A Multicenter Open Label Phase II Study of Pomalidomide and Dexamethasone in Progressive Relapsed or Refractory Multiple Myeloma Patients With Deletion 17p or Translocation (4;14) Adverse Karyotypic Abnormalities-IFM2010-02

BACKGROUND AND RATIONALE. Multiple myeloma (MM) is an incurable disease that is characterized by the accumulation of clonal plasma cells in the bone marrow [1]. The median overall survival for patients with myeloma is approximately 4-5 years, and MM remains an incurable disease. Despite front line treatment approaches, the disease eventually relapses. While patients with relapsed disease may achieve responses to subsequent antimyeloma therapies, the duration of response decreases with successive relapses until resistant disease develops. Until recently, the median survival following relapse after induction therapy was approximately one year. The recent US Food and Drug Administration approvals of bortezomib (2003) and combination lenalidomide plus dexamethasone (2006) therapies for the treatment of previously treated MM has provided effective therapeutic options that give patients with relapsed or refractory MM the prospect for a prolongation of overall and progression-free survival times [2-4].

Although the introduction of novel agents to the autologous transplant procedure in patients less than 65 years old or to the Melphalan Prednisone regimen in elderly patients has significantly improved response rates and survival times, MM is a heterogeneous disease with divergent outcomes driven by the biologic characteristics, especially cytogenetic characteristics [5, 6]. Various studies have demonstrated that cytogenetic characteristic as detected by fluorescent in situ hybridization (FISH) was one of the most powerful prognostic marker in MM, especially presence of deletion of 17p13 (del17p) [6, 7] and translocation t(4;14) [6, 7] that represent approximately 20% to 25% of patients in the series [8]. The del(17p) and t(4;14) chromosomal abnormalities are associated with poor progression-free survival and shorter overall survival in newly diagnosed MM patients treated with traditional chemotherapy … The conclusion of recent studies were that a clear unmet medical need still exists for additional novel therapeutic options for the treatment of MM with del17p and t(4;14) and that novel agents should be proposed earlier in the patient evolution.

Pomalidomide belongs to the immunomodulators compounds which thalidomide is the parent compound and lenalidomide the most recently approved agent [14]. It is derived from thalidomide and shares a number of the beneficial pharmacologic properties with thalidomide. The efficacy of thalidomide has been limited by adverse effects, which include sedation, neuropathy, constipation, and deep vein thrombosis. This toxicity profile seems dose and duration-related,which have the potential of improved potency and reduced toxicity. By modifying the thalidomide structure through the addition of an amino group at the 4 position of the phthaloyl ring, pomalidomide was generated.

… A phase 2 randomised open label study of 2 modalities of Pomalidomide plus low-dose Dexamethasone in patients with Multiple Myeloma, refractory to both lenalidomide and bortezomib was conducted. This study was addressed to patients with MM who were symptomatic and progressive following at least two cycles of lenalidomide and two cycles of bortezomib (either separately or in combination). This study provides further evidence that pomalidomide has no-cross resistance with lenalidomide and suggests that it can provide benefit for patients who have relapsed after other novel therapies. This data demonstrated that pomalidomide has significant efficacy in MM and can be safely administered to myeloma patients.

STUDY RATIONALE. There is an increasing number of patients with adverse karyotypic abnormalities, such as del17p and t(4;14), that requires new therapeutic options to improve progression free survival and ultimately overall survival. Based on recent studies, we hypothesized that these patients might benefit from the combination of pomalidomide and dexamethasone. We have therefore designed a Multicenter Open label Phase II study of Pomalidomide and Dexamethasone in Progressive Relapsed or refractory Multiple Myeloma patients with deletion 17p or translocation (4;14) Adverse Karyotypic Abnormalities. This study will determine the efficacy and toxicity profile of pomalidomide and dexamethasone in patients with adverse prognostic factors as determined using adverse karyotypic abnormalities and that are in desperate need of novel therapeutics. This study will be conducted in accordance with "good clinical practice" and all applicable regulatory requirements, including, where applicable, the 2008 version of the Declaration of Helsinki.