Multiple Myeloma

Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes B lymphocytes B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins. Osteoclastic activity results in bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones resorption, bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, pathologic fractures, and metabolic disturbances. Excessive secretion of antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins results in proteinuria and associated kidney damage as well as production and tissue deposition of amyloid fibrils. Metabolic disturbances combined with tissue amyloid deposition cause end-organ damage. Diagnosis is established by plasma electrophoresis and bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow biopsy. Treatments to slow down the disease progression are available; however, there is no cure for MM. The median survival is approximately 3 years.

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Overview

Definition

Multiple myeloma (MM) is a bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow malignancy arising from monoclonal plasma cells.

Epidemiology

  • MM accounts for 10% of all hematologic malignancies
  • Incidence is 3–8 per 100,000 (race dependent).
  • The highest rate is in African Americans.
  • Men > women (2:1)
  • A disease of the elderly: Median age is 65–70 years old (race dependent).

Etiology

  • Monoclonal proliferation of plasma cells that produce monoclonal antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins
  • MGUS is considered a precursor.
  • The causative mechanism is unknown but proposed and/or contributing mechanisms include:
    • Chronic inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation:
      • Chronic infection ( hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus, hepatitis C Hepatitis C Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C virus can cause both acute and chronic hepatitis, ranging from a mild to a serious, lifelong illness including liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C Virus)
      • Autoimmune disease ( rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis, Sjögren’s syndrome)
    • Environmental/occupational exposure:
      • Herbicides and insecticides
      • Benzene and other organic solvents
      • Radiation
    • Genetic causes:
      • No strong evidence suggesting a hereditary pattern
      • 13q14 deletions, 17p13 deletions, and 11q abnormalities predominate
      • The most common translocation is t(11;14)(q13;q32).
      • C-myc, NRAS, and KRAS mutations have been inconsistently associated with the disease.

Pathophysiology

Pathogenesis

  • Commonly preceded by MGUS, progresses to smoldering MM, then progresses to full-blown MM
  • Approximately 1% of MGUS per year will progress to MM.
  • Exact mechanism of progression is unknown, but likely due to additional mutations.
  • Tumor cells show mixed morphology:
    • Some look like mature plasma cells
    • Some appear immature (large, multinucleated, bizarrely shaped)
    • Cells are positive for CD138 and CD56.
  • Monoclonal plasma cell proliferation is associated with antibody production:
    • IgG > IgA > IgD > IgM
    • Myeloma protein (M protein) is a monoclonal antibody and detected in > 95% of cases:
      • 1 heavy chain + 1 light chain
      • OR only light chains
  • Cytokines: 
    • Promote proliferation and survival of myeloma cells
    • Secreted by tumor cells themselves and bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow stromal cells:
      • Tumor necrosis factor Tumor necrosis factor Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) ( TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF))
      • Interleukin-1 (IL-1)
      • Interleukin-6 (IL-6)

Pathophysiologic effects

  • Bone lesions:
    • Myeloma cells upregulate the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) by bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow stromal cells.
    • RANKL stimulates osteoclast activity.
    • Tumor cells also release modulators of the Wnt pathway, resulting in osteoblast inhibition.
    • The result is lytic bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones lesions and hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia.
  • Bone marrow infiltration:
    • Tumor cells infiltrate and replace normal bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow.
    • The result is cytopenia.
  • Monoclonal antibody production:
    • Bence Jones proteinuria:
      • Light chains are excreted by the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys.
      • Light chains are toxic to the renal tubular epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium.
      • The result is renal dysfunction.
    • Amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis: from deposition of excess light chains in kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys and other tissues
  • Hyperviscosity:
    • Associated with excessive M proteins
    • Sludging in capillary beds
    • Mostly in MM subtypes associated with excessive IgA (approximately 7% of patients)
Bone resorption in mm

Bone resorption in MM:
Cytokine release by plasma cells results in osteoclastic activation

Image: “Myeloma bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones disease” by Sanderson RD, Epstein J. License: CC BY 2.5

Clinical Presentation

  • Skeletal:
    • Bone pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain/tenderness
    • Pathologic fractures
    • Possible spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord compression with vertebral involvement
  • Constitutional symptoms:
    • Weight loss
    • Malaise/fatigue
    • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
  • Hypercalcemia:
    • Renal stones
    • Confusion
    • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
  • Hematologic abnormalities: 
    • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview
    • Thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia
    • Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia: increased susceptibility to infections ( urinary tract Urinary tract The urinary tract is located in the abdomen and pelvis and consists of the kidneys, ureters, urinary bladder, and urethra. The structures permit the excretion of urine from the body. Urine flows from the kidneys through the ureters to the urinary bladder and out through the urethra. Urinary Tract infection ( UTI UTI Urinary tract infections (UTIs) represent a wide spectrum of diseases, from self-limiting simple cystitis to severe pyelonephritis that can result in sepsis and death. Urinary tract infections are most commonly caused by Escherichia coli, but may also be caused by other bacteria and fungi. Urinary Tract Infections), pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia)
    • Coagulopathy: M protein interacts directly with clotting factors and prevents aggregation.
  • Hyperviscosity:
    • Microvascular hemorrhage (purpura, retinal hemorrhage, etc.)
    • Coronary ischemia
    • Stroke
    • Somnolence, headache
  • Renal failure (multifactorial):
    • Amyloid deposition
    • Renal stones
    • Hypercalcemia
    • Direct tubular injury from filtration load (protein, calcium, etc.)
  • Amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis
    • AL subtype: IgG lambda light chain
    • Clinical manifestations typical of amyloidosis:
      • Muscle deposition: shoulder pad sign
      • Tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue deposition: macroglossia
      • Bruising: eyelid purpura (raccoon eyes)
  • Neuropathy:
    • Compressive neuropathies: carpal tunnel syndrome Carpal Tunnel Syndrome Carpal tunnel syndrome (CTS) is a complex of signs and symptoms caused by compression of the median nerve as it crosses the carpal tunnel. Presentation is with pain and paresthesia of the dermatomal target tissues innervated by the median nerve as well as weakness and atrophy of the nerve's myotomal targets. Carpal Tunnel Syndrome in the setting of amyloidosis
    • Traditional “glove-and-stocking” peripheral neuropathy from small vessel disease (amyloid deposition in the nerves and vasoneurosum)
    • Dermatomal neurologic deficits from spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord compression

Mnemonics

Features of MM: “CRAB

  • HyperCalcemia
  • Renal abnormality
  • Anemia and Amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis
  • Bone fractures

Diagnosis

Laboratory workup

  • CBC:
    • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview (normocytic)
    • Thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia
    • Leukopenia
  • Chemistry:
    • ↑ Ca
    • ↑ LDH
    • ↑ Erythrocyte sedimentation rate (ESR)
    • ↑ Albumin
    • ↑ 𝛽2-microglobulin
    • ↑ Creatinine
  • Screening urinalysis: 
    • Elevated protein
    • Increased susceptibility to UTI UTI Urinary tract infections (UTIs) represent a wide spectrum of diseases, from self-limiting simple cystitis to severe pyelonephritis that can result in sepsis and death. Urinary tract infections are most commonly caused by Escherichia coli, but may also be caused by other bacteria and fungi. Urinary Tract Infections
  • 24-hour urine collection: 
    • Bence Jones proteinuria (lambda free light chains in urine)
    • Creatinine clearance (indicates severity of renal impairment)
  • Electrophoresis (screening test):
    • M spike on SPEP
    • M spike on urine protein electrophoresis (UPEP)
  • Peripheral smear: rouleaux formation (aggregation of RBCs)
  • Bone marrow biopsy:
    • Confirmatory test
    • > 10% plasma cells

Imaging

  • X-rays X-rays X-rays are high-energy particles of electromagnetic radiation used in the medical field for the generation of anatomical images. X-rays are projected through the body of a patient and onto a film, and this technique is called conventional or projectional radiography. X-rays (skeletal survey) of the skull Skull The skull (cranium) is the skeletal structure of the head supporting the face and forming a protective cavity for the brain. The skull consists of 22 bones divided into the viscerocranium (facial skeleton) and the neurocranium. Skull, long bones, and spine:
    • Lytic lesions
    • Pathologic fractures
    • Osteopenia
  • MRI of thoracic and lumbar spine to evaluate for:
    • Paraspinal involvement
    • Pathologic fractures
    • Spinal cord compression

Management

Management

  • Patients < 65 years old:
    • Cytoreduction (steroids/immunomodulators) followed by stem cell transplantation
    • Cytoreduction (aka primary induction therapy) regimens:
      • Bortezomib/lenalidomide/dexamethasone
      • Bortezomib/cyclophosphamide/dexamethasone (used in the setting of acute renal insufficiency)
  • Patients > 65 years old:
    • Stem cell transplantation is poorly tolerated and not routinely performed.
    • Chemotherapy:
      • Thalidomide, as a monotherapy, combined with steroids or melphalan
      • Lenalidomide combined with dexamethasone
      • Bortezomib combined with melphalan
      • Vincristine, doxorubicin (Adriamycin), and dexamethasone (VAD)
      • Melphalan combined with prednisone
  • Supportive treatment:
    • Treatment of hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia:
      • Bisphosphonates Bisphosphonates Bisphosphonates are pyrophosphate analogs most well-known for treating osteoporosis by preventing bone loss. Bisphosphonates end in the suffix "-dronate" or "-dronic acid" (e.g., alendronate, risedronate, pamidronate) and bind to hydroxyapatite crystals in bone, inhibiting osteoclast-induced bone resorption. Bisphosphonates
      • Calcitonin
      • Hydration
      • Natriuresis
    • Radiation to areas of pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain or impending pathological fractures
    • Plasmapheresis
    • Erythropoietin Erythropoietin Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. Erythrocytes for anemia
    • Vaccinations for prevention of pneumococcal infections
    • Pain management Pain Management Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Pain is a subjective experience. Acute pain lasts < 3 months and typically has a specific, identifiable cause. Pain Management:
      • Analgesics
      • Spinal decompression: 
        • Kyphoplasty
        • Surgical decompression
      • Nerve root blocks/peripheral nerve blocks

Prognosis

  • Poor prognostic factors include the following:
    • Tumor burden
    • Hypercalcemia
    • Bence Jones proteinuria
    • Renal involvement
  • The median survival rate is 3 years.
  • 5-year survival rate < 50%
  • Infections are an important cause of early death in MM.

Differential Diagnosis

  • Waldenstrom macroglobulinemia: another plasma cell neoplasm that produces IgM specifically, resulting in hyperviscosity syndrome and splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly. Waldenstrom macroglobulinemia (aka lymphoplasmacytic lymphoma) is more indolent than MM. The diagnosis is established with electrophoresis (IgM spike) and bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow biopsy. Asymptomatic cases do not always require treatment. Chemotherapy is the mainstay of management for symptomatic disease.
  • Monoclonal gammopathy of undetermined significance: moderate elevation of M protein without clinical symptoms. Serum M protein concentration is < 3 g/dL and plasma cell concentration is < 10%. The disease shows no evidence of end-organ damage. Diagnosis is established with plasmapheresis and bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow biopsy. The significance is the risk of progression to MM. No specific treatment is required.
  • Metastatic bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones malignancy: distant spread of primary tumors to the bones. Metastatic bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones malignancy is frequently observed in prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands, breast, and lung cancers, among others. Presentation may include bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, pathologic fractures, and constitutional symptoms. Diagnosis is usually established with imaging in the context of known malignancy. Treatment is mostly supportive.

References

  1. Azevedo, A. (2020). Multiple myeloma. Retrieved February 26, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/25360/
  2. Longo, D., et al. (2012). Harrisons Manual of Medicine, 18th Edition. US: McGraw-Hill Professional. Pages 2107–2114.
  3. Shah, D. (2021). Multiple Myeloma. Medscape. Retrieved February 26, 2021, from https://emedicine.medscape.com/article/204369-overview
  4. Robbins and Cotran Pathologic Basis of Disease. (2015). 9th Edition. Pages 599–601.
  5. Van de Donk N.W.C.J., Pawlyn C., Yong K.L. (2021). Multiple myeloma. Lancet. 397(10272),410–427. Retrieved February 26, 2021, from https://pubmed.ncbi.nlm.nih.gov/33516340/

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