Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Related Publications
Trial Contact Information

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II	Treatment	Completed	up to 65	NHLBI	NHLBI-92-H-57 NCI-T92-0139N, T92-0139

Objectives

I.  Investigate the safety and efficacy of treating chemotherapy-responsive 
multiple myeloma patients with high-dose melphalan and total-body irradiation 
rescued by autologous bone marrow and peripheral blood stem cell 
transplantation followed by maintenance interferon alpha.

II.  Investigate in vitro and in vivo the feasibility, safety, and efficacy of 
using retroviral vectors to transduce human hematopoietic stem cells for 
treatment of multiple myeloma in hopes of applying this genetic therapy 
approach in vivo in future autologous transplantation protocols.

III.  Improve retroviral transduction efficiency into true repopulating stem 
cells in order to achieve the above objectives.

IV.  Compare in the same patient population three transduction techniques:  
retroviral supernatant with hematopoietic growth factors, without 
hematopoietic growth factors, and with stromal cells.

Entry Criteria

Disease Characteristics:

Multiple myeloma with a detectable serum or urine monoclonal paraprotein at
the time of diagnosis or relapse
  Marrow cellularity greater than 30% with an average of no greater than 30%
  plasma cells on prestudy bilateral bone marrow aspiration and biopsy
  required

  No extensive marrow fibrosis

Chemotherapy-sensitive disease (PR or CR to initial or salvage therapy), i.e.:
  At least a 50% reduction in detectable serum paraprotein or at least a 90%
  reduction in detectable urine monoclonal light chains with response stable
  off therapy for at least 4 weeks prior to entry

Ineligible for standard allogeneic transplantation because of one of the
following factors:
  Age 50 or over
  No sibling matched for 5 or 6 HLA antigens
  Lack of means to undergo allogeneic transplantation

Prior/Concurrent Therapy:

Biologic therapy:
  At least 4 weeks since interferon

Chemotherapy:
  At least 4 weeks since chemotherapy

Endocrine therapy:
  Not specified

Radiotherapy:
  No prior extensive radiotherapy that would preclude bone marrow harvest
     Patients with radiotherapy to more than 10 sqcm of lung tissue or greater
     than 2,000 rads to the thoracic spine are eligible but receive
     higher-dose ablative chemotherapy rather than chemoradiotherapy
  Radiotherapy for active lytic lesions or plasma cytomas must be completed
  before entry

Surgery:
  Not specified

Patient Characteristics:

Age:
  No greater than 65 at transplant

Performance status:
  ECOG 0 or 1

Life expectancy:
  Greater than 3 months

Hematopoietic:
  ANC greater than 1,500
  Platelets greater than 100,000

Hepatic:
  Bilirubin less than 2.0 mg/dl
  Transaminases less than 2 x ULN

Renal:
  Creatinine less than 2.0 mg/dl

Cardiovascular:
  LVEF greater than 50%
  No coronary artery disease

Pulmonary:
  FEV1/FVC greater than 75% of predicted
  DLCO greater than 50% of predicted

Other:
  No serious infection
  No HIV positivity
  No uncontrolled diabetes mellitus
  No other significant medical illness that would jeopardize the patient's
     ability to tolerate aggressive chemoradiotherapy or that would be
     aggravated by the treatment regimen
  No prior malignancy except:
     Localized nonmelanomatous skin cancer
     Localized bladder cancer
     Other malignancies not treated with chemotherapy and that were cured by
        local surgery (e.g., head and neck carcinoma, Stage I breast) are
        considered on an individual basis

Expected Enrollment

Up to 35 patients will be entered.  If no more than 2 of the first 12 patients 
treated experience a partial or complete remission sustained for at least 6 
months, the study will be closed.  An accrual rate of 15 patients/year is 
anticipated.

Outline

All patients are treated on Regimen A, then Regimen B.  Patients with 
extensive prior radiotherapy that precludes TBI are ablated on Regimen D, all 
others on Regimen C.  All patients then proceed to Regimen E.

The following acronyms are used:
  ABM         Autologous Bone Marrow
  CTX         Cyclophosphamide, NSC-26271
  5-FU        Fluorouracil, NSC-19893
  G-CSF       Granulocyte Colony Stimulating Factor (Amgen),
              NSC-614629
  IL-3        Interleukin-3 (Sandoz-Schering), NSC-641115
  IFN-A       Interferon alpha (Hoffmann-La Roche), NSC-367982
  L-PAM       Melphalan, NSC-8806
  Mesna       Mercaptoethane Sulfonate, NSC-113891
  PBSC        Peripheral Blood Stem Cell
  r-metHuSCF  Recombinant Human Methionyl Stem Cell Factor
  TBI         Total Body Irradiation

Regimen A:  Stem Cell Mobilization with Urothelial Protection.  CTX; G-CSF; 
with Mesna.

Regimen B:  Bone Marrow Priming.  5-FU.

Regimen C:  Ablative Single-Agent Chemotherapy and Radiotherapy followed by 
Stem Cell Support followed by Growth Factor Therapy.  L-PAM; and TBI, using 
x-rays with energies of 15 MV; followed by ABM and PBSC (with selection for 
CD34-positive cells); followed by G-CSF.  Portions of ABM and PBSC are 
retrovirally transfected in vitro with the neomycin-resistance marker genes 
(neo-r) G1N.40 and LNL6, with the addition of exogenous hematopoietic growth 
factors (IL-3 and r-metHuSCF), without growth factors, and with stromal cells.

Regimen D:  Ablative Single-Agent Chemotherapy followed by Stem Cell Support 
followed by Growth Factor Therapy.  L-PAM; followed by ABM and PBSC; followed 
by G-CSF.  Stem cells are retrovirally transfected as in Regimen C.

Regimen E:  Biological Response Modifier Therapy.  IFN-A.

Dunbar CE, Cottler-Fox M, O'Shaughnessy JA, et al.: Retrovirally marked CD34-enriched peripheral blood and bone marrow cells contribute to long-term engraftment after autologous transplantation. Blood 85 (11): 3048-57, 1995.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

National Heart, Lung, and Blood Institute

Cynthia Dunbar, MD, Protocol chair		Ph: 301-496-1434 Email: dunbarc@nhlbi.nih.gov