Multiple myeloma is a neoplastic proliferation of plasma cells that produce monoclonal immunoglobulins. It commonly presents with anemia, bone pain, elevated creatinine, and fatigue. Diagnosis requires clonal bone marrow plasma cells ≥10% plus biomarkers of end organ damage like hypercalcemia, renal insufficiency, or bone lesions. Treatment involves managing complications, chemotherapy like bortezomib/lenalidomide with dexamethasone, and sometimes stem cell transplant. Prognosis depends on staging systems like ISS which incorporate serum albumin and beta-2 microglobulin levels.

1. MULTIPLE MYELOMA
DR.BIKAL LAMICHHANE
1ST YEAR IM RESIDENT

2. INTRODUCTION
• Neoplastic proliferation of plasma cells
derived from a single clone
• Myeloma cells produce monoclonal
immunoglobulins - produce
symptoms

3. BASIC OF IMMUNOGLOBULIN

4. DEVELOPMENT OF B-CELL

5. EPIDEMIOLOGY
• Occurs in all races and all geographic locations
• Blacks> whites
• Lowest in asia and developing countries
• M>F
• Obese
• Older adults-Median age=69 yearRS

6. ETIOLOGY
• No single common molecular pathogenetic pathway has yet emerged.
• Radiation
• Farmers, wood workers, leather workers, and those exposed to petroleum
products
• Hyperdiploidy, 13q14 deletions, translocations t(11;14)(q13;q32),
t(4;14)(p16;q32), and t(14;16), 1q amplification or 1p deletion, and
17p13 deletions
• N-ras, K-ras, and B-raf mutations are most common

7. Pathogenesis

9. CLINICAL PRESENTATION
Common features Uncommon features
Anemia Hyperviscosity syndrome
Bone pain Paresthesias
Elevated creatinine Hepatomegaly - splenomegaly
Fatigue/generalized weakness Spinal cord compression from an
extramedullary plasmacytoma -
Medical emergency
Hypercalcemia Lymphadenopathy
Weight loss Pleural effusion
Infection

10. CLINICAL PRESENTATION
• Anemia
• normocytic, normochromic
• Bone marrow replacement
• Kidney damage
• Dilution in the case of a large M-protein
• Bone pain- OAF(Osteoclast activating factor)
• Fractures
• Vertebral collapse- spinal cord compression
• Bone pains induced by movement
• No night pain
• Lytic lesions – no osteoblastic activity

13. CLINICAL PRESENTATION
• Elevated creatinine
• Light chain cast nephropathy (also called myeloma kidney)
• Hypercalcemia
• Amyloid
• Hyperuricemia
• Recurrent UTI
• NSAIDS/bisphosphonates
• Myeloma cell infiltration in kidney
• Earliest manifestation of tubular damage- FANCONI SYNDROME
• AKI- if dehydration

14. • Fatigue/generalized weakness
• Hypercalcemia
• Due to osteolytic lesions
• lethargy, weakness, depression, and confusion
• Weight loss
• Clotting abnormalities
• failure of antibody-coated platelets to function properly
• Interaction of the M component with clotting factors I, II, V,VII, or VIII;
• Antibody to clotting factors; or
• amyloid damage of endothelium

15. CLINICAL PRESENTATION
• Infection
• Impaired lymphocyte function
• Suppression of normal plasma cell function
• Hypogammaglobulinemia
• Streptococcus pneumoniae and gram-negative organisms are the most
frequent pathogens.
• Most common infections are pneumonias and pyelonephritis
• Streptococcus pneumoniae, Staphylococcus aureus, and Klebsiella
pneumoniae in the lungs
• Escherichia coli and other gram-negative organisms in the urinary tract

16. CLINICAL PRESENTATION
• Hyperviscosity syndrome( normal relative serum viscosity is 1.8)
• IgM > IgA/IgG(IgG3 max)
• Encephalopathy
• Headache , visual disturbances, ataxia, vertigo, retinopathy
• Shortness of breath
• Chest pain
• Vaso-occlusion, exacerbation or precipitation of heart failure
• Raynaud’s phenomenon and impaired circulation
• if the M component forms cryoglobulins
• Paresthesias
• Thoracic or lumbosacral Radiculopathy- M/C neurologic complication of MM
• Infiltration of peripheral nerves by amyloid
• carpal tunnel syndrome
• sensorimotor mono- and polyneuropathies ( S>M)
• More with IgM isotypes

17. CLINICAL PRESENTATION
• Hepatomegaly -4 percent cases
• Splenomegaly -1 percent cases.
• Spinal cord compression from an extramedullary plasmacytoma/#(
5%) - Medical emergency
• Lymphadenopathy -1 percent
• Pleural effusion(rare)

18. PATHOLOGIC FEATURES
• Secretory Myeloma
• 97 % secrete Monoclonal (M) protein
• IgG – 52 percent
• IgA – 21 percent
• Kappa or lambda light chain only (Bence Jones) – 16 percent
• IgD – 2 percent
• Biclonal – 2 percent
• IgM – 0.5 percent
• Negative – 6.5 percent

19. PATHOLOGIC FEATURES
• Oligo-secretory myeloma
• 5 to 10 % of MM patients at diagnosis
• Absence of measurable disease in serum or urine by the following parameters
• Serum M protein <1 g/dL, and
• Urine M protein <200 mg/24 hours
• Monitoring using FLC

20. PATHOLOGIC FEATURES
• Light Chain Myeloma
• 16%
• Kappa > Lambda
• Lambda light chains are more common in IgD myeloma and myeloma
associated with amyloidosis
• Higher chance of Renal failure( Lambda> kappa)

21. PATHOLOGIC FEATURES
• Non-secretory myeloma
• 3% of all cases
• Serum, urine immunofixation - normal
• 60 % - monoclonal FLC +ve
• Nonmeasurable, FLC only myeloma
• 40% - normal serum FLC ratio
• 85 % = M-protein that can be detected in the cytoplasm of the neoplastic plasma cells
• 15 % = True non-producer myeloma

24. INVESTIGATIONS
• Haemogram- Anemia, Leukopenia, Thrombocytopenia, Raised
ESR(often>100)
• values correlate neither with tumor burden nor with
treatment response. Hence its importance is uncertain.
• Peripheral smear
• Rouleaux formation
• Pancytopenia
• Monoclonal plasma cells can be seen
• > 2000/mm3 S/O Plasma cell leukemia

25. • SPEP/UPEP
• Serum & urine Immunofixation
• Free light chain assay

28. FREE LIGHT CHAIN ASSAY
Indicated where serum and M protein are either
-Undetectable i.e Non secretory Myeloma
-Decreased
-FLC ASSAY MEASURES:
-Free kappa light chain:- 0.33 t0 1.94 mg/dl
--Free lambda light chain :- 0.57 to 2.63mg/dl
-Free light cahin ratio is assesed:-
-Kappa/ lambda = 0.26 to 1.65
-< 0.26 = monoclonal lambda free light chain disease
-> 1.65 = monoclonal kappa free light chain disease

29. INVESTIGATIONS
• Urinalysis
• Protein- near all light chains initially-Bence Jones proteinuria
• After glomerular involvement
• non selective proteinuria
• Albumin
• Casts
• KFTs
• Elevated urea / creatinine
• Serum calcium- raised
• Serum uric acid- raised

30. • Anion gap decreased- M component and calcium ---unmeasured
cations.
• Serum ALP – Normal(absent osteoblastic activity)
• Serum protein – elevated
• Albumin- decreased
• Globulins- elevated
• Serum Beta -2 microglobulin- Higher= poorer prognosis

31. INVESTIGATIONS
• Bone marrow examination
• Percent monoclonal plasma cells = >10 %
• Morphology
• Oval with abundant basophilic cytoplasm
• Nucleus is round and eccentrically located
• Perinuclear halo
• "clock-face" or "spoke wheel" chromatin without nucleoli
• Cytoplasmic immunoglobulin inclusions -Mott cells, Morula cells, Russell bodies, Flame
cells

32. INVESTIGATIONS
• Bone marrow examination
• Immunophenotype – Flow cytometry or immunohistochemistry
• The normal kappa/lambda ratio in the bone marrow is 2:1. A ratio of more than 4:1 or
less than 1:2 is considered to meet the definition of kappa or lambda monoclonality,
respectively.
• CD79a, VS38c, CD138, and CD38 +ve
• CD19 -ve
• Cytogenetics

34. Diagnostic criteria –International Myeloma
Working Group Criteria
• Clonal bone marrow plasma cells ≥10 percent OR biopsy-proven
plasmacytoma
PLUS one of the following
• Anemia – Hemoglobin <10 g/dL OR >2 g/dL below normal(lower limit)
• Hypercalcemia – Serum calcium >11 mg/dL
• Renal insufficiency – eCrCl <40 mL/min or serum creatinine >2 mg/dL
• Bone lesions – One or more osteolytic lesions ≥5 mm
CRAB/MDE

35. Diagnostic criteria
• Biomarker associated with near inevitable progression to end-organ
damage
• ≥60 % clonal plasma cells in the bone marrow
• Involved/uninvolved FLC ratio > 100
• MRI with more than one focal lesion (involving bone or bone marrow)

36. DIFFERENTIAL DIAGNOSIS
Monoclonal gammopathy of undetermined significance
Smoldering multiple myeloma
Waldenström macroglobulinemia and IgM MM
Solitary plasmacytoma
AL amyloidosis
POEMS syndrome
Metastatic carcinoma

37. Monoclonal gammopathy of undetermined
significance
• M protein <3 g/dL
• Clonal bone marrow plasma cells <10 percent
• Absence of lytic lesions, anemia, hypercalcemia, and renal
insufficiency (end-organ damage) that can be attributed to the
plasma cell proliferative disorder
 Risk of progression to MM of approximately 1 % per year
Non-IgG subtype
abnormal kappa/lambda free
light chain ratio
serum M protein >1.5 g/dL

38. Smoldering multiple myeloma
• M-protein ≥3 g/dL or urinary monoclonal protein ≥500 mg per 24
hr and/or 10 to 60 percent bone marrow plasma cells
• No end-organ damage
 Progression to MM risk
bone marrow plasmacytosis >10%
abnormal kappa/lambda free light chain ratio
serum M protein >3 g/dL

39. Solitary plasmacytoma
• Biopsy-proven solitary lesion of bone or soft tissue with evidence of
clonal plasma cells
• Normal bone marrow
• Normal skeletal survey and MRI (or CT) of spine and pelvis (except for
the primary solitary lesion)
• Absence of end-organ damage
 Extramedullary plasmacytomas usually involve the submucosal
lymphoid tissue of the nasopharynx or paranasal sinuses without
marrow plasmacytosis.

40. Waldenström macroglobulinemia and IgM
multiple myeloma
• Lymphoplasmacytic lymphoma (LPL)
• Lymphoplasmacytic infiltration in bone marrow or lymphatic tissue
and an IgM monoclonal gammopathy in the blood.
• Features
• Tumor infilration- Cytopenias, fever, night sweats, weight loss, LN, HSM
• M-protein- Hyperviscosity, cryoglobulinemia, cold agglutinin, neuropathy,
amyloidosis
• CD56 -ve
• CD19, and CD20 +ve

41. POEMS syndrome
• POEMS syndrome (osteosclerotic myeloma: Polyneuropathy,
Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes)
• endocrinopathy (excluding diabetes mellitus or hypothyroidism)

42. AL amyloidosis
• previously referred to as primary amyloidosis
• plasma cell proliferative disorder
• <20 percent bone marrow plasma cells
• no lytic bone lesions on imaging
• modest amount of Bence Jones proteinuria
• tissue deposits of amyloid fibrils or non-fibrillar material
• nephrotic syndrome
• heart failure
• hepatomegaly, and other findings
that are not seen in MM.

43. Metastatic carcinoma
• Kidney, Breast, Non-small cell lung cancer etc
• Lytic bone lesions
• constitutional symptoms
• a small M component
• <10 percent clonal plasma cells in the bone marrow
likely to have metastatic carcinoma with an unrelated MGUS rather
than MM

44. DURIE SALMON STAGING FOR MULTIPLE MYELOMA

45. STAGING
International staging
system (ISS)
Revised ISS (R-ISS) = ISS +
Stage I B2M <3.5 mg/L and serum
albumin ≥3.5 g/dL
normal LDH and no del(17p),
t(4;14), or t(14;16) by FISH
Stage II neither stage I nor stage III neither stage I nor stage III
Stage III B2M ≥5.5 mg/L plus LDH above normal limits
and/or detection of one of
the following by FISH:
del(17p), t(4;14), or t(14;16).

47. Treatment
• 1. Supportive treatment / management of complications
• 2. Specific therapy

48. TREATMENT OF COMPLICATIONS
Hypercalcemia Asymptomatic
Anorexia, nausea, vomiting
Polyuria, polydipsia
Constipation
Weakness, confusion, or stupor
Renal insufficiency
Hydration- isotonic saline@200-300mL/h
Dexamethasone as part of myeloma
therapy
Bisphosphonate such as zoledronic acid
(4 mg I/V) once a month initially
Calcitonin (4 IU/kg q8h)
Denosumab
Hemodialysis
Renal insufficiency Uremic features Avoidance of nephrotoxins
HD

49. Infection Fever Influenza, pneumococcal
vaccine
IVIG
Antibiotic prophylaxis (1st
month of induction)-
fluoroquinolone
Rx according to agent
Skeletal lytic lesions Bone pain
Fractures
Bisphosphonate
Vertebroplasty/Kyphoplasty
# = Conservative, Surgery
Cord compression Features S/o myelopathy Dexamethasone
Local Radiation
Surgical decompression

50. +
Pain Pain NSAID
Opiods
Anemia Fatigue Blood tranfusion
Hyperviscosity syndrome oronasal bleeding, blurred
vision, neurologic
symptoms, confusion, and
heart failure.
Plasmapharesis
Thrombosis As per DVT Rx
Neuropathy Pain, tingling, numbness Stop bortezomib
Pregabalin/Gabapentin/
Duloxetine

53. Refrences
• Uptodate.com
• Harrison 20th edition
• ICMR consensus document on multiple myeloma 2017

54. THANK YOU

57. Resource poor setting
• Unavailability of HCT, Bortezomib, Lenalidomide etc
• Standard risk
• Melphalan + Prednisolone +/- Thalidomide
• Bortezomib + Cyclophosphamide + Dexamethasone
• High Risk
• Melphalan + Prednisolone + Thalidomide
• If HCT is available
• Induction with Thalidomide + Dexamethasone
• Avoid Melphalan

58. Effectiveness of various regimens
• Thalidomide + dexamethasone- 66%
• Lenalidomide/Bortezomib + Dexamethasone- >80%
• Lenalidomide + Bortezomib + Dexamethasone - 100% response rate and
30% complete response (CR) rate
• Bortezomib + thalidomide + dexamethasone or
bortezomib + cyclophosphamide + dexamethasone)- >90% response rate.

59. • Daratumumab is a monoclonal antibody targeted against CD38
• Elotuzumab is a humanized monoclonal antibody targeted against
SLAMF7, a glycoprotein expressed on MM and natural killer cells
• Panobinostat — Panobinostat is a histone deacetylase (HDAC)
inhibitor

60. • Bortezomib
• Herpes zoster prophylaxis
• Neuropathy can be decreased both by its subcutaneous administration and
administration on a weekly schedule.
• Lenalidomide
• Prophylaxis for deep-vein thrombosis (DVT) with either aspirin or if patients
are at a greater risk of DVT, warfarin or low-molecular-weight heparin.