Phase I Study of Bortezomib With or Without Total Marrow Irradiation (TMI) Using Intensity Modulated Radiation Therapy (IMRT) in Combination With Fludarabine (FLU) and Melphalan (MEL) as a Preparative Regimen for Allogeneic Hematopoietic Stem Cell (HSC) Transplantation in Patients With High Risk Multiple Myeloma
I. To determine the feasibility of escalating doses of bortezomib with or without total
marrow irradiation (TMI) at a fixed dose of 900 cGy in combination with fludarabine (FLU)
and melphalan (MEL) as preparative regimen for allogeneic hematopoietic stem cell transplant
in patients with high risk multiple myeloma who have human leukocyte antigen (HLA) matched
donor (sibling or matched unrelated donor).
II. To describe toxicities, maximum tolerated dose (MTD) and dose limiting toxicities (DLT)
of this preparative regimen.
I. To evaluate the frequency of clinical response, i.e., complete response [CR], partial
response [PR], very good partial response [VGPR]) at 6 month and 1 year post transplant.
II. To evaluate the frequency of primary and secondary engraftment failure.
III. To evaluate the time to neutrophil and platelet engraftment.
IV. To evaluate the incidence of acute and chronic graft-versus-host disease (GVHD).
V. To evaluate progression-free survival.
VI. To evaluate overall survival.
VII. To evaluate minimal residual disease (MRD) at 6 months and 1 year post transplant by
flow cytometry in the bone marrow.
OUTLINE: This is a dose-escalation study of bortezomib. Patients are assigned to 1 of 2
treatment groups. GROUP I (patients eligible for TMI): Patients receive bortezomib
intravenously (IV) on days -6 and -3 and undergo TMI twice daily (BID) on days -9 to -7.
Patients also receive fludarabine phosphate IV on days -9 to -5 and melphalan IV on day -4.
GROUP II (patients ineligible for TMI): Patients receive bortezomib IV on days -6, -3, 1,
and 4. Patients also receive fludarabine phosphate IV and melphalan IV as in Group I.
TRANSPLANT: All patients undergo allogeneic peripheral blood stem cell (PBSC) transplant on
GVHD PROPHYLAXIS: All patients receive tacrolimus IV or orally (PO) and sirolimus PO
beginning on day -3.
After completion of study treatment, patients are followed up at day 100, 6 months, and then
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose of bortezomib as defined as the highest dose tested in which none or only one patient experiences dose limiting toxicity attributable to the study regimen
Assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Dose-limiting toxicity will be defined using Bearman Scale for events that occur.
6 weeks post transplant
Firoozeh Sahebi, MD
Beckman Research Institute
United States: Institutional Review Board
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