Melphalan, Peripheral Stem Cell Transplantation, and Interleukin-2 Followed by Interferon Alfa in Treating Patients With Advanced Multiple Myeloma

Study Overview
=================
Brief Summary
-----------------
This phase II trial studies the effectiveness of melphalan, peripheral stem cell transplantation, and interleukin-2 followed by interferon alfa in treating patients who have advanced multiple myeloma (MM). Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. Interleukin-2 (IL2) may stimulate a person's white blood cells to kill multiple myeloma cells. Interferon alfa may interfere with the growth of cancer cells

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Evaluate initial response to therapy, time to disease progression, and overall survival in MM patients treated with melphalan, IL2- incubated peripheral blood stem cells, and sequential IL2. SECONDARY OBJECTIVES: I. Evaluate grade 3-4 toxicities encountered by younger (< 56 years old) and older (>56 years old) advanced multiple myeloma patients treated with melphalan, IL2-incubated peripheral blood stem cells, and sequential IL2. OUTLINE: Patients receive melphalan intravenously (IV) over 2-3 hours on day -2 and an infusion of IL-2-treated autologous or syngeneic peripheral blood stem cells on day 0. Beginning on day 0, patients also receive IL-2 IV continuously over 5 days followed by 2 days off. Treatment with IL-2 repeats weekly for 4 weeks. Beginning 1 month later, patients undergo maintenance therapy comprising interferon alfa subcutaneously (SC) 3 times a week in the absence of disease progression or unacceptable toxicity.

Official Title
-----------------
Immunotherapy for Autologous/Syngeneic Peripheral Blood Stem Cell (PBSC) Transplant Patients as Treatment for Advanced Multiple Myeloma

Conditions
-----------------
Refractory Multiple Myeloma, Stage I Multiple Myeloma, Stage II Multiple Myeloma, Stage III Multiple Myeloma

Intervention / Treatment
-----------------
* Drug: melphalan
* Biological: recombinant interferon alfa
* Biological: aldesleukin
* Procedure: in vitro-treated peripheral blood stem cell transplantation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient must be less than 70 years old Patients with advanced Multiple Myeloma that meet the eligibility requirements for mobilization/debulking with Cytoxan/VP-16/G-CSF, Cytoxan/Taxol/G-CSF, or Cytoxan/G-CSF (according to protocol 506.03); if clinically indicated a lower dose of cytoxan than 4g/m2 may be used for mobilization based on the attending's discretion; also, if the patients had previously collected PBSC of sufficient number in the past and meet the other eligibility requirements, they may be entered on this study after approval by the PI Patients with advanced Multiple Myeloma that have an identical syngeneic twin for donation of PBSCs Patients have advanced Multiple Myeloma if they were diagnosed initially with stage II or III disease or had stage I disease that progressed after initial therapy or failed to respond to therapy Syngeneic Donor Inclusion: Donor and patient have adequate documentation that donor and recipient are syngeneic; including ABO typing, HLA typing and VNTR studies Donor > 20 kg Donor meets eligibility to donate according to Standard Practice Guidelines Exclusion Criteria: Patient's age >= 70 Karnofsky score less than 80 A left ventricular ejection fraction less than 50%; Patients with congestive heart disease, history of myocardial infarction (MI), coronary artery disease or any arrhythmia history Total bilirubin > 1.5 mg/ml (unless history of Gilbert's disease) Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvic transaminase (SGPT) > 2 x upper limit of normal Estimated creatinine clearance < 60 ml/min or creatinine serum > 2.0 mg/dl Pregnancy Seropositivity for human immunodeficiency virus Patients who cannot give informed consent Secondary malignancies other than basal cell carcinoma of the skin or carcinoma in situ within the last five years History of seizures or requirement for medicines, such as haldol, for controlling mental disorders Concurrent need for corticosteroid therapy Active connective tissue disease Pleural effusion, pericardial effusion or ascites Patients allergic to gentamicin Patients with positive PCR for hepatitis C or hepatitis B Patients with hypersensitivity to E. coli - derived preparations Patients with systemic infection at time of IL2 therapy Patients who previously have had more than 50% of their pelvic area irradiated Patients with pulmonary function tests that show diffusion capacity (corrected) < 60%, and/or forced expiratory volume in 1 second (FEV1) < 65% of predicted

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 69 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (immunotherapy)<br>Patients receive melphalan IV over 2-3 hours on day -2 and an infusion of IL-2-treated autologous or syngeneic peripheral blood stem cells on day 0. Beginning on day 0, patients also receive IL-2 IV continuously over 5 days followed by 2 days off. Treatment with IL-2 repeats weekly for 4 weeks. Beginning 1 month later, patients undergo maintenance therapy comprising interferon alfa SC 3 times a week in the absence of disease progression or unacceptable toxicity. | Drug: melphalan<br>* Given IV<br>* Other names: L-Sarcolysin;Biological: recombinant interferon alfa<br>* Given SC<br>* Other names: Roferon-A;Biological: aldesleukin<br>* Undergo IL2-treated autologous or syngeneic peripheral blood stem infusion<br>* Other names: recombinant interleukin-2;Procedure: in vitro-treated peripheral blood stem cell transplantation<br>* Undergo IL2-treated autologous or syngeneic peripheral blood stem infusion<br>* Other names: peripheral blood progenitor cell transplantation, in vitro-treated;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival in Multiple Myeloma patients treated with melphalan, IL2-incubated peripheral blood stem cells, and sequential IL2 and interferon maintenance. | 12.9 Median Years | 
| Initial Response to Therapy | Evaluate initial response to therapy (complete remission, partial remission, stable response, or progression of disease) | Evaluated at Day +84-90 Post-Transplant | 
| Time to Disease Progression |  | 12.9 years (median) | 
| Proportion of Patients Alive and in Remission |  | 12.9 Median Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients <56 Years Old Experiencing Grade 3-4 Regimen Related Toxicity | Grade 3-4 toxicities by the Bearman common toxicity criteria, encountered by younger (< 56 years old) advanced multiple myeloma patients treated with melphalan, IL2-incubated peripheral blood stem cells, and sequential IL2. | First 100 days post-transplant | 
| Number of Patients ≥56 Years Old Experiencing Grade 3-4 Regimen Related Toxicity | Grade 3-4 toxicities by the Bearman common toxicity criteria, encountered by older (≥56 years old) advanced multiple myeloma patients treated with melphalan, IL2-incubated peripheral blood stem cells, and sequential IL2. | First 100 days post-transplant |