**10. Management of MM patients having renal failure**

targeting BCMA and CD3E (BI 836909) has been developed and it has been shown to be highly potent and efficacious to selectively deplete BCMA-positive MM cells; thus, it represents a novel immunotherapeutic approach in the treatment of MM [180]. CARs are proteins that incorporate antigen domain, costimulatory domains and T-cell activation domains [181]. Only a limited number of patients with MM received CAR T-cell therapy, but preliminary

BCMA is only expressed on some B cells, normal plasma cells and malignant plasma cells. The first clinical trial using CAR T cells targeting BCMA that is expressed in most cases of MM included 12 patients [181]. After dose escalation in the infusion of CAR-BCMA cells was used, the trial showed remarkable success and impressive activity against MM cells as BM plasma cells became undetectable by flow cytometry and patients entered stringent CR lasting for 17 weeks before relapse [181]. Another clinical trial using CAR-BCMA that included 21

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

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

patients showed increase in response rate from 89 to 100% after dose escalation [182].

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

results are encouraging [179].

138 Update on Multiple Myeloma

treatment [40].

Renal impairment (RI) is one of the most common complications of MM as 20–50% of patients with newly diagnosed MM present with RI, while 40–50% of patients develop RI during the course of the disease and about 5% of myeloma patients have dialysis-dependent renal failure (RF) at presentation [187–191]. In patients with MM, the causes of RI include myeloma cast nephropathy, excess of monoclonal free light chains causing proximal renal tubular damage, dehydration, infectious complications, hypercalcemia, hyperuricemia, use of nephrotoxic drugs and contrast media, hyperviscosity, myeloma cell infiltration and amyloid deposition [187–189, 192].

Bortezomib, thalidomide, lenalidomide and dexamethasone in various combinations can be used in the treatment of MM patients having RF and their use has been associated with high response rates and recovery of even partial or complete recovery of renal function [187–189, 191, 192]. In early chemotherapy trials, RF was considered a predictor of poor prognosis, patients with hemodialysis were reported to have a poorer prognosis and RF was considered an exclusion criterion from autologous HSCT because of the concerns about higher rates of treatment-related toxicity and nonrelapse mortality (NRM) due to mucositis, infectious complications and encephalopathy [187, 190]. However, recent studies have shown that autologous HSCT in patients with MM and RF has been associated with partial or complete recovery of renal function even in dialysis-dependent patients [190]. Therefore, autologous HSCT can be offered to patients with MM and RF with acceptable toxicity and NRM and a significant improvement in renal function that may be encountered in approximately one third of patients [187, 190]. In patients with MM and RF, a melphalan dose of 200 mg/m2 can be administered in the conditioning therapy of auto-HSCT without an increase in toxicity and NRM [190].

Kidney transplantation is the treatment of choice for most patients with end-stage renal failure (ESRD) as it is associated with improved survival and QoL compared to hemodialysis [193]. Even in patients with MM having RF, kidney transplantation is a valid therapeutic option in well-selected patients who achieve control of their disease and maintain a durable remission preferably for 3–5 years and have stable light chain levels but this option should be considered early in the course of the disease [194–197]. Combined HSCT, predominantly autologous HSCT, and renal transplantation have been performed for patients having various hematological disorders such as plasma cell dyscrasias [198–202]. Patients with MM having ESRD, either on regular hemodialysis or not, can be offered not only HSCT but also combined HSCT and renal transplantation either simultaneously or sequentially [198, 199, 203–206].
