Introduction: Multiple myeloma (MM) is a plasma cell dyscrasia characterized by monoclonal plasma cells proliferation in bone marrow, resulting in an overabundance of monoclonal paraprotein (M protein), destruction of bone, and displacement of other hematopoietic cell lines. [1]. In India prevalence is in 1.4/1,00,000 population with  incidence of 6000 new cases/year. [2]. The overall 5-year survival rate for people with multiple myeloma is 54%. Survival rates though have steadily increased over time.  Risk factors of multiple myeloma include  age > 65 years, male , family history , over weight or obese , radiation exposure , contact with chemicals [ 3] . Common symptoms may include, bone pain, often in the back or ribs, fractures , weakness or fatigue, weight loss, frequent infections and fevers, feeling  thirsty and  frequent urination. The diagnostic criteria for multiple myeloma require confirmation of (a) one major criterion and one minor criterion or (b) three minor criteria in an individual who has signs or symptoms of multiple myeloma.

Table 1: Types of Diagnostic Criteria

In healthy bone marrow, < 5% of the cells are plasma cells, whereas in  people with MM, > 10 % of the cells may be plasma cells [4]. 

Figure 1: Pathogenesis of Multiple myeloma

Radiographic features : Numerous, well-circumscribed, lytic bone lesions , punched out lucencies and raindrop skull , endosteal scalloping can be visualized. Vertebral compression fractures, long bone fractures are also seen. The predominant areas of bone disease involvement are the axial skeleton, including the vertebral bodies (49%), skull (35%), pelvis (34%), and ribs (33%), and the proximal metaphysis of long bones, especially the femur and humerus [5] 

Staging of Multiple myeloma: Early : Asymptomatic: This means the person does not have symptoms and signs of the disease. Late: Symptomatic Calcium levels are increased, which is known as hypercalcemia. Calcium level greater than 0.25 mmol/L. Renal, or kidney, problems, identified as a creatinine level higher than 173 mmol/L. Hemoglobin level that is less than 10 g/dl and Bone lesions( refer as CRAB). [6]

Table 2: Progressive stages of Multiple myeloma

[7]

Drugs for managing Multiple myeloma:

Table 3 : Classification of Drugs

[8]

Table 4 : Classification of Proteasomes:

[9]

Bortezomib is a dipeptide boronic acid derivative and proteasome inhibitor used to treat multiple myeloma and mantle cell lymphoma. The 26S proteasome is a protein complex that degrades ubiquitinated proteins in the ubiquitin-proteasome pathway: reversible inhibition of the 26S proteasome, leading to cell cycle arrest and apoptosis of cancer cells, is thought to be the main mechanism of action of bortezomib. Proteasomes are large protein complexes inside cells they degrade misfolded   proteins. Proteasome inhibitors are drugs that block the action of proteasomes cellular complexes that break down proteins.

Figure 2: Mode of action  of Bortezomib

The mechanism of action of bortezomib involves stabilization of NF-κB, p21, p27, p53, Bid, and Bax, inhibition of caveolin-1 activation, and activation of JNK as well as the endoplasmic reticulum stress response.  [10] Subcutaneous administration of bortezomib appears to be comparable with intravenously administered bortezomib in terms of overall systemic availability and response rates in multiple myeloma, but may have an improved safety profile, with fewer dose reductions and discontinuations due to adverse events. Peripheral neuropathy and thrombocytopenia are the key dose-limiting toxicities of bortezomib-based combination regimens. Carfilzomib has demonstrated activity against bortezomib-resistant cell lines and primary multiple myeloma (MM) cells [11]

Immunomodulatory drugs : IMiDs are known to suppress the production of tumor necrosis factor-alpha (TNF-α), interleukin-12 (IL-12), IL-16, IL-1β, macrophage inflammatory protein-1 alpha (MIP-1α and monocyte chemoattractant protein-1 (MCP-1), while increasing the yield of IL-2, IFN-γ, IL-10 . Acts on NK cells directly or indirectly. As such, IMiDs , enhances NK-cell cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) in MM cells.  These drugs also downregulate tumor necrosis factor also appears to augment NK cell activity via a variety of mechanisms. The treatment of MM cells with lenalidomide significantly increased the expression of b-catenin , suggesting that b-catenin might be an IMiDs’ target protein’s indirect downstream factor. These are promising anti-myeloma agent that has the ability to induce remission in patients with heavily pre-treated MM. Lenalidomide can cause significant neutropenia and thrombocytopenia ,  pulmonary embolism (PE) in patients with multiple myeloma

Figure 3: Mode of action of IMIDs

 [12]

Panobinostat is a potent oral nonselective pan-histone deacetylase inhibitor (HDAC). It has been approved by the FDA and EMA in combination with bortezomib and dexamethasone for the treatment of multiple myeloma, in patients who have received at least two prior regimens, including bortezomib and an immunomodulatory agent.[13] . Panobinostat is an inhibitor of all class I (HDACs 1, 2, 3, and 8), class II (HDACs 4, 5, 6, 7, 9, and 10), and class IV (HDAC 11) HDACs, with half maximal inhibitory concentrations in the nanomolar range. 

Figure 4: Mode of action of Panobinostat

Panobinostat produces dose related grade 3/4 adverse events (AE) included thrombocytopenia (42%), fatigue (21%), and neutropenia (21%). The most common dose-limiting toxicities included thrombocytopenia, fatigue, and cardiac-related events .[14]

Doxorubicin : is used in combination with (bortezomib) for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy. Doxorubicin inhibits the enzyme topoisomerase II, causing DNA damage and induction of apoptosis. The liposomal formulation of doxorubicin has FDA approval for the treatment of ovarian cancer in patients who have failed platinum-based chemotherapy, AIDS-related Kaposi sarcoma, and multiple myeloma

Figure 4 : Action of Doxorubicin

fatigue, alopecia, nausea and vomiting, and oral sores and bone marrow suppression are common side effects. [15]

Alkylating Agents : Bendamustine has proven activity in both newly diagnosed and relapsed-refractory MM. Bendamustine has also demonstrated activity in MM after relapse from ASCT ( Autologous stem cell transplant )  and has recently been used successfully as a conditioning regimen for ASCT in combination with melphalan .  PFS and the OR rate were at least 2-fold greater with bendamustine than with chlorambucil  [16]

Figure 5 : Mode of action of Bendamustine

The antineoplastic effect of bendamustine is due to production of both single- and double-strand breaks The DNA breaks, observed after bendamustine exposure, are more extensive and significantly more durable than those induced by other alkylators.  Side effects reported are fever, chills, or itching during or shortly after the injection; low white cell count are reported . signs of tumor cell breakdown such as confusion, weakness, muscle cramps, nausea, vomiting, bradycardia or tachycardia , decreased urination are also observed.

Melphalan, Cyclophosphamide, and Dexamethasone (MCD) as a salvage regimen for heavily treated relapsed or refractory multiple myeloma patients [17]

Daratumumab: is an IgG1κ fully human mAb that targets CD38, a type II transmembrane glycoprotein composed of extracellular, transmembrane, and intracellular domains. Direct effects are mediated by inhibition of intracellular signal transduction, and by inhibition of CD38 enzymatic activity, which leads to decreased levels of immunosuppressive adenosine. Fc-dependent mechanisms include complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC),  Daratumumab has shown encouraging results both as monotherapy and in combination with other regimens in both R/R MM and untreated disease. [18]

Figure 6 : Daratumumab action

Elotuzumab is a humanized monoclonal antibody used in relapsed multiple myeloma. Elotuzumab directly activates Natural Killer cells through both the SLAMF7 pathway and Fc receptors. Elotuzumab also targets SLAMF7  (Surface antigen CD319 (SLAMF7) is a robust marker of normal plasma cells and malignant plasma cells in multiple myeloma.) and facilitates the interaction with Natural Killer cells to mediate the killing of myeloma cells through antibody-dependent cellular cytotoxicity (ADCC). Useful in relapsed / refractory MM. Elotuzumab , pomalidomide and dexamethasone combination is used in refractory cases. Fatigue, diarrhoea , constipation and cough are commonly observed. [19]

Figure 7: Elotuzumab action

Steroids are commonly used for multiple myeloma treatment and are used at all stages of the disease. In high doses, steroids can lyse multiple myeloma cells. Dexamethasone and the other steroids are useful in myeloma treatment because they can stop white blood cells from traveling to areas where cancerous myeloma cells are causing damage. This decreases the amount of swelling or inflammation in those areas and relieves associated pain and pressure.[20]

Drug combinations in Multiple myeloma :

• In a prospective study of lenalidomide/bortezomib/dexamethasone in patients with newly diagnosed MM, the rate of partial response (PR) was 100%, with 74% VGPR  [very good partial response ]or better and 52% complete response (CR)/near CR. The triple-drug regimen group had significantly longer PFS (43 months vs 30 months;) and improved median OS (75 vs 64 months.
• Bortezomib/Cyclophosphamide/Dexamethasone (70% rates of CR/near CR; rate of at least VGPR or better was 74%.
• Carfilzomib/Cyclophosphamide/Dexamethasone :  The median PFS was 35.7 months in the once-weekly group and 35.5 months in the twice-weekly group , The 3-year OS was 70% and 72%, respectively .
• ORR after initial therapy with ixazomib/cyclophosphamide/dexamethasone was 73%. 
• The results of the randomized phase III trial by the Spanish Myeloma Group (PETHEMA/GEM) demonstrated a significantly higher CR rate with bortezomib/thalidomide/dexamethasone as primary therapy overall (35% vs 14%, P=.001) and in patients with high-risk cytogenetics (35% vs 0%, P=.002)

            [21]     

Table V : Comparative Trials on Multiple myeloma

Drugs under evaluation:  Many therapeutic drugs are under evaluation for multiple myeloma, mostly in combination with dexamethasone and Proteasome inhibitors

Table VI : Drugs under evaluation

PVX vaccine is a tri-peptide vaccine for multiple myeloma. This vaccine recognizes three different proteins that are present in on multiple myeloma cells.

[22]

Table 7 : Algorithm for treating Multiple myeloma : Frontline Therapy of Symptomatic Multiple myeloma

 [ASCT – Autologous Stem Cell Transplant, MPT, melphalan, prednisone, thalidomide; VMP, bortezomib, melphalan, prednisone;

CTD, cyclophosphamide, thalidomide, dexamethasone; MP, melphalan, prednisone; VTD, bortezomib, thalidomide,

dexamethasone; VCD, bortezomib, cyclophosphamide, dexamethasone; PAD, bortezomib, doxorubicin, dexamethasone;

RVD, lenalidomide, bortezomib, dexamethasone, BP, bendamustin, prednisolone]

[23]

Indications of radiation therapy: Palliation of bone pain, spinal cord compression , involvement of cranial nerves .  RT can produce definitive cures in solitary plasmacytomas, its role in MM is only palliative.

Conclusion: MM accounts for 1.8% of all malignancies and 10–15% of hematologic malignancies. The historic induction therapy for MM consisted of corticosteroids alone, melphalan/prednisone, or the combination of vincristine, doxorubicin, and dexamethasone (VAD) , with median survival of 2- 3 years. The introduction of immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (MABs) have improved treatment outcomes and extended the median OS 5–15+ years.  Daratumumab , Elotuzumab have  shown encouraging results both as monotherapy and in combination with other regimens in both R/R MM and untreated disease. ASCT is not curative in MM, but improves median OS by ~12 months.  The treatment-related mortality rate is 1–2%. In ~50% of patients, ASCT can be done on an outpatient basis. Renal impairment (RI) is one of the most common complications of symptomatic MM, affecting 20–30% of patients at the time of diagnosis and around 10% of them require haemodialysis, with a negative impact on prognosis.