Tuesday Case Conference
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Multiple Myeloma
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Multiple Myeloma
Myeloma related renal failure
Treatment
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Myeloma
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A clonal disorder of plasma cells
Affects 1 in 300,000
1% of all new malignancies (16,000 per year)
 10% of all new hematologic malignancies
 2% of all cancer deaths (11,3000 per year)
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Median age of onset: 66
Most common hematologic malignancy in
African Americans
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Development of Myeloma Cells
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Transformation of a
normal B cell into a
malignant plasma cell
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Cytokines
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Environmental/occupation
al exposures have been
implicated
IL-6, RANK, TNF
VEGF
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Multiple Myeloma - diagnosis
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Clonal plasma cells >10% on bone marrow
biopsy or (in any quantity) in a biopsy from
other tissues (plasmacytoma)
A monoclonal protein (paraprotein) in either
serum or urine
Evidence of end-organ damage
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Structure of immunoglobulin
Nelson DL, Cox MM. Lehninger principles of biochemistry, 4th ed. WH
Freeman pub. New York 2005.
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Serum Protein Electrophoresis
Astion ML, Rank J, Wener MH, Torvik P, Schneider JB, Killingworth LM. Electrophoresis-tutor: an image-based personal computer program that teaches clinical interpretation of protein
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electrophoresis patterns of serum, urine and CSF. Clin chem. 1995 Sep;41(9):1328-32
Immunofixation Electrophoresis
(IFE)
Astion ML, Rank J, Wener MH, Torvik P, Schneider JB, Killingsworth LM. Electrophoresis-tutor: an image based personal computer program that teaches clinical interpretation of
protein electrophoresis patterns of serum, urine, and CSF. Clin Chem. 1995 Sep;41(9):1328-32.
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Frequency of isotypes of heavy and light chains produced by
non–immunoglobulin (Ig) M myelomas
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Staging and Prognostic Factors
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Epidemiology
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In two large multiple myeloma studies,
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The one-year survival was
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80% in pts with Cr < 1.5 compared to
50% in pts with a Cr > 2.3
5, 10, and 20 year survivals
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43% (of 998 pts) had a creatinine > 1.5 and
22% (of 423 pts) had a Cr > 2.0
31, 10, and 4% respectively
Prognosis is especially poor in pts who require dialysis
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Types of renal involvement in
dysproteinemias
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Pathogenesis of the different types of
renal lesions in dysproteinemias
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Myeloma Kidney
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Most common
Dx by demonstration of tubular casts in the
distal nephron
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Myeloma Kidney
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Two main pathogenetic mechanisms:
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Intracellular cast formation
Direct tubular toxicity by light chains
Contributing factors to presence of renal failure due to
multiple myeloma:
High rate of light chain excretion (tumor load)
 Concurrent volume depletion
Prognosis
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Serum creatine (mg/dL)
Median survival
<1.4
44 mo
1.4-2
18 mo
>2
<4
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Rayner HC, Haynes AP, Thompson JR, Russell N, Fletcher J: Perspectives in multiple myeloma: Survival, prognostic factors and disease complications in a single center between 1975 and 1988. Q J Med 79: 517–525, 1991
Light Chain Deposition Disease
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Most commonly presents with both renal
insufficiency and nephrotic syndrome
Usually due to kappa immunoglobulin fragments
which deposit in kidneys (basement membrane)
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Amyloidosis
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Usually due to lambda light chains (AL)
Light chains are taken up and partially
metabolized by macrophages and then secreted
– then precipitate to form fibrils that are Congo
red positive, b-pleated
Like LCDD, due to tubular injury and also
presents as nephrotic syndrome
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Hypercalcemia
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Hypercalcemia occurs in multiple myeloma due
to bone resorption from lytic lesions
Serum calcium > 11.0 mg/dL occurs in 15% of
pts with multiple myeloma
Hypercalcemia commonly contributes to renal
failure by renal vasoconstriction, leading to
intratubular calcium deposition
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Renal Tubular Dysfunction –
Acquired Fanconi syndrome
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On occasion, light chains cause tubular
dysfunction without renal insufficiency
Most commonly occurs with kappa light chains
This presents as Fanconi syndrome – proximal
renal tubular acidosis with wasting of potassium,
phosphate, uric acid, and bicarbonate
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Renal Insufficieny
Fang LS. Light-chain nephropathy. Kidney Int. 1985 Mar;27(3):582-592.
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Presentation and outcome in
myeloma-associated renal disease
Multiple Myeloma_Korbet_JASN_2006
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Plasmapheresis in MM
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Theoretical benefit in removing the toxic circulating
light chains to spare renal function
Would seem to be most effective when circulating light
chains in serum are present (i.e. significant M-spike on
SPEP)
Limited data to support efficacy
Treatment of choice if hyperviscosity symptoms are
present
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Plasmapheresis in MM
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Plasmapheresis studies
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Johnson et al., Arch Intern Med. 1990
N
Improvement of
renal function
Recovery from
dialysis
Forced diuresis /
chemo
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Plasmapheresis /
diuresis / chemo
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7/11 (64%)
5/10 (50%)
3/7 (43%)
0/5
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Plasmapheresis studies
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Zuchelli et al., Kidney Int 1988
Chemo with PD
N
Plasmapheresis /
chemo / HD
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11/13 (84%)
2/14 (14%)
66%
28%
Recovery from
dialysis
One year survival
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Plasmapheresis studies –
Limitations
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Few prospective trials done
Available trials have small numbers of patients
enrolled
A larger prospective, randomized trial would be
beneficial in establishing the clinical utility of
plasmapheresis in preventing ESRD in MM
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Multiple Myeloma - treatment
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Novel Therapies
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Velcade (bortezomib)
Proteasome inhibitor
 Induces apoptosis via
caspase-8, 9
 Anti-myeloma effects by
blocking NF-kB
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Revamid
IMiD
 Induce G1 growth arrest
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Revlimid (lenalidomide)
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First of new class of drugs called IMiDs
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Alkylating agents,
Bortemozid, corticosteroids
inhibit cell growth and induce
apoptosis
Bortemozid inhibits NF-kB
Thalidomide and Bortemozid
inhibit interaction between
myeloma cells & stromal cells
as well as cytokine production
(TNF-alpha, IL-6)
Thalidomide inhibits
angiogenesis and enhances
CD8+ and NK cell functions
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Incidence of renal
involvement in
dysproteinemias
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Causes of renal failure in MM
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Cast nephropathy
Light chain deposition disease
Primary amyloidosis
Hypercalcemia
Renal tubular dysfunction
Volume depletion
IV contrast dye, nephrotoxic meds
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Treatment of renal failure in MM
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Hydration with IV fluids
Treatment of hypercalcemia
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Treatment of myeloma
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Loop diuretics
Caution with bisphosphonates
Pulse steroids +/- thalidomide
VAD chemotherapy
Possible role for plasmapheresis
Dialysis, as necessary
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Multiple Myeloma - treatment
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Arsenic trioxide
Thalidomide +/- Melphalan
Cyclosporin A nonimmunosuppresive analogs
Anti-IL-6 and anti-IL-6R antibodies
Bortezomid (Velcade)
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Proteasome inhibitor
Bone marrow transplantation
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