LAUSR

Multiple myeloma (MM) is still considered an incurable disease by the majority of experts in the field. Thus, new drugs with novel mechanisms of action are needed. Besides the next generations of proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs), monoclonal antibodies (mAbs), especially those targeting CD38, have become the backbone of the anti-myeloma armamentarium, leading to prolonged overall survival (Mateos et al., 2019; Moreno et al., 2019). There are two approved agents with distinct mechanisms of action (selinexor and panobinostat), but their indications and use are currently limited (Chari et al., 2019). Moreover, there is an emerging and highly promising group of agents targeting B cell maturation antigen (BCMA), both mAbs and cell-based therapies that might be approved soon (Lonial et al., 2019; Raje et al., 2019). Nevertheless, treatment of the so-called ‘triple-class refractory’ MM patients still remains highly challenging. The members of the B cell leukaemia/lymphoma 2 (Bcl-2) family play a crucial role in the regulation of the intrinsic apoptotic pathway. The overexpression of these antiapoptotic proteins (Bcl-2, Bcl-XL, Mcl-1) ranks amongst one of the hallmarks of cancer that favours tumour cell growth and induces resistance to therapy (Touzeau et al., 2018). It was demonstrated both in vitro and in vivo that a subgroup of patients with myeloma is Bcl-2 dependent. Venetoclax, a potent, selective, oral inhibitor of Bcl-2, demonstrated singleagent activity in human myeloma cell lines, as well as in primary MM samples that were positive for t(11;14). The presence of t(11;14) is correlated with high Bcl-2/Bcl-XL and Bcl2/Mcl-1 mRNA ratios, which is crucial for sensitivity to venetoclax. It is important to note that sensitivity to venetoclax was not exclusive to samples with t(11;14) (Touzeau et al., 2014; Kumar et al., 2017). Venetoclax monotherapy was examined in a phase 1 trial in 66 patients with relapsed/ refractory MM (RRMM), with a median of five prior lines of therapy. The overall response rate (ORR) was 21% (14/66); in the subgroup with t(11;14) the ORR was 40% (27/66) (Kumar et al., 2017). Resistance to venetoclax may be caused by the high expression of Bcl-XL or Mcl-1, but may be mitigated by the co-administration of proteasome inhibitors, such as bortezomib, which can inhibit Mcl-1 (Qin et al., 2005). The combination of venetoclax with PIs is indeed a logical step due to its anticipated synergism. The regimen consisting of venetoclax, bortezomib and dexamethasone (Ven-VD) was examined in a phase 1b clinical trial enrolling 66 patients with RRMM, with a median of three previous therapies. The ORR was 65% in patients without t(11;14) and 78% in patients with t(11;14) (Moreau et al., 2017). Finally, the preliminary analysis of the ongoing phase 3 randomised study comparing venetoclax vs. placebo plus VD in patients with RRMM with one to three previous lines of therapy has shown superior median progressionfree survival (mPFS) of Ven-VD vs. placebo (mPFS 22 9 vs. 11 4 months; hazard ratio [HR] 0 587), and even better results for t(11;14)-positive patients (mPFS not reached vs. 9 3 months; HR 0 095). Unfortunately, the study was halted by the US Food and Drug Administration (FDA) due to an increased rate of deaths alongside the trend of worsening OS in the experimental arm (HR 2 027). Most treatment-emergent deaths were due to infections. The clinical trial continues to enrol only a subset of patients with present t(11;14) who demonstrated the best benefit (Moreau, 2019). Testing for t(11;14) using the FISH (fluorescence in situ hybridisation) technique is a part of the comprehensive panel recommended by the International Myeloma Working Group (IMWG) and patients with MM positive for t(11;14) are considered as a standard risk group. Determination of the presence of t(11;14) is routinely available and is easily obtainable in the majority of centres, making it the perfect biomarker. There are also other techniques that could be used to predict sensitivity to venetoclax, such as BH3 profiling, determination of Bcl-2 expression by immunohistochemistry (≥50% of cells) or assessment of Bcl-2 family Correspondence: Tomas Jelinek, MD, Department of Haematooncology, University Hospital Ostrava, 17. listopadu 1790, 708 52 Ostrava, Czech Republic. E-mail: [email protected] commentary