**9. Refractory and/or relapsed MM (R/R-MM)**

The course of MM progression is highly variable as almost all patients with MM who respond to initial therapy will eventually relapse and require further treatment [6]. The introduction of novel agents over the last 15 years, the implementation of new therapeutic strategies and the adoption of drug combinations that include highly effective and tolerable drugs have improved (1) the clinical outcome dramatically as response rates have increased from approximately 30% with single agents to about 90% with combination therapies and (2) the QoL even in heavily pretreated patients. However, determining the optimal sequence and combination as well as timing of each agent is necessary [6]. In a retrospective analysis of 628 patients with newly diagnosed MM who developed relapse after initial therapy, it was found that prolonged duration of treatment was associated with improved survival [141]. Unfortunately, secondary plasma cell leukemia and EMD still present difficult therapeutic challenges [16].

There is no standard of care for MM relapse after autologous HSCT [183, 184]. Regimens that are composed of combination therapy with (1) drugs having synergistic effect and no crossresistance and (2) one or two novel therapies are generally preferred as they lead to deeper and longer responses that are translated into improved survival [16, 183–185]. However, treatment should be individualized based on toxicity as well as patient and disease characteristics [184]. A meta-analysis of phase III randomized controlled trials showed that, compared to doublet regimens, triplets resulted in improved OS, PFS, very good partial response and CR although the risk of having grade III/IV drug adverse effects was higher with triplet regimens [185].

Mechanisms of drug resistance in MM include (1) multidrug-resistant gene polymorphism, (2) P-glycoprotein overexpression in MM cells, (3) microenvironmental changes, (4) clonal evolution including, (5) cancer stem cells, (6) upregulation and downregulation of various micro-RNAs and (7) selected CD34+, CD 138+, B7-, H1+, CD19- plasma cell accumulation after treatment [40].

Therapeutic options for patients with R/R-MM include (1) salvage therapy; combination of old and new therapies such as (a) bortezomib, thalidomide, cisplatin, cyclophosphamide, etoposide and doxorubicin (VTD-PACE); (b) KRD/carfilzomib, pomalidomide and dexamethasone (KPD) ± PACE or (c) daratumumab-based therapy; (2) second autologous HSCT; (3) allogeneic HSCT in carefully selected patients and (4) enrollment in clinical trials [8, 11, 13, 16]. Specific agents that are used in the treatment of R/R-MM include (1) immunomodulatory agents such as thalidomide, lenalidomide and pomalidomide; (2) proteasome inhibitors such as bortezomib, carfilzomib and ixazomib; (3) monoclonal antibodies such as daratumumab and elotuzumab; (4) histone deacetylase inhibitors such as panobinostat and (5) pembrolizumab [6, 142, 157, 158, 164, 186]. The use of pembrolizumab (antiprogrammed cell death 1) in combination with lenalidomide and dexamethasone in patients with R/R-MM resulted in 76% ORR [142, 158].
