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a.       Primary Objectives

To evaluate the role of TEMODAR in the management of relapsed refractory multiple myeloma


b.      Secondary Objectives

Safety: To evaluate the toxicity of TEMODAR in Multiple Myeloma patients




    1. Multiple Myeloma and Induction Therapy:


Multiple myeloma (MM) is a neoplastic disease characterized by the expansion of monoclonal plasma cells that seed throughout bone marrow, causing lytic bone lesions, and introduce monoclonal immunoglobulins, hence the term monoclonal gammopathy.

Multiple myeloma is a fatal neoplasm of plasma cells with a median patient survival of about 30 months[i], [ii] The disease is regarded as responsive to alkylating agents, corticosteroids and irradiation although few patients achieve true and complete remissions. The disease is not considered curable with standard therapy. Thirty percent of patients with multiple myeloma show chemotherapy resistance to initial treatment, and all of those who initially respond will ultimately relapse after a median of 15 months[iii]. Treatment with more aggressive, multi-agent chemotherapy has not demonstrated significantly improved results over conventional therapy with an alkylating agent and corticosteroids[iv] ,[v]. Overall, patients with relapsed disease after one or more first-time therapies are a particularly difficult group to treat. The efficacy of melphalan and prednisone (MP), first introduced for MM more than 25 years ago, has been compared with several alternative regimens.  Other regimens are equivalent to MP, but should be employed only in special cases such as renal failure, or to prevent stem cell damage[vi]. Presently, the mainstay of treatment is Melphalan (L‑PAM) and Prednisone.  Introduced more than 30 years ago, this therapy has shown a 30‑40% resistant rate and median survival not greater than 3 years.  A cure, however, is exceedingly rare. Combination chemotherapy with cytoxan was introduced in the early 1970's, after observing that human and murine‑plasmacytoma already resistant to Melphalan were still sensitive to Cyclophosphamide[vii].


    1. TEMODAR (temozolomide)

Description of Temozolomide

 Temozolomide is an oral alkylating agent of the imidazotetrazine derivatives, which exhibits broad-spectrum antitumor activity against murine tumors[viii]. Temozolomide was developed as a potential alternative to dacarbazine in view of its demonstrated antitumor activity and better toxicity profile in pre-clinical testing[ix],[x],[xi],[xii],[xiii] Both compounds are cytotoxic alkylating agents whose active metabolite is the linear triazine, monomethyl triazenoimidazole carboxamide (MTIC)1,[xiv The cytotoxicity of MTIC is thought to be primarily due to alkylation at the O6 position of guanine with additional alkylation also occurring at the N7 position[xv],[xvi]

 Efficacy and Safety 


Based on encouraging preclinical data, a phase I trial with temozolomide was conducted by the Cancer Research Campaign (CRC)/Phase I-II Clinical Trials Unit in the United Kingdom (UK)[xvii],[xviii],[xix],[xx]. This trial was conducted in two phases, and cycles of temozolomide were repeated every 28 days. Of these patients enrolled, 331 courses (cycles) of temozolomide were administered and received orally, once a day for 5 consecutive days, every 28 days.  The total doses administered over 5 days were 750, 900, 1000, and 1200 mg/m2. Based on the results of this study, the recommended starting dose of temozolomide for CRC Phase II trials were 150 mg/m2/day, orally, once a day for 5 days (total dose 750 mg/m2) during the first cycle. Subsequent dose escalations to 200 mg/m2/day, once a day for 5 days (total dose 1000 mg/m2) in the absence of myelotoxicity were also indicated.  There was only infrequent hematological toxicitiy noted.



  1. Treatment Plan


    1. Patients who are eligible will be started on temodar for 5 days. This is to be repeated every 28 days if counts and response criteria are met. Therapy will continue for a minimum of 6 cycles or two cycles after best response.
    2. Patients will receive two cycles after best response, then start on maintenance therapy with prednisone.
    3. Patients who fail to respond after 2 cycles of Temodar at a low dose, will proceed with two more cycles if:

1.       Performance status is unchanged from date of enrollment on study.

2.       Renal function is unchanged from the time of enrollment on study (i.e no greater than 0.3mg/dl increase of serum creatinine.)


4.       Patient selection


a.       Inclusion Criteria: 

1.       Relapsed, refractory patients who have failed at least one regimen, and no more than 3 previous regimens.

2.       Pancytopenia related to Myeloma

3.       Eastern Cooperative Group (ECOG) performance status of 0-2.

4.       Adequate organ function is required; including serum creatinine<2.0mg/dl.


b.       Exclusion Criteria:

1.       Concurrent involvement in any other therapeutic regimen, clinical trial using an investigational drug or device within 4 weeks of registration.

2.       Severe infection requiring IV antibiotic treatment within 14 days of enrollment

3.       Patients with a life expectancy of 3 months.

4.       Pregnant or breastfeeding

5.       MI within 6 months

6.       No prior than 3 regimens


5.       Study Measurements


Patients will undergo appropriate serum and urine electrophoresis, immuno-typing of serum and urine.  Patients must have a clearly detectable and quantifyable monoclonal M- component in the serum or 24-hour urine collection. Radiologic imaging via MRI or Skeletal survey to document baseline disease will be done within 28 days prior to the first dose of the study drug.  M-component in the serum and/or urine will be measured every cycle (four weeks).  Additionally, radiologic imaging, as clinically indicated, will be repeated every 6 cycles to assess the progression of lytic lesions if clinically indicated.


[i] Gobbi M, Cavo M, Savelli GA, et al.  Prognostic factors and survival in multiple myeloma:  Analysis of 91 cases treated by melphalan and prednisone.  Haematologica 1980, 65: 437-445

 [ii] Hansen OP, Galton DAG.  Classification and prognostic variables in myelomatosis.  Scand J Haematol 1985, 35: 10-19.

 [iii] Woodruff R. Treatment of multiple myeloma. Cancer Treat Rev 1981, 8:225-270.

 [iv] Alexanian R.  Treatment of multiple myeloma.  Rev Acta Haematol 1980, 63: 237-240.

 [v] Ahre A, Bjorkholm M, Mellstodt H, et al.  Intermittent high dose melphalan/prednisone vs. continuous low dose melphalan treatment in multiple myeloma.  Euro J Cancer Clinical Oncology 1983, 19: 499-506.

[vi] Boccardo M, Marmount F, Tribalto M, et al.  Multiple myeloma:  VMCP/VBAP alternating combination chemotherapy is not superior to melphalan and prednisone even in high-risk patients.  J Clin Oncol 9:444, 1991.

[vii] Boccadora M, Alessandro P.  Standard chemotherapy for myelomatosis:  An area of great controversy.   Haematology/Oncology Clinica of North America, 6(2): 371, 1992.
[viii] Stevens MFG, Hickman JA, Stone R et al.  Antitumor imidazotetrazines 1.  Synthesis and chemistry of 8-carbamoyl-3-(2-chloroethyl) imidazo [5,1,d]-1,2,3,5-tetrazin-4(3H)-one, a novel broad-spectrum antitumor agent.  J. Med. Chem 1984; 27:196.
[ix] Tsang LLH, Quarterman CP, Gescher A, Slack JA:  Comparison of cytotoxicity in vitro of temozolomide and dacarbazine, prodrugs of 3-methyl-(triazen-1-yl) imidazole-4-carboxide.  Cancer Chemother Phramacol 1991; 27:342-346.

 [x] Bull VL, Tinsdale MJ:  Antitumor imidazotetrazines XVI.  Macromolecular alkylation by 3-substituted imidazotetrazines.  Biochem Pharmacol 1987; 36:3215-3220.

 [xi] Tinsdale, MJ:  Antitumor imidazotetrazines-XVIII. Modification of the level of 5-methylcytosine in DNA by 3-substituted imidazotetrazinones.  Biochem Pharmacol 1989; 38 1097-1101.

 [xii] Tsang LLH, Farmer PB, Gescher A, Slack JA:  Characterization of urinary metabolites of temozolomide in humans and mice and evaluation of their cytotoxicity.  Cancer Chemother Pharmacol 1990; 26:429-436.

 [xiii] Clark AS, Stevens MF, Sansom CE, Schwalbe CH:  Antitumor imidazotetrazines.  XXI.  Mitozolamide and temozolomide:  probes for the major groove of DNA. Anticancer Drug Design 1990; 5:63-68.

 [xiv] Stevens MFG, Hickman JA, Langdon SP et al.  Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-(2-chloroethyl) imidazo [5,1,dí-1,2,3,5-terazin-4(3H)-one (CCRG 81045; M&B 39831) a novel drug with potential as an alternative to dacarbazine.  Cancer Res. 1987; 47: 5846.

 [xv] Gibson NW, Hickman AJ, Erickson LD.  DNA cross-linking and cytotoxicity in normal and transformed human cells treated in vitro with 8-Carbamoyl-3-(2-chloroethyl) imidazo [5,1-d]-1,2,3,5-tetrazin-4(3H)-one.  Cancer Research 1984; 44:1772.

 [xvi] Hartley JA, Gibson NW, Kohn KW et al.  DNA sequence selectivity of guanine-N7 alkylation by three antitumor chloroethylating agents.  Cancer Research 1986; 46:1943.

[xvii] Newlands ES, Blackledge GR, Slack JA, Ruestin GJ et al:  Phase I trial of temozolomide (CCRG 81045, M&B 39831:  NSC 362856).  Br J Cancer 1992; 65 (2): 287-291.

 [xviii] O'Reilly SM, Newlands ES, Stevens MFG, Brampton MH, Slack JA et al:  Temozolomide (CCRG 81045; M&B 39831; NSC 362856):  a new oral cytotoxic agent with activity against melanoma, mycosis fungoides and high grade glioma.  Proc AACR 1992; 33:  A1267.

 [xix] O'Reilly SM, Newlands ES, Glaser MG et al:  Temozolomide:  a new oral cytotoxic agent with promising activity against gliomas.  ProcASCO 1993; 12: 499.

 [xx] O'Reilly SM, Newlands ES, Glaser MG et al.  Temozolomide:  A new oral cytotoxic chemotherapeutic agent with promising activity against brain tumors.  Eur J Cancer 1993; 29A:  940.


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