               
   
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:
- 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
- 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.
- 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.
- 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.
- Gisselbrecht C, Maraninchi D, Pico JL, et al. Interleukin-2 treatment
in lymphoma: A phase II Multicenter study. Blood 1994, 83: 2081-2085.
- 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.
- 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.
- 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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