Nonmyeloablative Allogeneic Stem Cell Transplant Followed by Bortezomib in High-risk Multiple Myeloma Patients
Nonmyeloablative Allogeneic Stem Cell Transplant Followed by Bortezomib in High-risk Multiple Myeloma Patients
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.
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.
Inclusion Criteria:

 -  Age 18 to 65 years, inclusively

 -  Newly diagnosed multiple myeloma patients (according to IMWG criteria) with measurable
 disease at diagnosis, based on presence of any of the following:

 1. Serum intact immunoglobulin ≥ 10 g/L;

 2. Bence-Jones proteinuria ≥ 200 mg/day;

 3. Serum free light chain (sFLC) assay ≥ 100 mg/L (difference between involved and
 uninvolved FLC levels) and an abnormal sFLC ratio

 -  High-risk patients presenting any of the following:

 1. International Staging System (ISS) III;

 2. del(17p13), t(4;14) with ISS II or III, t(14;16), t(14;20) and chromosome 1
 abnormalities by FISH. At this time, there is no international consensus on the
 threshold to consider these cytogenetic abnormalities as significant. For this
 study, investigators will consider arbitrarily a percentage ≥ 10% as significant.

 3. Plasma cell leukemia,defined as an absolute blood plasma cell count > 2 x 109/L
 and the presence of > 20% plasma cells among peripheral blood white cells;

 4. Patients ≤ 50 years, regardless of cytogenetics or ISS stage

 -  Having received a Bortezomib-containing regimen (VTD, CyBorD, VRD or PAD [in patients
 with PCL]) for a minimum of 4 cycles with ≥ PR.

 -  Received high-dose Melphalan ≥ 140 mg/m2 followed by autologous stem cell
 transplantation.

 -  Available HLA-identical sibling donor or 8/8 allele matched (HLA-A, -B, -C, -DR)
 matched unrelated donor

 Exclusion Criteria:

 -  Failure to achieve at least PR with a Bortezomib-based induction therapy.

 -  Progressive disease at any time

 -  Having received tandem autologous stem cell transplantation.

 -  Having received maintenance or consolidation therapy with Bortezomib after ASCT. If
 delays to allogeneic transplant are expected, Lenalidomide at 10 mg die for a maximum
 of three months will be allowed after ASCT (initiated after day +90) and discontinued
 at least 14 days before the start of the conditioning regimen.

 -  Karnofsky score < 70% or comorbidity index HCT-CI > 3.

 -  Bilirubin > 2 x upper limit of normal (ULN) unless felt to be related to Gilbert's
 disease or hemolysis; AST and ALT > 2.5 x ULN; alkaline phosphatase > 5 x ULN.

 -  Peripheral neuropathy or neuropathic pain ≥ grade II.

 -  Poor organ function

 -  Known hypersensitivity to boron, mannitol or Bortezomib.

 -  Active infection with any of the following viruses: HIV, HTLV-1 or 2, hepatitis B
 (defined as HBsAg positivity) or hepatitis C (defined as anti-HCV positivity or
 HCV-RNA positivity).

 -  Presence of another malignancy with an expected survival estimated < 75% at 5 years
 (complete resection of basal cell carcinoma or squamous cell carcinoma of the skin,
 complete resection of a ductal carcinoma in situ of the breast, presence of lobular
 carcinoma in situ of the breast, complete resection of carcinoma in situ of the
 cervix, or an in situ or low-risk prostate cancer after curative therapy are not
 exclusion criteria).

 -  Positive β-hCG pregnancy test. Female study participants who are surgically sterile
 (hysterectomy) or who have been postmenopausal for at least 12 consecutive months are
 automatically eligible for this criterion.

 -  Study participants not agreeing to remain abstinent or to practice double-barrier
 forms of birth control from trial screening through 90 days from the last dose of
 Bortezomib.

 -  Women who are lactating.

 -  Women of childbearing potential who are planning to become pregnant while enrolled in
 this study up to 30 days after the last Bortezomib injection.

 -  Participation in a trial with an investigational agent within 30 days prior to entry
 in the study.

 -  Inability to provide written informed consent prior to initiation of any study-related
 procedures, and inability, in the opinion of investigators, to comply with all
 requirements of the study

 -  Estimated probability to survive less than 6 months after allogeneic transplant.

 -  Suspicion of cardiac amyloidosis.

 -  Current history of drug and/or alcohol abuse.