Multiple Myloma

Multiple myeloma (MM) is a plasma cell malignancy in which monoclonal plasma cells proliferate in bone marrow, resulting in an overabundance of monoclonal paraprotein (M protein), destruction of bone, and displacement of other hematopoietic cell lines.

Diagnosis

The classic triad

• marrow plasmacytosis (>10%)
• lytic bone lesions
• serum and/or urine M component.

Note: The diagnosis may be made in the absence of bone lesions if the plasmacytosis is associated with a progressive increase in the M component over time or if extramedullary mass lesions develop.

Signs and symptoms

• Bone pain (70%), worse with motility
• Pathologic fractures
• Spinal cord compression (from pathologic fracture)
• Weakness, malaise
• Anemia (80%), bleeding.
• Infection (often pneumococcal)
• Hypercalcemia
• Renal failure (25%) commonest cause-hypercalcemia. Other causes: Glomerular deposits of amyloid, hyperuricemia, recurrent infections, frequent use of NSAIDS, iodinated contrast dye for imaging, and occasional infiltration of kidney by myeloma cells. Tubular damage associated with the excretion of excess light chains is almost always present, and results in adult Fanconi’s syndrome (a type 2 proximal renal tubular acidosis), with loss of glucose and amino acids, as well as defects in the ability of the kidney to acidify and concentrate the urine. Proteinuria is all light chains and very little albumin.
• Neuropathies

Physical examination:

• HEENT: Exudative macular detachment, retinal hemorrhage, or cotton-wool spots, Macroglossia
• Pallor from anemia, ecchymoses or purpura from thrombocytopenia; extramedullary plasmacytomas (most commonly in aerodigestive tract but also orbital, ear canal, cutaneous, gastric, rectal, prostatic, retroperitoneal areas), subcutaneous nodules
• Bone pains or tenderness, Shoulder pad sign (amyloidosis)
• Neurologic exam: Sensory level change (i.e. loss of sensation below a dermatome corresponding to a spinal cord compression), neuropathy, myopathy, positive Tinel sign, or positive Phalen sign (suggestive of Carpal tunnel syndrome)
• Hepatosplenomegaly
• Cardiomegaly

Investigations:

• Serum and urine assessment for monoclonal protein (densitometer tracing and nephelometric quantitation; immunofixation for confirmation). Serum M component will be IgG in 53% of patients, IgA in 25%. Serum Electrophoresis
• Serum free light chain assay (in all patients with newly diagnosed plasma cell dyscrasias)
• Bone marrow aspiration and/or biopsy
• Serum beta2-microglobulin, albumin, and lactate dehydrogenase measurement
• Standard metaphase cytogenetics
• Fluorescence in situ hybridization (FISH) for testing myeloma genetics in individual patients. FISH - 17p, FISH - del 13q or LSI D 13S319, FISH-Positive selection of CD138 cells in Multiple Myeloma (Prognostic marker).
• Skeletal survey
• MRI

Staging:

Stage	Criteria
I	All of the following: Hemoglobin >10 g/dL 2. Serum calcium <12 mg/dL Normal bone x-ray or solitary lesion Low M-component production. a. IgG level <50 g/L (<5 g/dL). b. IgA level <30 g/L (<3 g/dL).
II	Fitting neither I nor III
III	One or more of the following: Hemoglobin <8.5 g/dL Serum calcium >12 mg/dL Advanced lytic bone lesions High M-component production a. IgG level >70 g/L (>7 g/dL) b. IgA level >50 g/L (>5 g/dL)

International Staging System

Depends on levels of beta-2 microglobulin and albumin.

Stage	Criteria	Median Survival
I (28%)	Beta2M <3.5, alb ≥3.5	62
II (39%)	beta2M <3.5, alb <3.5 or beta2M = 3.5–5.5	44
III (33%)	beta2M >5.5	29

Other prognostic factors

Other factors that may influence prognosis are the presence of cytogenetic abnormalities and hypodiploidy by karyotype, fluorescent in situ hybridization (FISH)–identified chromosome 17p deletion, and translocations t(4;14), (14;16), and t(14;20).

Treatment

• MGUS: No specific intervention. Investigation 6-12 mthly interval.
• MGUS and severe polyneuropathy: plasmapheresis and occasionally rituximab in patients with IgM MGUS or myeloma-like therapy in those with IgG or IgA disease.
• SMM: No specific intervention, but lenalidomide and dexamethasone may prevent progression from high-risk SMM to active MM. Treatment only for symptomatic patients.
• Plasmacytomas: Local radiation therapy.
• Symptomatic / Progressive Myeloma:
  • Induction: Thalidomide (200 mg daily), with dexamethasone, achieved responses in two-thirds of newly diagnosed MM.
  • Lenalidomide (25 mg/d on days 1–21 every 4 weeks), an immunomodulatory derivative of thalidomide, and bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11 every 3 weeks), a proteasome inhibitor, combined with dexamethasone (40 mg once every week) has obtained close to a 100% response rate and 30% complete response rate, making it one of the preferred induction regimens in transplant-eligible patients.
  • Other similar three-drug combinations (bortezomib, thalidomide, and dexamethasone or bortezomib, cyclophosphamide, and dexamethasone) also achieve >90% response rate.
  • Herpes zoster prophylaxis if bortezomib is used. Lenalidomide use requires prophylaxis for deep vein thrombosis (DVT) with either aspirin or warfarin.
  • In patients receiving lenalidomide, stem cells should be collected within 6 months, because the continued use of lenalidomide may compromise the ability to collect adequate numbers of stem cells.
  • Initial therapy is continued until maximal cytoreduction.
  • In patients who are transplant candidates, alkylating agents such as melphalan should be avoided because they damage stem cells, leading to decreased ability to collect stem cells for autologous transplant.
  • Age >70 years, significant cardiopulmonary problems, or other comorbid llnesses: not transplant candidates. Previously, intermittent pulses of melphalan, an alkylating agent, with prednisone (MP - melphalan, 0.25 mg/kg per day, and prednisone, 1 mg/kg per day for 4 days) every 4–6 weeks was used. Now, combining novel agents with MP achieve high complete response rates e.g. thalidomide with MP (MPT), bortezomib with MP. Most studies favor continuous therapy with non-MP-containing regimens (e.g. lenalidomide plus dexamethasone) due to longer term safety profile and efficacy
  • High-dose therapy and consolidation/maintenance are standard practice in the majority of eligible patients.
  • Relapsed myeloma can be treated with a number of agents including lenalidomide and/or bortezomib.
  • The median overall survival of patients with myeloma is 7–8+ years, with subsets of younger patients surviving more than 10 years.
  • Hypercalcemia generally responds well to bisphosphonates, glucocorticoid therapy, hydration, and natriuresis, and rarely requires calcitonin as well.
  • Bisphosphonates (e.g., pamidronate 90 mg or zoledronate 4 mg once a month) reduce osteoclastic bone resorption and preserve performance status and quality of life, decrease bone-related complications.
  • In the event of acute renal failure: plasmapheresis.
  • The anemia associated with myeloma may respond to erythropoietin along with hematinics

  Prognosis

  Serum beta2-microglobulin is the single most powerful predictor of survival and can substitute for staging. Patients with beta2-microglobulin levels <0.004 g/L have a median survival of 43 months, and those with levels >0.004 g/L have a survival of only 12 months. Combination of serum beta2-microglobulin and albumin levels forms the basis for a three stage International Staging System (ISS).

  Benign monoclonal gammopathies or monoclonal gammopathies of uncertain significance (MGUS)

  MGUS are vastly more common than myeloma, occurring in 1% of the population over age 50 and in up to 10% over age 75. Patients with MGUS usually have <10% bone marrow plasma cells; <30 g/L (3 g/dL) of M components; no urinary Bence Jones protein; and no anemia, renal failure, lytic bone lesions, or hypercalcemia.
  25% of patients with MGUS go on to develop myeloma. Typically, patients with MGUS require no therapy. Their survival is about 2 years shorter than age-matched controls without MGUS.

  Smoldering Multiple Myeloma (Asymptomatic Myeloma / SMM)

  M protein in serum > 30 g/L, Bone marrow clonal plasma cells > 10%, but no myeloma-related organ or tissue impairment or symptoms.

  Nonsecretory Myeloma

  Like MM, but no M protein in serum and/or urine.

  Solitary Plasmacytoma of Bone

  No M protein in serum and/or urine. Single area of bone destruction due to clonal plasma cells. Bone marrow not consistent with multiple myeloma. Normal skeletal survey (and magnetic resonance imaging of spine and pelvis if done). No related organ or tissue impairment (no end organ damage other than solitary bone lesion)

  POEMS Syndrome

  POEMS: polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes.
  All of the following four criteria must be met:
  
  1. Polyneuropathy.
  2. Monoclonal plasma cell proliferative disorder
  3. Any one of the following:
     • sclerotic bone lesions
     • Castleman’s disease
     • Elevated levels of vascular endothelial growth factor (VEGF)
  4. Any one of the following:
     • organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy)
     • Extravascular volume overload (edema, pleural effusion, or ascites)
     • Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, and pancreatic)
     • Skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing, and white nails)
     • Papilledema
     • Thrombocytosis/polycythemia

  Waldenstroms macroglobulinemia:

  Go to Waldenstroms macroglobulinemia