Study of Bendamustine, Lenalidomide and Low-dose Dexamethasone, for the Treatment of Patients With Relapsed Myeloma

This is an open Label, Phase I/II, multicenter study. In the first phase it defines the maximum tolerated dose (MTD) of Bendamustine (B) given in combination with Lenalidomide (L) and low-dose Dexamethasone (d) and in the second phase it evaluates the antitumour activity of Bendamustine, Lenalidomide and Low-dose Dexamethasone (BdL) given in combination, in relapsed multiple myeloma patients.

Multiple myeloma is a B-cell malignancy resulting from the monoclonal proliferation of plasma cells within the bone marrow. According to the American Cancer Society, 14,600 new cases of multiple myeloma will be diagnosed in 2002, and these will account for approximately 1% of all new cancer cases. Multiple myeloma will contribute to 2% of all cancer deaths this year; an estimated 10,800 deaths will occur overall. The disease is more prevalent in men and is twice as common in African-Americans as in Caucasians. Multiple myeloma is commonly thought of as a disease of older patients; the median age at diagnosis is 68 years, and the incidence increases more than 4%/year in those older than 85 years. The median survival with standard treatment is only 3 years.

Therapeutic options for patients with multiple myeloma (MM) are rapidly changing. The emergence of two highly active novel agents, bortezomib and lenalidomide, have dramatically changed the landscape of treatment options and have improved outcomes for many patients. Combinations of conventional agents with novel agents have also demonstrated significant efficacy for patients with newly diagnosed and relapsed myeloma. Among the conventional agents that are being explored is the bifunctional alkylator agent bendamustine, which has demonstrated single-agent activity and activity with novel agents.

Lenalidomide is a new immunomodulating agent effective in multiple myeloma, especially when associated with dexamethasone or melphalan and prednisone. The role of lenalidomide in the treatment of relapsed/refractory patients with MM has been established and current research is focused on the combination of lenalidomide with chemotherapy to further improve results.

Bendamustine is a bi-functional alkylating agent with a purine- like benzimidazole ring that has been administered successfully to patients with MM. In vitro studies showed that bendamustine possesses a unique profile of activity, which was clearly divergent from other common nitrogen mustard drugs. Bendamustine and prednisone in newly diagnosed MM patients results in superior complete response rate, prolonged time to treatment failure and improved quality of life compared to treatment with melphalan and prednisone. The role of bendamustine, thalidomide and prednisolone (BPT) in patients with relapsed or refractory diseases stage II/III has been investigated by the East German Study group of Hematology and Oncology (OSHO). The response rate was higher than 80%.

Despite the impressive efficacy of the lenalidomide/dexamethasone in relapsed MM, treated patients will eventually relapse (median Time to Progression (TTP) is expected to be nearly a year according the results of the two phase III randomized studies). Combination with an effective novel agent as bendamustine could further increase both the response rate and the TTP of lenalidomide/dexamethasone and induce durable responses in relapsed or refractory MM patients. The identification of an appropriate lenalidomide dose to be adopted in combination with bendamustine and dexamethasone and the generation of exploratory data on the efficacy of this novel combination appears to be important in terms of future development of even more effective treatments of MM.

Eligibility Criteria:
Inclusion Criteria:

* Voluntary written informed consent
* Men and women age ≥ 18 years
* Female subjects are either post-menopausal or surgically sterilized or willing to use 2 simultaneous methods of contraception
* Male patients must agree to use a latex condom during sexual contact with females of childbearing potential throughout the study and for at least 28 days following discontinuation of lenalidomide;
* Confirmed diagnosis of Multiple Myeloma with measurable disease .Patients with evidence of relapsed disease after more than 1 and equal but not more than 3 prior lines of therapy.
* ECOG Performance Status 0 - 2
* Required baseline haematology and chemistry parameters

Exclusion Criteria:

* Myocardial infarction within 6 months prior to enrollment or has NYHA class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
* Female subjects either pregnant or breast-feeding (negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test result)
* Patients have received other investigational drugs with 14 days before enrollment.
* Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
* Any of the following laboratory abnormalities:

Absolute neutrophil count (ANC) \<1,000 /μl (1x109 /L) Untransfused platelet count \< 50,0000cell/μl (50x109 /L) Serum SGOT/AST or SGPT/ALT \> 2.0 upper limit of normal (ULN) Total bilirubin \> 2.0 mg/dL Renal insufficiently (serum creatinine level \> 2.5 mg/dl or Creatinine clearance \< 30 mL/min calculated by Cockcroft-Gault estimation)

* Patients with active infections are ineligible.
* Patients who are HIV positive are ineligible.
* Patients with active leptomeningeal involvement are ineligible.
* Patients with a history of previous CSF tumor involvement without symptoms or signs are eligible provided the CSF is now free of disease on lumbar puncture, and MRI of the brain shows no tumor involvement.
* History of other malignancies within 3 years prior to study entry except for adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer or breast, low grade, early stage localized prostate cancer treated surgically with curative intent (TNM stage of T1a or T1b),
* Patients with uncontrolled insulin-dependent diabetes mellitus or uncompensated major thyroid or adrenal dysfunction are ineligible.
* Patients with an ECOG performance status of \> 2 are ineligible.
* Malabsorption syndrome or uncontrolled gastrointestinal toxicities
* Clinically significant pleural effusion in the previous 12 months or current ascitis
* Clinically-significant coagulation or platelet function disorder
* Intolerance to bendamustine and/or lenalidomide