Targeting Intracellular Signaling Cascades for Patients with Relapsed, Refractory Multiple Myeloma: A Systematic Review of Clinical Trials

• Published in: Blood 2018-11, Vol.132 (Supplement 1), p.5659-5659
• Main Authors: Aslam, Shehroz, Malik, Mustafa Nadeem, Rafae, Abdul, Riaz, Rida, Durer, Seren, Durer, Ceren, Mahfooz, Faisal, Khalil, Muhammad Jahanzeb, Jose, Jemin Aby, Shah, Zunairah, Sohail, Chaudhry Saad, Yusufi, Maaz Ahmed, Anwer, Faiz
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2018-99-115721

Introduction: Intracellular signaling cascades including mTOR (mammalian target of rapamycin), MEK (mitogen-activated protein kinase), BCL2 (B-cell lymphoma 2), MET, AKT, and BTK (Bruton's tyrosine kinase) pathways are involved in the growth, proliferation, and survival of tumor cells. Drugs that inhibit these signaling cascades lead to apoptosis and cell cycle arrest making them an important therapeutic modality for treatment of malignancies. The aim of our review is to analyze the published literature on the clinical efficacy of these intracellular signaling cascade inhibitors in patients with relapsed, refractory multiple myeloma (RRMM). Methods: We performed a comprehensive literature search on articles published after 2010. Four hundred and twenty-three articles were identified using the following five databases (Pubmed, Embase Cochrane, Web of Science and Clinical Trials.gov). After a detailed screening, we finalized 11 studies involving 525 RRMM patients. Clinical trials (phase I/II, II and III) with non-FDA approved drugs were included. Results: mTOR inhibitors (Everolimus and Temsirolimus): A total of 157 RRMM patients were included. All trials were early phase (I/II). Everolimus in combination with panobinostat (n=32) achieved an overall response rate (ORR) of 7%. A total of 82 patients received everolimus in combination with sorafenib and achieved a complete response (CR) of 8.5%. Temsirolimus was used in combination with bortezomib (V) (n=43). CR was observed in 5% patients, very good partial response (VGPR) in 9% and stable disease (SD) in 44% patients. AKT Inhibitors (Perifosine and Uprosertib): A total of 153 RRMM patients were included. Eighty-four patients were tested in phase I/II trials while 69 patients were tested in phase III trials. All patients were given perifosine (50 mg) in combination with V with or without dexamethasone (d). In 142 evaluable patients, the pooled ORR was 31%. Uprosertib is currently under phase II evaluation, no clinical data is available while one ongoing phase I/II trial is summarized in Table 2. MEK inhibitor (Selumetinib): A total of 36 RRMM patients were included. All patients were tested in phase II trials. Single-agent selumetinib (75 mg) was given (n= 32). The ORR was 5.6%, VGPR in 3.12%, partial response (PR) in 3.12%, SD in 53.13% and progressive disease (PD) in 40.63% patients. The median progression-free survival (mPFS) was 3.52 months. BCL2 inhibitor (Venetoclax): A total of 66 RRMM patients were in