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Pilot Study to Evaluate rIL-2 Maintenance Therapy Following Chemotherapy with Vincristine, Adriamycin, and Decadron (VAD) for Multiple Myeloma ( Closed to Accrual and awaiting data maturation)

 

General Information:

There is no curative therapy available for multiple myeloma. Maintenance with chemotherapy after initial response is not effective in controlling the disease and carries significant risks.

The myeloma cell is controlled by several immune cells and proteins. There is data to suggest that patients have a disrupted immune system. Also, information is accumulating quickly to suggest a role for cytokines (proteins controlling the immune system) in maintaining multiple myeloma in an inactive state following the initial decrease of tumor load by chemotherapy.

The purpose of the study is to evaluate the role of IL-2 in controlling the disease and keeping it in a stable phase by reorganizing the immune system.

Eligibility Criteria:

Induction Phase (Chemotherapy with VAD)

  • All newly diagnosed multiply myeloma patients will be eligible.
  • All patients that have failed or progressed after a non Vinca- alkaloid, non-anthracycline regimen.
  • Patients who have received Vinca alkaloids and/or anthracycline and have been in stable phase > 6 months.
  • Patients with pancytopenia related to multiple myeloma will be eligible for treatment; i.e. patients with > 50% plasma cells in the BM, or have splenomegaly, or have plasma cell leukemia.

Maintenance Phase (Therapy with IL-2)

  • Patients achieving stable disease or better, that is maintained for a period of 8 weeks following the completion of chemotherapy.
  • Patients who receive VAD pre-registration on the study will be eligible and will be evaluated for the clinical and laboratory effects, pre and post GM-CSF and IL-2.

Ineligibility Criteria:

Induction Phase (Chemotherapy with VAD)

  • Evidence of active infection requiring IV antibiotics.
  • Patients with clinical evidence of congestive heart failure.
  • Patients with solitary bone or extramedullary plasmacytoma.
  • Patients who are HIV positive.

Maintenance Phase ( Therapy with IL-2)

The patient will be evaluated within three weeks prior to entry. Any one of the following conditions eliminates a patient from participating in this protocol.

  • Concurrent involvement in any other clinical trial using an investigational drug or device, or participation in any investigational drug study within 4 weeks prior to study registration. Exceptions may be made by the study investigators for participation in certain studies (e.g. antimicrobial studies) on a case by case basis.
  • Sero-positive for HIV antibody or any evidence of serious or active infection which is chronic or is requiring intravenous antibiotic treatment.
  • Severe hepatic disease (e.g. SGOT or SGPT, bilirubin, alkaline phosphatase more than 2.5 times the normal laboratory range).
  • Compromised renal function as evidenced by a serum creatinine > 2.0.
  • Other major organ system dysfunction (including cardiac, pulmonary, gastrointestinal, neurologic or psychiatric) that would impair tolerance of therapy.
  • Concomitant use of corticosteroids or colony stimulating factor agents.
  • Patients who fail to have a granulocyte count > 750/mL, platelet count > 75k/mL.

Allowable Concomitant Therapy

  • Standard radiation therapy to treat extra-skeletal and/or skeletal tumor sites. If radiation is needed during the study period, the investigator must document that there is no sign of progressive disease leading to radiation as a treatment. Comparisons of area to be radiated with baseline bone survey films must be provided to document lack of disease progression.
  • Erythropoietin for severe symptomatic anemia.
  • GM-CSF is the only growth factor that will be allowed if necessary in the induction phase
  • Aredia and Immunoglobulin therapy will be allowed at any stage of the therapy.

Scientific Background:

lnterleukin-2

Natural Interleukin-2 is a lymphokine which is produced and secreted by T lymphocytes1. This glycoprotein molecule is intimately involved in the induction of virtually all immune responses in which T cells play a role. Recombinant human Interleukin-2 (rIL-2) has been tested in murine model systems both as primary anti-tumor therapy and as an adjunct to various other therapeutic modalities including chemotherapy and adoptive Immunotherapy with cultured cytotoxic cells. Each of these types of studies indicate that in certain circumstances, rIL-2 has anti-tumor effectiveness.

Recombinant Interleukin-2 has been found in some murine tumor models to be effective as an anti-tumor agent when administered by itself. This has been demonstrated in both pulmonary and hepatic metastatic tumor models and in several other primary murine tumors(2,3). Tumor regression may be mediated by lymphokine-activated killer cells (CD56+) which are induced by IL-2 treatment.

IL-2 has been used recently in the treatment of various hematologic malignancies. Of particular interest is its use as remission maintenance therapy for leukemia and lymphomas (4,5).

Use Of IL-2 in Multiple Myeloma: "Rationale"

Available data suggest that high serum IL-2 levels is one of the most useful predictor indices for longer survival in multiple myeloma patients. In particular, 87% of the multiple myeloma patients with IL-2 serum levels > 10 U/ML were alive at 5 years, while only 13% of the remaining patients with IL-2 < 10 U/ML were alive. This data may reflect the existence of an active T-cell response to B-cell neoplasia, and suggest that the use of IL-2 as a therapeutic strategy for multiple myeloma might have a significant impact on the disease (6). This has led to the consideration of use of IL-2 in the therapy of Multiple Myeloma. Few patients have received IL-2 for induction or consolidation.

IL-2 As Maintenance Therapy in Multiple Myeloma:

There is only preliminary data on the effects of IL-2 in multiple myeloma. Gottlieb, et al have administered IL-2 to 4 patients with multiple myeloma after autologous bone marrow transplantation. The 4 patients received seven infusions of IL-2 after autologous bone marrow transplant. IL-2 infusions were initiated 29-119 days past autologous bone marrow transplantation at doses varying from 1.0 to 2.0 x 106 U/day by continuous infusion for 3-5 days. Increases in natural killer cells and lymphokine activated killer activity of peripheral blood mononuclear cells occurred during IL-2 infusion. IL-2 infusion also induced substantial increase in the production of the cytokine TNF, and g-interferon from peripheral blood lymphocytes. They have demonstrated that malignant plasma cells isolated from patients with multiple myeloma are sensitive to lysis by IL-2 induced LAK cells, derived from patients peripheral blood mononuclear cells. In addition, the thymidine uptake and survival of myeloma cells was reduced by tumor necrosis factor and gamma interferon, two cytokines produced by lymphocytes following exposure to IL-2. They have not shown any evidence that IL-2 induces the growth of clones of malignant plasma cells (7).

References:

  1. Farra JJ, Benjamin WR, Hilfiker ML, et al. The biochemistry, biology and role of Interleukin-2 in the induction of cytotoxic T-cell and antibody-forming B-cell responses. Immunological Rev 1982, 63:129-166
  2. Mule JJ, Sze S, Rosenberg SA. The antitumor efficacy of lymphokine-activated killer cells and recombinant interleukin-2 in vivo. J Immuno 1985, 135: 646-652.
  3. Rosenberg SA, Mule JJ, Spless PJ, et al. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high dose recombinant interleukin-2. J Exp. Med 1985, 161:1169-1188.
  4. Benyunes MC, Massuntoto C, York A, et al. Interleukin-2 with or without lymphokine-activated killer cells as consolidative immunotherapy after autologous bone marrow transplantation for acute myelogenous leukemia. Bone Marrow Transplantation 1993, 12:159-163.
  5. Gisselbrecht C, Maraninchi D, Pico JL, et al. Interleukin-2 treatment in lymphoma: A phase II Multicenter study. Blood 1994, 83: 2081-2085.
  6. Cimino G, Avvisati G, Amadori S, Cava MC, Giannarelli D, DiNucci GD, Maglidcca V, Petrucci MT, Poti G, Sgadari C. High serum IL-2 levels are predictive of prolonged survival in multiple myeloma. British Journal of Haematology (JC:axc) 1990, 75(3):373-7.
  7. Peest D, Leo R, Bloche S, et al. Low dose recombinant interleukin-2 therapy in advanced multiple myeloma. British Journal of Haematology 1995, 89:328-337.
  8. Gottlieb DJ, Prentice G, Mehta AB, et al. Malignant plasma cells are sensitive to LAK cell lysis: preclinical and clinical studies of interleukin-2 in the treatment of multiple myeloma. British Journal of Hematology 1990, 75:499-505.
 
 
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