**8. Novel therapies in MM**

The novel therapies that have recently been introduced into the treatment of MM include (1) proteasome inhibitors such as bortezomib, carfilzomib and ixazomib; (2) immunomodulatory agents such as thalidomide, lenalidomide and pomalidomide; (3) monoclonal antibodies such as daratumumab and elotuzumab and (4) histone deacetylase inhibitors such as panobinostat, in addition to other classes of medications that can also be used in the treatment of MM such as glucocorticoids, DNA alkylating agents, as well as doxorubicin, cisplatinum and etoposide [10, 13, 15, 62–64]. Novel agents and targeted therapies that are either currently used or under development for the treatment of MM are shown in **Table 1** [61, 62, 142–150].

Several cell cycle regulatory proteins have been proposed as therapeutic targets in patients with MM. Other targets that have already been identified in MM include microtubules,


The use of novel therapies in the consolidation phase following single or tandem autologous HSCT has been shown to enhance the rate as well as the quality of response thus contributing to improvements in clinical outcomes including prolongation of PFS [126]. Bortezomib-based regimens used as consolidation therapy after autologous HSCT in patients with MM have

Maintenance therapy represents an important therapeutic strategy to delay disease progression and relapse [125, 126]. The following drugs have been used in postautologous HSCT maintenance: interferon, thalidomide, bortezomib and carfilzomib [125, 126, 128–130]. Bortezomib is safe, well tolerated and efficacious and it can be used with no risk of second malignancy till disease progression, but its disadvantages include cost and effects on quality

In February 2017, the Food and Drug Administration in the USA approved the use of lenalidomide as maintenance therapy after autologous HSCT for patients with MM, after showing efficacy and safety in several studies [131]. Lenalidomide has tumoricidal and immunomodulatory activities against MM [132]. Several studies have shown the efficacy of lenalidomide maintenance after autologous HSCT as this therapy has been shown to be associated with significant improvements in OS, PFS and longer time to disease progression [133–136]. A multicenter, randomized double-blind study that included 306 patients with newly diagnosed MM ≥65 years of age and ineligible for autologous HSCT treated initially with melphalan, prednisolone and lenalidomide induction followed by lenalidomide versus placebo maintenance showed the following results: (1) significant prolongation of PFS, (2) maximum benefit was achieved in patients 65–75 years of age and (3) 3-year second primary tumor of 7% in the lenalidomide arm versus 3% in the placebo arm [132]. Other studies on lenalidomide maintenance have shown more toxicity and low rate of development of second tumors [133, 134]. Lenalidomide maintenance can be initiated as early as day 100 postautologous HSCT [133]. Duration of lenalidomide maintenance longer than 3 years has been associated with further improvement in survival [134]. Several studies performed in patients with newly diagnosed MM subjected to autologous HSCT have shown continuous therapy to be more effective in prolongation of OS and PFS that limited the duration of

The novel therapies that have recently been introduced into the treatment of MM include (1) proteasome inhibitors such as bortezomib, carfilzomib and ixazomib; (2) immunomodulatory agents such as thalidomide, lenalidomide and pomalidomide; (3) monoclonal antibodies such as daratumumab and elotuzumab and (4) histone deacetylase inhibitors such as panobinostat, in addition to other classes of medications that can also be used in the treatment of MM such as glucocorticoids, DNA alkylating agents, as well as doxorubicin, cisplatinum and etoposide [10, 13, 15, 62–64]. Novel agents and targeted therapies that are either currently used or under

Several cell cycle regulatory proteins have been proposed as therapeutic targets in patients with MM. Other targets that have already been identified in MM include microtubules,

development for the treatment of MM are shown in **Table 1** [61, 62, 142–150].

been shown to be effective in the improving PFS and decreasing relapse rate [127].

of life (QoL) [126, 130].

134 Update on Multiple Myeloma

treatment [137–141].

**8. Novel therapies in MM**

	- **a.** CD-19
	- **b.** CD-38
	- **c.** B-cell maturation antigen
	- **d.** Cell surface glycoprotein

**Table 1.** Novel agents and targeted therapies that are either currently used or under development for the treatment of multiple myeloma.

kinesin motor proteins, aurora kinases, polo-like kinases and the anaphase-promoting complex/cyclosome [151]. The novel therapies that are used in the treatment of MM differ in their modes of action. Nevertheless, each drug has its own side effects that should be considered particularly once treating patients with comorbid medical conditions and once these novel agents are used in combination with other drugs [152].

#### **8.1. Daratumumab**

Daratumumab is a human IgG<sup>k</sup> monoclonal antibody that targets CD38, which is a cell surface protein that is overexpressed in MM cells. It is given IV at a dose of 16 mg/kg weekly [153–156]. It induces death of MM cells by several mechanisms including (1) complement-dependent cytotoxicity, (2) antibody-dependent cell-mediated cytotoxicity, (3) antibody-dependent cellular phagocytosis and (4) apoptosis [153–156].

Daratumumab has shown substantial efficacy as monotherapy in heavily pretreated patients with MM as well as in combination with bortezomib in patients with newly diagnosed MM [154]. Two phase III randomized clinical trials in R/R MM using daratumumab in combination with either bortezomib and dexamethasone or lenalidomide and dexamethasone showed significantly longer PFS with manageable toxicity [154, 156]. In a phase III randomized clinical trial performed in patients with newly diagnosed MM, not eligible for autologous HSCT, the addition of daratumumab to bortezomib, melphalan and prednisolone decreased the risk of death and disease progression but was also associated with higher rates of infections [155]. The adverse effects of daratumumab include infusion-related reactions, hematologic toxicity in the form of neutropenia and thrombocytopenia and various infectious complications [153–156].

median PFS of 7.8 months for panobinostat, bortezomib and dexamethasone in comparison with placebo, bortezomib and dexamethasone [168–171]. Panobinostat, in combination with bortezomib and dexamethasone, was recently approved in the USA, Europe and Japan for the treatment of patients with MM who had failed at least two prior regimens including bortezomib and an immunomodulatory agent [168–171]. A meta-analysis that included 11 clinical trials and 700 patients with R/R-MM treated with panobinostat demonstrated not only efficacy but also safety of panobinostat in combination with other agents [172]. The main toxic effects of panobinostat are thrombocytopenia and diarrhea. However, several studies showed other adverse effects including lymphopenia, neutropenia and anemia, nausea, vomiting, constipation and abdominal pain, asthenia, fatigue, peripheral edema and peripheral neuropathy [167–172]. Ongoing clinical trials are evaluating the role of panobinostat in combination with drugs other than bortezomib in R/R-MM, in combination with various drugs in newly diag-

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CAR is a hybrid antigen receptor that is composed of an extracellular antigen-binding domain and an intracellular signaling domain. T cells genetically targeted with a CAR to B-cell malignancies have demonstrated tremendous clinical outcome [173]. Immunotherapy using CARmediated T cells has demonstrated high response rates in patients with B-cell malignancies. CAR T-cell therapy is a cellular therapy that redirects a patient's T cells to specifically target and destroy tumor cells [174]. CARs are genetically engineered fusion proteins composed of antigen recognition domain derived from a monoclonal antibody as well as an intracellular

There are multiple steps in the production of CAR T cells and these include (1) leukapheresis to separate leukocytes; (2) enrichment of leukapheresis product with T cells; (3) separation of T-cell subsets at the level of CD4/CD8 composition using specific antibody-based conjugates or markers; (4) T-cell selection or activation, gene transfer or genetic modification and viral transduction; (5) volume expansion of T cells, isolation, washing and culture followed by

Adverse effects of CAR T-cell therapy include cytokine release syndrome (CRS), neurotoxicity, on target/off tumor recognition and anaphylaxis. Additionally, theoretical toxicities of CAR T cells include clonal expansion secondary to insertional oncogenesis, GVHD and offtarget antigen recognition [176]. Management of CAR T-cell toxicity includes supportive measures, immunosuppression with tocilizumab (IL-6) receptor blockade for CRS and suicide or

CAR expressing T cells have demonstrated success in the treatment of B-cell lymphoid malignancies particularly CD19+ acute lymphoblastic leukemia and chronic lymphocytic leukemia [177]. Cell surface glycoprotein (CS1) is highly expressed on MM cells and is an ideal target for the treatment of MM, that is, CS1 can be targeted by CAR natural killer cells to treat MM [177]. A patient with advanced and refractory MM received myeloablative treatment

CAR resulted in CR with no disease progression for 12 months after CAR T-cell infusion [178]. CAR T cells can target the following antigens in patients with MM: B-cell maturation antigen (BCMA), CD138, CD19 and kappa-light chain [179]. A bispecific T-cell engager (BiTE)

, followed by autologous HSCT, and then infusion of CTL019

nosed disease and in maintenance therapy of myeloma [169].

T-cell signaling domain and a costimulatory domain [174].

cryopreservation and (6) infusion of CAR T cells [174, 175].

elimination genes to allow for selective depletion of CAR T cells [176].

**8.6. CAR T cells**

with melphalan 140 mg/m2

#### **8.2. Elotuzumab**

Elotuzumab is an immunostimulatory monoclonal antibody targeting signaling lymphocyte activation molecule F7 (SLAMF7) [157]. While no responses to elotuzumab as a single agent were obtained, the addition of elotuzumab to lenalidomide and dexamethasone in RR-MM patients resulted in overall response rate (ORR) of 79% compared to 66% ORR obtained with lenalidomide and dexamethasone alone [142, 158]. Also, in a phase III randomized clinical trial in patients with R/R-MM, the combination of elotuzumab, lenalidomide and dexamethasone decreased the risks of death and disease progression by 30% [157].

#### **8.3. Pomalidomide**

Pomalidomide is a third-generation immunomodulatory agent that has been approved for patients with progressive MM or those who have received at least two lines of therapy [159]. It has been shown to be effective in combination with dexamethasone ± carfilzomib or other agents in patients with R/R-MM or in those with HR cytogenetics [159–162]. The use of pomalidomide combined with low-dose dexamethasone in heavily pretreated patients with R/R-MM has been shown to be cost-effective as the combination has produced clinical outcomes comparable to those obtained by daratumumab alone or carfilzomib alone [5].

#### **8.4. Carfilzomib**

Carfilzomib is a second-generation proteasome inhibitor [163]. It is well tolerated and causes minimal neurotoxicity. It has demonstrated promising activity in patients with MM who are refractory to bortezomib or immunomodulatory agents [163–165]. It can be combined with dexamethasone or other novel agents [164–166].

It is able to sensitize 24% of bortezomib-refractory MM patients. When combined with dexamethasone in R/R-MM, it resulted in superior outcome in terms of ORR and PFS compared to bortezomib and dexamethasone combination [158]. Also, it is under evaluation for patients with newly diagnosed MM [166].

#### **8.5. Panobinostat**

Histone deacetylase inhibitors such as panobinostat and vorinostat have demonstrated some activity against MM and they have multiple proposed mechanisms of actions once used in the treatment of MM [167]. Panobinostat is a potent oral pan-deacetylase inhibitor. It affects growth and survival of MM cells through alteration of (1) gene expression through epigenetic modification and (2) protein metabolism by inhibiting protein degradation [168–171]. The approval of panobinostat for the treatment of MM was based on the results of phase III randomized double-blind clinical trial (PANORAMA 1), which demonstrated improvement in median PFS of 7.8 months for panobinostat, bortezomib and dexamethasone in comparison with placebo, bortezomib and dexamethasone [168–171]. Panobinostat, in combination with bortezomib and dexamethasone, was recently approved in the USA, Europe and Japan for the treatment of patients with MM who had failed at least two prior regimens including bortezomib and an immunomodulatory agent [168–171]. A meta-analysis that included 11 clinical trials and 700 patients with R/R-MM treated with panobinostat demonstrated not only efficacy but also safety of panobinostat in combination with other agents [172]. The main toxic effects of panobinostat are thrombocytopenia and diarrhea. However, several studies showed other adverse effects including lymphopenia, neutropenia and anemia, nausea, vomiting, constipation and abdominal pain, asthenia, fatigue, peripheral edema and peripheral neuropathy [167–172]. Ongoing clinical trials are evaluating the role of panobinostat in combination with drugs other than bortezomib in R/R-MM, in combination with various drugs in newly diagnosed disease and in maintenance therapy of myeloma [169].

#### **8.6. CAR T cells**

significantly longer PFS with manageable toxicity [154, 156]. In a phase III randomized clinical trial performed in patients with newly diagnosed MM, not eligible for autologous HSCT, the addition of daratumumab to bortezomib, melphalan and prednisolone decreased the risk of death and disease progression but was also associated with higher rates of infections [155]. The adverse effects of daratumumab include infusion-related reactions, hematologic toxicity in the form of neutropenia and thrombocytopenia and various infectious complications [153–156].

Elotuzumab is an immunostimulatory monoclonal antibody targeting signaling lymphocyte activation molecule F7 (SLAMF7) [157]. While no responses to elotuzumab as a single agent were obtained, the addition of elotuzumab to lenalidomide and dexamethasone in RR-MM patients resulted in overall response rate (ORR) of 79% compared to 66% ORR obtained with lenalidomide and dexamethasone alone [142, 158]. Also, in a phase III randomized clinical trial in patients with R/R-MM, the combination of elotuzumab, lenalidomide and dexametha-

Pomalidomide is a third-generation immunomodulatory agent that has been approved for patients with progressive MM or those who have received at least two lines of therapy [159]. It has been shown to be effective in combination with dexamethasone ± carfilzomib or other agents in patients with R/R-MM or in those with HR cytogenetics [159–162]. The use of pomalidomide combined with low-dose dexamethasone in heavily pretreated patients with R/R-MM has been shown to be cost-effective as the combination has produced clinical outcomes comparable to those obtained by daratumumab alone or carfilzomib alone [5].

Carfilzomib is a second-generation proteasome inhibitor [163]. It is well tolerated and causes minimal neurotoxicity. It has demonstrated promising activity in patients with MM who are refractory to bortezomib or immunomodulatory agents [163–165]. It can be combined with

It is able to sensitize 24% of bortezomib-refractory MM patients. When combined with dexamethasone in R/R-MM, it resulted in superior outcome in terms of ORR and PFS compared to bortezomib and dexamethasone combination [158]. Also, it is under evaluation for patients

Histone deacetylase inhibitors such as panobinostat and vorinostat have demonstrated some activity against MM and they have multiple proposed mechanisms of actions once used in the treatment of MM [167]. Panobinostat is a potent oral pan-deacetylase inhibitor. It affects growth and survival of MM cells through alteration of (1) gene expression through epigenetic modification and (2) protein metabolism by inhibiting protein degradation [168–171]. The approval of panobinostat for the treatment of MM was based on the results of phase III randomized double-blind clinical trial (PANORAMA 1), which demonstrated improvement in

sone decreased the risks of death and disease progression by 30% [157].

**8.2. Elotuzumab**

136 Update on Multiple Myeloma

**8.3. Pomalidomide**

**8.4. Carfilzomib**

**8.5. Panobinostat**

dexamethasone or other novel agents [164–166].

with newly diagnosed MM [166].

CAR is a hybrid antigen receptor that is composed of an extracellular antigen-binding domain and an intracellular signaling domain. T cells genetically targeted with a CAR to B-cell malignancies have demonstrated tremendous clinical outcome [173]. Immunotherapy using CARmediated T cells has demonstrated high response rates in patients with B-cell malignancies. CAR T-cell therapy is a cellular therapy that redirects a patient's T cells to specifically target and destroy tumor cells [174]. CARs are genetically engineered fusion proteins composed of antigen recognition domain derived from a monoclonal antibody as well as an intracellular T-cell signaling domain and a costimulatory domain [174].

There are multiple steps in the production of CAR T cells and these include (1) leukapheresis to separate leukocytes; (2) enrichment of leukapheresis product with T cells; (3) separation of T-cell subsets at the level of CD4/CD8 composition using specific antibody-based conjugates or markers; (4) T-cell selection or activation, gene transfer or genetic modification and viral transduction; (5) volume expansion of T cells, isolation, washing and culture followed by cryopreservation and (6) infusion of CAR T cells [174, 175].

Adverse effects of CAR T-cell therapy include cytokine release syndrome (CRS), neurotoxicity, on target/off tumor recognition and anaphylaxis. Additionally, theoretical toxicities of CAR T cells include clonal expansion secondary to insertional oncogenesis, GVHD and offtarget antigen recognition [176]. Management of CAR T-cell toxicity includes supportive measures, immunosuppression with tocilizumab (IL-6) receptor blockade for CRS and suicide or elimination genes to allow for selective depletion of CAR T cells [176].

CAR expressing T cells have demonstrated success in the treatment of B-cell lymphoid malignancies particularly CD19+ acute lymphoblastic leukemia and chronic lymphocytic leukemia [177]. Cell surface glycoprotein (CS1) is highly expressed on MM cells and is an ideal target for the treatment of MM, that is, CS1 can be targeted by CAR natural killer cells to treat MM [177]. A patient with advanced and refractory MM received myeloablative treatment with melphalan 140 mg/m2 , followed by autologous HSCT, and then infusion of CTL019 CAR resulted in CR with no disease progression for 12 months after CAR T-cell infusion [178]. CAR T cells can target the following antigens in patients with MM: B-cell maturation antigen (BCMA), CD138, CD19 and kappa-light chain [179]. A bispecific T-cell engager (BiTE) 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 results are encouraging [179].

(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

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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

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

can be administered in

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

[187, 190]. In patients with MM and RF, a melphalan dose of 200 mg/m2

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].

76% ORR [142, 158].

[187–189, 192].

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