**2.1 Staging in myeloma**

According to the International Myeloma Working Group (IMWG) criteria, the diagnosis of MM requires a 10% or more clonal plasma cells infiltration of the bone marrow and/or a biopsy proven plasmacytoma plus any one or more of the myeloma defining events (MDE) which include end-organ damage, characterized by hypercalcemia, renal insufficiency, anemia, or bone lesions which attributable to the underlying plasma-cell disorder; bone marrow clonal plasma cells ≥60%; serum involved to uninvolved free light chain (FLC) ratio ≥ 100 (provided involved FLC level is ≥100 mg/L); or magnetic resonance imaging (MRI) result of more than 1 focal lesion (5 mm or more in size) [10].

### **2.2 Revised international staging system for myeloma**

The following staging is as per the IMWG [13].


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

Lenalidomide-dexamethasone

Thalidomide-dexamethasone

Pomalidomide-dexamethasone

Bortezomib-thalidomidedexamethasone (VTd)b

Bortezomib-Lenalidomide-Dexamethasone (VRd)b

Carfilzomib-Lenalidomide-Dexamethasone (KRd)e

Carfilzomib-Pomalidomide-Dexamethasone (KPd)e

Daratumumab-Lenalidomide-Dexamethasone (DRd)

Daratumumab-Bortezomib-Dexamethasone (DVd)b

Bortezomib-melphalanprednisone (VMP)b

(Rd)

(Td)b

(Pom/Dex)

Bortezomib-Cyclophosphamide-Dexamethasoneb (VCd or CyBord)

Carfilzomib-Cyclophosphamide-Dexamethasone (KCd)

**Regimen Usual dosing schedulea**

every 4 wk

Lenalidomide 25 mg oral days 1–21 every 28 days

oral days 1–4

Dexamethasone 40 mg oral on days on days 1, 8, 15, 22

Dexamethasone 40 mg oral on days on days 1, 8, 15, 22

(subsequent doses) intravenously on days 1, 2, 8, 9, 15, 16

Dexamethasone 40 mg oral on days on days 1, 8, 15, 22

(subsequent doses) intravenously on days 1, 2, 8, 9, 15, 16

(subsequent cycles) intravenously on days 1, 2, 8, 9, 15, 16

Daratumumab 16 mg/ kg intravenously weekly × 8 weeks, and then

Dexamethasone 40 mg intravenous days 1, 8, 15, 22 (given oral on days

Lenalidomide-Dexamethasone repeated in usual schedule every 4 weeks

 subcutaneous on days 1, 8, 15, 22 Dexamethasone 40 mg intravenous days 1, 8, 15, 22 (given oral on days

Daratumumab 16 mg/ kg intravenously weekly × 8 weeks, and then

Bortezomib-Dexamethasone repeated in usual schedule every 4 weeks

Dexamethasone 40 mg oral on days on days 1, 8, 15, 22

2 weeks for 4 months, and then once monthly Lenalidomide 25 mg oral days 1–21

when no daratumumab is being administered)

2 weeks for 4 months, and then once monthly

when no daratumumab is being administered)

oral days 1 to 4

Thalidomide 200 mg oral days 1–28 Dexamethasone 40 mg oral days 1, 8, 15, 22

Repeated every 4 weeks

Bortezomib 1.3 mg/m2

Prednisone 60 mg/m2

Repeated every 35 days

Repeated every 4 wk

Bortezomib 1.3 mg/m2

Repeated every 4 weeksc

Bortezomib 1.3 mg/m2

40 mg days 1, 8, 15, 22)

Carfilzomib 20 mg/m2

Repeated every 4 weeks

Bortezomib 1.3 mg/m2

40 mg days 1, 8, 15, 22) Repeated every 3 weeksd

Carfilzomib 20 mg/m2

Repeated every 4 weeks

Carfilzomib 20 mg/m2

Repeated every 4 weeks

Bortezomib 1.3 mg/m2

every

every

Cyclophosphamide 300 mg/m2

Lenalidomide 25 mg oral days 1–14

Lenalidomide 25 mg oral days 1–21 Dexamethasone 40 mg oral days 1, 8, 15, 22

Pomalidomide 4 mg oral on days 1–21

Pomalidomide 4 mg days 1–21

Cyclophosphamide 300 mg/m2

Thalidomide 100–200 mg oral days 1–21

Melphalan 9 mg/m2

Dexamethasone 40 mg oral days 1, 8, 15, 22 every 28 days Repeated

subcutaneous days 1, 8, 15, 22

subcutaneous on days 1, 8, 15, 22

subcutaneous days 1, 8, 15, 22

(days 1 and 2 of Cycle 1) and 27 mg/m2

orally on days 1, 8, 15

(days 1 and 2 of Cycle 1) and 27 mg/ m2

(days 1 and 2 of Cycle 1) and 27 mg/ m2

Dexamethasone 20 mg oral on day of and day after bortezomib (or

Repeated every 4 weeks 3 4 cycles as pretransplant induction therapy

subcutaneous days 1, 8, 15

Dexamethasone 20 mg oral on day of and day after bortezomib (or

orally on days 1, 8, 15, and 22

*Multiple Myeloma*

step closer to radical cure [10].

ing techniques (i.e., MRI, PET/CT) [11].

focal lesion (5 mm or more in size) [10].

**2.2 Revised international staging system for myeloma**

2.**Stage II** patient will have neither stage I or III criteria

The following staging is as per the IMWG [13].

serum lactate dehydrogenase level.

**2.1 Staging in myeloma**

**2. Diagnosis**

computed tomography (LDCT) is now considered as novel in detecting lytic lesions, and more sensitive than conventional radiography in depicting osteolytic

The treatment landscape and clinical outcome of MM have changed in the last two decades, with an improved median survival of 8–10 years [9]. The initial impact seen with the introduction of three drugs, thalidomide, bortezomib, and lenalidomide [10]. Multiple combinations of proteasome inhibitors (PIs) like bortezomib, carfilzomib, and ixazomib; immunomodulatory drugs (IMIDs) such as Thalidomide, lenalidomide, and pomalidomide; corticosteroids (Cs) such as dexamethasone, prednisone; monoclonal antibodies (MAs) like Daratumumab and isatuximab; and alkylating agents such as melphalan, cyclophosphamide have been tried and evaluated in the transplant and non-transplant settings, and studies are still ongoing [9]. The approval of carfilzomib, pomalidomide, panobinostat, ixazomib, elotuzumab, and daratumumab by the Food and Drug Administration (FDA) for the treatment of relapsed multiple myeloma, in the last five years is an

Clinical investigation of MM requires the evaluation of bone marrow for plasma

cell infıltration, and detection and quantification of monoclonal protein in the serum or urine, and evidence for end-organ damage (i.e., hypercalcemia, renal insuffıciency, anemia, or bone lesions) [11, 12]. This can be done by grouping the different diagnostic and prognostic factors measurable parameters, such as protein analysis, morphology, immunophenotyping, genetics and cytogenetics, and imag-

According to the International Myeloma Working Group (IMWG) criteria, the diagnosis of MM requires a 10% or more clonal plasma cells infiltration of the bone marrow and/or a biopsy proven plasmacytoma plus any one or more of the myeloma defining events (MDE) which include end-organ damage, characterized by hypercalcemia, renal insufficiency, anemia, or bone lesions which attributable to the underlying plasma-cell disorder; bone marrow clonal plasma cells ≥60%; serum involved to uninvolved free light chain (FLC) ratio ≥ 100 (provided involved FLC level is ≥100 mg/L); or magnetic resonance imaging (MRI) result of more than 1

1.**Stage I** MM patient will have (all of the following): normal serum lactate

3.**Stage III** MM patient will have serum beta-2-microglobulin >5.5 mg/L; and either high risk cytogenetics [t(4;14), t(14;16), or del(17p)] or an elevated

dehydrogenase level and without high cytogenetic features; and they will have serum beta-2-microglobulin of <3.5 mg/L and serum albumin level > 3.5 g/dL.

disease as per the recommendations of the EMN [7, 8].

**28**



*a All doses need to be adjusted for performance status, renal function, blood counts, and other toxicities.*

*b Doses of dexamethasone and/or bortezomib reduced based on other data showing lower toxicity and similar efficacy with reduced doses; subcutaneous route of administration of bortezomib preferred based on data showing lower toxicity and similar efficacy compared to intravenous administration.*

*c The day 22 dose of all 3 drugs is omitted if counts are low, or after initial response to improve tolerability, or when the regimen is used as maintenance therapy; When used as maintenance therapy for high risk patients, further delays can be instituted between cycles.*

*d Omit day 15 dose if counts are low or when the regimen is used as maintenance therapy; When used as maintenance therapy for high risk patients, lenalidomide dose may be decreased to 10–15 mg per day, and delays can be instituted between cycles as done in total therapy protocols.*

*e Carfilzomib can also considered in a once a week schedule of 70 mg/m2 on days 1, 8 and 15 every 28 days (cycle 1, day 1 should be 20 mg/m2 ); Day 8, 9 doses of carfilzomib can be omitted in maintenance phase of therapy after a good response to improve tolerability; KCd dosing lowered from that used in the initial trial which was conducted in newly diagnosed patients.*

#### **Table 1.**

*Major treatment regimens in multiple myeloma [9, 10].*

Different ranges of regimens have been developed to retard progression of disease using potentially effective in controlling and promising for survival. The most commonly used drug combinations are listed in **Table 1**.

#### **2.3 Symptomatic versus asymptomatic myeloma**

Urgent management of indolent myeloma is not recommended at the present time; rather treatment should be considered in all symptomatic patients with an active myeloma criteria (the CRAB criteria) (hypercalcaemia >11.0 mg/dl), creatinine >2.0 mg/ml, anemia (Hb < 10 mg/dL), active bone lesions), [9].
