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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

Phase 1
18 Years
70 Years
Open (Enrolling)
Refractory Multiple Myeloma, Stage I Multiple Myeloma, Stage II Multiple Myeloma

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Trial Information

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
day 0.

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
annually thereafter.

Inclusion Criteria:

- Recipient must have signed a voluntary, informed consent in accordance with
institutional and federal guidelines

- Recipients must have histopathologically confirmed diagnosis of multiple myeloma

- Age:

- Stratum I (TMI containing arm): 18-60 years of age

- Stratum II (non TMI arm): 18-70 years of age

- Patients with primary progressive disease on induction therapy with new targeted

- Relapsed/refractory disease on new targeted therapies, i.e. thalidomide,
lenalidomide, bortezomib, or other new novel agents such as carfilzomib, pomalidomide

- Patients with relapsed multiple myeloma following previous autologous stem cell

- Plasma cell leukemia at diagnosis

- High-risk patients with presence of chromosome 17p deletion (> 60%) in the bone
marrow by fluorescence in situ hybridization (FISH); patients are not required to
have prior autologous stem cell transplant

- Able to lie supine for approximately 60 minutes, the anticipated duration of each
treatment session

- Performance status evaluated by Eastern Cooperative Oncology Group (ECOG) or
Karnofsky Performance Scales (KPS) patients must have a score of 0-II (ECOG) or >=
70% (KPS)

- Cardiac ejection fraction >= 50% by multiple gate acquisition (MUGA) scan and/or by

- Forced expiratory volume in one second (FEV1) >= 50%

- Diffusing lung capacity for carbon monoxide (DLCO) >= 50%

- Creatinine clearance or glomerular filtration rate (GFR) >= 60 ml/min

- Serum bilirubin =< 2.0 mg/dl

- Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic
transaminase (SGPT) =< 2.5 times the institutional upper limits of normal

- Pre-treatment tests must be performed within 30 days prior to enrollment

- No other medical and or psychosocial problems, which in the opinion of the primary
physician or principal investigator would place the patient at unacceptable risk from
this regimen

- Patients with no previous radiation or up to a maximum 2000 cGy to non thoracic-spine
and rib bone lesions or < 20% of bone marrow are eligible for TMI conditioning

- Patients with previous history of irradiation at any dose to thoracic-spine, ribs or
>= 20% of bone marrow cannot undergo TMI and will be eligible for bortezomib,
fludarabine, and melphalan regimen

Stratum II); patients can be enrolled on stratum II at their physician's discretion or if
patients decline radiation therapy

DONOR: Any matched sibling donor (matched at HLA A, B, C by intermediate resolution typing
and HLA-DRB1 by high resolution typing), or unmatched unrelated donor (matched at HLA A,
B, C, DRB1 by high resolution typing) will be considered a suitable donor

Exclusion Criteria:

- Patients with peripheral neuropathy greater than grade II

- Major medical or psychiatric disorders that would seriously compromise patient
tolerance of this regimen

- Human immunodeficiency virus (HIV) infection, active hepatitis B or C infection, or
evidence of liver cirrhosis

- Active viral, bacterial or fungal infection unless adequately treated. For fungal
infection, patient should have completed full course of antifungal therapy with
resolution of infection.

- Patients with radiographic changes including pulmonary disease, including but not
limited to: pulmonary nodules, infiltrates, pleural effusion are excluded unless
cleared by pulmonary biopsy showing no evidence for pulmonary infection

- Patients with renal insufficiency or cr clearance < 60 ml/min

DONOR: Donors will be excluded if for medical or psychological reasons they are unable to
tolerate the procedure of peripheral stem cell donation

Type of Study:


Study Design:

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

Outcome Measure:

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

Outcome Description:

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.

Outcome Time Frame:

6 weeks post transplant

Safety Issue:


Principal Investigator

Firoozeh Sahebi, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Beckman Research Institute


United States: Institutional Review Board

Study ID:




Start Date:

January 2011

Completion Date:

Related Keywords:

  • Refractory Multiple Myeloma
  • Stage I Multiple Myeloma
  • Stage II Multiple Myeloma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell



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