               
   
Phase II Trial to Evaluate the Role of PEG
L-Asparaginase in Multiple Myeloma
General information:
Therapy for Multiple Myeloma has not changed the patient survival or
response since the introduction of Melphalan and Prednisone in the early 1960's.
L-Asparaginase is an enzyme that depletes L-Asparagine "an important nutrient for
cancer cells" resulting in cancer cell starvation and death. The drug
used in this regimen ( PEG L-Asparaginase, ONCOSPAR®) is approved by the Food and Drug
Administration (FDA) and is commercially available.
Eligibility Criteria:
 Diagnosis of multiple myeloma.
Relapsed or refractory multiple myeloma of
any stage.
ECOG performance status of less than or
equal to 2.
18 years or older.
Signed consent form.
Ineligibility Criteria:
Patient with overt or active infection
requiring IV antibiotics.
Patients who have received any
chemotherapeutic regimen <4 weeks prior to therapy and blood counts have not recovered.
Total bilirubin > 2.0 gm/dl, SGOT, or
SGPT > 3 x ULN.
Prior thrombotic disorder.
Previous radiation therapy to areas
encompassing the pancreas with doses 25 cGY
Prior treatment with Asparaginase.
Elevated PT or PTT (> 1.5 x normal).
Platelets < 50,000.
Patients with pancreatitis or a history of
pancreatitis.
Patients on anticoagulant therapy with
coumarin, heparin, aspirin, dipyridamole.
Patients with CHF or history of CHF less
than 6 months prior to planned therapy.
Scientific Background:
Multiple Myeloma:
Advances in the therapy for Multiple Myeloma over the past 30 years
have resulted in increasing survival from less than 1 year without therapy to more than 3
years with therapy. Agents which include alkylator, steroids, natural products and
biological response modifiers have proven to result in a response rate of about 60% with
initial therapy and survival at a median duration of 48 months (1-3). Unfortunately,
patients who do not respond to initial therapy are not likely to respond to other types of
therapy and have a survival rate of around 15 months. Multiple Myeloma remains a disease
to which cure is a rarity, despite the advances in therapy.
Because of the lymph node origin of malignant B cells in Multiple
Myeloma, L-Asparagine may be an essential amino acid for their cell metabolism, and,
consequently, L-Asparaginase may be of value in managing the disease. Ohnuma, T. et al
have studied the L-Asparagine requirements of human T-lymphocytes and B lymphocytes in
vitro. They demonstrated that T-cells were 800 to 2000 times more sensitive to E. coli
L-Asparaginase than were B cells. The cytotoxic effects of a high concentration of
L-Asparaginase on B cells were not related to the hydrolysis of L-Asparagine but were due
to heat labile and heat resistant substances in the enzyme (4). Clinical data employing
L-Asparaginase in myeloma patients is very limited. In a study published by Chauduri TK,
et al, 14CO2 excretion in the breath was measured after IV
administration of 14C-labeled L-Asparagine to two patients with plasmablastic
myeloma and lymphoblastic leukemia. Excretion was measured before and after therapy with
L-Asparaginase The two patients demonstrated increased 14C02
excretion following14C-Asparagine administration, after therapy compared with
before therapy with L-Asparaginase. Preclinical data suggest myeloma cells may be
sensitive to L-Asparaginase, but clinical trials investigating its efficacy are limited
and inconclusive (5-7)
The humoral immune system:
The humoral immune system is usually compromised in-patients who
have multiple myeloma. It could be hypothesized that allergic and anaphylactic reactions
to L-Asparaginase would be decreased. (8)
References:
- Macintyre W. Case of mollities and fragilitas ossium, accompanied
with urine strongly charged with animal matter. Med Chir Trans Lon 1850; 33:211.
- Hussein MA: Multiple Myeloma: An Overview on Diagnosis and
Management. Cleveland Clinic Journal of Medicine 61(4):285-298, 1994.
- Ohnurna T, Arkin H, Minowada J, Holland JF. Differential
chemotherapeutic susceptibility of human T-lymphocytes and B-lymphocytes in culture.
Journal of the National Cancer Institute 60(4): 749-752,1978 April.
- Ito M, Kawato M. Effects and side effects of L-Asparaginase in acute
leukemia and multiple myeloma. Gan-No-Rinsho,217-222, 1971.
- Ohnuma T, Holland JF, Freeman A, Sinks LF. Biochemical and
pharmacological studies with Asparaginase in man. Cancer Res. 30:2297-2305.
- Capizzi RL: Biochemical interaction between Asparaginase and
Methotrexate (MTX) in leukemia cells. Proc Am Assoc Cancer Res 15:77,1974 (abstr).
- Nesbit ME, Ertel I, Hammona GD. L-Asparaginase as a single agent in
acute Lymphocytic leukemia: survey studies from Children's Cancer Study Group. Cancer
Treatment Reports 65 Supplemental 4:101-7, 1981.
- Jacobson DR, Zolla-Pazner S: Immunosuppression and infection in
multiple myeloma Semin Oncol 13:282, 1986.
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