UARK 89-001 Phase II Study of Intensive TOTAL THERAPY For Untreated or Minimally Treated Patients With Multiple Myeloma

Study Overview
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Brief Summary
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This experimental study evaluates the effects of a series of intensive drug regimens as initial treatment for Multiple Myeloma followed by 2 bone marrow transplantations 4-6 months apart in support of high-dose Melphalan, followed by Interferon treatment indefinitely.

Official Title
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Phase II Study of Intensive TOTAL THERAPY for Untreated or Minimally Treated Patients With Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: VAD
* Drug: High-Dose cyclophosphamide
* Procedure: Hemopoietic stem cell procurement
* Drug: EDAP
* Procedure: Autologous Hemopoietic Stem Cell Transplant 1
* Procedure: Autologous Hemopoietic Stem Cell Transplant 2
* Drug: Maintenance


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previously untreated patients with the diagnosis of multiple myeloma are eligible. Similarly, patients who have not had more than one cycle of standard chemotherapy or up to one month of interferon and/or glucocorticoids are eligible. Patients must have objective evidence of, or be symptomatic from, complications due to myeloma (e.g., bone pain from fractures, weakness from anemia). Asymptomatic patients may be treated only if the diagnosis is confirmed and if there is evidence of increasing tumor mass (e.g., rising myeloma protein and/or increasing lytic lesions). Asymptomatic patients with idiopathic monoclonal peaks, localized plasmacytomas, or indolent, asymptomatic myeloma are not eligible for this study. Any patient without documented increasing disease and/or clearly symptomatic disease is not eligible. Measurable, direct manifestations of myeloma must be present, such as monoclonal serum or urine globulins. Plasma cell tumors must also be documented. Patients without protein criteria are eligible if bone marrow has > 30% plasmacytosis documented by bilateral bone marrow aspirations and biopsies. Patients with all stages of multiple myeloma (I, II, III) are eligible. Necessary baseline studies must be obtained to determine the stage prior to registration. Patients may have received local radiation to painful compression fractures or lytic bone lesions, provided that adequate autologous bone marrow can still be harvested. Patients presenting with clinical conditions requiring radiotherapy (e.g. spinal cord compression) may proceed with concurrent local radiation and VAD. Should compression fractures of known prestudy lytic lesions occur during later, more myelosuppressive phases of induction therapy, radiotherapy should be completed first prior to proceeding with high-dose cyclophosphamide, EDAP or melphalan. Patients should be older than 15 years of age and may be up to 65 years old. Pregnant females are excluded from study. Eligibility criteria change with the progress through the different phases of the induction program towards the two cycles of marrow-ablative therapy. These are summarized in the eligibility checklist. Briefly, prior to VAD, patients must have a normal cardiac ejection fraction of > 50% (on ECHO cardiography or MUGGA scan), and fairly normal liver function tests (bilirubin < 2 mg% and serum transaminase levels less than 2 x normal). Screening for viral hepatitis should be negative for acute or chronic active hepatitis. Positive antibody (anti-HAV, HBSAb) suggestive of remote exposure is acceptable. However, patients who test positive for Hepatitis C antibody (anti-HCV) or HIV are ineligible. Those with renal failure are eligible and should start VAD promptly and receive additional medical measures as needed. Patients presenting with infections upon presentation shall receive proper medical management prior to starting therapy. Patient's performance status is not a criterion for entry on the VAD portion of this program. After 2 or 3 cycles of VAD, serum creatinine levels must be 2 mg% and carbon monoxide diffusion capacity 50%. Cardiac and liver function requirements as with VAD. Not until reaching the high-dose melphalan stage of 70 mg/M2 will there be a requirement for Zubrod performance of 0 and 1 which must also be fulfilled with each of the 2 marrow-ablative doses of melphalan (200 mg/M2). Exclusion Criteria: Less than 10 x 108 cells/kg stored. a granulocyte count of less than 1500/µl and a platelet count less than 150,000/µl.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study Treatment<br>Protocol therapy consists of a remission induction phase with mutually non-cross resistant combinations of vincristine, adriamycin, dexamethasone (VAD), high-dose cyclophosphamide with stem cell procurement and etoposide, dexamethasone, cytarabine, cisplatin (EDAP) followed by two courses of melphalan-based high-dose therapy supported by autologous stem cell transplants 4-6 months apart. Maintenance with interferon alpha will be administered until disease progression. | Drug: VAD<br>* 3 Cycles (3rd cycle optional): Vincristine 0.5 mg/d d 1 - 4 CI Adriamycin 10 mg/m2/d d 1 - 4 CI Dexamethasone 40 mg/d d 1-4, 9-12, 17-20<br>Drug: High-Dose cyclophosphamide<br>* Approximately 5-6 weeks after VAD 2 or 3: Cytoxan 1.2g/m2/d d 1 - 5 Mesna 3.6 g/m2 d 1<br>Procedure: Hemopoietic stem cell procurement<br>* Collection target = 10 x 10^6 cells/kg<br>Drug: EDAP<br>* Approximately 5-6 weeks after high-dose cyclophosphamide Etoposide 100 mg/m2/d d 1 - 4 CI Cisplatin 25 mg/m2/d d 1 - 4 CI Ara C l g/m2 d 5 Dexamethasone 40 mg d 1-5<br>Procedure: Autologous Hemopoietic Stem Cell Transplant 1<br>* 4-6 weeks after EDAP: Melphalan 100 mg/m2 days -1 and -2<br>Procedure: Autologous Hemopoietic Stem Cell Transplant 2<br>* 4-6 months after Transplant 1: Melphalan 100 mg/m2 days -1 and -2<br>Drug: Maintenance<br>* 3 months after Transplant 2: Intron A 3 X 10^6 units /m2 M-W-F subcutaneously until relapse<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants That Are Relapse-free 5 Years After Initial Therapy | Relapse is defined by the unequivocal objective evidence of recurrent disease such as: myeloma-related cytogenetic abnormalities; bone marrow plasmacytosis >10% or >5% light chain restricted, non-diploid, plasma cells on clg/DNA; new skeletal or MRI lesions; hypercalcemia not explained by any other cause; or reappearance of M-protein in blood or urine not related to immune recovery, recent infection, and present for >2 months. | 5 years |