**4. Management of newly diagnosed cases**

Currently, for fit newly diagnosed MM patients (NDMM), autologous stem cell transplant (ASCT) considered as the standard care of treatment. But it should be noted that there is also a remarkable results obtained from the non-transplant setting with novel agent-based treatment, which later raised questions as to the role of upfront versus delayed ASCT [9].

Numerous rescue alternatives that incorporate distinctive combinations of medicines have been developed after the emergence of 2nd generation PIs and IMIDs, monoclonal antibodies (MAs), histone deacetylase inhibitors (HDIs), and, more as of late, check-point inhibitors (CPIs) and small molecules [17, 18]. These promising improvement requests a critical evaluation of treatment options to adequately top up the advantages of different induction, consolidation and maintenance approaches, and to set, a treatment ground so as to compare forthright ASCT, salvage ASCT and allotransplant in the era of novel agent [9].

Several drugs have shown promising activity against MM and are being used in clinical practice [19].

#### **4.1 Induction therapy for ASCT-eligible patients**

For patients with ASCT-eligible newly diagnosed MM, induction therapy with triple drugs should contain an IMiD, a PI, and a corticosteroid (Cs), usually lenalidomide-bortezomib-dexamethasone (RVd) [20]. The preferred induction therapy is combination of bortezomib with lenalidomide or thalidomide and dexamethasone (VRd or VTD), as well as the combination of daratumumab with VTD (DaraVTD) [21].

For patients presenting with renal impairment, cyclophophosphamidebortezomib-dexamethasone is preferred, with the option to switch to RVd up on improvement of renal function. For patients intolerant to the triple therapy, double therapy can be used such as bortezomib-dexamethasone (Vd) and lenalidomidedexamethasone (Rd), (**Figure 1**) [22].

Induction treatment can be administered for an extended period for up to 6–8 cycles [23]. A third drug can be added up on improvement of the patient started with two drugs. Recent data with carfilzomib-lenalidomide-dexamethasone (KRd) induction has shown much promise, and ongoing studies comparing the upfront KRd versus RVd have shown equivalent outcomes, if not improved [24].

Looking at the options of the novel triple (or quadruple) upfront Vs postpone for NDMM patients, it is widely advised that mobilization, stem cell harvest, conditioning and ASCT should be postponed due to the fear of immunosuppression in the upfront [25]. In patients receiving daratumumab and or lenalidomide-based induction, stem cell harvest without ASCT can be considered so as to achieve an adequate stem cell yield [8]. In this case, Granulocyte colony-stimulating factor (G-CSF) only mobilization with the potential addition of plerifaxor should be considered in order to avoid the immunosuppressive effect of high-dose cyclophosphamide. However, in cases of viral supra-infections like COVID-19, stem cell harvests and any transplant procedures should not be performed within at least 14, and preferably 21, days from the last contact (**Table 1**) [8].

#### **Figure 1.**

*Approach to the treatment of newly diagnosed multiple myeloma in transplant eligible A, and transplant ineligible B, patients. Abbreviations: ASCT, autologous stem cell transplantation; Dara-VRd, daratumumab, bortezomib, lenalidomide, dexamethasone; DRd, daratumumab, lenalidomide, dexamethasone; VRd, bortezomib, lenalidomide, dexamethasone [10].*

The treatment schedule can be modified, for patients with sufficient response. Patients with high-risk disease features may receive ASCT after 6–8 induction cycles due to otherwise increased probability of progression [8]. Quadruple drugs trials are also offering good outcomes and will be available as alternative very soon [26].

### **4.2 Induction therapy for ASCT-ineligible patients**

Patients who are fit or intermediate-fit to Rd. can be put on as a bridge therapy for 2–3 cycles in hospitals with peak prevalence of the current pandemic terror of the COVID-19. Otherwise, the approved VRd or daratumumab-based therapies (DaraRd or DaraVMP) can be administered. Dose of Dexamethasone should be lowered to 20 mg weekly, whereas de-escalation (or even interruption) can be made in patients responding well after the completion of 9 cycles of treatment [8]. Generally, RVd showed an excellent progression-free survival (PFS) and objective response rate (ORR). The triple therapy of daratumumab-lenalidomide-dexamethasone (DRd) showed much improved rates of partial response, better PFS, and tolerance compared to Rd. [27].

#### **4.3 Treatment regimens**

Wide ranges of regimens have been developed using a potentially effective combination of drugs that have proven efficacy in controlling disease progression

**33**

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

into some multi-agent combinations [19].

**4.4 Treatment algorithm**

**4.5 Consolidation therapy**

regimens [27].

MM treatment [27].

**4.6 Maintenance therapy**

fore is standard practice [29].

cells should be begun after four cycles of RVd [31].

ment of MM [28].

and improving survival. The most commonly used drug combinations are listed in **Table 1**. The combinations are usually consists of IMIDs, Cs, PIs, and MAs targeting specific cell receptors like CD38, and are playing an important role in the manage-

Other active agents and approved for the treatment of MM include elotuzumab,

a MA that is targeting the signaling lymphocytic activation molecule called SLAMF7 also known as CRACC, CS1, CD319\*; panobinostat, a histone deacetylase inhibitor; selinexor, an inhibitor of exportin-1 called XPO1.; anthracyclines, doxorubicin and liposomal doxorubicin. However, elotuzumab, panobinostat, selinexor, and the anthracyclines do not have significant single-drug activity and hence should not be used individually; rather can be used to exert their therapeutic effect in combination with other active agents. Additionally, the anthracyclines are used infrequently in the treatment of MM because of the availability of other more active agents. In aggressive and refractory cases doxorubicin can be incorporated

\* CRACC: The CD2-like receptor-activating cytotoxic cell; CS1: subset 1.

The aim of consolidation is to increase the depth of response after induction, because achieving complete response or better is associated with improved survival (**Figure 1**) [16]. Consolidation may consist of ASCT (current standard of care for eligible patients) and/or single or multiple-drug agents after ASCT [29]. In ASCT-ineligible patients, consolidation may consist of single- or multiple-drug

Different types of stem-cell transplantations (SCT) has been used in MM including single ASCT, tandem ASCT, and, rarely, allogeneic stem-cell transplantation (alloSCT)) [30]. A three-arm trial that compared the outcome of RVd induction alone, single ASCT, and tandem ASCT, followed by all on lenalidomide maintenance therapy, unearthed that there was no differences on PFS and OS among all arm and concluded that the single ASCT followed by lenalidomide maintenance therapy has to be continued as the standard of care

For all eligible patients, after detail discussion on the outcomes of therapy, upfront ASCT can be used with four cycles of RVd followed by ASCT and four more cycles of RVd. Alternatively, eight cycles of RVd upfront, before ASCT can also be tried. Some patients prefer the latter option, to minimize treatment disruptions in case complications arise because of ASCT. If patients choose to defer upfront ASCT after being informed of the risks and benefits, then collection and storage of stem

Maintenance therapy improves PFS and OS as compared to therapy cessation, indeed in high-risk patients [29, 32]. The survival benefit is present regardless of whether or not patients receive ASCT before maintenance. The use of maintenance does not seem to lead to decreased efficacy of therapy after first relapse and there-

The IMWG reach on consensus that thalidomide maintenance therapy after ASCT improves the quality of response and increases the PFS as well as the OS significantly

[33] though no improvement was seen in OS among elderly patients [33, 34].

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

*Multiple Myeloma*

The treatment schedule can be modified, for patients with sufficient response. Patients with high-risk disease features may receive ASCT after 6–8 induction cycles due to otherwise increased probability of progression [8]. Quadruple drugs trials are also offering good outcomes and will be available as alternative very

*Approach to the treatment of newly diagnosed multiple myeloma in transplant eligible A, and transplant ineligible B, patients. Abbreviations: ASCT, autologous stem cell transplantation; Dara-VRd, daratumumab, bortezomib, lenalidomide, dexamethasone; DRd, daratumumab, lenalidomide, dexamethasone; VRd,* 

Patients who are fit or intermediate-fit to Rd. can be put on as a bridge therapy for 2–3 cycles in hospitals with peak prevalence of the current pandemic terror of the COVID-19. Otherwise, the approved VRd or daratumumab-based therapies (DaraRd or DaraVMP) can be administered. Dose of Dexamethasone should be lowered to 20 mg weekly, whereas de-escalation (or even interruption) can be made in patients responding well after the completion of 9 cycles of treatment [8]. Generally, RVd showed an excellent progression-free survival (PFS) and objective response rate (ORR). The triple therapy of daratumumab-lenalidomide-dexamethasone (DRd) showed much improved rates of partial response, better PFS, and

Wide ranges of regimens have been developed using a potentially effective combination of drugs that have proven efficacy in controlling disease progression

**4.2 Induction therapy for ASCT-ineligible patients**

*bortezomib, lenalidomide, dexamethasone [10].*

tolerance compared to Rd. [27].

**4.3 Treatment regimens**

**32**

soon [26].

**Figure 1.**

and improving survival. The most commonly used drug combinations are listed in **Table 1**. The combinations are usually consists of IMIDs, Cs, PIs, and MAs targeting specific cell receptors like CD38, and are playing an important role in the management of MM [28].

Other active agents and approved for the treatment of MM include elotuzumab, a MA that is targeting the signaling lymphocytic activation molecule called SLAMF7 also known as CRACC, CS1, CD319\*; panobinostat, a histone deacetylase inhibitor; selinexor, an inhibitor of exportin-1 called XPO1.; anthracyclines, doxorubicin and liposomal doxorubicin. However, elotuzumab, panobinostat, selinexor, and the anthracyclines do not have significant single-drug activity and hence should not be used individually; rather can be used to exert their therapeutic effect in combination with other active agents. Additionally, the anthracyclines are used infrequently in the treatment of MM because of the availability of other more active agents. In aggressive and refractory cases doxorubicin can be incorporated into some multi-agent combinations [19].

\* CRACC: The CD2-like receptor-activating cytotoxic cell; CS1: subset 1.

#### **4.4 Treatment algorithm**

#### **4.5 Consolidation therapy**

The aim of consolidation is to increase the depth of response after induction, because achieving complete response or better is associated with improved survival (**Figure 1**) [16]. Consolidation may consist of ASCT (current standard of care for eligible patients) and/or single or multiple-drug agents after ASCT [29]. In ASCT-ineligible patients, consolidation may consist of single- or multiple-drug regimens [27].

Different types of stem-cell transplantations (SCT) has been used in MM including single ASCT, tandem ASCT, and, rarely, allogeneic stem-cell transplantation (alloSCT)) [30]. A three-arm trial that compared the outcome of RVd induction alone, single ASCT, and tandem ASCT, followed by all on lenalidomide maintenance therapy, unearthed that there was no differences on PFS and OS among all arm and concluded that the single ASCT followed by lenalidomide maintenance therapy has to be continued as the standard of care MM treatment [27].

For all eligible patients, after detail discussion on the outcomes of therapy, upfront ASCT can be used with four cycles of RVd followed by ASCT and four more cycles of RVd. Alternatively, eight cycles of RVd upfront, before ASCT can also be tried. Some patients prefer the latter option, to minimize treatment disruptions in case complications arise because of ASCT. If patients choose to defer upfront ASCT after being informed of the risks and benefits, then collection and storage of stem cells should be begun after four cycles of RVd [31].

#### **4.6 Maintenance therapy**

Maintenance therapy improves PFS and OS as compared to therapy cessation, indeed in high-risk patients [29, 32]. The survival benefit is present regardless of whether or not patients receive ASCT before maintenance. The use of maintenance does not seem to lead to decreased efficacy of therapy after first relapse and therefore is standard practice [29].

The IMWG reach on consensus that thalidomide maintenance therapy after ASCT improves the quality of response and increases the PFS as well as the OS significantly [33] though no improvement was seen in OS among elderly patients [33, 34].

Lenalidomide maintenance treatment after ASCT and after conventional melphalan, prednisone, and lenalidomide induction therapy showed a significant risk reduction of PFS as well as improvement in OS. Nevertheless, the role of thalidomide maintenance after induction therapy of melphalan, prednisone, and thalidomide is not yet well established [33].

Compared with conventional induction and thalidomide maintenance treatment a significantly increase in OS was seen with a bortezomib-based induction and bortezomib maintenance therapy after a single-agent bortezomib or in combination with thalidomide or prednisone maintenance therapy [35].

Appropriate therapeutic monitoring has to be taken so as to minimize drug associated toxicities during maintenance therapy. The risks and benefits should also be discussed with patients. Since there is no a single guiding principle reached as a consensus of standard care throughout all health care systems, clinical decisions for individual patients must be balanced with the potential benefits and risks specific management approach [36].

The standard agent for maintenance therapy of MM in U.S.A is lenalidomide, and maintenance therapy with lenalidomide is now favored following induction with or without ASCT because of prolonging response and improving PFS and OS. However, the risks with lenalidomide maintenance such as hematologic and solid secondary primary malignancies has to be given adequate focus [37].

Major trials of maintenance therapy for MM prescribed that all standard-risk patients have be managed with lenalidomide maintenance until improved. For highrisk patients, who are characterized as having either del (17p), t(4;14), or t(14;16), have be managed with dual maintenance comprising of lenalidomide and bortezomib each other week as long as safely endured. For patients with contraindications to bortezomib, ixazomib have to be considered once per weekly in lieu of bortezomib [38]. For very young and elderly patients systematic maintenance therapy is not recommended following induction because of the lack of sufficient data [39].

#### **5. Prognostic factors**

Cytogenetic abnormalities such as del(17p), t(14; 16), and t(14; 20) have important prognostic implications. Patients with del(17p), occurs in approximately 10% of newly diagnosed MM and in upwards of 80% in relapsed or refractory MM, are classified as high risk because of shortened OS and PFS [27]. Immunoglobulin heavychain translocations associated with the highest risk of poor outcomes include t(4;14) which is present in 5% and t(14;16) in 15% of newly diagnosed MM. Patients with both translocations are considered high risk and experience inferior survival [40].

The prognostic factors of MM is divided into four major parts as: 1) Risk Stratification, which includes Staging of MM, Plasma Cell Labeling index (PCLI), Cytogenetics and Gene Expression Profiling (GEP); 2) Monitoring of Response Tools, which includes Serum-Free Light Chain Assay, serum Heavy/Light Chain (HLC) Assay (Hevylite™), and Advanced Imaging Modalities; 3) Minimal Residual Disease (MRD) Monitoring Methods, which includes Circulating Plasma Cells, MRD Monitoring in General, and the Value of Depth of Response; and 4) Novel Prognostic Markers [41].

#### **6. Management of relapsed and refractory cases**

Treatment choice of a relapsed or refractory MM, depends on several parameters including age, the type of comorbidities, performance status, aggressiveness of

**35**

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

cases, ASCT may be a good option [44].

ORR, PFS, and OS in this population [45].

(ERd) may be considered [10, 46].

showed good prognostic factor [48].

phamide-dexamethasone [27, 49].

dexamethasone is recommended [27].

initiating treatment at the earliest sign is advised [27].

options in frail patients [51].

**7. Supportive therapy**

relapse, efficacy and tolerance with the previously used medications, the number of prior drugs, the available remaining treatment options, the cytogenetic data at the

Generally, During relapse a triple therapy is preferred over two drug treatment [43]. It should also be noted that, if patients relapse while receiving lenalidomide maintenance, carfilzomib-pomalidomide-dexamethasone and pomalidomidebortezomib-dexamethasone are options in fit patients [44]. In transplant deferred

For patients who were receiving bortezomib maintenance at the time of relapse or treatment failure, KRd may be used in fit patients. KRd demonstrated improved

KRd and DRd may be considered for fit patients not receiving maintenance during relapse [46], and for frail patients or for those with indolent relapse ixazomiblenalidomide-dexamethasone (IRd) or elotuzumab-lenalidomide-dexamethasone

Pomalidomide-dexamethasone (Pd) is an option for patients with relapsed or refractory MM who have failed lenalidomide and bortezomib, and have received at least two prior therapies [47], the regimen improves PFS and OS in this population. The use of Pd in patients with relapsed or refractory MM who harbor del(17p)

carfilzomib-cyclophosphamide-dexamethasone, and pomalidomide-cyclophos-

Data comparing second ASCT to salvage therapy with novel PIs, IMiDs, or monoclonal antibodies not sufficient [17]. In addition, since lenalidomide maintenance is currently the standard of care after ASCT, the goal of considering a second transplantation should be closer to 36 months compared with 18 months on the basis of historical data [52]. If patients relapse after lenalidomide maintenance, considering a pomalidomide-based regimen, such as carfilzomib-pomalidomide-

Supportive care is critical throughout the clinical course of patients with MM because they are particularly susceptible to infections. Diligence in identifying and

All MM patients with newly diagnosed MM and with adequate renal function should be initiated with monthly bone-modulating therapy at diagnosis with either

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

denosumab, zoledronic acid or pamidronate (high recommendation) [27].

For frail patients or for those with indolent relapse who relapsed during bortezomib maintenance, DRd, IRd, or ERd are effective [50]. Daratumumab-bortezomibdexamethasone (DVd) or ixazomib-cyclophosphamide-dexamethasone are also

Other combinations for relapsed or refractory MM include daratumumab-pomalidomide-dexamethasone, a PI with panobinostat,

time of relapse and the interval since the last therapy [27, 42].

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

*Multiple Myeloma*

thalidomide is not yet well established [33].

management approach [36].

**5. Prognostic factors**

Prognostic Markers [41].

**6. Management of relapsed and refractory cases**

with thalidomide or prednisone maintenance therapy [35].

Lenalidomide maintenance treatment after ASCT and after conventional melphalan, prednisone, and lenalidomide induction therapy showed a significant risk reduction of PFS as well as improvement in OS. Nevertheless, the role of thalidomide maintenance after induction therapy of melphalan, prednisone, and

a significantly increase in OS was seen with a bortezomib-based induction and bortezomib maintenance therapy after a single-agent bortezomib or in combination

Appropriate therapeutic monitoring has to be taken so as to minimize drug associated toxicities during maintenance therapy. The risks and benefits should also be discussed with patients. Since there is no a single guiding principle reached as a consensus of standard care throughout all health care systems, clinical decisions for individual patients must be balanced with the potential benefits and risks specific

The standard agent for maintenance therapy of MM in U.S.A is lenalidomide, and maintenance therapy with lenalidomide is now favored following induction with or without ASCT because of prolonging response and improving PFS and OS. However, the risks with lenalidomide maintenance such as hematologic and solid

Major trials of maintenance therapy for MM prescribed that all standard-risk patients have be managed with lenalidomide maintenance until improved. For highrisk patients, who are characterized as having either del (17p), t(4;14), or t(14;16), have be managed with dual maintenance comprising of lenalidomide and bortezomib each other week as long as safely endured. For patients with contraindications to bortezomib, ixazomib have to be considered once per weekly in lieu of bortezomib [38]. For very young and elderly patients systematic maintenance therapy is not recommended following induction because of the lack of sufficient data [39].

Cytogenetic abnormalities such as del(17p), t(14; 16), and t(14; 20) have important prognostic implications. Patients with del(17p), occurs in approximately 10% of newly diagnosed MM and in upwards of 80% in relapsed or refractory MM, are classified as high risk because of shortened OS and PFS [27]. Immunoglobulin heavychain translocations associated with the highest risk of poor outcomes include t(4;14) which is present in 5% and t(14;16) in 15% of newly diagnosed MM. Patients with both translocations are considered high risk and experience inferior survival [40]. The prognostic factors of MM is divided into four major parts as: 1) Risk Stratification, which includes Staging of MM, Plasma Cell Labeling index (PCLI), Cytogenetics and Gene Expression Profiling (GEP); 2) Monitoring of Response Tools, which includes Serum-Free Light Chain Assay, serum Heavy/Light Chain (HLC) Assay (Hevylite™), and Advanced Imaging Modalities; 3) Minimal Residual Disease (MRD) Monitoring Methods, which includes Circulating Plasma Cells, MRD Monitoring in General, and the Value of Depth of Response; and 4) Novel

Treatment choice of a relapsed or refractory MM, depends on several parameters

including age, the type of comorbidities, performance status, aggressiveness of

secondary primary malignancies has to be given adequate focus [37].

Compared with conventional induction and thalidomide maintenance treatment

**34**

relapse, efficacy and tolerance with the previously used medications, the number of prior drugs, the available remaining treatment options, the cytogenetic data at the time of relapse and the interval since the last therapy [27, 42].

Generally, During relapse a triple therapy is preferred over two drug treatment [43]. It should also be noted that, if patients relapse while receiving lenalidomide maintenance, carfilzomib-pomalidomide-dexamethasone and pomalidomidebortezomib-dexamethasone are options in fit patients [44]. In transplant deferred cases, ASCT may be a good option [44].

For patients who were receiving bortezomib maintenance at the time of relapse or treatment failure, KRd may be used in fit patients. KRd demonstrated improved ORR, PFS, and OS in this population [45].

KRd and DRd may be considered for fit patients not receiving maintenance during relapse [46], and for frail patients or for those with indolent relapse ixazomiblenalidomide-dexamethasone (IRd) or elotuzumab-lenalidomide-dexamethasone (ERd) may be considered [10, 46].

Pomalidomide-dexamethasone (Pd) is an option for patients with relapsed or refractory MM who have failed lenalidomide and bortezomib, and have received at least two prior therapies [47], the regimen improves PFS and OS in this population. The use of Pd in patients with relapsed or refractory MM who harbor del(17p) showed good prognostic factor [48].

Other combinations for relapsed or refractory MM include daratumumab-pomalidomide-dexamethasone, a PI with panobinostat, carfilzomib-cyclophosphamide-dexamethasone, and pomalidomide-cyclophosphamide-dexamethasone [27, 49].

For frail patients or for those with indolent relapse who relapsed during bortezomib maintenance, DRd, IRd, or ERd are effective [50]. Daratumumab-bortezomibdexamethasone (DVd) or ixazomib-cyclophosphamide-dexamethasone are also options in frail patients [51].

Data comparing second ASCT to salvage therapy with novel PIs, IMiDs, or monoclonal antibodies not sufficient [17]. In addition, since lenalidomide maintenance is currently the standard of care after ASCT, the goal of considering a second transplantation should be closer to 36 months compared with 18 months on the basis of historical data [52]. If patients relapse after lenalidomide maintenance, considering a pomalidomide-based regimen, such as carfilzomib-pomalidomidedexamethasone is recommended [27].
