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 nearly 40 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
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 humerus5
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( known as as CRAB).6
Table 2
Progressive stages of multiplemyeloma 7
Table 3
Classification of drugs8
Table 4
Types of proteasomes 9
Drugs for Managing Multiple Myeloma
Bortezomib is a dipeptide boronic acid derivative and proteasome inhibitor used to treat multiple myeloma. Complete remission (CR) or very good partial remission (VGPR) has been observed in multiple myeloma (MM) therapy.
Proteasomes are large protein complexes inside cells they degrade misfolded proteins 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.
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 irreversibly binds to the active sites of the 20S proteasome, as well as the core component within the 26S proteasome. It has activity bortezomib-resistant cell lines and primary multiple myeloma (MM) cells Used in combination with dexamethasone or with lenalidomide plus dexamethasone or with daratumumab and dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.11
Immunomodulatory drugs: (Lenalidomide, Pomalidomide, Thalidomide)
Their mechanism of action is not exactly clear , but it is known that they inhibit the production of tumour necrosis factor, interleukin 6 and immunoglobulin G and VEGF (which leads to its anti-angiogenic effects), co-stimulates T cells and NK cells and increases interferon gamma and interleukin 2 production . 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. Lenalidomide can cause significant neutropenia and thrombocytopenia, pulmonary embolism (PE) in patients with multiple myeloma
Panobinostat is a potent oral nonselective pan-histone deacetylase inhibitor (HDAC). It is used 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. Panobinostat inhibits class I (HDACs 1, 2, 3, 8), class II (HDACs 4, 5, 6, 7, 9, 10) and class IV (HDAC 11) proteins.13 It is administered orally at a starting dose of 20 mg three times a week for 2 weeks every 3 weeks. It is given in combination with bortezomib and dexamethasone. Thrombocytopenia, neutropenia, fatigue, electrolyte abnormalities, and increased creatinine are adverse effects of Panobinostat. Panobinostat prescribing information has a boxed warning, describing a 25% incidence of grade 3–4 diarrhoea.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
Fatigue, alopecia, nausea and vomiting, and oral sores and bone marrow suppression are common side effects.15
Alkylating Agents
Bendamustine is a purine analogue similar to cladribine and fludarabine, which has proven activity in both newly diagnosed and relapsed-refractory MM, also in patients above 65 years of age. 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 chlorambucil16
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 patients17
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 Relapsed MM and untreated disease.18
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
Table 5
Comparative trials on multiple myeloma
Table 6
Drugs under investigations
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. Dexamethasone inhibits the messenger RNA expression of interleukin-6 (IL-6) in myeloma cells, a growth factor considered to be a major mediator of plasma cell pro1iferation.21
Drug Combinations in Multiple Myeloma 22
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)
ASCT – Autologous Stem Cell Transplant, The combination of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone, or VRD. VD bortezomib (Velcade), lenalidomide, or RD lenalidomide (Revlimid), and dexamethasone RD regimens, Cyclophosphamide, bortezomib and dexamethasone (CyBorD) induction for newly diagnosed multiple myeloma.
Indications of radiation therapy23
RT remains is a therapeutic component for the management in 34% of patients, and it effectively provides pain relief. RT aims in reducing bone pain, spinal cord compression with the involvement of cranial nerves RT has a palliative role in MM, and produces cure in solitary plasmacytomas.
Conclusion
MM is a neoplasm of clonal plasma cells which originate from the post-germinal lymphoid B-cell lineage which accounts for 1.8% of all malignancies and 10–15% of hematologic malignancies. MM induction therapy consisted of corticosteroids alone, melphalan/prednisone, or the combination of vincristine, doxorubicin, and dexamethasone (VAD), with a median survival of 2- 3 years. The introduction of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies (MABs) have improved treatment outcomes and extended the median OS to over 15 years in some individuals. Daratumumab, Elotuzumab have shown encouraging results both as monotherapy and in combination with other regimens in both Relapsed multiple myeloma 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, Autologous stem cell transplantation can be done on an outpatient basis. One of the most common complications of symptomatic MM is renal impairment affecting 20–30% of patients at the time of diagnosis and around 10% of them require haemodialysis, with a negative impact on prognosis.
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