**7. Consolidation and maintenance therapies in MM**

Almost all patients with MM relapse after autologous HSCT. Hence, treatment given in the postautologous HSCT period is aimed at suppression of residual disease in order to prolong duration of response, OS and PFS while minimizing toxicity [125, 126].

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

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 of life (QoL) [126, 130].

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 treatment [137–141].

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

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

1. **Monoclonal antibodies:** Anti-CD 38 (daratumumab, elotuzumab, isatuximab, MOR202), anti-CD138 (indatuximab ravtansine), anti-interleukin-6 (siltuximab), anti-RANKL (denosumab), anti-KIR2DL1/2/4 (IPH2101)

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2. **Immunomodulatory agents:** thalidomide, lenalidomide, pomalidomide

8. **BCL2 antagonists (BH3 mimetics):** venetoclax, obatoclax, navitoclax

13. **Phosphoinositide 3-kinase-Akt inhibitors:** perifosine, afuresertib

16. **Chimeric antigen receptor T cells (CAR T cells):** directed against:

4. **Histone deacetylase inhibitors:** panobinostat, vorinostat, romidepsin, ricolinostat

6. **Checkpoint (programmed cell death protein 1) inhibitors:** nivolumab, pembrolizumab

3. **Proteasome inhibitors:** bortezomib, carfilzomib, ixazomib

5. **mTOR inhibitors:** everolimus, temsirolimus

7. **Bruton's tyrosine kinase inhibitors:** ibrutinib

9. **Cyclin-dependent kinase inhibitors:** dinaciclib

11. **Kinesin spindle protein 1 inhibitors**: filanesib, array 520 12. **Selective inhibitors of nuclear transport**: selinexor

10. **MEK inhibitors:** selumetinib

14. **PIM kinase inhibitors:** LGH 447

**c.** B-cell maturation antigen **d.** Cell surface glycoprotein

15. **Vaccines:** PVH-410

**a.** CD-19 **b.** CD-38

multiple myeloma.

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

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

monoclonal antibody that targets CD38, which is a cell surface

these novel agents are used in combination with other drugs [152].

**8.1. Daratumumab**

Daratumumab is a human IgG<sup>k</sup>

cellular phagocytosis and (4) apoptosis [153–156].
