Pomalidomide for the treatment of relapsed–refractory multiple myeloma: a review of biological and clinical data

Abstract

Despite the improvements thanks to the introduction of proteasome inhibitors and immunomodulatory drugs (IMiDs), nearly all myeloma patients eventually become refractory to these drugs. Consequently, the outcome of these patients is very poor. Pomalidomide is a new IMiD with a similar structure to the commonly used IMiD thalidomide and lenalidomide. Pomalidomide exhibited more potent anti-myeloma activity and a similar favorable safety profile compared with thalidomide and lenalidomide. In Phase I–II studies pomalidomide plus low-dose dexamethasone demonstrated activity in myeloma patients refractory to both bortezomib and IMiDs. Based on the results of a Phase III trial, the FDA and EMA agencies granted accelerated approval to pomalidomide, which is now considered a new effective strategy for relapsed and/or refractory myeloma patients. Very promising results were obtained when pomalidomide-dexamethasone was used in combination with other compounds. This review provides updated information about pharmacokinetics, mechanism of action, resistance, clinical efficacy and safety of pomalidomide.

Keywords::

• immunomodulatory drugs
• multiple myeloma
• pomalidomide
• refractory
• relapsed
• treatment

Financial & competing interests disclosure

M Offidani has received honoraria from Celgene, Janssen, Onix, Novartis, Amgen, Mundipharma, Sanofi; L Corvatta has received honoraria from Celgene and Janssen; PCaraffa has received honoraria from Celgene and Janssen; P Leoni has no conflict of interest to declare; A Larocca has received honoraria from Celgene and Janssen; A Palumbo has received honoraria and consultancy fees from Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millennium Pharmaceuticals and Onyx. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. The authors wish to thank Giorgio Schirripa for editorial assistance.

Key issues

• Pomalidomide is a new oral immunomodulatory drug exerting a potent antimyeloma activity by direct antiproliferative and proapoptotic effects, by bone marrow microenvironment modulation and by immunomodulation.

• Although the optimal schedule has not been yet established, pomalidomide at 2–4 mg orally for 21–28 days alone or with low-dose dexamethasone showed to be effective in relapsed/refractory multiple myeloma (MM). Yet, the recommended dose is 4 mg/day.

• In several Phase II studies, pomalidomide plus low-dose dexamethasone was effective in patients with advanced disease, with disease refractory to lenalidomide, to bortezomib or both.

• In a Phase III study, Pd demonstrated significantly better response rate, progression-free survival and overall survival compared with high-dose dexamethasone in patients with MM who became resistant to both lenalidomide and bortezomib.

• Pomalidomide in combination with ‘old’ and novel drugs has a very promising activity in relapsed/refractory MM.

• Pomalidomide alone or in combination, similarly to lenalidomide, has a manageable safety profile: hematological toxicity, pneumonia and fatigue are the most common adverse events, whereas thromboembolic complications and neurological toxicity are very rare.

• Pd has been recently approved in USA and in Europe for the treatment of patients with MM who have received at least two prior therapies including lenalidomide and bortezomib and progressed on the last therapies.

• The efficacy of combinations including Pomalidomide in less advanced disease stages, in first-line therapy and in maintenance strategies should be urgently explored.