-23) as consolidation therapy, starting 3 months after
last transplant. Maintenance therapy comprise dexamethasone 40 mg, days 1-4, repeated
monthly until relapse or progression.

Inclusion Criteria

Inclusion criteria:

- Confirmed diagnosis of symptomatic MM based on standard criteria.

- No prior or current systemic therapy for MM, including steroids.

- At least 18 years and less than 65 years of age.

- Presence of quantifiable M protein in serum (e.g. greater than 1 g/dL for IgG MM,
greater than 0.5 g/dL of IgA or IgD MM) or urine (e.g. greater than 200 mg/day for BJ

- Karnofsky performance status (PS) at least 60%.

- Willing and able to comply with the protocol requirements.

- Agreement from both male and female patients to follow the risk management program
established for the prevention of pregnancy, including double methods for
contraception and beta-HCG tests for women of childbearing potential and
contraception for males.

- Adequate organ function, including heart, liver, kidney (serum creatinine less than 2

- Platelet count at least 70 x 10/mcL and absolute neutrophil count at least 1 x 10/mcl

Exclusion criteria:

- Diagnosis of asymptomatic MM or of MGUS based on standard criteria.

- Diagnosis of non-secretory MM.

- Diagnosis of AL Amyloidosis.

- Prior or current systemic therapy for MM, including steroids (with exception of

- Patient has received other investigational drugs within 30 days before enrollment.

- Female subjects pregnant or breastfeeding

- Patient has Grade 2 or higher peripheral neuropathy (NCI criteria).

- Patient has a prior history of thrombosis or venous thromboembolism or pulmonary

- Patient has a previous diagnosis of antiphospholipid antibodies or lupus
anticoagulant, factor V Leiden mutation, prothrombin G21210A mutation, antithrombin,
protein C or S deficiency.

- Patient has a clear indication to receive a specific other anti-platelet therapy
(e.g. clopidogrel, ticlopidine).

- Patient has a clear indication to receive long-term anticoagulant therapy (e.g.
prosthetic heart valve, atrial fibrillation).

- Active bleeding or high risk of bleeding (gastrointestinal bleeding within the past
12 months; endoscopic diagnosis of peptic ulcer disease or ulcerative esophagitis
within the past 6 months unless there is documented endoscopic evidence of healing;
intracranial bleeding within the past year; amyloidosis; known bleeding diathesis).

- Seropositive for HIV, or active hepatitis A, B or C infection.

- Poorly controlled hypertension or diabetes mellitus (if receiving antidiabetic
agents, subjects must be on a stable dose for at least 3 months before the start of
therapy) or other serious medical or psychiatric conditions that could interfere with
adherence to or completion of this study.

- Patient has hypersensitivity to bortezomib, boron or mannitol.

- Serious medical or psychiatric illness likely to interfere with participation in this
clinical study

- Previous or concurrent malignancies at other sites, with the exception of
appropriately treated localized epithelial skin or cervical cancer. Patients with
remote histories (>5 years) of other cured tumors may be entered.

- Receipt of extensive radiation therapy, systemic chemotherapy, or other
antineoplastic therapy within 4 weeks before enrolment.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Rate of CR+nCR to induction treatment

Outcome Description:

Responses to induction therapy were reported by study investigators and centrally reassessed by study coordinator(s). Criteria are those initially proposed by the European Group for Blood and Marrow Transplantation (EBMT), with the addition of nCR (100% M-protein reduction by electrophoresis, but immunofixation-positive) and very good partial response (VGPR) (at least 90% serum and urine M-protein reduction) categories. Comparisons of response rates between treatment arms are performed using Fisher's exact test.

Outcome Time Frame:

63 days after the start day of either TD or VTD as induction therapy

Safety Issue:


Principal Investigator

Michele Cavo, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Azienda Ospedaliera Universitaria di Bologna Policlinico S. Orsola Malpighi


Italy: Ethics Committee

Study ID:




Start Date:

May 2006

Completion Date:

December 2015

Related Keywords:

  • Multiple Myeloma
  • autologous stem cell transplantation
  • complete remission
  • bortezomib
  • thalidomide
  • progression free survival
  • induction and consolidation therapy
  • Multiple Myeloma
  • Neoplasms, Plasma Cell