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Nonmyeloablative Allogeneic Stem Cell Transplant Followed by Bortezomib in High-risk Multiple Myeloma Patients

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ClinicalTrials.gov Identifier: NCT02308280
Recruitment Status : Active, not recruiting
First Posted : December 4, 2014
Last Update Posted : October 18, 2018
Sponsor:
Information provided by (Responsible Party):
Dr Richard LeBlanc, Maisonneuve-Rosemont Hospital

Brief 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.


Condition or disease Intervention/treatment Phase
Multiple Myeloma High-Risk Cancer Drug: Bortezomib following nonmyeloablative allogeneic transplant Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II, Open-label Study of Bortezomib Following Nonmyeloablative Allogeneic Stem Cell Transplant in Patients With High-risk Multiple Myeloma
Study Start Date : November 2014
Estimated Primary Completion Date : November 2019
Estimated Study Completion Date : November 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma
Drug Information available for: Bortezomib

Arm Intervention/treatment
Experimental: Bortezomib post-transplantation

Non myeloablative allogeneic transplantation followed by Bortezomib for 1 year after a Bortezomib-based induction and autologous stem cell transplantation.

Bortezomib: 1,3 mg/m2 subcutaneously every 2 weeks for 26 injections.

Drug: Bortezomib following nonmyeloablative allogeneic transplant
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 Name: Velcade




Primary Outcome Measures :
  1. Progression-free survival [ Time Frame: At 2 years after allogeneic transplantation ]
    Progression-free survival is defined as the duration from start of the treatment to disease progression or death (regardless of cause of death), whichever comes first. A 2- sided confidence interval for this proportion will be computed. Minimal residual disease results from negativity to positivity using flow cytometry will not be used to define progression.


Secondary Outcome Measures :
  1. Incidence of ≥ grade III non hematologic toxicity (including ≥ grade II peripheral neuropathy) and incidence of ≥ grade IV hematologic toxicity [ Time Frame: At each medical visit up to 5 years from allogeneic transplantation ]
    Non hematologic toxicity and hematologic toxicity will be graded according to CTCAE v.4.0.

  2. Cumulative incidence of grade I-IV and grade II-IV acute GVHD [ Time Frame: At day 100 days, 6 months and 1 year after allogeneic transplantation ]
    Acute GVHD will be graded according to modified Glucksberg criteria

  3. Cumulative incidences of chronic GVHD [ Time Frame: At 1 and 2 years after allogeneic transplantation ]
    Chronic GVHD will be evaluated according to NIH criteria

  4. Maximum grades of acute and chronic GVHD [ Time Frame: At each medical visit up to 5 years from allogeneic transplantation ]
    Acute and chronic GVHD evaluation will based on modified Glucksberg and NIH criteria, respectively

  5. Response rates and quality of responses [ Time Frame: Before allogeneic transplantation, before bortezomib, 1 year after bortezomib, then every 8 to 12 weeks up to 5 years from allogeneic transplantation ]
    Response categories will be assessed based on the IMWG criteria

  6. Nonrelapse mortality [ Time Frame: At 100 days and 2 years ]
    Nonrelapse mortality is defined as time to deaths without relapse or recurrence. Deaths from any cause without prior progression are events.

  7. Overall survival [ Time Frame: At 2 years ]
    Overall survival is defined as time to death, irrespective of the cause.

  8. Incidence of relapse [ Time Frame: At 2 years ]
    Relapse is defined as progression of the disease previously treated, based on the IMWG criteria.

  9. Minimal residual disease on bone marrow using multiparametric flow cytometry [ Time Frame: Before the allogeneic transplantation, before Bortezomib administration (day +120), at 3, 6, 9, 12, 15, 18, 21 and 24 months from day +120 of the allogeneic transplantation ]
    From ≥ 5 million events, specimens with less than 50 aberrant phenotype plasma cells will be considered as MRD negative

  10. Quality of life after allogeneic transplantation [ Time Frame: Evaluated before allogeneic transplantation, at 100 days from transplantation, before Bortezomib administration, then every 3 months up to 5 years from allogeneic transplantation ]
    Quality of life will be assessed prospectively by the EORTC QLQ-MY20, EORTC QLQ-C30 (version 3) and FACT-BMT (version 4) questionnaires



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02308280


Locations
Canada, Quebec
Hôpital Maisonneuve-Rosemont
Montreal, Quebec, Canada, H1T 2M4
Sponsors and Collaborators
Maisonneuve-Rosemont Hospital
Investigators
Principal Investigator: Richard LeBlanc, M.D. Hôpital Maisonneuve-Rosemont, affiliated to University of Montreal

Responsible Party: Dr Richard LeBlanc, Chair holder, Myeloma Canada Chair, Maisonneuve-Rosemont Hospital
ClinicalTrials.gov Identifier: NCT02308280     History of Changes
Other Study ID Numbers: HMR-MM-001
First Posted: December 4, 2014    Key Record Dates
Last Update Posted: October 18, 2018
Last Verified: October 2018

Keywords provided by Dr Richard LeBlanc, Maisonneuve-Rosemont Hospital:
High-risk myeloma
Non myeloablative allogeneic transplantation
Bortezomib

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Bortezomib
Antineoplastic Agents