This document discusses multiple myeloma (MM), a plasma cell malignancy characterized by proliferation of monoclonal plasma cells in the bone marrow. Key points include: MM commonly precedes other premalignant conditions like MGUS; genetic defects contribute to disease heterogeneity and drug resistance; MM causes skeletal destruction and can involve other organ systems; diagnosis involves tests like serum and urine protein assays, bone marrow biopsy, and imaging; and treatment involves chemotherapy while considering prognostic factors like tumor mass, hypercalcemia, and renal impairment.

1. Dr.S.Sethupathy,M.D.,Ph.D.,
Professor of Biochemistry,
Rajah Muthiah Medical College,
Annamalai University

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

5. Etiology
 The precise etiology of MM has not yet been
established.
 Genetic causes
 Environmental or occupational causes
 MGUS
 Radiation
 Chronic inflammation
 Infection-Human herpesvirus 8 (HH8) infection of
bone marrow dendritic cells

6. Genetic defects - MM
 About 50% are hyperdiploid, with extra copies of the
odd-numbered chromosomes.
 A primary translocation involving the Ig heavy-chain
gene at 14q32.
 Gysregulation of the cyclin D/retinoblastoma (cyclin
D/RB) pathway.
 This genetic heterogeneity contributes to the rapid
emergence of drug resistance in MM.

7. Pre MM conditions
 MM is commonly preceded by monoclonal gammopathy of
undetermined significance (MGUS), a premalignant
condition
 In MGUS, these clonal plasma cells take up less than 10% of
bone marrow.
 The serum protein value is less than 3 g/dL and myeloma-
related end-organ damage is absent.
 An intermediate disease stage between MGUS and MM,
termed smoldering MM, is characterized by an M protein
level of 3 g/dL or more and over 10% clonal plasma cells in
bone marrow
 But no symptoms of myeloma-related end-organ damage.

8. Pre MM conditions
conditions
Clonal plasma cells
in BM
Myeloma defining
events
progression
treatment

9. MM and cytokines
 Interleukin (IL)-6 is also an important factor
promoting the in vitro growth of myeloma
cells.
 Other cytokines are tumor necrosis factor
and IL-1b.
 MM involves the skeletal, hematologic,
renal, and nervous systems

10. Skeletal manifestations
 Plasma-cell proliferation causes extensive skeletal
destruction with osteolytic lesions, anemia,
and hypercalcemia through production of the
osteoclast-activating factor.
 Destruction of bone and its replacement by tumor may
lead to pain, spinal cord compression, and pathologic
fracture.
 Compression fracture of a vertebral body destroyed by
multiple myeloma
 Bony involvement is typically lytic in nature.

11. Hematologic processes
Bone marrow infiltration by plasma
cells results in neutropenia, anemia,
and thrombocytopenia.
M components may interact with
clotting factors, leading to defective
aggregation.

12. Renal processes
 Direct tubular injury, amyloidosis, or
involvement by plasmacytoma.
 Hypercalcemic nephropathy, hyperurcemia
 Due to renal infiltration of plasma cells
resulting in myeloma, light-chain
nephropathy
 Amyloidosis
 Glomerulosclerosis.

13. Hyperviscosity syndrome.
 Due to overproduction of IgG1, IgG3, or
IgA. Sludging in the capillaries
 It results in purpura, retinal hemorrhage,
papilledema, coronary ischemia, or central
nervous system (CNS) symptoms (eg,
confusion, vertigo, seizure).
 Cryoglobulinemia causes Raynaud
phenomenon, thrombosis, and gangrene in
the extremities.

14. Complications
 Renal failure
 Nephrocalcinosis due to hypercalcemia
 Anemia, neutropenia, or thrombocytopenia
is due to bone marrow infiltration of plasma
cells.
 Thrombosis and Raynaud phenomenon due
to cryoglobulinemia may be present.

15. Clinical features
 Severe bone pain, pathologic fracture due to
lytic lesions
 Increased bone resorption leading to
hypercalcemia
 Spinal cord compression: Symptoms
typically include back pain, weakness or
paralysis in the legs, numbness, or
dysesthesias in the lower extremities.

16. Clinical features
 Radiculopathy and/or cord compression may occur
because of skeletal destruction and nerve
compression.
 Bacterial infection may develop
 Purpura, retinal hemorrhage, papilledema,
coronary ischemia, seizures, and confusion may
occur as a result of hyperviscosity syndrome.
 Hypercalcemia may cause polyuria and polydipsia,
muscle cramps, constipation
 A change in the patient’s mental status.

17. Signs and symptoms
 Bone pain
 Pathologic fractures
 Spinal cord compression (from pathologic fracture)
 Weakness, malaise
 Bleeding, anemia
 Infection (often pneumococcal)
 Hypercalcemia
 Renal failure
 Neuropathies
 Shoulder pad sign
 Macroglossia
 Typical skin lesions

18. Amyloidosis infiltrating tongue in
MM

19. Skull Lytic lesions - MM

20. Lytic lesions -MM

21.  Exudative macular detachment, retinal
hemorrhage, or cotton-wool spots
 Dermatologic evaluation
 Pallor from anemia
 Ecchymoses or purpura from thrombocytopenia
 Extramedullary plasmacytomas
 Bony tenderness or pain without tenderness
 Sensory level change, neuropathy, myopathy,
positive Tinel sign, or positive Phalen sign
 Abdominal examination: Hepatosplenomegaly
 Cardiovascular evaluation: Cardiomegaly

23. Myeloma-defining events
 Serum calcium level >0.25 mmol/L (>1 mg/dL) higher than
the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
 Renal insufficiency (creatinine >2 mg/dL [>177 μmol/L] or
creatinine clearance < 40 mL/min)
 Anemia (hemoglobin < 10 g/dL or hemoglobin >2 g/dL
below the lower limit of normal)
 One or more osteolytic bone lesions on skeletal
radiography, CT, or PET-CT
 Clonal bone marrow plasma cells ≥60%
 Abnormal serum free light chain (FLC) ratio ≥100 (involved
kappa) or < 0.01 (involved lambda)
 One or more focal >5 mm lesions on MRI scans

24. Differential Diagnoses
Primary (Malignant) Lymphoma of
Bone
Metastatic Bone Disease
Monoclonal Gammopathies of
Undetermine Significance (MGUS)
Waldenstrom Macroglobulinemia

26. Lab tests
 Serum and urine assessment for monoclonal
protein (densitometer tracing and
nephelometric quantitation;
immunofixation for confirmation)
 Serum-free light chain assay
 Bone marrow aspiration and/or biopsy
 Serum beta-2 microglobulin
 Albumin,
 LDH

27. Free Light Chain (FLC) assay

28. Lab tests
 Total protein, albumin, and globulin
 Blood urea nitrogen (BUN) and creatinine
 Uric acid
 Quantitative Immunoglobulin Levels (IgG, IgA, IgM)
 C-reactive protein (CRP) is a surrogate marker of
interleukin (IL)-6 activity.
 IL-6 is often referred to as the plasma cell growth
factor.
 beta-2 microglobulin is useful for prognostic marker

29. Urine Collection
 24-hour urine for quantification of the
Bence Jones protein (ie, lambda light
chains), protein, and creatinine clearance.
 > 1 g of protein in 24 h is a major criterion
for MM
 For monitoring the response to therapy
 Creatinine clearance - renal impairment.

30. Serum Viscosity
Check the serum viscosity in patients
with central nervous system (CNS)
symptoms, nosebleeds, or very high M
protein levels.
 These findings may
indicate hyperviscosity syndrome.

31. MM band

32. Polyclonal and monoclonal band

33. M band

34. Bone marrow aspirate - plasma cells of multiple
myeloma.- Blue cytoplasm, eccentric nucleus, and
perinuclear pale zone

35. Bone marrow biopsy demonstrating sheets of
malignant plasma cells in multiple myeloma.

36. Special tests
Standard metaphase
cytogenetics
Fluorescent in situ
hybridization
Skeletal survey
Magnetic resonance imaging

37. Prognosis
 C-reactive protein (CRP) and beta-2
microglobulin:
 If levels of both proteins are less than 6
mg/L, the median survival is 54 months.
 If the level of only one component is less
than 6 mg/L, the median survival is 27
months.
 If levels of both protein values are greater
than 6 mg/L, the median survival is 6
months.

38. Poor prognostic factors
Tumor mass
Hypercalcemia
Bence Jones proteinemia
Renal impairment

39. Treatment
Chemotherapy
Adjunctive therapy such as:
Erythropoietin
Corticosteroids
Surgical intervention
Plasmapheresis

40. Thank you