This document summarizes several plasma cell disorders including multiple myeloma, Waldenstrom's macroglobulinemia, POEMS syndrome, heavy chain diseases, and amyloidosis. Multiple myeloma is a malignant proliferation of plasma cells that commonly presents with bone pain, anemia, kidney dysfunction, and infections. Diagnosis involves detection of monoclonal proteins by serum protein electrophoresis and treatment involves chemotherapy, stem cell transplantation, and newer agents. Waldenstrom's macroglobulinemia is characterized by lymphadenopathy, hyperviscosity, and peripheral neuropathy and is associated with IgM paraproteinemia. Heavy chain diseases involve truncated immunoglobulin heavy chains without light chains. POEMS syndrome is associated with polyneuropathy

1. PLASMA CELL DISORDERS
PRESENTER: DR. JITHIN GEORGE

4. • Electrophoretic analysis permits separation of
components of the serum proteins.
• The immunoglobulins move heterogeneously
in an electric field and form a broad peak in
the gamma region, which is usually increased
in the sera of patients with plasma cell
tumors.
• There is a sharp spike in this region called an
M component (M for monoclonal).

6. • The monoclonal antibody must be at least 5
g/L (0.5 g/dL) to be accurately quantitated by
this method. This corresponds to ~109 cells
producing the antibody.
• M component an excellent tumor marker to
manage therapy, yet it is not specific enough
to be used to screen asymptomatic

8. M PROTEINS

9. • In ~20% of myelomas, only light chains are
produced and, in most cases, are secreted in
the urine as Bence Jones proteins.
• IgG myelomas are more common than IgA and
IgD myelomas.

10. MULTIPLE MYELOMA

11. • a malignant proliferation of plasma cells
derived from a single clone.
• cause of myeloma is not known
• More in nuclear radiation exposure
• More in farmers, wood workers, leather
workers, and those exposed to petroleum
products.
• N-ras, K-ras, and B-raf mutations are most
common and combined occur in over 40% pts

12. • The neoplastic event in myeloma may involve
cells earlier in B-cell differentiation than the
plasma cell. Interleukin (IL) 6 may play a role
in driving myeloma cell proliferation.

13. INCIDENCE & PREVALENCE
• The median age at diagnosis is 70 years; it is
uncommon under age 40.
• Males are more commonly affected than
females, and blacks have nearly twice the
incidence of whites.

14. PATHOGENESIS
• Multiple myeloma (MM) cells bind via cell-
surface adhesion molecules to bone marrow
stromal cells (BMSCs) and extracellular matrix
(ECM), which triggers MM cell growth,
survival

15. • induction of various cytokines, including IL-6,
insulin-like growth factor type I (IGF-I),
vascular endothelial growth factor (VEGF), and
stromal cell–derived growth factor (SDF)-1α.
• Growth, drug resistance, and migration are
mediated via Ras/Raf/mitogen-activated
protein kinase, PI3K/Akt, and protein kinase C
signaling cascades, respectively

17. CLINICAL MANIFESTATIONS

19. • SUSCEPTIBILITY TO BACTERIAL INFECTIONS
• most common infections: pneumonias and
pyelonephritis.
• Streptococcus pneumoniae, Staphylococcus
aureus, and Klebsiella pneumoniae in the
lungs
• Escherichia coli and other gram-negative
organisms in the urinary tract

20. Causes for increased susceptibity for
infections

21. • Renal failure: Hypercalcemia is the most
common cause
• Glomerular deposits of amyloid,
hyperuricemia, recurrent infections, frequent
use of nonsteroidal anti-inflammatory agents,
iodinated contrast dye for imaging,
bisphosphonate use, and occasional
infiltration of the kidney by myeloma cells all
may contribute to renal dysfunction.

27. NEUROLOGICAL SYMPTOMS

29. Myeloma-related organ or tissue
impairment (end organ damage):

31. • Non-IgG subtype, abnormal kappa/ lambda
free light chain ratio, and serum M protein
>15 g/L (1.5 g/ dL) are associated with higher
incidence of progression of MGUS to
myeloma.

32. higher risk of progression from SMM
to MM
• bone marrow plasmacytosis >10%,
• abnormal kappa/lambda free light chain ratio,
• serum M protein >30 g/L (3 g/dL).

35. • Serum calcium, urea nitrogen, creatinine, and
uric acid levels may be elevated.
• Protein electrophoresis and measurement of
serum immunoglobulins and free light chains are
useful for detecting and characterizing M spikes,
supplemented by immunoelectrophoresis.
• A 24-h urine : quantitate Bence Jones protein
excretion.
• Serum alkaline phosphatase is usually normal

36. PROGNOSIS

38. TREATMENT

40. Patients with symptomatic and/or
progressive myeloma

41. • Thalidomide (200 mg daily) with
dexamethasone
• lenalidomide (25 mg/d on days 1–21 every 4
weeks), and bortezomib (1.3 mg/m2 on days
1, 4, 8, and 11 every 3 weeks),combined with
dexamethasone (40 mg once every week) :

43. • In patients who are transplant candidates,
alkylating agents such as melphalan should be
avoided because they damage stem cells.

44. • Improvement in the serum M component may
lag behind the symptomatic improvement
• Light chain excretion, with a functional half-
life of ~6 h, may fall within the first week of
treatment.
• Allogenic transplantation
• Maintenance therapy prolongs remissions
following standard dose regimens as well as
HDT

45. • Relapsed myeloma : lenalidomide and/or
bortezomib. These combination with
dexamethasone : response rate of up to 60% and
a 10–15% complete response rate in patients
with relapsed disease.
• The combination of bortezomib and liposomal
doxorubicin is active in relapsed myeloma.
• Thalidomide, if not used as initial therapy, can
achieve responses in refractory cases.
• The second-generation proteasome inhibitor
carfilzomib and immunomodulatory agent
pomalidomide
• High-dose melphalan and stem cell
transplantation

47. • Prophylactic administration of intravenous γ
globulin preparations is used in the setting of
recurrent serious infections.
• The anemia associated with myeloma may
respond to erythropoietin along with
hematinics

48. WALDENSTROMS
MACROGLOBULINEMIA
• associated with lymphadenopathy and
hepatosplenomegaly, but the major clinical
manifestation was hyperviscosity syndrome.
• originates from a post– germinal center B cell
that has undergone somatic mutations and
antigenic selection in the lymphoid follicle and
has the characteristics of an IgM-bearing
memory B cell.

49. • Familial occurance common
• MYD88 L265P somatic mutation
• molecular pathogenesis of the disease, with
involvement of Toll-like receptor (TLR) and
interleukin 1 receptor (IL-1R) signaling.
• activation of IL-1R–associated kinase (IRAK) 4
and IRAK1 followed by nuclear factor-κB (NF-
κB) activation.

50. • develop a peripheral neuropathy
• half of these patients are positive for anti-
MAG antibody. The neuropathy may precede
the appearance of the neoplasm.
• IgM in some patients with macroglobulinemia
may have specificity for myelin-associated
glycoprotein (MAG),

53. TREATMENT
• Plasmapheresis For hyperviscosity symptoms
• Median survival of affected individuals is ~50
months.
• Bortezomib and bendamustine are two agents
with significant efficacy in WM.
• Rituximab (anti-CD20) can produce responses,
alone or combined with either of these two
agents

54. • Fludarabine (25 mg/m2 per day for 5 days
every 4 weeks) and cladribine (0.1 mg/kg per
day for 7 days every 4 weeks) are also highly
effective single agents.
• With identification of the MYD88 mutation,
BTK and IRAK1/4 inhibitors are being
evaluated and show significant responses.

55. POEMS SYNDROME

58. HEAVY CHAIN DISEASE

59. • diagnosis depends on the demonstration of an
anomalous serum M component (often <20
g/L [<2 g/dL]) that reacts with anti-IgG but not
anti–light chain reagents.
• The M component is typically present in both
serum and urine. Most of the paraproteins
have been of the γ1 subclass
• Therapy is indicated when symptomatic and
involves chemotherapeutic combinations used
in lowgrade lymphoma. Rituximab has also
been reported to show efficacy.

60. ALPHA HEAVY CHAIN DISEASE
(SELIGMANN’S DISEASE)
• Mc heavy chain disease
• Closely related to meditteranean lymphoma
• infiltration of the lamina propria of the small
intestine with lymphoplasmacytoid cells that
secrete truncated alpha chains.
• Demonstrating alpha heavy chains is difficult
because the alpha chains tend to polymerize
and appear as a smear instead of a sharp peak
on electrophoretic profiles

61. • Light chains are absent from serum and urine.
• patients present with chronic diarrhea, weight
loss, and malabsorption and have extensive
mesenteric and paraaortic adenopathy.
Respiratory tract involvement occurs rarely
• Chemotherapy plus antibiotics may be more
effective than chemotherapy alone.

62. • Immunoproliferative small-intestinal disease
(IPSID) is recognized as an infectious
pathogen–associated human lymphoma that
has association with Campylobacter jejuni.
• It involves mainly the proximal small intestine
resulting in malabsorption, diarrhea, and
abdominal pain.

63. MU HEAVY CHAIN DISEASE

64. AMYLOIDOSIS

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