Multiple Myeloma

Overview

Definition

Multiple myeloma (MM) is a 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. Bones: Structure and Types marrow malignancy Malignancy Hemothorax arising from monoclonal plasma cells Plasma cells Specialized forms of antibody-producing B-lymphocytes. They synthesize and secrete immunoglobulin. They are found only in lymphoid organs and at sites of immune responses and normally do not circulate in the blood or lymph. Humoral Adaptive Immunity.

Epidemiology

• MM accounts for 10% of all hematologic malignancies
• Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency 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 Plasma cells Specialized forms of antibody-producing B-lymphocytes. They synthesize and secrete immunoglobulin. They are found only in lymphoid organs and at sites of immune responses and normally do not circulate in the blood or lymph. Humoral Adaptive Immunity that produce monoclonal antibodies Monoclonal antibodies Antibodies produced by a single clone of cells. Ebolavirus and Marburgvirus
• 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 Insecticides Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. Trypanosoma cruzi/Chagas disease
    • Benzene and other organic solvents
    • Radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma
  • 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 c-MYC Basic helix-loop-helix transcription factors encoded by the c-myc genes. They are normally involved in nucleic acid metabolism and in mediating the cellular response to growth factors. Elevated and deregulated (constitutive) expression of c-myc proteins can cause tumorigenesis. Non-Hodgkin Lymphomas, 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 Tumor Inflammation cells show mixed morphology:
  • Some look like mature plasma cells Plasma cells Specialized forms of antibody-producing B-lymphocytes. They synthesize and secrete immunoglobulin. They are found only in lymphoid organs and at sites of immune responses and normally do not circulate in the blood or lymph. Humoral Adaptive Immunity
  • Some appear immature (large, multinucleated, bizarrely shaped)
  • Cells are positive for CD138 and CD56.
• Monoclonal plasma cell Plasma cell Specialized forms of antibody-producing B-lymphocytes. They synthesize and secrete immunoglobulin. They are found only in lymphoid organs and at sites of immune responses and normally do not circulate in the blood or lymph. Lymphocytes: Histology proliferation is associated with antibody production:
  • IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis > IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions > IgD IgD An immunoglobulin which accounts for less than 1% of plasma immunoglobulin. It is found on the membrane of many circulating B lymphocytes. Immunoglobulins: Types and Functions > IgM IgM A class of immunoglobulin bearing mu chains (immunoglobulin mu-chains). Igm can fix complement. The name comes from its high molecular weight and originally being called a macroglobulin. Immunoglobulins: Types and Functions
  • Myeloma protein (M protein) is a monoclonal antibody and detected in > 95% of cases:
    • 1 heavy chain + 1 light chain
    • OR only light chains Light chains Polypeptide chains, consisting of 211 to 217 amino acid residues and having a molecular weight of approximately 22 kda. There are two major types of light chains, kappa and lambda. Two ig light chains and two ig heavy chains (immunoglobulin heavy chains) make one immunoglobulin molecule. Immunoglobulins: Types and Functions
• Cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response: 
  • Promote proliferation and survival of myeloma cells
  • Secreted by tumor Tumor Inflammation cells themselves and 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. Bones: Structure and Types 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 Interleukin-1 A soluble factor produced by monocytes; macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. Interleukin-1 is a general term refers to either of the two distinct proteins, interleukin-1alpha and interleukin-1beta. The biological effects of il-1 include the ability to replace macrophage requirements for t-cell activation. Interleukins (IL-1)
    • Interleukin-6 Interleukin-6 A cytokine that stimulates the growth and differentiation of B-lymphocytes and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-lymphocytes; monocytes; and fibroblasts. Interleukins (IL-6)

Pathophysiologic effects

• 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. Bones: Structure and Types lesions:
  • Myeloma cells upregulate the expression of receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors activator of nuclear factor kappa-B Nuclear factor kappa-B Ubiquitous, inducible, nuclear transcriptional activator that binds to enhancer elements in many different cell types and is activated by pathogenic stimuli. The NF-kappa B complex is a heterodimer composed of two DNA-binding subunits: NF-kappa B1 and relA. MALT Lymphoma ligand ( RANKL RANKL A tumor necrosis factor receptor family member that is specific for rank ligand and plays a role in bone homeostasis by regulating osteoclastogenesis. It is also expressed on dendritic cells where it plays a role in regulating dendritic cell survival. Signaling by the activated receptor occurs through its association with tnf receptor-associated factors. Paget’s Disease of Bone) by 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. Bones: Structure and Types marrow stromal cells.
  • RANKL RANKL A tumor necrosis factor receptor family member that is specific for rank ligand and plays a role in bone homeostasis by regulating osteoclastogenesis. It is also expressed on dendritic cells where it plays a role in regulating dendritic cell survival. Signaling by the activated receptor occurs through its association with tnf receptor-associated factors. Paget’s Disease of Bone stimulates osteoclast activity.
  • Tumor Tumor Inflammation cells also release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology 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. Bones: Structure and Types 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 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. Bones: Structure and Types marrow infiltration:
  • Tumor Tumor Inflammation cells infiltrate and replace normal 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. Bones: Structure and Types marrow.
  • The result is cytopenia.
• Monoclonal antibody production:
  • Bence Jones proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children:
    • Light chains Light chains Polypeptide chains, consisting of 211 to 217 amino acid residues and having a molecular weight of approximately 22 kda. There are two major types of light chains, kappa and lambda. Two ig light chains and two ig heavy chains (immunoglobulin heavy chains) make one immunoglobulin molecule. Immunoglobulins: Types and Functions 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: Anatomy.
    • Light chains Light chains Polypeptide chains, consisting of 211 to 217 amino acid residues and having a molecular weight of approximately 22 kda. There are two major types of light chains, kappa and lambda. Two ig light chains and two ig heavy chains (immunoglobulin heavy chains) make one immunoglobulin molecule. Immunoglobulins: Types and Functions 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: Histology.
    • 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 Light chains Polypeptide chains, consisting of 211 to 217 amino acid residues and having a molecular weight of approximately 22 kda. There are two major types of light chains, kappa and lambda. Two ig light chains and two ig heavy chains (immunoglobulin heavy chains) make one immunoglobulin molecule. Immunoglobulins: Types and Functions 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: Anatomy and other tissues
• Hyperviscosity Hyperviscosity Hypercoagulable States:
  • Associated with excessive M proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis
  • Sludging in capillary beds Capillary beds Groups of 10–100 individual capillary vessels supplied by a single metarteriole. Capillaries: Histology
  • Mostly in MM subtypes associated with excessive IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions (approximately 7% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship)

Clinical Presentation

• Skeletal:
  • Bone pain/tenderness
  • Pathologic fractures
  • Possible spinal cord compression with vertebral involvement
• Constitutional symptoms:
  • Weight loss
  • Malaise/fatigue
  • Fever
• Hypercalcemia:
  • Renal stones
  • Confusion
  • Constipation
• Hematologic abnormalities: 
  • Anemia
  • Thrombocytopenia
  • Neutropenia: increased susceptibility to infections (urinary tract infection (UTI), 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: 
  • AL subtype: IgG lambda light chain
  • Clinical manifestations typical of amyloidosis:
    • Muscle deposition: shoulder pad sign
    • Tongue deposition: macroglossia
    • Bruising: eyelid purpura (raccoon eyes)
• Neuropathy:
  • Compressive neuropathies: carpal tunnel syndrome in the setting of amyloidosis
  • Traditional “glove-and-stocking” peripheral neuropathy Peripheral Neuropathy Neurofibromatosis Type 2 from small vessel disease (amyloid deposition in the nerves and vasoneurosum)
  • Dermatomal Dermatomal Dermatologic Examination neurologic deficits Neurologic Deficits High-Risk Headaches 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: Anatomy compression Compression Blunt Chest Trauma

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 and Types (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 CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)
  • ↑ LDH LDH Osteosarcoma
  • ↑ Erythrocyte sedimentation rate Erythrocyte Sedimentation Rate Soft Tissue Abscess ( ESR ESR Soft Tissue Abscess)
  • ↑ Albumin Albumin Serum albumin from humans. It is an essential carrier of both endogenous substances, such as fatty acids and bilirubin, and of xenobiotics in the blood. Liver Function Tests
  • ↑ 𝛽2-microglobulin
  • ↑ Creatinine
• Screening Screening Preoperative Care urinalysis Urinalysis Examination of urine by chemical, physical, or microscopic means. Routine urinalysis usually includes performing chemical screening tests, determining specific gravity, observing any unusual color or odor, screening for bacteriuria, and examining the sediment microscopically. Urinary Tract Infections (UTIs) in Children: 
  • 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 (UTIs)
• 24-hour urine collection: 
  • Bence Jones proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children (lambda free light chains Light chains Polypeptide chains, consisting of 211 to 217 amino acid residues and having a molecular weight of approximately 22 kda. There are two major types of light chains, kappa and lambda. Two ig light chains and two ig heavy chains (immunoglobulin heavy chains) make one immunoglobulin molecule. Immunoglobulins: Types and Functions in urine)
  • Creatinine clearance Creatinine clearance Kidney Function Tests (indicates severity of renal impairment)
• Electrophoresis Electrophoresis An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. Blotting Techniques ( screening Screening Preoperative Care test):
  • M spike on SPEP
  • M spike on urine protein electrophoresis Electrophoresis An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. Blotting Techniques (UPEP)
• Peripheral smear: rouleaux formation ( aggregation Aggregation The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin; collagen) and is part of the mechanism leading to the formation of a thrombus. Coagulation Studies of RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology)
• 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. Bones: Structure and Types marrow biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma:
  • Confirmatory test
  • > 10% plasma cells Plasma cells Specialized forms of antibody-producing B-lymphocytes. They synthesize and secrete immunoglobulin. They are found only in lymphoid organs and at sites of immune responses and normally do not circulate in the blood or lymph. Humoral Adaptive Immunity

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 Skeletal Survey Child Abuse) 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: Anatomy, long bones Long bones Length greater than width. Bones: Structure and Types, and spine Spine The human spine, or vertebral column, is the most important anatomical and functional axis of the human body. It consists of 7 cervical vertebrae, 12 thoracic vertebrae, and 5 lumbar vertebrae and is limited cranially by the skull and caudally by the sacrum. Vertebral Column: Anatomy:
  • Lytic lesions
  • Pathologic fractures
  • Osteopenia Osteopenia Osteoporosis
• MRI of thoracic and lumbar spine Spine The human spine, or vertebral column, is the most important anatomical and functional axis of the human body. It consists of 7 cervical vertebrae, 12 thoracic vertebrae, and 5 lumbar vertebrae and is limited cranially by the skull and caudally by the sacrum. Vertebral Column: Anatomy to evaluate for:
  • Paraspinal involvement
  • Pathologic fractures
  • 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: Anatomy compression Compression Blunt Chest Trauma

Management

Management

• Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship < 65 years old:
  • Cytoreduction ( steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors/immunomodulators) followed by stem cell transplantation
  • Cytoreduction (aka primary induction therapy) regimens:
    • Bortezomib Bortezomib A pyrazine and boronic acid derivative that functions as a reversible proteasome inhibitor. It is used as an antineoplastic agent in the treatment of multiple myeloma and mantle cell lymphoma. Targeted and Other Nontraditional Antineoplastic Therapy/ lenalidomide Lenalidomide Has immunomodulatory (↓ tumor necrosis factor-⍺, ↑ natural killer cells and IL-2) and antiangiogenic activity. Induces cell-cycle arrest and death → inhibiting tumor cell growth. Cancer Immunotherapy/ dexamethasone Dexamethasone An anti-inflammatory 9-fluoro-glucocorticoid. Antiemetics
    • Bortezomib Bortezomib A pyrazine and boronic acid derivative that functions as a reversible proteasome inhibitor. It is used as an antineoplastic agent in the treatment of multiple myeloma and mantle cell lymphoma. Targeted and Other Nontraditional Antineoplastic Therapy/ cyclophosphamide Cyclophosphamide Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It has been used in the treatment of lymphoma and leukemia. Its side effect, alopecia, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. Immunosuppressants/ dexamethasone Dexamethasone An anti-inflammatory 9-fluoro-glucocorticoid. Antiemetics (used in the setting of acute renal insufficiency)
• Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship > 65 years old:
  • Stem cell transplantation is poorly tolerated and not routinely performed.
  • Chemotherapy Chemotherapy Osteosarcoma:
    • Thalidomide Thalidomide A piperidinyl isoindole originally introduced as a non-barbiturate hypnotic, but withdrawn from the market due to teratogenic effects. It has been reintroduced and used for a number of immunological and inflammatory disorders. Thalidomide displays immunosuppressive and anti-angiogenic activity. It inhibits release of tumor necrosis factor-alpha from monocytes, and modulates other cytokine action. Immunosuppressants, as a monotherapy, combined with steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors or melphalan Melphalan An alkylating nitrogen mustard that is used as an antineoplastic in the form of the levo isomer – melphalan, the racemic mixture – melphalan, and the dextro isomer – melphalan; toxic to bone marrow, but little vesicant action; potential carcinogen. Alkylating Agents and Platinum
    • Lenalidomide Lenalidomide Has immunomodulatory (↓ tumor necrosis factor-⍺, ↑ natural killer cells and IL-2) and antiangiogenic activity. Induces cell-cycle arrest and death → inhibiting tumor cell growth. Cancer Immunotherapy combined with dexamethasone Dexamethasone An anti-inflammatory 9-fluoro-glucocorticoid. Antiemetics
    • Bortezomib Bortezomib A pyrazine and boronic acid derivative that functions as a reversible proteasome inhibitor. It is used as an antineoplastic agent in the treatment of multiple myeloma and mantle cell lymphoma. Targeted and Other Nontraditional Antineoplastic Therapy combined with melphalan Melphalan An alkylating nitrogen mustard that is used as an antineoplastic in the form of the levo isomer – melphalan, the racemic mixture – melphalan, and the dextro isomer – melphalan; toxic to bone marrow, but little vesicant action; potential carcinogen. Alkylating Agents and Platinum
    • Vincristine Vincristine An antitumor alkaloid isolated from vinca rosea. Microtubule and Topoisomerase Inhibitors, doxorubicin (Adriamycin), and dexamethasone Dexamethasone An anti-inflammatory 9-fluoro-glucocorticoid. Antiemetics (VAD)
    • Melphalan Melphalan An alkylating nitrogen mustard that is used as an antineoplastic in the form of the levo isomer – melphalan, the racemic mixture – melphalan, and the dextro isomer – melphalan; toxic to bone marrow, but little vesicant action; potential carcinogen. Alkylating Agents and Platinum combined with prednisone Prednisone A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. Immunosuppressants
• 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 Calcitonin A peptide hormone that lowers calcium concentration in the blood. In humans, it is released by thyroid cells and acts to decrease the formation and absorptive activity of osteoclasts. Its role in regulating plasma calcium is much greater in children and in certain diseases than in normal adults. Other Antiresorptive Drugs
    • Hydration
    • Natriuresis
  • Radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma to areas of pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways or impending pathological fractures
  • Plasmapheresis Plasmapheresis Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. Stevens-Johnson Syndrome
  • 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: Histology for 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 and Types
  • Vaccinations for prevention of pneumococcal infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
  • Pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways management:
    • Analgesics
    • Spinal decompression: 
      • Kyphoplasty
      • Surgical decompression
    • Nerve root blocks/ peripheral nerve blocks Peripheral Nerve Blocks Anesthesiology: History and Basic Concepts

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

• Poor prognostic factors include the following:
  • Tumor Tumor Inflammation burden
  • 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
  • Bence Jones proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children
  • Renal involvement
• The median survival rate is 3 years.
• 5-year survival rate < 50%
• Infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease are an important cause of early death in MM.

Differential Diagnosis

• Waldenstrom macroglobulinemia: another plasma cell Plasma cell Specialized forms of antibody-producing B-lymphocytes. They synthesize and secrete immunoglobulin. They are found only in lymphoid organs and at sites of immune responses and normally do not circulate in the blood or lymph. Lymphocytes: Histology neoplasm that produces IgM IgM A class of immunoglobulin bearing mu chains (immunoglobulin mu-chains). Igm can fix complement. The name comes from its high molecular weight and originally being called a macroglobulin. Immunoglobulins: Types and Functions specifically, resulting in hyperviscosity Hyperviscosity Hypercoagulable States 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 Lymphoplasmacytic lymphoma Non-Hodgkin Lymphomas) is more indolent than MM. The diagnosis is established with electrophoresis Electrophoresis An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. Blotting Techniques ( IgM IgM A class of immunoglobulin bearing mu chains (immunoglobulin mu-chains). Igm can fix complement. The name comes from its high molecular weight and originally being called a macroglobulin. Immunoglobulins: Types and Functions spike) and 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. Bones: Structure and Types marrow biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma. Asymptomatic cases do not always require treatment. Chemotherapy Chemotherapy Osteosarcoma is the mainstay of management for symptomatic disease.
• Monoclonal gammopathy Monoclonal gammopathy Conditions characterized by the presence of m protein (monoclonal protein) in serum or urine without clinical manifestations of plasma cell dyscrasia. MALT Lymphoma of undetermined significance: moderate elevation of M protein without clinical symptoms. Serum M protein concentration is < 3 g/dL and plasma cell Plasma cell Specialized forms of antibody-producing B-lymphocytes. They synthesize and secrete immunoglobulin. They are found only in lymphoid organs and at sites of immune responses and normally do not circulate in the blood or lymph. Lymphocytes: Histology concentration is < 10%. The disease shows no evidence of end-organ damage. Diagnosis is established with plasmapheresis Plasmapheresis Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. Stevens-Johnson Syndrome and 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. Bones: Structure and Types marrow biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma. 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. Bones: Structure and Types malignancy Malignancy Hemothorax: 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. Bones: Structure and Types malignancy Malignancy Hemothorax 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. , 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. Bones: Structure and Types pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, pathologic fractures, and constitutional symptoms Constitutional Symptoms Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis. Diagnosis is usually established with imaging in the context of known malignancy Malignancy Hemothorax. Treatment is mostly supportive.