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Tuesday Case Tuesday Case ConferenceConference

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Multiple Myeloma

Multiple Myeloma Myeloma related renal failure Treatment

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Myeloma

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)

Median age of onset: 66 Most common hematologic malignancy

in African Americans

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Development of Myeloma Cells

Transformation of a normal B cell into a malignant plasma cell Environmental/

occupational exposures have been implicated

Cytokines IL-6, RANK, TNF

VEGF

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Multiple Myeloma - diagnosis

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 electrophoresis patterns of serum, urine and CSF. Clin chem. 1995 Sep;41(9):1328-32

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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

In two large multiple myeloma studies, 43% (of 998 pts) had a creatinine > 1.5 and 22% (of 423 pts) had a Cr > 2.0

The one-year survival was 80% in pts with Cr < 1.5 compared to 50% in pts with a Cr > 2.3

5, 10, and 20 year survivals 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

Most common Dx by demonstration of tubular casts

in the distal nephron

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Myeloma Kidney Two main pathogenetic mechanisms:

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

PrognosisSerum creatine

(mg/dL)Median survival

<1.4 44 mo

1.4-2 18 mo

>2 <4Rayner 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

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Light Chain Deposition Disease

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

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, -pleated

Like LCDD, due to tubular injury and also presents as nephrotic syndrome

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Hypercalcemia

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 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 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

Johnson et al., Arch Intern Med. 1990

Forced diuresis /

chemo

Plasmapheresis / diuresis /

chemo

N 10 11

Improvement of renal function

7/11 (64%) 5/10 (50%)

Recovery from dialysis

3/7 (43%) 0/5

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Plasmapheresis studies

Zuchelli et al., Kidney Int 1988

Plasmapheresis / chemo /

HD

Chemo with PD

N 15 14

Recovery from dialysis

11/13 (84%) 2/14 (14%)

One year survival

66% 28%

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Plasmapheresis studies –Limitations

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

Velcade (bortezomib) Proteasome inhibitor Induces apoptosis via

caspase-8, 9 Anti-myeloma effects

by blocking NF-kB Revamid

IMiD Induce G1 growth

arrest

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Revlimid (lenalidomide)

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 dysproteinemia

s

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Causes of renal failure in MM

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

Hydration with IV fluids Treatment of hypercalcemia

Loop diuretics Caution with bisphosphonates

Treatment of myeloma Pulse steroids +/- thalidomide VAD chemotherapy

Possible role for plasmapheresis Dialysis, as necessary

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Multiple Myeloma - treatment

Arsenic trioxide Thalidomide +/- Melphalan Cyclosporin A nonimmunosuppresive

analogs Anti-IL-6 and anti-IL-6R antibodies Bortezomid (Velcade)

Proteasome inhibitor Bone marrow transplantation

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