Temsirolimus and Dexamethasone in Treating Patients With Recurrent or Refractory Multiple Myeloma

PRIMARY OBJECTIVES:

I. To assess the toxicity and safety of temsirolimus in combination with dexamethasone in
patients with recurrent or refractory multiple myeloma.

II. To assess a dose of temsirolimus that is capable of inhibiting the mammalian target of
rapamycin (mTOR) in myeloma tumor cells.

SECONDARY OBJECTIVES:

I. To assess the efficacy of temsirolimus in combination with dexamethasone in these
patients.

II. To correlate the efficacy of this regimen with molecular characteristics of the
individual tumor clones.

OUTLINE: This is a multicenter, dose-escalation study of temsirolimus.

Patients receive temsirolimus intravenously (IV) over 30 minutes once weekly on days 1, 8,
15, and 22 and oral dexamethasone once on days 1, 2, 8, 9, 15, 16, 22, and 23. Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo bone marrow aspiration and blood sample collection periodically for
correlative studies. Correlative studies include analysis of p70S6 kinase activity in
peripheral blood mononuclear cells and in multiple myeloma cells; analysis of the degree of
AKT phosphorylation and degree of PTEN expression in multiple myeloma cells by
immunohistochemistry; Ras mutational analysis; and Myc 5'UTR mutational analysis.

After completion of study treatment, patients are followed for 4 weeks.

Inclusion Criteria:

- Pathologically confirmed multiple myeloma

- Measurable levels of M protein in serum and/or urine

- Recurrent or refractory disease

- Progressive disease after treatment with ≥ 2 separate chemotherapeutic regimens

- At least 1 of the regimens must have included high-dose dexamethasone (40
mg on days 1-4, 9-12, and 17-20) or medium-dose dexamethasone (40 mg on
days 1, 8, 15, and 22) of a 28-day course

- ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%

- Life expectancy ≥ 8 weeks

- Absolute neutrophil count > 1,000/mm^3

- Platelet count > 100,000/mm ^3

- Total bilirubin < 2 mg/dL

- AST and ALT < 3 times upper limit of normal

- Creatinine < 2 mg/dL

- Fasting cholesterol < 350 mg/dL

- Fasting triglycerides < 400 mg/dL

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No history of allergic reactions attributed to compounds of similar chemical or
biological composition to temsirolimus or dexamethasone

- No concurrent uncontrolled illness including, but not limited to, any of the
following:

- Ongoing or active infection

- Poorly controlled hypertension

- Diabetes mellitus

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness or social situation that would limit compliance with study
requirements

- See Disease Characteristics

- At least 4 weeks since prior cytotoxic therapy

- More than 4 weeks since prior chemotherapy and recovered

- No concurrent anticonvulsive or antiarrhythmic medications

- No concurrent enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine, or
phenobarbital) or other CYP3A4 inhibitors or inducers (e.g., rifampin or Hypericum
perforatum [St. John wort])

- No concurrent prophylactic hematopoietic colony-stimulating factors

- No other concurrent investigational therapy

- No other concurrent anticancer therapy