**7. Supportive therapy**

Supportive care is critical throughout the clinical course of patients with MM because they are particularly susceptible to infections. Diligence in identifying and initiating treatment at the earliest sign is advised [27].

All MM patients with newly diagnosed MM and with adequate renal function should be initiated with monthly bone-modulating therapy at diagnosis with either denosumab, zoledronic acid or pamidronate (high recommendation) [27].

Patients with clinical manifestation of MM but without objective evidence of lytic lesions using the conventional radiography can be managed with zoledronic acid (intermediate recommendations), though its advantages using the more advanced objective measurements like CT and MRI is not yet well established [53].

In patients without clinical manifestations of myeloma, the use of bisphonphonates is not generally advised (high evidence of toxicities) [8]. The continuous use of Zoledronic acid recommended as long as the cycles of treatments are on progress, but sufficient data are lacking supporting it after partial response to therapy is

achieved [54, 55]. Denosumab doses can be administered at home if nursing facility is available or the patient should be trained for self-administration. Long-term discontinuation of denosumab treatment is associated with rebound effect and thus should be circumvented [8].

Sufficient data are available that prohibits the use of bortezomib-based regimens in patients with baseline clinical renal impairments. However, evidences are lacking supporting the discontinuation of therapy in patients who develop drug induced renal impairments [56, 57].

Severely anemic patients who do not respond to the conventional anemia management or deteriorating should be urgently switched to erythropoiesis stimulating agents (ESAs) in order to prevent the need for blood transfusions and frequent hospital visits. At present, the whole blood supplies has been extensively restricted due to the COVID-19 lockdown [8]. There are only few data advocating the use of ESAs in patients with persistent symptomatic anemia (hemoglobin <10 g/dL) where other causes of anemia have ruled out. Hence, ESAs should be discontinued after 6–8 weeks of therapy in patients' who fail to respond adequately to anemia treatment [58].

Immunization against influenza is recommended for specific infections caused by streptococcus pneumonia and hemophilus influenza, but sufficient data are lacking supporting the efficacy of the vaccination due to the fact that suboptimal immune responses are fairly seen after management [59].

If patients are receiving PIs & ASCT, the prophylactic use of antiviral agents such as acyclovir (or valacyclovir) are highly recommended [8, 60]. Acyclovir should be prescribed according to local protocols. Immunoglobulin administration may be given in an individualized basis, depending on the depth of suppression of polyclonal immunoglobulins and patient history of recurrent infections [34].

Antiviral prophylaxis has to be recommended in drugs associated with increased risk of herpes zoster reactivation such as Daratumumab and PIs. The prophylaxis is recommended for at least 3 months after exposure if no contraindications are observed [61].

Routine prophylaxis immunization should be considered with a series of pneumococcal conjugate vaccine 13 and pneumococcal polysaccharide vaccine, as well as annual influenza immunization [62]. Drugs such as IMiDs enhance the risk of venous thromboembolism, so preventive measures should be considered during active therapy [61], and the antithrombotic prophylaxis should be considered according to local or international guidelines. For countries with high incidence of COVID-19, low-molecular-weight heparin (LMWH) has to be preferred over aspirin as thromboprophylaxis in MM patients under IMiD administration, irrespective of their thrombotic risk [8, 63].

Patients with a history of neutropenias and/or recurrent infections should receive prophylactic G-CSF injections. Co-trimoxazole prophylaxis for Pneumocystis jirovecii for all patients and levofloxacin prophylaxis for the first three months of treatment for NDMM patients are also highly recommended [8, 55].

#### **8. Follow-up and monitoring**

Patients should be followed-up and monitored for complete blood counts (CBC), serum and urine electrophoresis with or without the use of serum-FLC determination, and also for serum calcium and creatinine measurements; at least in 2–3 months interval. In patients are complaining of bone pain, skeletal X-ray, MRI or CT scan should be carried out to detect and rule out new bone lesions [64].

**37**

*Treatment Approaches of Multiple Myeloma DOI: http://dx.doi.org/10.5772/intechopen.97390*

**cellular therapies**

**9.1 Venetoclax**

venetoclax [27].

BELLINI trial [27, 68].

undergoing [71].

refractory MM [73].

treatment paradigm [74, 75].

**9.2 BRAF & BRAF/MEK inhibitors**

**9.3 Monoclonal antibodies (CAR T cells and BCMA)**

**9. Emerging role of targeted therapies, monoclonal antibodies, and** 

Venetoclax is an orally bioavailable selective B-cell lymphoma 2 (Bcl-2) inhibitor. Bcl-2 and cyclin D1 are over expressed in MM patients with a translocation of (11;14), which is present in approximately 20% of patients with MM [65]. Venetoclax is an antiapoptotic protein and an emerging and effective treatment for relapsed or refractory MM [66, 67], and also being tried for treatment of chronic lymphocytic leukemia (CLL) cells [66] and non-Hodgkin lymphoma (NHL) [65]. Although response rates with venetoclax-dexamethasone are impressive in patients with t(11;14), PIs, which inhibit induced myeloid leukemia cell differentiation protein (Mcl-1), have synergistic activity when combined with

Currently the venetoclax is suspended by the Food and Drug Administration (FDA) because of a report obtained from the BELLINI trial, which stated an increased relative risk of death in the venetoclax group. As more recent data are being collected to have a better understanding of the safety concerns raised by the

BRAF is a proto-oncogene, that its protein product is a serine/threonine-protein kinase B-Raf that make conform the MAP kinase/ERKs signaling pathway, which works during cell division and differentiation [69]. In patients with MM, the incidence of BRAF V600E mutations is about 7–12% [70]. Trials evaluating BRAF and BRAF/MEK inhibitors in patients with MM harboring BRAF mutations are still

Monoclonal antibodies represent an emerging class of agents in MM treatment [72]. Daratumumab-RVd versus RVd, are being evaluated for ASCT-eligible patients [27]. Isatuximab, a humanized immunoglobulin G1 monoclonal antibody, has distinct characteristics in contrast to other anti-CD38 monoclonal antibodies [72]. Isatuximab in combination with IMROZ, isatuximab-RVd in ASCT-ineligible patients with newly diagnosed MM are being studied [72]; and isatuximab-Kd (IKEMA) and isatuximab-Pd (ICARIA) have been tried in patients with relapsed or

B-cell maturation antigen (BCMA) is a significant target communicated on MM cells, with other targets counting GPR5CD, CD138, CD74, CD48, CD38, SLAMF7, and transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI). Several strategies targeting BCMA include conjugated antibodies, cellular approaches, and bispecific T-cell engagers. Clinical trials evaluating BCMA-directed Chimeric antigen receptor redirected T cells (CAR-T cells) are furthest in development. Two notable BCMA CAR T-cell products are bb2121 and LCAR-B38M.69–71 Trials are evaluating CAR T cells in patients with relapsed or refractory MM to better understand their role in the MM

Newly introduced therapies that uses CAR T cells and BCMA antibodies bid promises of adding agents to the antimyeloma armamentarium of neoadjuvant mechanisms of actions [49]. Enduring trials will permit for the integration of
