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Tandem Autologous HCT / Nonmyeloablative Allogeneic HCT From HLA-Matched Related and Unrelated Donors Followed by Bortezomib Maintenance Therapy for Patients With High-Risk Multiple Myeloma

Phase 2
18 Years
Open (Enrolling)
Refractory Multiple Myeloma, Stage I Multiple Myeloma, Stage II Multiple Myeloma, Stage III Multiple Myeloma

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Trial Information

Tandem Autologous HCT / Nonmyeloablative Allogeneic HCT From HLA-Matched Related and Unrelated Donors Followed by Bortezomib Maintenance Therapy for Patients With High-Risk Multiple Myeloma


I. Progression-free survival (PFS) at 2 years after the autograft (=< 50% in historic


I. Overall survival (OS) at 2 years after the autograft.

II. Non-relapse mortality (NRM) at 200 days and 1 year after allograft.

III. Incidence of grades II-IV acute graft-versus-host-disease (GVHD) and chronic extensive

IV. Safety of bortezomib maintenance therapy after stem cell transplantation.


collection using the preferred regimens at the participating institution.

TRANSPLANTATION (HSCT): Patients receive high-dose melphalan intravenously (IV) on day -2
followed by an autologous or syngeneic HSCT on day 0.

NON-MYELOABLATIVE ALLOGENEIC HSCT: Beginning 40-180 days after autologous HSCT, patients
receive 1 of the following regimens:

1. HLA-IDENTICAL RELATED DONOR: Patients receive cyclosporine IV or orally (PO) twice
daily (BID) starting on days -3 to 56, and taper until day 180. Patients then undergo
total-body irradiation (TBI) and non-myeloablative allogeneic HSCT on day 0. Four to
six hours after completion of allogeneic HSCT, patients receive mycophenolate mofetil
(MMF) PO BID on days 0-27.

2. HLA-UNRELATED DONOR: Patients receive fludarabine phosphate IV on days -4 to -2.
Patients also receive cyclosporine IV or PO BID starting on days -3 to 100 and taper
until day 180. Patients then undergo TBI and non-myeloablative allogeneic HSCT on day
0. Four to six hours after completion of allogeneic HSCT, patients receive MMF PO
thrice daily (TID) on days 0-27 and then BID on days 27-40 with taper of MMF on days

MAINTENANCE THERAPY: Beginning 60-120 days after allogeneic HSCT, patients receive
bortezomib subcutaneously (SC) on days 1 and 4 of 14-day cycles for 9 months or for up to 18
cycles in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up every 3 months for 1 year and
then annually for up to 5 years.

Inclusion Criteria:

- Newly diagnosed patients must have received induction therapy (e.g., vincristine,
doxorubicin, dexamethasone [VAD], thalidomide/dexamethasone) for a minimum of 4

- Must have the capacity to give informed consent

- Must have an human leukocyte antigen (HLA) genotypically identical sibling or a
phenotypically matched relative or, at a minimum, a high likelihood of identifying an
HLA-matched unrelated donor; the determination of availability of a suitable
unrelated donor may be based on a World-Book search

- In addition, patients must meet at least one of the criteria A-I (A-G at time of
diagnosis or pre-autograft):

- A) Any abnormal karyotype by metaphase analysis except for isolated t(11,14) and
constitutional cytogenetic abnormality

- B) Fluorescence in situ hybridization (FISH) translocation 4;14

- C) FISH translocation 14;16

- D) FISH deletion 17p

- E) Beta2-microglobulin > 5.5 mg/mL

- F) Cytogenetic hypodiploidy

- G) Plasmablastic morphology (>= 2%)

- H) Recurrent or non-responsive (less than partial response [PR]) MM after at
least two different lines of conventional chemotherapy

- I) Progressive MM after a previous autograft (provided stored autologousCD34
cells are available)

- DONOR: HLA genotypically identical sibling or phenotypically matched relative OR

- DONOR: HLA phenotypically matched unrelated donor (according to Standard Practice HLA
matching criteria, Grade #2.1)

- Matched HLA-A, B, C, DRB1, and DQB1 alleles by high resolution typing.

- Only a single allele disparity will be allowed for HLA-A, B, or C as defined by
high resolution typing

Exclusion Criteria:

- Life expectancy severely limited by disease other than malignancy

- Seropositive for the human immunodeficiency virus (HIV)

- Females who are pregnant or breastfeeding

- Fertile men or women unwilling to use contraceptive techniques during and for 12
months following treatment

- Patients with active non-hematological malignancies (except non-melanoma skin
cancers) or those with non-hematological malignancies (except non-melanoma skin
cancers) who have been rendered with no evidence of disease, but have a greater than
20% chance of having disease recurrence within 5 years; this exclusion does not apply
to patients with non-hematologic malignancies that do not require therapy

- Patients with fungal infection and radiological progression after receipt of
amphotericin B or active triazole for greater than 1 month

- Patients with the following organ dysfunction:

- Symptomatic coronary artery disease or ejection fraction < 40% or other cardiac
failure requiring therapy; myocardial infarction within 6 months prior to
enrollment or has New York Heart Association (NYHA) Class III or IV heart
failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or
electrocardiographic evidence of acute ischemia or active conduction system

- Ejection fraction is required if the patient has a history of anthracyclines or
history of cardiac disease;

- Diffusing lung capacity for carbon monoxide (DLCO) < 50%, forced expiratory
volume in 1 second (FEV) < 50% and/or receiving supplementary continuous oxygen;
the Fred Hutchinson Cancer Research Center (FHCRC) principle investigator (PI)
of the study must approve of enrollment of all patients with pulmonary nodules

- Liver function abnormalities: Patient with clinical or laboratory evidence of
liver disease will be evaluated for the cause of liver disease, its clinical
severity in terms of liver function, bridging fibrosis, and the degree of portal
hypertension; the patient will be excluded if he/she is found to have fulminant
liver failure; cirrhosis of the liver with evidence of portal hypertension;
alcoholic hepatitis; esophageal varices; a history of bleeding esophageal
varices; hepatic encephalopathy; uncorrectable hepatic synthetic dysfunction
evinced by prolongation of the prothrombin time ascites related to portal
hypertension; bacterial or fungal liver abscess; biliary obstruction; chronic
viral hepatitis with total serum bilirubin > 3mg/dL; and symptomatic biliary

- Karnofsky score < 70% for adult patients

- Patient with poorly controlled hypertension and on multiple antihypertensives

- Patients with current >= grade 2 peripheral neuropathy

- Patient has an active bacterial or fungal infection unresponsive to medical therapy

- DONOR: Identical twin

- DONOR: Donors unwilling to donate PBSC

- DONOR: Pregnancy

- DONOR: Infection with HIV

- DONOR: Inability to achieve adequate venous access

- DONOR: Known allergy to G-CSF

- DONOR: Current serious systemic illness

- DONOR: Failure to meet FHCRC criteria for stem cell donation

- DONOR: Age < 12 years

- DONOR: A positive anti-donor cytotoxic crossmatch

- DONOR: Patient and donor pairs must not be homozygous at mismatched allele

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:


Outcome Description:

Confidence intervals will be estimated.

Outcome Time Frame:

At 2 years after the autograft

Safety Issue:


Principal Investigator

Marco Mielcarek

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium


United States: Institutional Review Board

Study ID:




Start Date:

October 2008

Completion Date:

Related Keywords:

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



Fred Hutchinson Cancer Research Center/University of Washington Cancer ConsortiumSeattle, Washington  98109