Nonmyeloablative Allogeneic Stem Cell Transplant Followed by Bortezomib in High-risk Multiple Myeloma Patients
Condition: Multiple Myeloma; High-Risk Cancer
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Study type: Interventional
Phase: Phase 2

Summary: 
      Multiple myeloma is a morbid disease associated with a poor outcome, particularly those with
      high-risk cytogenetics. While standard therapies have modestly improved survival in these
      high-risk patients, myeloma remains incurable. To date, the only potential curative treatment
      remains allogeneic hematopoietic stem cell transplantation. However, the high incidences of
      toxicities including chronic GVHD and disease progression are currently the two most
      important obstacles to this therapy. Better approaches to maintain and improve benefits of
      allogeneic transplant, while decreasing toxicity, are urgently needed.

      The investigators hypothesize that Bortezomib administration after non myeloablative
      allogeneic hematopoietic stem cell transplantation in high-risk myeloma patients might
      improved the outcome of these patients by decreasing myeloma relapse and the severity of
      chronic GVHD while preserving the graft-versus-myeloma effect. Our goal is to improve the
      poor clinical outcome of high-risk myeloma patients.
    

Detailed description: 
      To date, the only potential curative treatment for multiple myeloma remains allogeneic
      hematopoietic stem cell transplantation. Achievement of remission in myeloma patients
      allotransplanted with advanced disease, achievement of complete response in relapsed patients
      following infusion of donor leucocyte infusions, decreased incidence of relapse associated
      with chronic GVHD, better survival in myeloma patients who have relapsed after allogeneic
      transplant with rescue medication and production of an allo-immune response after allogeneic
      transplant, all support the existence of a graft-versus-myeloma effect. However, chronic GVHD
      participating to the morbidity and mortality of allogeneic transplantation, in addition to
      the significant relapse rate despite the transplantation are two important obstacles to this
      therapeutic modality in myeloma.

      Bortezomib (VelcadeTM) is a dipeptidyl boronic acid-based reversible proteasome inhibitor.
      Several mechanisms of action have been proposed for its effects against multiple myeloma:
      direct induction of myeloma cells apoptosis, inhibition of NF-κB activation, reduction of
      myeloma cells adherence to the bone marrow microenvironment (decreasing drug resistance),
      inhibition of production, secretion and intracellular signalling of myeloma-mediators. It is
      one of the most effective drugs in the treatment of multiple myeloma. As consolidation
      treatment after autologous stem cell transplantation, the drug has been associated with an
      improvement in response rate and more importantly, in quality and depth of response.
      Maintenance treatment with Bortezomib after autologous transplantation has led to survival
      improvement, a benefit particularly obvious in myeloma patients with high-risk cytogenetics
      such as those carrying del(17p13).

      In addition to its anti-myeloma properties, Bortezomib has immunomodulatory effects. Indeed,
      proteasome inhibitors affect several aspects of immune and inflammatory responses by
      interfering with antigen presenting cell function and effector cell function. Given its
      immunomodulatory properties, Bortezomib has recently been shown to be safe and effective in
      HLA-mismatched reduced-intensity conditioning transplantation as a GVHD prophylaxis.

      This is a prospective phase II, open label, single institution study evaluating a novel
      treatment strategy in newly diagnosed multiple myeloma patients with high-risk disease or
      patients ≤ 50 years old. After an optimal Bortezomib-based induction treatment (VTD, CyBorD,
      RVD or PAD [in patients with plasma cell leukemia]) for a minimum of 4 cycles, followed by
      Melphalan ≥ 140 mg/m2 and autologous stem cell transplantation, eligible patients who accept
      to participate will be included in the study.

      Within 6 months of autologous transplantation, patients will receive a non myeloablative
      allogeneic transplantation. Patients with a 6/6 compatible sibling donor will receive a
      conditioning regimen with Fludarabine 30 mg/m2 and Cyclophosphamide 300 mg/m2 per day for 5
      days from day -8 to day -4 with 3 rest days before donor stem cell infusion on day 0.
      Patients without a sibling donor who have an 8/8 allele matched unrelated donor will receive
      a conditioning regimen of Fludarabine 30 mg/m2 per day for 3 days from day -4 to -2 and TBI 2
      Gy on day -1 with donor stem cell infusion on day 0.

      In sibling transplant recipients, GVHD prophylaxis will consist of Tacrolimus 3 mg p.o. BID
      starting on day -8, adjusted thrice weekly to obtain blood levels between 8-12 ng/mL.
      Tacrolimus tapering will start day +50 to be completed by day +100 in the absence of GVHD. In
      matched unrelated donor recipients, Tacrolimus will be initiated as in siblings, but started
      on day -4, and taper will be initiated on day +100 to be completed by day +180 in the absence
      of GVHD. MMF 15 mg/kg p.o. BID will be given from day +1 to +50 in sibling recipients. It
      will be given at same dose but TID from day +1 to +40, then tapered gradually until day +100
      in matched unrelated donor recipients. Patients without progressive disease after allogeneic
      transplantation will receive Bortezomib 1.3 mg/m2 s.c. every 14 days ± 3 days starting on day
      +120, for a total of 26 doses (1 year treatment).

      Patients will be followed regularly for disease evaluation, using the IMWG criteria. Toxicity
      will be evaluated using the NCI common terminology criteria for adverse events (CTCAE)
      version 4.0. Occurrence and severity of acute GVHD will be evaluated using the modified
      Glucksberg criteria. Chronic GVHD will be evaluated using the NIH criteria. The trial will be
      terminated when all patients have been followed for 5 years after allogeneic hematopoietic
      stem cell transplantation.
    

Intervention name(s): Bortezomib following nonmyeloablative allogeneic transplant
Intervention type(s): Drug
Intervention description(s): Bortezomib 1,3 mg/m2 subcutaneously every 2 weeks for 1 year (26 injections) starting on day +120 from a non myeloablative sibling or 10/10 unrelated allogeneic transplantation
Other intervention name(s): Velcade
Intervention MeSH terms: Bortezomib
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: High-risk myeloma; Non myeloablative allogeneic transplantation; Bortezomib