Multiple myeloma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]

Multiple myeloma (MM) is a mature B-cell neoplastic proliferative disease. Multiple myeloma is part of the broad group of diseases called hematological malignancies and is also known as plasma cell myeloma, myelomatosis, or Kahler disease.^[1]There are no established causes for multiple myeloma. Multiple myeloma must be differentiated from monoclonal gammopathy of undetermined significance(MGUS), isolated plasmacytoma of the bone, and extramedullary plasmacytoma.^[2] The most potent risk factor in the development of multiple myeloma is old age.^[3][4][5] The prognosis of multiple myeloma is good with treatment, while without treatment, multiple myeloma will result in death with a median survival of 7 months.^[6][7] Multiple myeloma is the second most common blood cancer after non-Hodgkin’s lymphoma & 14th most common cancer overall in United States.^[8][9][10] There is insufficient evidence to recommend routine screening for multiple myeloma.^[11][12] If left untreated, most of patients with multiple myeloma may progress to develop fatigue, bone pain, and pallor.^[10] Multiple myeloma may be divided into three stages based on either the International Staging System or Durie-Salmon Staging System.^[13] The most common symptoms of multiple myeloma include bone pain, pallor, and fatigue.^[10][14][15] Patients with multiple usually appear fatigued and lethargic.^[10][14] Laboratory findings consistent with the diagnosis of multiple myeloma include abnormal complete blood count, erythrocyte sedimentation rate (ESR), basic metabolic panel, electrophoresis and immunohistochemistry.^[14][10] Pharmacological regimes for patients with active (symptomatic) multiple myeloma include steroid therapy, immune modulator therapy, and chemotherapy.^[16][17] Whereas patients with smoldering (asymptomatic) multiple myeloma are managed by observation and undergoing follow up tests every 3 to 6 months.^[16][17]

Multiple myeloma arises from post-germinal center B lymphocytes, that are normally involved in production of human immunoglobulins.^{[4][10][18][19]} Development of multiple myeloma is the result of multiple genetic translocation between the immunoglobulin heavy chain gene and oncogenes which leads to dysregulated multiplication of plasma cells.^[10][18] On microscopic histopathological analysis, abundant eosinophilic cytoplasm, eccentrically placed nucleus, and russell bodies bodies are characteristic findings of multiple myeloma.^[7]

There are no established causes for multiple myeloma.

Multiple myeloma must be differentiated from monoclonal gammopathy of undetermined significance(MGUS), isolated plasmacytoma of the bone, and extramedullary plasmacytoma.^[20]

In 2012, the incidence of multiple myeloma was approximately 6.3 per 100,000 cases with a mortality rate of 3.3 per 100,000 cases in the United States.^[21] The prevalence of multiple myeloma was estimated to be 89,658 cases in 2012 in the United States.^[9][10] Multiple myeloma is the second most common blood cancer after non-Hodgkin’s lymphoma & 14th most common cancer overall in United States.^[8][9][10] Male are more commonly affected with multiple myeloma than female. The male to female ratio is approximately 1.54 to 1.^[10][4] Multiple myeloma usually affects individuals of the African American and Native Pacific Islanders race. Asian individuals are less likely to develop multiple myeloma.^[10] The incidence of multiple myeloma increases with age; the median age at diagnosis is between 65 to 70 years years.^[10]

The most potent risk factor in the development of multiple myeloma is old age. Other risk factors include positive family history, positive history of monoclonal gammopathy of undetermined significance (MGUS), and occupational exposure to radiation and toxic chemicals.^[10][4][22]

There is insufficient evidence to recommend routine screening for multiple myeloma.^[23][24]

If left untreated, most of patients with multiple myeloma may progress to develop fatigue, bone pain, and pallor.^[10] Complications that can develop as a result of multiple myeloma are anemia, renal failure, skeletal complications, and neurological complications.^[6] The prognosis of multiple myeloma is good with treatment, while without treatment, multiple myeloma will result in death with a median survival of 7 months.^[6][7] Multiple myeloma is associated with a 10 year survival of 3%. The presence of plasma cell leukemia or soft tissue plasmacytomas is associated with a particularly poor prognosis among patients with multiple myeloma.^[25] According to a report published by National Cancer Institute there is a 43.25% chance of 5 year survival.^[6]

The International Myeloma Working Group (IMWG) proposed updated criteria for the diagnosis of multiple myeloma in November 2014. The diagnosis requires >10% clonal plasma cell proliferation in the bone marrow, or biopsy-proven plasmacytosis at an extramedullary site plus one of more of the multiple myeloma-defining CRAB features (hypercalcemia, renal failure, anaemia, and bone lesions) or one or more of the newly added biomarkers of malignancy (clonal bone marrow plasma cell percentage ≥60%, involved:uninvolved serum free light chain ratio ≥100, and >1 focal lesions on MRI studies).^[26]

Multiple myeloma may be divided into three stages based on either the International Staging System or Durie-Salmon Staging System.^[27] The International Staging System for multiple myeloma was published by International Myeloma Working Group in 2003 and is the most widely used staging system.^[28][29] It is used for both guiding treatment as well as predicting prognosis. The Durie-Salmon staging system, first published in 1975, is a clinical staging system for multiple myeloma that correlates measured myeloma cell mass to the presenting clinical features, response to treatment, and survival.^[30] Durie-Salmon Staging System is still in use, but has been largely superseded by the more practical ISS.^[31]

The most common symptoms of multiple myeloma include bone pain, pallor, and fatigue.^[10][14][15] However, the presenting symptoms of multiple myeloma may vary greatly due to involvement of many organ systems. The common symptoms of multiple myeloma can be remembered by the mnemonic CRAB – C = Calcium (elevated), R =Renal failure, A = Anemia, B = Bone lesions.^[32][14][15]

Patients with multiple usually appear fatigued and lethargic.^[10][14] Physical examination of patients with multiple myeloma is usually remarkable for pallor, purpura, hepatosplenomegaly, carpal tunnel syndrome, and signs of cord compression.^[10][14] Any of these physical findings may warrant further evaluation, and thus leads to an incidental diagnosis of multiple myeloma.

Laboratory findings consistent with the diagnosis of multiple myeloma include abnormal complete blood count, erythrocyte sedimentation rate (ESR), basic metabolic panel, electrophoresis and immunohistochemistry. An elevated concentration of serum protein level without concomitant elevation of serum albumin level is very suggestive of multiple myeloma.^[14][10]

X-ray may be helpful in the diagnosis of multiple myeloma. Findings on X-ray suggestive of multiple myeloma include punched out bony lesions, generalized osteopenia, and hair on end appearance.^[4]

CT scan does not have a great role in the diagnosis of disseminated multiple myeloma.^[4]

MRI may be diagnostic of multiple myeloma. Findings on MRI suggestive of multiple myeloma include infiltration and replacement of the bone marrow.^[4]

Positron Emission Tomography (PET) scan may be diagnostic of multiple myeloma.^{[14][4][33][34]} Findings on PET scan suggestive of multiple myeloma include uptake of the F18-FDG molecule by lesions of bone lysis seen on PET-CT scan.^[4]

Biopsy and genetic testing may be helpful in the diagnosis of multiple myeloma.^[14] On bone marrow biopsy, multiple myeloma is characterized by an increase in percentage of abnormal plasma cells.^[14] On genetic testing, multiple myeloma is characterized by chromosome 13 deletion and chromosome 14 translocation.^[14][10]

Pharmacological regimes for patients with active (symptomatic) multiple myeloma include steroid therapy, immune modulator therapy, and chemotherapy.^[16][17] Whereas patients with smoldering (asymptomatic) multiple myeloma are managed by observation and undergoing follow up tests every 3 to 6 months.^[16][17] The optimal therapy for active multiple myeloma depends on whether or not a patient is eligible for bone marrow transplantation.^[16][17] Pharmacologic medical therapy for active multiple myeloma patients who are eligible for a bone marrow transplant include either dexamethasone, lenalidomide, bortezomib, thalidomide, carfilzomib, cyclophosphamide, vincristine, or doxorubicin.^[16][17] In addition to the aforementioned agents, pharmacological regimes used for treatment of active multiple myeloma patients who are not eligible for a bone marrow transplant include either melphalan or prednisone.^[16][17] Alkylating agents are not recommended among transplant eligible patients, as the toxicity of such agents makes the harvest process of bone marrow stem cell difficult later in the course of the disease.^[16][17]

Surgery is not a main treatment for multiple myeloma. Emergency surgery may be needed to help support weight-bearing bones in the spine or legs to prevent bones from breaking.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2] Shyam Patel [3]

Multiple myeloma was first discovered by Dr. Samuel Solly, a surgeon working in St.Thomas hospital in London in 1844.^[1]The Bence Jones protein was first discovered by Dr. Henry Bence Jones and found to be associated with multiple myeloma in 1850; And  the  term  “Bence  Jones  protein”  was  first  used  by Fleischer in 1880.^[2]

• In 1844, Dr. Samuel Solly reported the first case of multiple myeloma. He was a a surgeon working in St. Thomas Hospital at London.^[3][4] Dr. Solly treated patients with rhubard and orange peel.
• In 1845, abnormal urinary proteins were found to be associated with multiple myeloma. These were eventually coined as Bence Jones proteins. Dr. T. Watson treated patients with steel and quinine.
• In 1856, Dr. Heller described precipitation of urinary protein above a temperature of 50 degrees Celcius. This was eventually found to be the Bence Jones protein.
• In 1850, Dr. Henry Bence Jones first described the Bence Jones protein and found it to be associated with multiple myeloma.^[5]
• In 1895, plasma cells were first described. It was later found that plasma cell proliferation was the cellular basis for multiple myeloma.^[4]
• In 1928, Copeland and Geschickter reported the first large case series of multiple myeloma patients. They described 412 patients from 1848 to 1928 and noted that these patients had pathologic fractures, Bence Jones protein in the urine, renal dysfunction, and anemia.^[4][4]
• In 1939, the monoclonal protein spike (M-spike) was described on protein electrophoresis. The M-spike was noted to be the gamma-globulin region.^[4]
• In 1947, Dr. N. Alwall treated multiple myeloma patients with urethane.
• In 1956, light chains were recognized to be a component of multiple myeloma.^[4]
• In the 1960s, the chemotherapy agent melphalan was shown to improve overall survival in multiple myeloma.^[6]
• In 1958, Dr. N. Blokhin first used melphalan as a chemotherapy agent to treat multiple myeloma.^[4]
• In 1961, the use of thalidomide was prohibited since it was found to be associated with birth defects.^[6]
• In 1962, Gally and Edelman recognized that Bence Jones urinary protein and the serum immunoglobulin light chain had the same amino acid composition. The In the same year, R.E. Maas demonstrated that corticosteroids could be used to treat multiple myeloma.^[4]
• In 1975, the Durie-Salmon staging system was developed.^[4]
• In 1983, T.J. McElwain and R.L. Powles showed that autologous stem cell transplant could be used to treat multiple myeloma.^[4]
• In the 1990s, it was shown that high-dose therapy with autologous stem cell rescue led to improved patient outcomes.^[6]
• In 1999, Singhal and colleagues showed that thalidomide had a 32% response rate in a phase II clinical trial of relapsed/refractory multiple myeloma.
• In 2003, the proteasome inhibitor bortezomib was approved by the U.S. Food and Drug Administration for the treatment of multiple myeloma.
• In 2005, the International Staging System (ISS) was developed and cytogenetic classification was described.
• In 2014, the International Myeloma Working Group (IMWG) revised the diagnostic criteria for active multiple myeloma to include bone marrow [[plasma cell burden of 60% or greater, serum free light chain ratio of involved-to-uninvolved light chain of 100 or greater, and greater than 1 bony lesion on MRI measuring at least 5mm. The advent of the 2014 diagnostic criteria increased the proportion of patients diagnosed with active multiple myeloma.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2] Shyam Patel [3]

Multiple myeloma can be classified into several subtypes based on the extent of organ involvement (medullary or extramedullary) and the disease clinical presentation (active symptomatic or smoldering asymptomatic).^[1]

Plasma cell disorders such as multiple myeloma and its related diseases are classified according to disease burden and the extent of organ involvement, as follows:

Disease	Diagnostic Criteria	Management Approach
Solitary bone plasmacytoma or extraosseous plasmacytoma	Biopsy of solid mass with histology and immunohistochemistry consistent with clonal plasma cells as a homogenous infiltrate plus Absence of clonal plasma cells in bone marrow plus Absence of end-organ damage such as anemia, hypercalcemia, renal dysfunction, or osseous lesions	Localized fractionated radiation therapy of 40-50 Gy over 4 weeks[2] Surgery if there is a need for spine stabilization, fixation of fracture, or decompressive laminectomy[2] Adjuvant chemotherapy is some cases, though not consistently recommended[2]
Monoclonal gammopathy of undetermined significance	Presence of M-spike that quantitates < 3 g/dl on protein electrophoresis, or Presence of bone marrow plasma cell burden of < 10% plus Absence of end-organ damage such as anemia, hypercalcemia, renal dysfunction, or osseous lesions	Monitoring of complete blood count every 6-12 months
Smoldering multiple myeloma	Presence of M-spike that quantitates > 3 g/dl on protein electrophoresis, or Presence of bone marrow plasma cell burden of > 10% but < 60% plus Absence of end-organ damage such as anemia, hypercalcemia, renal dysfunction, or osseous lesions	Monitoring of complete blood count at specified intervals, depending on risk stratification Chemotherapy with lenalidomide and dexamethasone for high-risk patients
Active multiple myeloma	Presence of M-spike that quantitates > 3 g/dl on protein electrophoresis, or Presence of bone marrow plasma cell burden of > 10% but < 60% plus Presence of at least one of the following: anemia, hypercalcemia, renal dysfunction, osseous lesions, bone marrow plasma cell burden > 60%, serum free light chain ratio (of involved to uninvolved light chain) > 100, MRI showing > 1 bony lesion of at least 5mm	Induction chemotherapy with bortezomib, lenalidomide, and dexamethasone High-dose therapy plus autologous stem cell transplantation Post-transplant lenalidomide maintenance (Please see Therapy section for details

Multiple myeloma can be classified according to risk status. The risk stratification for multiple myeloma consists of three groups, as follows:^[3][4]

Risk group	Chromosomal Abnormalities	Frequency
Standard risk	t(11;14) (CCND1;IgH) t(6;14) (CCND3;IgH) Trisomies (chromosomes 3, 5, 7, 9, 11, 15, 19, 21) Hyperdiploidy	75%
Intermediate Risk	t(4;14) (FGFR3;IgH) Gain(1q21)	10%
High risk	t(14;16) (IgH;MAF) t(14;20) (IgH;MAFB) del(17p) (p53 deletion) Non-hyperdiploidy	15%|-

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Hannan Javed, M.D.[2]; Haytham Allaham, M.D. [3]; Shyam Patel [4]

Multiple myeloma, a disorder of clonal late B-cells, arises from post-germinal center plasma cells that are normally involved in production of human immunoglobulins.^[1][2][3] Although the exact pathogenesis and the stage at which myeloma cells arise from post-germinal B-cells remain unclear, a variety of factors have been implicated in pathogenesis of multiple myeloma. Of these, chromosomal abnormalities are thought to be the most important. It has been suggested that all cases of multiple myeloma pass through MGUS. Renal involvement by multiple myeloma is catergorized into three entities: light chain cast nephropathy, monoclonal immunoglobulin deposition disease, and amyloidosis. Osseous involvement by multiple myeloma is based on cytokine and cellular interactions that lead to bone breakdown. On microscopic histopathological analysis, abundant eosinophilic cytoplasm, eccentrically placed nucleus, and Russell bodies are characteristic findings of multiple myeloma.^[4]

• Plasma cells are terminally differentiated B-cells which function to produce immunoglobulins. plasma cells arise from B lymphocytes through a series of events. These events take place in bone marrow and secondary lymphoid tissues.
• These events include immunoglobulin heavy-chain (IgH) VDJ gene rearrangement, migration into lymphoid tissues, somatic hypermutation (SMH) in the IgH and light-chain genes, antigen selection, switch in Ig class from IgM to IgG, IgA, IgD, or IgE, migration back to bone marrow and terminal differentiation into plasma cells.^{[5] [6][7]}

Stem cells → Pre-B cells → Immature B-cells → Mature B-cells (naïve) → Activated B-cells → Memory B-cells and Plasmablasts → Plasma cells

• During these events, B cells express variety of surface markers which may be used to denote their developmental stage such as CD19, CD20, CD27, CD38, CD10, CD138. These markers and IgH chain gene sequences are important to define the nature of myeloma cells.^[5][6][7]
• Plasma cells secrete antibodies which function in humoral immunity.^{[5][6] [7]}
• Plasma cells are typically polyclonal and can respond to a variety of antigens, which helps combat infections. Under normal circumstances, there is no monoclonality amongst the plasma cell population in a person. These plasma cells are functionally intact in their ability to contribute to humoral immunity.^[5][6][7]
• Transcription factors such as interferon regulatory factor 4 (IRF4), BCL6, B-lymphocyte-induced maturation protein 1 (BLIMP1, also known as PRDM1), paired box gene 5 (PAX5) and X box binding protein 1 (XBP1) play an important role in differentiation and survival of plasma cells.^[8][9][10]

Interferon regulatory factor 4 (IRF4) → Down-regulation of BCL6 → Up-regulation of B-lymphocyte-induced maturation protein 1 (BLIMP1) → Down-regulation of paired box gene 5 (PAX5) and Up-regulation of X box binding protein 1 (XBP1).^[11][12][13]

For more information on plasma cells, click here.

• Immunoglobulins (also known as Antibodies) are proteins that are found in blood or other bodily fluids of vertebrates, and are used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses.
• They are made of a few basic structural units called chains; each antibody has two large heavy chains H and two small light chains L. There are several different types of antibody heavy chains, and several different kinds of antibodies, which are grouped into different isotypes based on which heavy chain they possess.^[14][15]
• Five different antibody isotypes are known in mammals, which perform different roles, and help direct the appropriate immune response for each different type of foreign object they encounter.^[14][15]
• Class switch recombination (CSR), a region specific deletion recombination process, generates different immunoglobulin (Ig) isotypes by replacing one switch region with another. This process leads to enhanced functionality of immunoglobulins.^[16][17]
• Class switch recombination (CSR), just like somatic hypermutation (SMH), requires the expression of activation-induced deaminase (AID) and both are dependent on creation of double-stranded DNA breaks (DSB) in the Ig loci.^[18][19][20]

For more information on immunoglobulins, click here.

The pathogenesis of multiple myeloma is complex and probably is a result of multiple and multi-step oncogenic events such as hyperdiploidy and deregulation of cyclin D1, and interaction of myeloma cells with marrow environment. Recently it has been suggested that all cases of multiple myeloma pass through an MGUS phase. The events surrounding the progression of MGUS into multiple myeloma are not well-defined but environmental and genetic factors have been proposed to have an association. A brief description of events thought to play a role in pathogenesis of multiple myeloma is given here.

• Myeloma cells are malignant plasma cells which exhibit the morphology of mature plasma cells or plasmablasts. Majority of these cells seem to be mature, differentiated and quiescent, appearing to be without long-term proliferative potential.^[21][22]
• Cells with similar morphology to mature B-cells but with immunoglobulin gene sequences and idiotype similar to myeloma cells have also been found in myeloma patients, both in bone marrow and the peripheral blood.^[23][22]
• Current hypothesis is the presence of functional heterogeneity in myeloma cells with only a minor group of specialized myeloma cells exhibiting clonogenic growth potential. Although studies have shown the presence of myeloma cells sub-populations with distinct phenotypes and functionality in multiple myeloma such as presence of CD138+ and CD138− sub-populations, the phenotype of these so-called clonogenic cells is yet to be determined. ^[23][22][24]
• Myeloma cells express surface markers associated with plasma cells such as CD138, natural killer (NK) cells such as CD56/NCAM, T cells such as CD28, and sometimes the pan-B-cell marker CD20. Presence of CD19 and CD20 on sub-population of myeloma cells may suggest either early-lineage precursor for myeloma cells or possible de-differentiation of myeloma cells.^{[5][22][25][26][27]}
• Myeloma cells show complex chromosomal abnormalities and mutations. Studies have demonstrated the presence of translocations in up to 75% of the myeloma cases.^[5]

• The Key environmental and hereditary factors thought to confer a greater risk of developing multiple myeloma or play a part in pathogenesis are summarized in the table below.^{[8][28][29][30][31][32][33][34][35][36][37]}

Environmental and hereditary risk factors
Increasing age Gender (increased incidences in male) Familial history Past history of MGUS (Monoclonal gammopathy of undetermined significance) Obesity Immune dysfunction such as auto-immune disease, HIV (human immunodeficiency virus) and transplant recipients Exposure to chemicals, pesticides or radiation Greater prevalence of MGUS and multiple myeloma in African Americans* Inherited variation in genetic loci at 2p, 3p, 3q, 6p, 7p, 17p and 22q
* Likely influenced by environmental and behavioral confounding factors.

• Two major sets of chromosomal abnormalities seen in multiple myeloma are translocations with extensive IgH rearrangements and numerical aberrations, either trisomy or monosomy.^[8][5]

• Majority of translocations in multiple myeloma take place through class switch recombination (CSR). But few may occur through D_H–J_H recombination, possibly in early stages of B-cell development such as pre-B cell stage.^[8][38]
• Majority of these translocations put oncogenes such as cyclin D1 (CCND1), CCND3, fibroblast growth factor receptor 3 (FGFR3), multiple myeloma SET domain (MMSET; also known as WHSC1), MAF and MAFB under the influence of enhancers present at Ig loci. .^{[5][8][39][40]}
• These translocations cause over-expression of these oncogenes that in turn leads to dysregulation of cell-cycle such as increased cell survival, growth, progression and DNA repair. One of the key abnormality being the increased G1/S transition during the cell-cycle.^[8][41]
• Many other translocations may occur in later phases of multiple myeloma. One important example is translocation of MYC, an oncogene that encodes transcription factors.^[8][42][43]

• Gain of the odd numbered chromosomes including 3, 5, 7, 9, 11, 15, 19 and 21 is the other major abnormality observed in multiple myeloma.^{[5] [8]}
• The mechanism of this gain phenomena is not well understood, one hypothesis being the gain of chromosome during single mitosis.^[8]

Chromosomal aberrations in multiple myeloma (MM)
Chromosomal Abnormality	Chromosome(s)/Protein(s) affected	Consequence
Trisomies	Odd-numbered chromosomes with the exception of chromosomes 1, 13, and 21
t(11;14)(q13;q32) t(6;14q)(p21;32) t(12;14)(p13;q32)	Cyclin D1 Cyclin D3 Cyclin D2	Over-expression; cell cycle dysregulation
t(4;14)(p16;q32)	FGFR3 or MMSET	Over-expression and activation; multiple myeloma cell proliferation/apoptosis prevention MMSET probably linked to crucial transforming event
t(14;16)(q32;q23) t(14;20)(q32;q11) t(8;14)(q24;q32)	c-MAF MAFB MAFA	Over-expression; involvement in IL-4 regulation
del 17p13	p53	Cell-cycle dysregulation/apoptosis
Monosomy 14	Chromosome 14
Chromosome 13 deletion and monosomy	Chromosome 13
Gain(1q21)	Chromosome 1
Abbreviations used: FGFR3:fibroblast growth factor receptor 3; MMSET:multiple myeloma SET domain; MAF:musculoaponeurotic fibrosarcoma oncogene homolog.

• Studies have demonstrated the presence of approximately 35 mutations per sample in multiple myeloma. These mutations cause loss of tumor suppressors and NFKB alterations.^[8]

• These mutations result in cell-cycle dysregulation with an increase in G1/S transition. Some of these mutations are mentioned in the table below.^{[8][44][45][46]}
• The loss of tumor suppressors allows the cells to survive and grow without check points.

Tumor suppressor genes commonly affected in myeloma
FAM46C (family with sequence similarity 46, member C)
DIS3 (Exosome complex exonuclease RRP44)
CYLD (Cylindromatosis)
Baculoviral IAP repeat containing protein 2 (BIRC2; also known as cIAP1)
BIRC3 (Baculoviral IAP repeat containing protein 3)
tumor necrosis factor receptor associated factor 3 (TRAF3)
CDKN2C
CDKN2A
TP53

• NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex which regulates DNA transcription, production of cytokine and cell survival. NF-κB plays a key role in generating cellular responses to stimuli such as stress, free radicals, heavy metals, ultraviolet radiations, and foreign antigens. NF-κB is also crucial in response of the immune system towards infections.^[47][48][23]
• Deregulated NF-κB system leads to increased growth factors and cytokines such as IL-6 which promote growth and survival in myeloma cells.^[23]
• Mutations in multiple genes can cause activation of NF-κB system which in turn plays a role in pathogenesis of multiple myeloma. Some of these mutations, that have been documented in genes regulating NF-κB pathway, are mentioned below.^[49][50]

Genes mutated associated with canonical signaling	Genes mutated associated with non-canonical signaling
TLR4 TNFRSF1A IKBKB IKBIP CARD11 MAP3K1 RIPK4 CYLD BTRC	MAP3K14 TRAF3

• Epigenetic events such as methylation of DNA and histones play an important role in pathogenesis of multiple myeloma.
• Of these events, the most notable is the global hypomethylation and gene-specific hypermethylation that takes place during progression of MGUS to myeloma.^[8]
• A subset of patients with t(4;14) translocation show prominent DNA methylation changes that lead to MMSET overexpression.^[8][39]
• Other dysregulations related to epigenetics in multiple myeloma may effect KDM6A (UTX), a histone demethylase, mixed lineage leukemia (MLL) protein, lysine demethylase 6B (KDM6B) and homeobox A9 (HOXA9).^[8][51]

• Bone marrow microenvironment comprises of bone marrow stromal cells (BMSCs), extracellular matrix (ECM) proteins such as collagen, fibronectin and laminin, and the extracellular fluid containing cytokines and growth factors. This microenvironment is conducive to normal hematopoiesis but this also helps myeloma cells to have increased replication activity and anti-apoptotic resistance.^[5][8][52]
• One of the key processes is the interaction and adherence of myeloma cells with bone marrow stromal cells (BMSCs) and extracellular matrix proteins through cellular adhesion molecules (CAMs) such as CD44 (H-CAM), CD56 (N-CAM), members of the CD49 integrin family (including very-late antigen VLA-4 and VLA-5), lymphocyte function-associated antigen-1, syndecan-1, and selectin.^[5][8][53]
• This interaction leads to activation of p42/44 mitogen-activated protein kinase, and nuclear factor κB (NF-κB) which cause increased adhesion molecules, both on myeloma cells and bone marrow stromal cells. These events ultimately lead to increased production of cytokines. Of these cytokines IL-6, TNFα, BAFF, IGF and HGF are of particular importance.^{[5][8][54][55][56]}
• These events cause localization of tumor cells in bone marrow, increased proliferation and survival, and resistance to apoptosis and chemotherapy. Bone marrow niche thus plays a crucial role in pathogenesis of multiple myeloma.^{[5][8][54][55][56]}
• Decreased cellular adhesion molecules such as CD56 and chemokine receptors such as CXCR4 on myeloma cells lead to decreased adhesion to bone marrow stromal cells and immune evasion, allowing the myeloma cells to spread outside the bone marrow.^[57][58]

• A variety of cytokines have been implicated in pathogenesis of multiple myeloma. Some of the relevant cytokines, their mechanisms and effects on tumor cells have been summarized in the table below.^{[5][59][60][60][61][62][63][64][65][66][67][68]}

Cytokines	Mechanism	Effects on tumor cells and pathogenesis
Interleukin 6 IL-6	Activates signal transduction pathways (JAK/STAT3 and PI3K/Akt)	Increased proliferation Increased production of vascular endothelial growth factor (VEGF) Decreased apoptosis Drug resistance Increased osteoclasts differentiation
Tumor necrosis factor α TNF-α	Activation of NF-κB Activation of the MAPK pathways	Increased survival Increased proliferation Increased cell migration Increased inflammatory mediators Increased osteoclast differentiation Increased bone resorption
B-cell activating factor (BAFF)	Activation of NF-κB	Increased survival Increased adhesion
Insulin-like growth factor-1 (IGF-1)	Activation of PI3K/Akt Activation of IKK/NF-κB	Increased growth and proliferation Decreased apoptosis and increased survival
Vascular endothelial growth factor (VEGF)	VEGF Receptor activation	Increased angiogenesis Increased tumor cell migration Increased growth, Increased survival Increased IL-6 production
Interleukin 17 (IL-17)	Interleukin 17 receptors activation	Increased survival Increased cytokines production Lytic bone lesions

Abnormal antibody fragments are produced in multiple myeloma and are deposited in various organs, such as the kidneys. There are three major forms of renal damage in patients with multiple myeloma.

• Cast nephropathy: End-organ damage to the kidneys is typically due to light chain cast nephropathy. The pathophysiology of this type of renal involvement is based on light chain deposition in the renal tubules, which results in obstruction. Free light chains are readily filtered at the glomerulus and are reabsorbed in the proximal tubule of the nephron. This reabsorption occurs via the megalin-cubulin transport system.^[69] In patients with multiple myeloma, there is excess production of free light chains, and the ability of the nephron to resorb light chains in the proximal tubule cannot meet the demands of the freely filtered light chains. This results in excess secretion of free light chains in the urine (known as Bence-Jones protein). Eosinophilic proteinaceous casts and crystalline structures can be seen. Cast formation occurs in the tubules due to excess abundance of free light chains that interact with Tamm-Horsfall proteins in the thick ascending loop of Henle.^[69] Tubular obstruction ensues, triggering local inflammation which results in interstitial nephritis and fibrosis.^[69] The onset of cast nephropathy can be very quick, requiring prompt treatment. Risk factors for development of cast nephropathy include monoclonal immunoglobulin secretion of >10 g/day, sepsis, and volume depletion.^[70] Patients can also develop Fanconi syndrome, resulting in dysfunctional reabsorption ability by the proximal tubule, and type II renal tubular acidosis.

• Monoclonal immunoglobulin deposition disease (MIDD): In this subtype of renal involvement by multiple myeloma, the initial pathophysiological process is filtration of monoclonal immunoglobulins and subsequent deposition of immunoglobulins along the tubular or glomerular basement membrane.^[70] Deposits of immunoglobulin can have a similar appearance as Kimmelstein-Wilson lesions (seen in diabetes). The immunoglobulins can appear fibroblast-like.

• Light chain amyloidosis: The pathophysiology of renal involvement by light chain amyloidosis begins with beta-pleated sheet formation in the tubules or glomeruli. Beta-pleated sheets form as a result of electrostatic interactions between heparan sulfate proteoglycan and amyloid proteins. Amyloid fibrils usually consist of immunoglobulin light chains (usually lambda light chain) and deposit in the basement membrane. The size of the fibrils vary from 7 to 10 nanometers. A diagnosis of this type of renal involvement is made by the visualization of apple green birefringence upon Congo red staining of the renal specimen.^[70] It is frequently associated with nephrotic range proteinuria, in which greater than 3 grams of protein is excreted daily.

Bone disease characterized by progressive osteolytic bone lesions leading to bone resorption is hallmark of multiple myeloma. Abnormal bone remodeling is thought to be the cause. It has been reported that up to 80% of the patients have characteristic osteolytic bone lesions at presentation and 60% of the patients with multiple myeloma will develop at least one pathological fracture at some stage.The pathophysiology of bony involvement in multiple myeloma is complex and is briefly described here..^[71][72][73]

Osteoclasts are large, multinucleated cells of monocyte–macrophage lineage and play a crucial role in bone remodeling. Myeloma cells, in addition to their direct interaction with other cells, produce and release a number of factors which promote osteoclast differentiation and activation. Some of these factors and interactions have been described below in the tables.^[71][74][75]

Cell-cell interactions	Consequences
Myeloma cells to bone marrow stromal cells	Decreased production of OPG Increased RANKL expression Activation of the NF-kB system that has following effects on myeloma cells: ↑ growth ↑ survival ↑ drug resistance migration
Alpha4-beta1 integrin to vascular cell adhesion molecule 1 (VCAM-1) interaction	Increased osteoclastic activity independent of IL-6, TNF or PTHrP. Increased RANKL expression
Myeloma cells to osteoblasts	Decreased production of OPG
Myeloma cells to osteoclasts	Direct adherence of myeloma cells to osteoclasts may result in myeloma cell proliferation ↑ osteoclastic differentiation ↑ proangiogenic factors
Myeloma cells to immune cells	Increased production of cytokines, chemokines and factors associated with growth, survival and migration.

.

Molecular pathways and factors associated with increased osteoclastic activity	Association with multiple myeloma
RANK/RANKL pathway Binding of RANKL to RANK → fusion of osteoclast precursors into multinucleated cells → mature osteoclasts → ↑ bone resorption Osteoprotegerin (OPG) is a soluble decoy receptor for RANKL → ↓ binding of RANKL to RANK → ↓ bone resorption RANK is a transmembrane receptor of TNF superfamily and is expressed by osteoclast precursors RANKL, a membrane-bound protein on BMSCs of osteoblastic lineage and activated T-lymphocytes, is a cytokine Osteoprotegerin (OPG), released by BMSCs and osteoblasts, is a member of the TNF superfamily ↑ RANKL and/or ↓ OPG → ↑ Bone resorption and destruction	Myeloma cells lead to increased RANKL and decreased OPG causing bone resorption and destruction. RANKL/OPG ratio is an idependent prognostic factor in multiple myeloma Myeloma cells produce and release soluble RANKL → ↑ Bone resorption Plasma cells secrete PTHrP that stimulates paracrine pathway → ↑ expression of RANKL by osteoblasts and BMSCs → ↑ Bone resorption Syndecan-1, an heparan sulfate proteoglycan expressed by myeloma cells, binds to OPG → endocytosis and degradation of OPG by myeloma cells → ↑ Bone resorption
Notch pathway Binding of Notch receptors to its ligands → ↑ RANKL production → ↑ bone resorption Notch family contains four transmembrane receptors (Notch 1–4) Their ligands include Jagged 1,2 and Delta-like 1,3,4	Myeloma cells express Notch 1,2,3 and their ligands Jagged 1,2 and Delta-like 1,3,4. This pathway, in addition to bone resorption, may also be involved in metastasis of myeloma cells by increasing expression of adhesion molecules, migratory chemokines, and angiogenetic factors, and disruption of the immune surveillance. Notch receptors on myelomacells can bind to Jagged 1,2 ligands on the same cell (homotypical interaction) → ↑ RANKL Notch receptors on myeloma cells can bind to Jagged or Delta-like ligands on adjacent BMSCs and myeloma cells (heterotypical interaction) → ↑ RANKL Notch receptors on BMSCs can bind to Jagged ligands on myeloma cells → ↑ RANKL
CCL-3 (MIP-1α)/CCL-20 Chemokine (C-C motif) ligand 3 (CCL-3), previously known as macrophage inflammatory protein-1α (MIP-1α), is a chemokine that binds to CCR1 and CCR5. Chemokine (C-C motif) ligand 20 (CCL-20) is a chemokine involved in Th17 pathway that binds to CCR6 and has been implicated in osteoclastogenesis and osteolytic lesions. CCL-3 may: attract osteoclast precursors and induce osteoclastogenesis potentiate RANKL and IL-6 effects on osteoclasts down-regulate RUNX2 and osterix → ↓ osteoblast activity ↓ bone mineralization promote survival of myeloma cells promote migration of myeloma cells	Multiple myeloma patients have high levels of CCL-3/CCL-20 detected in their bone marrow and serum. In myeloma cells with translocation t(4;14), up-regulation of fibroblast growth factor 3 (FGFR-3) leads to induction of CCL-3. High levels of CCL-3/CCL-20 in myeloma patients correlate positively with bone disease and negatively with survival.
Activin A Binds to type II transmembrane serine/threonine kinase receptor (ActRIIA/B) → recruitment and phosphorylation the type I receptor (ActRI, also called activin receptor-like kinase 4 (ALK4) receptor) → heterodimer formation → activation of the Smad signaling cascade → translocation of Smad2/3/4 complex in the nucleus → action as transcriptional factor → RANK expression and activation of NF-κB pathway → increased osteoclast differentiation It belongs to TGFβ superfamily. May also be involved in Akt/PI3K, MAPK/ERK, JNK, and WNT/β-catenin pathways.	Multiple myeloma patients have high levels of activin A detected in their bone marrow and serum. Increased activin A levels may be associated with advanced bone disease and worse prognosis in multiple myeloma. It has been suggested that interaction between BMSCs and myeloma cells may induce secretion of activin A. It is also involved in inhibition of BMP signaling in myeloma cells.
Osteopontin a non-collagenous bone matrix glycoprotein secreted by osteoclasts may cause ↑ Osteoclast activation ↑ angiogenesis	High levels may be associated with extensive osteolytic diseas advanced disease (myeloma) High levels may also play a protective role against bone resorption in myeloma patients with with maf gene translocations.
Interleukin 3 (IL-3) a bifunctional cytokine stimulates osteoclast formation, primarily through induction of activin A production inhibits osteoblast differentiation through participation of CD45 + hematopoietic cells.	Increased levels found in multiple myeloma Thought to be secreted by T-lymphocytes through a complex interaction with myeloma cells
Vascular endothelial growth factor (VEGF) important in angiogenesis and growth may promote osteoclast differentiation by substituting for M-CSF	Majority of myeloma cells secrete VEGF Increases survival and growth of myeloma cells
Interleukin 6 (IL-6) a multifunctional cytokine involved in bone metabolism stimulates osteoclast differentiation stimulates the PI3K/Akt/mTOR pathway. This pathway plays a role in regulation of expression of: IL-6 VEGF osteopontin	Increases survival of myeloma cells Stimulates myeloma cells to produce and release vascular endothelial growth factor (VEGF) that further stimulates osteoclasts correlates with bone turnover rate in multiple myeloma
Interleukin 17 (IL-17) a pro-inflammatory cytokine stimulates osteoclast activation	Primarily secreted by T-helper cells (Th17). Also secreted by T-lymphocytes and natural killer (NK) cells Associated with osteolytic lesions in myeloma models.
B cell-activating factor (BAFF) Binding to its receptor → activation of NF-κB → ↑ MM cell survival a member of TNF superfamily associated with increased osteoclast activation	Secreted by bone marrow stromal cells (BMSCs), osteoclasts, and myeloma cells Increased serum levels in multiple myeloma patients Increases survival of myeloma cells
Bruton’s tyrosine kinase (BTK) Osteoclast precursors with CXC chemokine receptor type 4 (CXCR4) and Bruton’s tyrosine kinase (BTK) expression → migration towards stromal cell-derived factor-1α (SDF-1α) → ↑ activation of Bruton’s tyrosine kinase (BTK) in myeloma cells. a nonreceptor tyrosine kinase involved in B cell receptor signaling pathway stimulates osteoclast differentiation	Expressed by myeloma cells Correlates with CXCR4 expression Associated with progression, invasion through the extracellular matrix and the blood vessels, and settling of myeloma cells
Stromal cell-derived factor-1α (SDF-1α) Osteoclast precursors with CXC chemokine receptor type 4 (CXCR4) and Bruton’s tyrosine kinase (BTK) expression → migration towards stromal cell-derived factor-1α (SDF-1α) → ↑ activation of Bruton’s tyrosine kinase (BTK) in myeloma cells. a chemokine stimulates osteoclasts by binding to CXC chemokine receptor type 4 (CXCR4)	Involved in migration of myeloma cells Plays a role in homing of tumor cells
Annexin II (Annexin A2) a calcium-dependent phospholipid-binding member of the annexin family normally expressed by: bone marrow stromal cells (BMSCs) endothelial cells mononuclear macrophages osteoblasts osteoclasts Promotes mineralization osteoclastogenesis	Secreted by myeloma cells, bone marrow stromal cells (BMSCs), osteoblasts, and osteoclasts Up-regulated in multiple myeloma Promotes myeloma cells‘ adhesion growth of myeloma cells angiogenesis
PU.1 a transcriptional activator binds to the PU-box, a lymphoid-specific enhancer may be associated with differentiation or activation of macrophages and B-cells involved in osteoclasts formations may modulate pre-mRNA splicing

Inhibition of osteoblasts leading to decreased bone formation is now considered to be a critical event in bone disease in multiple myeloma. This inhibition leads to bone loss as well as inability to repair the osteoytic lesions caused by increased osteoclastic activity. Several pathways and factors have been associated with suppressed osteoblastic activity. Some of them are mentioned below in the table.^[71][74][75]

Molecular pathways and factors associated with osteoblastic activity	Association with multiple myeloma
Wingless and integration-1 (Wnt) signaling Canonical pathway Activation of Wnt pathway → binding of Wnt ligands to Wnt co-receptors LRP5/6 and one trans-membrane receptor of the FDZ family → formation of DVL–Axin–FRAT1–GSK-3β complex → translocation of β-catenin from cytoplasm to nucleus → activation of T cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors → ↑ bone formation and ↓ bone resorption Non-canonical WNT–planar cell polarity (WNT–PCP) pathway Formation of WNT ligand–receptor tyrosine kinase-like orphan receptor 2 (ROR2) or the receptor-like tyrosine kinase (RYK)–FZD–DVL complex → activation of one of these 3 pathways: 1) Disheveled-associated activator of morphogenesis 1 (DAAM1)–RHO–RHO-associated kinase (ROCK) pathway; 2) RAC–Jun kinase (JNK)–RUNX2 pathway; WNT–Ca2+ pathway Binding of PTH to PTH1 receptor may result in activation of Wnt pathway This pathway is also involved in cell-cycle promotion and cell growth	Dickkopf 1 (Dkk-1) an extracellular inhibitor of this pathway expressed by osteoblasts and bone marrow stromal cells, is thought to play the crucial role in osteoblastic inhibition in multiple myeloma. The serum levels and the expression of Dickkopf 1 (Dkk-1) by bone marrow cells were found to increased in patients with multiple myeloma. Sclerostin secreted by osteocytes, sclerostin is a cysteine knot-containing protein activates the caspase pathway, resulting in apoptosis of mature osteoblasts binds to LRP5/6 transmembrane receptors preventing the Wnt ligand- LRP5/6 transmembrane receptors binding, that leads to inhibition of Wnt signaling pathway promotes osteoclastogenesis by increasing RANKL/OPG ratio elevated levels have been found in all phases of multiple myeloma and is considered to be a worse prognostic factor. Furthermore, myeloma cells have been shown to secrete sclerostin Secreted frizzled related protein-2 (sFRP-2) prevents binding of Wnt ligands to frizzled, a membrane bound receptor some studies suggest that myeloma cells express sFRP-2 that antagonizes bone formation Periostin produced by bone marrow stromal cells, periostin is an adhesion protein of fasciclin family thought to activate the integrin–AKT–FAK–β-catenin pathway although the role is still unclear, elevated levels have been found in almost all the patients presenting with multiple myeloma Runt-related transcription factor 2 (Runx2)/corebinding factor runt domain alpha subunit 1 (CBFA1) a transcription factor that is a part of the non-canonical WNT-signaling pathway myeloma cells decrease osteoblast differentiation by inhibiting RUNX2 activity in BMSCs and osteoblast precursor cells
EphrinB2/EphB4 signaling pathway Binding of ligands called ephrins (Eph receptor-interacting proteins) → activation of two cascades: 1) the forward signaling → ↑ osteoblast differentiation by downregulating RhoA; 2) the reverse signaling → ↓ osteoclast differentiation by ↓ Fos and Nfatc1 transcription EphrinB2 is found in osteoclasts EphB4 is found in osteoblasts and bone marrow stromal cells	Multiple myeloma patients have decreased expression of both EphrinB2 and EphB4 in bone marrow stromal cells.
Transforming growth factor-β (TGF-β) a ubiquitous, multifunctional growth factor produced by osteocytes and osteoblasts and is activated by osteoclasts primary effect in bone marrow is the inhibition of terminal differentiation of osteoblasts	Inhibition of Transforming Growth Factor-β have been shown to prevent myeloma cells to block osteoblastic differentiation.
Bone morphogenetic proteins (BMPs) belong to TGFβ superfamily promote osteoblastogenesis through Smad-dependent and Smad-independent pathways	Myeloma cells express negative regulators of bone morphogenetic proteins that result in decreased activity of these proteins which in turn causes decreased osteoblastogenesis.
Hepatocyte growth factor (HGF) inhibits BMP-induced osteoblastogenesis, thought to be mediated by inhibition of nuclear translocation of receptor-activated SMADs	Produced by myeloma cells Increased levels have been shown to correlate with worse prognosis
Interleukin 3 (IL-3) inhibits BMP-induced osteoblastogenesis, thought to be mediated indirectly by increasing CD45+ hematopoietic cells	Elevated levels had been demonstrated in bone marrow of myeloma patients.
Interleukin 7 (IL-7) Causes increased osteoclastic activity decreased osteoblasts stimulation and maturation decreased Runx2/CBFA1 activity
Growth factor independence-1 (GFI1) a transcriptional repressor that causes decreased expression of RUNX2	Bone marrow stromal cells (BMSCs) in myeloma patients have been shown to over-express growth factor independence-1 (GFI1).
Tissue necrosis factor-α (TNF-α) inhibits osteoblast differentiation through inhibits osteoblast precursor recruitment suppresses RUNX2 and its transcriptional co-activator, TAZ	Tissue necrosis factor-α (TNF-α) levels are increased in multiple myeloma and it is thought to play a complex role in pathogenesis of multiple myeloma.
Adiponectin adipocyte-derived hormone thought to act on osteoblasts and osteoclasts	Increased adiponectin secretion through pharmacologic interventions have shown to decrease osteolytic lesions in myeloma.

Renal involvement is common in multiple myeloma as up to 50% of the patients go on to develop kidney disease at some point during the disease course. Half of these patients recover kidney function while the rest of them develop chronic kidney dysfunction. The causes of renal involvement in multiple myeloma are multiple and diverse. They can broadly be classified into Ig dependent and Ig independent mechanisms. Some of them have been discussed below in the table and then described briefly.^[76][77][70]

Ig-dependent renal injury		Ig-independent renal injury
Cause	Notes	Cause	Notes
Cast nephropathy (myeloma kidney)	Risk factors light chain myeloma with >10 g/d monoclonal Ig excretion volume depletion sepsis medications Ig deposition is primarily in the renal tubules	Volume depletion	May cause pre-renal azotemia acute tubular necrosis and/or contribute to cast nephropathy
Monoclonal Ig deposition disease	May be associated with systemic syndrome Ig deposition may be demonstrated in either tubules or glomeruli but typically not in both	Sepsis	May cause pre-renal azotemia acute tubular necrosis and/or contribute to cast nephropathy
Light chain amyloidosis (AL)	May be associated with systemic syndrome often with nephrotic-range albuminuria and λ-light chains amyloid deposition is primarily in the glomeruli	Hypercalcemia	May result in acute kidney injury directly or contribute to cast nephropathy
Glomerulonephritis	Following types have been demonstrated membranoproliferative diffuse proliferative crescentic cryoglobulinemic	Tumor lysis syndrome	Caused by uric acid or phosphate nephropathy
Tubulointerstitial nephritis	May be caused be either Ig-dependent or Ig-independent mechanisms	Direct parenchymal invasion by plasma cells	Rare cause. Association with advanced or aggressive multiple myeloma
Minimal change disease	Often with albuminuria and light chain proteinuria	Pyelonephritis	Rare cause. Pathogenesis is typically multifactorial and may include: immunodeficiency deficient Ig chemotherapy
Hyperviscosity syndrome	Seen primarily in cases of IgA, IgG3, or IgM myeloma	Medication toxicity	Following drugs may cause kidney injury: Zoledronate: May cause acute renal failure in rare cases Pamidronate: May be associated with collapsing focal and segmental glomerulosclerosis in rare cases Nonsteriodal anti-inflammatory drugs Angiotensin converting enzyme inhibitor Angiotensin receptor blocker Loop diuretics Iodinated contrast
Henoch–Scholein purpura/IgA nephropathy	Associated with IgA myeloma
Immunotactoid glomerulopathy (and possibly fibrillary GN)	Rare conditions. The association between fibrillary disease and paraproteins is is not understood at this point.
Thrombotic microangiopathy (TMA)	Endothelial injury caused by paraprotein leads to thrombotic microangiopathy.
Membranous glomerulopathy

 

• Normally circulating monoclonal free light chains are relatively freely filtered through the glomerulus and a receptor-mediated process leads to their endocytosis in proximal tubule cells. They bind to the tandem scavenger receptor system cubilin/megalin, followed by endocytosis through the clathrin-dependent endosomal/lysosomal pathway. They are then degraded within lysosomes.
• In multiple myeloma, myeloma cells produce excess of monoclonal free light chains that overwhelms the capacity of the proximal tubule cells to absorb and catabolize them. This leads to large amounts of monoclonal free light chains reaching distal renal tubules.
• In distal renal tubules, they interact with Tamm-Horsfall protein (uromodulin), a glycoprotein produced in the medullary thick ascending limb of the loop of Henle in kidneys. This interaction leads to formation of myeloma casts.
• These casts block the glomerular flow, compromising renal function and may lead to proximal tubular atrophy. This may also contribute to interstitial fibrosis.
• This blockage leads to increased luminal pressure, resulting in decreased blood flow and causing further renal injury.
• The excessive amounts of monoclonal free light chains being absorbed in proximal renal tubules leads to induction of apoptosis and DNA damage in proximal renal tubules.
• Free light chains also leads to increased pro-inflammatory cytokines such as IL-6, macrophage chemoattractant protein-1 (MCP-1), and tumor necrosis factor α (TNFα) through transcription factors nuclear factor kappa B (NFκB) and mitogen-activated protein kinases.
• All these events leads to kidney injury and inability of renal cells to repair the injury. On histopathological studies, chronic tubulointerstitial nephropathy with marked tubular atrophy, laminated casts in the tubules, and interstitial fibrosis may be observed.

Factors associated with increased risk of AKI or CKD in multiple myeloma	Mechanism of injury
Volume depletion	Increased FLC concentration Decreased GFR Pre-renal azotemia
Hypercalcemia	Renal vasoconstriction Decreased GFR Pre-renal azotemia
Iodinated contrast media	Nephrotoxicity
Nonsteroidal anti-inflammatory drugs	Renal vasoconstriction Decreased GFR Medullary hypoxia
Diuretics	Increased sodium chloride concentration Increased cast formation
Aminoglycosides	Renal vasoconstriction Decreased GFR
Hyperuricemia
Comorbidities such as chronic kidney disease, diabetes, aging, hypertension, and cardiovascular disease.

• Hypercalcemia in multiple myeloma primarily results from increased osteoclastic bone resorption. It is the second most common cause of renal injury in myeloma patients.
• Hypercalcemia leads to intra-tubular calcium deposition and vasoconstriction in renal vasculature. The resultant decrease in GFR not only causes renal injury by itself but also favors cast formation.
• By impairing renal concentrating ability through resistance to anti-diuretic hormone, it may also cause nephrogenic diabetes insipidus. Polyuria may develop, leading to hypovolemia. Net effect is decreased GFR, concentrated urine, reduced urine flow, and pre-renal azotemia.

• Deposition of immunoglobulins either in the form of amyloid or non-amyloid, typically resulting in non-selective proteinuria.
• Amyloid deposits are fibrillar structures, consist of variable region fragments of the light chain, and are seen primarily within the glomeruli.
• Some patients may have predominant vascular amyloid deposits rather than glomerular deposits and present with renal failure instead of nephrotic syndrome.

• Non-fibrillar, granular deposits are topically observed in mesangial area along with thickening of basement membrane which resembles type II membranoproliferative glomerulonephritis or diabetic glomerulopathy. The light chain deposits may also be observed in renal vasculature in addition to mesangial area.
• Typical clinical picture is that of nephrotic syndrome but renal impairment is more severe with almost all patients developing renal failure.

• Immunodeficiency is an important characteristic of multiple myeloma and is thought to associated with increased risk for infections, and affects disease progression and response to treatment.^[5][78]
• The typical clinical picture is that of global immunosuppression. The interaction between myeloma cells and bone marrow stromal cells and cytokines produced as a result of this interaction are thought to play a key role.^{[5][78][79][80]}
• Following abnormalities have been demonstrated in myeloma patients:^[79][81][80]
  • Decreased numbers of natural killer cells, B-cells, and memory T cells
  • Decreased non-myeloma immunoglobulins
  • Decreased expression of cell-surface markers on CD4+ and CD8+ T cells such as CD28 and CD152. These markers are associated with cell-signaling.
  • Abnormal signal transduction in T-cells
  • Abnormalities in cytokine production
  • Abnormalities in antibodies response and production
  • Aberrations in B-cells maturation
  • Defects in natural killer cells and antigen presenting cells

• 
  Vertebrae in multiple myeloma
  (Image courtesy of Melih Aktan M.D.)
• 
  Calvarium in multiple myeloma.
  (Image courtesy of Melih Aktan M.D.)

On microscopic histopathological analysis, multiple myeloma is characterized by the following:^[4]

• Abundant eosinophilic cytoplasm
• Eccentrically placed nucleus
• Clock face morphology of the nucleus due to chromatin clumps around the edges
• Russell bodies which are eosinophilic, large (10-15 micrometres), homogenous immunoglobulin-containing inclusions
• Dutcher bodies which are PAS stain +ve intranuclear crystalline rods

• Shown below is a series of microscopic images seen in multiple myeloma:

• 
  Bone marrow aspiration in multiple myeloma.
  (Image courtesy of Melih Aktan M.D.)
• 
  Bone marrow biopsy in multiple myeloma.
  (Image courtesy of Melih Aktan M.D.)
• 
  Bone marrow in multiple myeloma.
  (Image courtesy of Melih Aktan M.D.)
• 
  Bone marrow in multiple myeloma.
  (Image courtesy of Melih Aktan M.D.)
• 
  Multiple myeloma slide with intermediate magnification^[4]
• 
  Multiple myeloma slide with high magnification^[4]
• 
  Multiple myeloma slide with russell bodies^[4]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2] Shyam Patel [3]

The causes of multiple myeloma include sporadic mutations, such as TP53 mutation, and inherited predisposition.

The causes of multiple myeloma include:

• Mutations in the tumor suppressor TP53 (most common)
• Sporadic mutations and genetic predisposition
• Mutations in tumor suppressors or oncogenes
• Chromosomal aberrations such as translocations can trigger the onset of malignancy and allow for uncontrolled plasma cell proliferation.^[1]

• Familial causes are less contributory to the development of multiple myeloma compared to sporadic causes.^[1]

Cardiovascular	No underlying causes
Chemical/Poisoning	No underlying causes
Dental	No underlying causes
Dermatologic	No underlying causes
Drug Side Effect	No underlying causes
Ear Nose Throat	No underlying causes
Endocrine	No underlying causes
Environmental	No underlying causes
Gastroenterologic	No underlying causes
Genetic	Mutations in the tumor suppressor TP53, sporadic mutations and genetic predisposition, mutations in tumor suppressors or oncogenes, chromosomal aberrations such as translocations, familial inheritance
Hematologic	No underlying causes
Iatrogenic	No underlying causes
Infectious Disease	No underlying causes
Musculoskeletal/Orthopedic	No underlying causes
Neurologic	No underlying causes
Nutritional/Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	No underlying causes
Ophthalmologic	No underlying causes
Overdose/Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	No underlying causes
Renal/Electrolyte	No underlying causes
Rheumatology/Immunology/Allergy	No underlying causes
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Miscellaneous	No underlying causes

List the causes of the multiple myeloma in alphabetical order:

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Hannan Javed, M.D.[2] Haytham Allaham, M.D. [3] Shyam Patel [4]

Multiple myeloma must be differentiated from other causes of bone lesions such as osteoporosis, osteomalacia, scurvy, osteogenesis imperfecta, and homocystinuria. Each condition has unique causes, features, and treatment.

• The table below summarizes how to differentiate multiple myeloma from other conditions that have a similar presentation:^{[1][2][3][4][5][6][7]}

Differential Diagnosis	Causes	Features	Therapy
Multiple myeloma	Chromosomal aberrations or other genetic insults Malignant transformation of plasma cells Clonal plasma cell proliferation	Diffuse bone pain and tenderness with osteolytic lesions Renal failure Hypercalcemia Anemia	Induction chemotherapy with bortezomib, lenalidomide, and dexamethasone Bisphosphonates RANK ligand inhibitors (denosumab) Autologous stem cell transplantation
Monoclonal gammopathy of undetermined significance (MGUS)	Chromosomal aberrations or other genetic insults Clonal plasma cell proliferation	Asymptomatic Serum M protein of <30 g/L Fewer than 10% plasma cells in the bone marrow No evidence of bone or organ damage	Observation
Asymptomatic Plasma Cell Myeloma (Smoldering and Indolent plasma cell myeloma)	Chromosomal aberrations or other genetic insults Malignant transformation of plasma cells Clonal plasma cell proliferation	Asymptomatic Serum M protein of >30 g/L Greater than 10% plasma cells in the bone marrow No evidence of bone or organ damage	Observation
Plasma Cell Leukemia	Chromosomal aberrations or other genetic insults Malignant transformation of plasma cells	Renal failure Hypercalcemia Cytopenias No bone lesions	Chemotherapy
Plasmacytoma	Chromosomal aberrations or other genetic insults Malignant transformation of plasma cells	Solitary bone plasmacytoma (bone) Extramedullary plasmacytoma (soft tissues) Clinical manifestations related to tumor mass and compression symptoms	Surgery
Osteoporosis	Imbalance between bone resorption and bone formation Preceded by osteopenia Decreased bone mineral density	Acute musculoskletal pain if fractures develop Severe decrease in BMD on dual-energy X-ray absorptiometry (DEXA) test T score less than -2.5 on DEXA scan	Calcium and vitamin D supplementation Bisphosphonates Weight-bearing exercise Teriparatide RANK ligand inhibitors (denosumab)
Osteomalacia	Inadequate mineralization of bone Deficiency of vitamin D calcium, or phosphorus Renal tubular acidosis Malabsorption	Diffuse bone pain, fatigue, and fractures Low bone mineral density (BMD) Hypocalcemia	Vitamin D3 supplementation
Scurvy	Vitamin C deficiency Malabsorption Hemodialysis	Gum disease such as gum bleeding Loose teeth Easy bruising Impaired immune response Impaired wound healing	Vitamin C supplementation Citrus fruits
Osteogenesis imperfecta	Mutations in COL1A1 or COL1A2 Impaired type I collagen synthesis	Short stature, scoliosis, and propensity for fractures Blue discoloration of sclera	Bisphosphonates Physical therapy Surgical fixation of brittle bones Genetic counseling for offspring
Homocystinuria	Deficiency of cystathionine beta synthase Deficiency of folate, vitamin B12, or vitamin B6	Diffuse bone pain and musculoskeletal symptoms	High-dose vitamin B6 supplementation Betaine supplementation

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Hannan Javed, M.D.[2]; Haytham Allaham, M.D. [3]; Shyam Patel [4]

In 2012, the incidence of multiple myeloma was approximately 6.3 per 100,000 cases with a mortality rate of 3.3 per 100,000 cases in the United States. The prevalence of multiple myeloma was estimated to be 89,658 cases in 2012 in the United States. Multiple myeloma is the second most common blood cancer after non-Hodgkin’s lymphoma and 14th most common cancer overall in United States. Males are more commonly affected with multiple myeloma than females; the male to female ratio is approximately 1.54 to 1. Multiple myeloma usually affects individuals of the African American race. Asian individuals are less likely to develop multiple myeloma. The incidence of multiple myeloma increases with age.

• The age-standardized incidence rate of multiple myeloma worldwide is 1.5 per 100,000 persons per year.^[1][2]
• According to age-adjusted rates based in 2011-2015, the incidence of multiple myeloma was approximately 6.7 per 100,000 individuals with a case-fatality rate of 3.3 per 100,000 in the United States.^[3][2]
• In 2018, multiple myeloma will constitute approximately 1.8% of the estimated new cancer cases.^[4][2]
• In 2018, the estimated deaths caused by multiple myeloma will constitute 2.1% of all cancer mortality cases.^[5][2]
• In 2018, approximately 30,770 people will be diagnosed with multiple myeloma.^[6]
• In 2018, approximately 12,770 people die from multiple myeloma.^[2]
• According to 2013-2015 data, approximately 0.8% of all people will have a diagnosis of multiple myeloma at some point during their lifetime in US.^[2]
• According to an estimation in 2015, there were 124,733 people with myeloma living in the United States.^[2]
• Multiple myeloma is the second most common hematologic malignancy, after non-Hodgkin lymphoma.^[1]
• Since 1975, the overall multiple myeloma incidence has increased nearly 1 percent annually.^[4]
• Solitary plasmacytoma accounts for approximately 5% of plasma cell neoplasms.^[7]

Multiple Myeloma Epidemiology
Estimated New Cases in 2018	30,770
% of All New Cancer Cases	1.8%
Estimated Deaths in 2018	12,770
% of All Cancer Deaths	2.1%
5 Years Survival Rate (2008-2014)	50.7%
Adopted from National Cancer Institute[2]

• Myeloma is the 14th leading cause of cancer death in the United States.^[5]
• According to an estimation in 2015, there were 124,733 people with myeloma living in the United States.^[2]

• The incidence of multiple myeloma increases with age, and the median age at diagnosis is 69 years.^[2]

Percent of New Cases by Age Group
Age	Percent of New cases
<20
20-34	0.5%
35-44	2.8%
45-54	10.9%
55-64	23.2%
65-74	29.8%
75-84	23.7%
>84	9.0%
Adopted from National Cancer Institute[2]

• Males are more commonly affected with multiple myeloma than females. The male to female ratio is approximately 1.54 to 1.^[8]

• Among African Americans, multiple myeloma is one of the top 10 leading causes of cancer deaths.^[5]
• The incidence of multiple myeloma in the African American population is more than the European American population.
• African Americans have a 2-fold higher age-standardized incidence rate of multiple myeloma than Caucasians. The incidence of multiple myeloma in African Americans is 9.6 per 100,000 persons. The incidence of Caucasians is 4.1 per 100,000 persons.^[1]

New Cases per 100,000 Persons by Race/Ethnicity & Sex
Race	Female	Male
All Races	5.3	8.4
White	4.7	7.9
Black	11.6	15.9
Asian/Pacific Islander	3.1	4.9
American Indian/Alaska Native	5.5	6.2
Hispanic	5.0	7.6
Non-Hispanic	5.4	8.5
Adopted from National Cancer Institute[2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]; Shyam Patel [3]

Risk factors for multiple myeloma include advanced age, African American race, male gender, obesity, exposure to chemicals and radiation, the presence of family history of hematologic conditions.

The table below lists the risk factors for multiple myeloma:

Risk Factor	Description
Age	The chance of developing multiple myeloma increases with age, as somatic mutations in plasma cells accumulate with aging. The median age of diagnosis of multiple myeloma is 61. Only 1% of multiple myeloma cases are diagnosed in patients younger than 35 years.[1][2][3]
Race	African Americans and Native Pacific Islanders are at higher risk of developing multiple myeloma compared to Caucasians.[4][3][5]
Gender	Males are more commonly affected by multiple myeloma than females.[2][3]
Presence of other plasma cell disorders	Patients with other plasma cell disorders such as monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma are at increased risk for development of active multiple myeloma.[6][3] The risk for progression to active multiple myeloma depends on the plasma cell burden, free light chain ratio, and subtype of paraprotein.
Family history	A familial predisposition to myeloma exists due to hyperphosphorylation of specific proteins that may contribute to a higher rates of multiple myeloma in certain groups.[7][4][8][3] Patients with germline mutations in tumor suppressors such as TP53 may be at increased risk for multiple myeloma.
Obesity	Obesity increases a person’s risk of developing multiple myeloma, as is true for other types of malignancies.[6][3] The pathophysiologic basis for the link between obesity and multiple myeloma is not well described.
Workplace exposures	Petroleum workers and farmers tend to have higher incidence of multiple myeloma relative to other occupations.[9][6][3] Agent Orange exposure may also be linked to the development of multiple myeloma. Agent Orange exposure is common among U.S. veterans.
Presence of other diseases	There is a slight increase in the risk for developing multiple myeloma among patients with type 2 diabetes mellitus. There is a weak association between systemic lupus erythematosus (SLE) and multiple myeloma, especially in the United States and Canada. Other autoimmune conditions such as pernicious anemia and ankylosing spondylitis are associated with significantly increased risk for developing multiple myeloma.[10]
Radiation	People who were exposed to radiation (atomic bombs or nuclear accidents) have a higher risk for developing multiple myeloma.[6][3] Ionizing radiation is more likely to cause multiple myeloma compared to other types of radiation, as ionizing radiation induces DNA damage.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]; Shyam Patel [3]

Risk factors for multiple myeloma include advanced age, African American race, male gender, obesity, exposure to chemicals and radiation, the presence of family history of hematologic conditions.

The table below lists the risk factors for multiple myeloma:

Risk Factor	Description
Age	The chance of developing multiple myeloma increases with age, as somatic mutations in plasma cells accumulate with aging. The median age of diagnosis of multiple myeloma is 61. Only 1% of multiple myeloma cases are diagnosed in patients younger than 35 years.[1][2][3]
Race	African Americans and Native Pacific Islanders are at higher risk of developing multiple myeloma compared to Caucasians.[4][3][5]
Gender	Males are more commonly affected by multiple myeloma than females.[2][3]
Presence of other plasma cell disorders	Patients with other plasma cell disorders such as monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma are at increased risk for development of active multiple myeloma.[6][3] The risk for progression to active multiple myeloma depends on the plasma cell burden, free light chain ratio, and subtype of paraprotein.
Family history	A familial predisposition to myeloma exists due to hyperphosphorylation of specific proteins that may contribute to a higher rates of multiple myeloma in certain groups.[7][4][8][3] Patients with germline mutations in tumor suppressors such as TP53 may be at increased risk for multiple myeloma.
Obesity	Obesity increases a person’s risk of developing multiple myeloma, as is true for other types of malignancies.[6][3] The pathophysiologic basis for the link between obesity and multiple myeloma is not well described.
Workplace exposures	Petroleum workers and farmers tend to have higher incidence of multiple myeloma relative to other occupations.[9][6][3] Agent Orange exposure may also be linked to the development of multiple myeloma. Agent Orange exposure is common among U.S. veterans.
Presence of other diseases	There is a slight increase in the risk for developing multiple myeloma among patients with type 2 diabetes mellitus. There is a weak association between systemic lupus erythematosus (SLE) and multiple myeloma, especially in the United States and Canada. Other autoimmune conditions such as pernicious anemia and ankylosing spondylitis are associated with significantly increased risk for developing multiple myeloma.[10]
Radiation	People who were exposed to radiation (atomic bombs or nuclear accidents) have a higher risk for developing multiple myeloma.[6][3] Ionizing radiation is more likely to cause multiple myeloma compared to other types of radiation, as ionizing radiation induces DNA damage.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2] Shyam Patel [3]

The natural history of multiple myeloma begins with an asymptomatic phase, then progresses to symptomatic involvement and organ involvement. Outcomes are generally good if treatment is begun at an appropriate time. Complications of multiple myeloma include hematologic complications, such as cytopenias, and skeletal complications, such as pathologic fractures. The prognosis of multiple myeloma is based on chromosome changes, stage of disease, kidney function, labelling index, age, performance status, and various laboratory values.

• Multiple myeloma: The natural history of multiple myeloma usually begins with an asymptomatic phase. Monoclonal paraprotein or free light chains can be elevated in the absence of symptoms and are frequently detected on laboratory testing. If left untreated, most of the patients with multiple myeloma will gradually develop fatigue, bone pain, and pallor. In as many as 30-40% cases the diagnosis may be incidental and is often diagnosed on routine blood screening. Additional laboratory workup can reveal signs of end-organ damage, such as anemia, renal dysfunction, or elevated calcium. Bony pain can ensue if left untreated. Upon recognition of a possible diagnosis of multiple myeloma, a bone marrow biopsy is usually performed for definitive diagnosis. Once treatment with induction therapy is underway, patient typically experience improvement in laboratory measures, such as reduction in monoclonal paraprotein, reduction in free light chain levels, reduction in calcium, increase in hemoglobin, and improvement in glomerular filtration rate (GFR). The improvement in laboratory parameters is typically seen within 1-3 months after starting induction chemotherapy. After 6-8 cycles of induction chemotherapy, patients will typically proceed to autologous stem cell transplant. If transplant is not performed, the natural history of the disease is characterized by relapse, in which the malignant plasma cell clone is resistant to the initial induction chemotherapy regimen.
• Plasmacytoma: The natural history of plasmacytoma begins with a symptomatic phase, which typically presents as a solid mass. The first diagnostic step is typically a tissue biopsy, which reveals the presence of clonal plasma cells. Once the diagnosis is made, further workup includes assessment for systemic involvement. In most cases, a diagnosis of plasmacytoma is not concurrent with a diagnosis of multiple myeloma. However, the natural history of plasmacytoma is such that there is a risk of progression to active multiple myeloma after many years. After a median follow-up of 58 months, 67% of patients will develop progression to multiple myeloma. Approximately 20% of patients will die from progression of disease.^[1]

Complications that can develop as a result of multiple myeloma are divided into hematologic complications and systemic complications:^[2][3]

Hematologic complications of multiple myeloma are due to the accumulation of excess numbers of abnormal plasma cells, which impairs normal hematopoiesis. This is referred to as myelophthisis, or the replacement of normal bone marrow by infiltrating tumor cells. This can result in complications such as anemia, thrombocytopenia, and leukopenia.

• Anemia: Impaired erythroid progenitor formation leads to decreased red blood cell production, which results in anemia. The anemia is usually normocytic (mean corpuscular volume of 80-100 femtoliters). Patients can experience signs and symptoms including fatigue, mucosal and conjunctival pallor, shortness of breath, and decreased exercise tolerance. Severe anemia can occur in patients who have concurrent renal dysfunction from multiple myeloma, as erythropoietin production is impaired in patients with renal complications. Patients may require red blood cell transfusion if the hemoglobin level is less than 7 g/dl or if severe symptomatic anemia develops. Complications from transfusion include HIV infection, hepatitis B infection, hepatitis C infection, pulmonary edema from volume overload, alloimmunization to red blood cell products, and hemosiderosis (iron overload state).
• Thrombocytopenia: Impaired megakaryocyte formation leads to decreased platelet production, which results in thrombocytopenia. Patients can experience signs and symptoms including mucosal bleeding, upper and lower gastrointestinal bleeding, bruising, petechiae, and ecchymoses. In rare cases, fatal hemorrhage can occur. Patients may require platelet transfusion if the platelet count is less than 10,000 cells per microliter, or less than 50,000 cells per microliter in the setting of bleeding diathesis.
• Leukopenia: Impaired granulocyte and lymphocyte progenitor formation leads to decreased mature white blood cell production, which results in leukopenia. Patients can experience signs and symptoms including localized infections (pneumonia, urinary tract infections, cellulitis, dental infections), fevers, chills, and sepsis. In rare cases, infection can be very severe and lead to severe sepsis. Patients may require treatment with antibiotics. Of note, although the plasma cell burden is increased in multiple myeloma, these plasma cells do not function in a normal manner, and the abnormal paraprotein production in multiple myeloma does not confer adequate humoral immunity. Thus, patient can have normal plasma cell counts but can be functionally immunosuppressed.

Systemic complications of multiple myeloma are due to the effects of plasma cells on various non-hematologic organs, such as the kidneys, bones, and nervous system.

• Skeletal complications: Skeletal-related events are diverse and include asymptomatic lytic lesions, symptomatic lytic lesions, and pathologic fractures. Pathologic fractures in the appendicular skeleton (long bones) can result in functional impairment and impaired mobility. Pathologic fractures in the axial skeleton (vertebral column) can result in more serious complications. Spinal cord compression occurs if pathologic fractures occur in the vertebral column with impingement of bony fragments on the spinal cord. Symptoms include back pain, numbness, dysthesias, decreased deep tendon reflexes, and loss of bowel or bladder control. Spinal cord compression is an oncologic emergency and requires urgent neurosurgical decompression, radiation therapy, and administration of dexamethasone 10mg IV followed by 4 mg PO every 6 hours to prevent further cord compromise.
• Hypercalcemia: In patients with multiple myeloma, calcium is frequently greater than 11 mg/dl. Hypercalcemia can result in signs and symptoms include nephrolithiasis (kidney stones), psychiatric disturbance, bony pain, and constipation. Treatment of hypercalcemia includes calcitonin, bisphosphonates, denosumab, furosemide, and corticosteroids.
• Renal failure: Multiple myeloma is associated with both acute renal failure and chronic renal failure. The mechanism of renal failure is usually due to abnormal deposition of immunoglobulin light chains in renal tubules, a process known as cast nephropathy. Signs and symptoms of renal failure include decreased urine output, volume overload, nausea, pruritic, metallic taste, and normocytic anemia due to erythropoietin deficiency.
• Neurologic complications: The effects of abnormal plasma cells on the nervous system can result in neurologic impairment. Multiple myeloma can cause neurologic complications via various mechanisms, including plasma cell infiltration of tissues of the central nervous system, plasma cell infiltration of tissues of the peripheral nerves (resulting in carpel tunnel syndrome), osseous destruction in areas abutting nerve roots (resulting in radiculopathy), or osseous destruction in areas abutting the spinal cord (result in spinal cord compression).

The prognosis of multiple myeloma depends of a variety of factors. The most important factor that determines disease biology and prognosis is cytogenetics. Overall, prognosis is generally good with appropriate treatment. Without treatment, multiple myeloma will result in death with a median survival of 7 months. The median overall survival for newly diagnosed multiple myeloma ranges from 2 to 10 years. The 5-year overall survival rate of multiple myeloma is approximately 46%. However, the prognosis is far better in the current era since multiple new therapeutic interventions have been introduced. The table below lists common prognostic factors for multiple myeloma.^{[4][5][6][7][8]}

Prognostic Factor	Description
Chromosome changes	Cytogenetic analysis of multiple myeloma cells has prognostic value, with deletion of chromosome 13, non-hyperdiploidy, and the balanced translocations t(4;14), t(14;16), and t(14;20) conferring a poorer prognosis. Gain of chromosome 1q21 is associated with a somewhat poor prognosis. The 11q13 and 6p21 cytogenetic abnormalities are associated with a better prognosis.
Stage	Advanced stage of multiple myeloma, such as Durie-Salmon or International Staging System (ISS) stage III, are associated with poor prognosis.
Kidney function	An elevated level of creatinine is associated with poor prognosis.
Labelling index	The labeling index indicates how fast the cancer cells are growing. A high plasma cell labeling index (PCLI) or proliferation (reproduction) rate (Ki-67) is associated with poor prognosis.
Age	Older patients have worse prognosis than younger patients.
Associated plasma cell disorder	The presence of plasma cell leukemia or soft tissue plasmacytoma is associated with a particularly poor prognosis among patients with multiple myeloma.
Performance status	Performance status is ranked on a 0–5 scale per the Eastern Cooperative Oncology Group (ECOG) classification. The lower the number, the healthier and more active the person is, and the better the prognosis. Performance status is important in multiple myeloma because people who are healthier can withstand more intensive treatment.
Beta-2-microglobulin	A higher level of beta-2-microglobulin is associated with poor prognosis. This laboratory value is incorporated into the International Staging System (ISS).
Albumin level	A lower albumin level is associated with poor prognosis. This laboratory value is incorporated into the International Staging System (ISS).
Lactate dehydrogenase level	A higher level of lactate dehydrogenase (LDH) is associated with poor prognosis. This laboratory value is incorporated into the Revised International Staging System (R-ISS).
Response to treatment	Patients whose cancer responds to treatment and enters complete remission have a better prognosis than people whose cancer does not respond to the initial treatment.

The prognosis for solitary plasmacytoma is generally very good. The median survival is 10 years. The 5-year survival rate is 72% and the 20-year survival rate is 37%.^[1]