Case Studies in Multiple Myeloma and Amyloidosis

November 12, 2010

Beth Faiman RN, MSN, CNP, AOCN Nurse Practitioner and Pre-Doctoral Fellow, Cleveland Clinic

Kena Miller, MSN, FNP Nurse Practitioner, Roswell Park Cancer Institute

Elizabeth Sagatys, MD Hematopathologist, Moffitt Cancer Center

Objectives:

1. Describe common presenting features and criteria for diagnosis and management of Multiple Myeloma.

2. Identify the latest clinical laboratory tests, cytogenetics and clinicopathologic abnormalities associated with multiple myeloma.

3. Recognize the different types of amyloidosis with different prognoses and treatment options. 

Plasma Cell Disorders

• Multiple Myeloma

• Other Disorders-

• Monoclonal gammopathy of undetermined significance (MGUS)

• Smoldering multiple myeloma (SMM)

• Solitary Plasmacytoma

Bone or Extramedullary

• Waldenström’s Macroglobulinemia

• Primary Amyloidosis (AL)

• Heavy chain disease

• POEMS syndrome

• Type I and II cryoglobulinemia

Kyle, R. A. (1999). "Multiple myeloma, macroglobulinemia, and the monoclonal gammopathies." Current Practice on Medicine 2: 1131-1137.

MGUS62%

Myeloma15%

AL 10%

Lymphoproliferative2.5%

SMM 3.5% (44)Solitary or Extramedullary

1.5%

Macro 3%

Other 2.5%

N = 1296

AL, amyloidosis; MGUS, monoclonal gammopathy of uncertain significance; SMM, smoldering multiple myeloma.Kyle RA et al. Plasma cell disorders. In: Goldman L et al, eds. Cecil Textbook of Medicine. 22nd ed. Philadelphia, PA: WB Saunders Company; 2004.

Distribution of Plasma Cell Dyscrasias

Immunoglobulin Structure

• Made up of 2 heavy chains

– IgG, IgA and IgM

in myeloma or AL

• 2 light chains

–Kappa or Lambda

Open-access artwork used under the terms of the GNU free documentation license. On-;line. Available: http://en.wikipedia.org/wiki/File:Antibody.svg

Plasma Cells vs. Myeloma Cells

Myeloma cells can be distinguished from normal plasma cells by the presence of nucleoli, very large nuclei, irregular nuclear contours and multinucleation.

Pathophysiology of Myeloma

• Multiple organs and body systems affected

• Hallmarks:

•Anemia

•Renal failure

•Bone destruction (lytic bone lesions)

•Hypercalcemia

•Presence of monoclonal protein

• Increased risk of infection

Durie BGM et al. Hematol J. 2003;4:379

Pathobiology- What is Myeloma?

• Plasma cell malignancy characterized by production of abnormal immunoglobulin

• 3 different types

• Protein in serum

• Protein in urine

• Non-secretory

Normal Monoclonal protein in Myeloma

Kyle RA, Rajkumar SV. Cecil Textbook of Medicine, 22nd ed, 2004

Serum protein electrophoresis

Patient Evaluation and Diagnosis of PCDs

• Blood tests• CBC, differential• BUN/creatinine, electrolytes• Calcium, albumin• Quantitative immunoglobulins• Serum protein electrophoresis and immunofixation• β2M (surrogate marker for IL-6)• LDH• Serum free light chain assay (FREELITE™)

NCCN Clinical Practice Guidelines v2.2010. Available at:http://www.nccn.org/professionals/physician_gls/PDF/myeloma.pdf

Patient Evaluation and Diagnosis of PCDs

• Urine tests• 24-hr urine protein electrophoresis and immunofixation• monoclonal protein analysis, urine

• Skeletal survey• X-rays, CT, MRI, PET scan as indicated

• BM aspirate and biopsy • Cytogenetics as indicated

NCCN Clinical Practice Guidelines v2.2010. Available at:http://www.nccn.org/professionals/physician_gls/PDF/myeloma.pdf

Criteria for Diagnosis of MM

Durie BGM et al. Hematol J. 2003;4:379

Kyle RA et al. Mayo Clin Proc. 2003;78:21

Courtesy of Elizabeth Sagatys, MD

• Monoclonal plasma cells in bone marrow (10%/30% if non-secretory)

• Monoclonal protein present in serum and/or urine

• Myeloma-related organ dysfunction

• Calcium in serum (>10.5 mg/L)

• Renal insufficiency (SCr >2 mg/dL)

• Anemia (hemoglobin <10 g/dL or 2g <normal)

• Bone lesions or osteoporosis

International Staging System

Stage Criteria

ISerum 2-microglobulin <3.5 mg/L

Serum albumin ≥3.5 g/dL

II Serum 2-microglobulin <3.5 mg/L

Serum albumin <3.5 g/dL

OR

Serum 2-microglobulin 3.5 to <5.5 mg/L*

III Serum 2-microglobulin ≥5.5 mg/L

*Irrespective of serum albumin level

Greipp PR et al. J Clin Oncol. 2005;23:3412

Solitary Plasmacytoma

• Solitary lesion with ~25% M protein

• Treated with radiation or systemic therapy at second occurrence

Pretreatment After 4 Cycles

Plasmacytomas

Jagannath S, 2004

Skeletal Involvement

• Pathobiology: malignant cells produce osteoclast- activating factors that destroy bone cells and lead to extensive osteolysis, severe bone pain, and pathologic fractures

• Lumbar/thoracic vertebrae most commonly involved

• Ribs/skull/pelvis/proximal long bones frequently involved

• Spinal cord compression

Roodman et al, 2008

Myeloma Bone Pathology

Myeloma Disease Phases

Durie BGM. International Myeloma Foundation. 2006. www.myeloma.org.

M P

rote

ins

g/L

Myeloma Agents Work Through Different Mechanisms

• Alkylating agents- Melphalan (Alkeran®)

• Anthracyclines- Doxorubicin, liposomal (Doxil®)

• Mitotic inhibitors- Vincristine

• Corticosteroids- Dexamethasone, prednisone

• IMiDs- Thalidomide (Thalomid®)- Lenalidomide (Revlimid®)

• Proteasome inhibitors- Bortezomib (Velcade®)

Kyle RA, Rajkumar SV. N Engl J Med. 2004;351:1860-1873.

18

Treatment of MM – ASH 2009: Recent and Ongoing Clinical Studies

• Transplant-ineligible patients

• VMP – VT vs.. VTP – VP (maintenance improves response)

• VMPT – VT vs.. VMP (weekly velcade = decreased neuropathy)

• MP vs.. MPT

• MP vs.. MPR vs.. MPR (Lenalidomide maintenance)

• Transplant-eligible patients• Lenalidomide after ASCT (lenalidomide maintenance)

Patient Treatment Largely Determined by Transplant Eligibility

Case Study – Multiple Myeloma

• John is a 53 y.o history HTN but otherwise healthy

• Saw APN complaining of “lower back pain”, and “horrible back spasms”

• Thought he “pulled a muscle” while helping his son move into his new dorm room

• Using Tylenol and Motrin for pain, rates 8/10 and pain is getting worse

• Sudden onset chest pain prompted ER visit before he could get in to see his PCP

Case Study – Multiple Myeloma

• Localized pain to thoracic/lumbar spine

• No other associated symptoms on review of systems (head to toe) except for back spasms, insomnia from pain

• Does not greatly improve with lying down, standing

Case Study – Multiple Myeloma

• Physical exam: - No LE Weakness - No decreased sensation/ myelopathy- Point tenderness to the spine T5-6 with

kyphotic deformity - Visible muscle spastic activity Thoracic spine- Pallor

Case Study – Multiple Myeloma

• Labs/ Radiologic testing

• “Myeloma” labs - hypercalcemia 11.2 , Scr 2.1 (baseline 1.1 mg/dL)

• SPEP, UPEP, serum free light chains

Multiple MyelomaSerum Protein Electrophoresis

M protein spikes

Skeletal Survey

Images courtesy of Beth Faiman, MSN, CNP. Used with permission.

MRI

Images courtesy of Beth Faiman, MSN, CNP

Images courtesy of Beth Faiman, MSN, CNP. Used with permission.

Pathologic Diagnosis of MM: Bone Marrow Biopsy

• Aspirate average involvement (range also useful)

• Bone marrow cellularity

• % Involvement by plasma cells

• Amyloid present?

• Ancillary studies•

Images courtesy of Elizabeth Sagatys, MD. Used with permission

Core Biopsy Pathology

Plasma cells are usually in clusters/sheets. Some interstitial plasma cells may also be seen.

Images courtesy of Elizabeth Sagatys, MD. Used with permission.

Peripheral Blood Findings

• Rouleaux formation

• Circulating plasma cells (15% of cases)

• Leukoerythroblastic response –Circulating NRBC and

left shifted myeloid maturation

Plasma cell Rouleaux

formationImages courtesy of Elizabeth Sagatys, MD. Used with permission.

Ancillary Studies

CD138 IHC Flow cytometryImages courtesy of Elizabeth Sagatys, MD. Used with permission.

Other Ancillary Studies• Cytogenetics

• Changes in 1/3 of cases• FISH increases detection

• Numerical and structural

• IgH (14q32)

• Common onocogenes

• Cyclin D1 (11q13)

• FGFR3 (4p16.3)

• C-MAF (16q23)

• Cyclin D3 (6p21)

• MAFB (20q11)

• Can see gains in odd numbered chromosomes

• Help predict prognosis• Good:

• t(11;14) or t(6;14)

• Hyperdiploidy

• Poor:• Deletion 13 or aneuploidy

• t(4;14), t(14;16), t(14;20)

• P53 deletion

• Hypodiploidy

Fonseca, R., B. Barlogie, et al. (2004).

Example of Complex Karyotype

Images courtesy of Elizabeth Sagatys, MD. Used with permission.

Plasma Cells “Differentiated”

Hoff

Nucleolus

Images courtesy of Elizabeth Sagatys, MD. Used with Permission.

Plasmablastic Morphology

Images courtesy of Elizabeth Sagatys, MD. Used with permission.

Case Study – Multiple Myeloma

• PLAN

- Analgesia with Oxycodone, monitor pain scores, Tylenol , anti-spasmotics

-Treatment of MM with lenalidomide, bortezomib and dexamethasone on clinical trial

- Bisphosphonates after dental exam for bone pain and improve bone quality

- Referral to orthopedics for kyphoplasty to augment collapsed vertebrae at multi- levels

Amyloidosis – Overview

• Amyloidosis: extracellular tissue deposition of fibrils

• Composed of low molecular weight subunits (most of which are in the molecular weight range of 5 to 25 kD) of a variety of proteins

• These proteins often circulate as constituents of plasma.

• Hereditary and non hereditary types

• Patients with MM can have amyloidosis concurrently

Kyle, R. A. (2001)Madan, S., A. Dispenzieri, et al. (2010)

Formation of the Types of Amyloid

Used with Permission.

Amyloidosis Classification

• AL amyloid - deposition of protein derived from Ig light chain fragments (usually lambda)

- Detectable M protein in serum or urine

- Accounts for approx 80%.

• AA amyloid – chronic inflammatory states (i.e. RA or spondyloarthropathy)

- Fibrils are composed of fragments of the acute phase reactant - serum amyloid A (SAA) protein

•Gertz, M. A. (2010).•Kyle, R. A. (2001).

Amyloidosis Classification

• Hemodialysis-Associated Amyloidosis

• Deposition of fibrils derived from B2M

• Accumulates in patients with end-stage renal disease being maintained for prolonged periods on dialysis

• Cannot pass through dialysis filters

• Predilection for osteoarticular structures (synovium, tendons sheaths, and joints)

•Drueke, T. M. (2000)

Amyloidosis Classification

• Senile Systemic Amyloidosis — Deposition of transthyretin in myocardium and other sites

- Compared to patients with AL amyloidosis, those with the senile systemic disease survive longer (75 vs. 11 mos) despite having ventricular free wall and septal thickening due to amyloid deposits

- Significant renal involvement is rare

• Organ-Specific Amyloid (aka Localized Amyloidosis)

- Amyloid deposition isolated to a single organ, such as the skin, eye, heart, tongue, urinary bladder, lung and larynx.

- Frequent infiltrates of lymphocytes and plasma cells at periphery

- AL protein identified in some cases

Kyle, R. A. (2001)

Primary (AL) Amyloidosis and Light and Heavy Chain Deposition Diseases

• Amyloidosis results from clonal plasma cell proliferative disorders

• Characterized by tissue deposits of light chain or heavy chain fragments

• Leading to organ dysfunction such as heart or renal failure, GI blood loss, or disruption of nerve endings

Kyle, R. A. (2001)Gertz, M. A. (2010)Sanchorawala, V. (2006)

Primary (AL) Amyloidosis and Light and Heavy Chain Deposition Diseases

• Amyloid fibrils – abnormal folding of proteins into cross-β-pleated sheets which are deposited extracellularly in various organs.

- Immunoglobulin (Ig) light chains (usually lambda)

- Can be identified by their characteristic appearance on electron microscopy

- Congo red (“apple green” birefringence with polarized light)

- Thioflavin T (producing an intense yellow-green fluorescence).

- Weakly stain with periodic acid Schiff's (PAS)

- Immunostains: amyloid PKyle, R. A. (2001)Gertz, M. A. (2010)

Primary (AL) Amyloidosis and Light and Heavy Chain Deposition Diseases

• Neuro – Sensorimotor changes, Peripheral neuropathy

• GI- Hepatomegaly, gastroparesis, malabsorption, obstruction

• MSK- amyloid arthropathy, ‘shoulder pad sign’

• Pulm- pleural effusions, CHF sxs if cardiac involvement

• Derm- waxy thickening, ecchymoses, purpura in a periorbital distribution, ‘raccoon eyes’ , and subcutaneous nodules or plaques

Kyle, R. A. (2001)Gertz, M. A. (2010)

Dx of Primary (AL) Amyloidosis- Cardiomyopathy

• Cardiac manifestations may be absent, minor

- In 1/3rd of patients, disease manifested by cardiac events

- Most common ECG abnormality in cardiac amyloidosis is low voltage in the limb leads (50%)

- ECHO may show LV wall thickening with evidence of diastolic dysfunction , granular, “sparkling” appearance of the myocardium, IVS thickness in more advanced disease

- Cardiac MRI - global and subendocardial late enhancement of the myocardium

- Endomyocardial bx definitive dx

- OS 6-9 mos if heart failure > yrs with tx

Selvanayagam, J. B., P. N. Hawkins, et al. (2007).

Dx of Primary (AL) Amyloidosis- Renal

• Proteinuria - may be severe enough to cause nephrotic syndrome

• Diffuse glomerular deposition of amorphous hyaline material, initially in the mesangium –With time mesangial deposits and

deposits along the basement membranes lead to capillary narrowing and obliteration

–Amyloid deposits also may be seen in the small arteries, arterioles, and tubular basement membranes.

Kyle, R. A. (2001)Gertz, M. A. (2010)Sanchorawala, V. (2006)

Dx of Primary (AL) Amyloidosis- Renal

• Immunofluorescence microscopy is negative for immunoglobulins and complement in secondary AA, but is typically positive for monoclonal lambda or kappa light chains in the primary form

• The amount of monoclonal protein in the beta/gamma region of patients w/ MM but albuminuria and nephrotic range proteinuria

• Elevated B2M, Hypoalbuminemia

Kyle, R. A. (2001)Gertz, M. A. (2010)Sanchorawala, V. (2006)

Dx and Monitoring of Primary (AL) Amyloidosis

• Some have systemic MM as well as AL amyloid

• SPEP, UPEP

• β2M

• CBC diff, CMP, ALB

• Monoclonal protein, blood and urine

• 24 hr urine for Protein

• Skeletal survey to r/o lesions

• High Sensitivity TNT assay – improves detection of cardiac involvement and powerful diagnostic determinant

• Serum Free Light Chain Assay – more sensitive for organ response

• Echocardiography, Fat-Pad Aspirate ‘Congo Red Stain’

Kyle, R. A. (2001)Gertz, M. A. (2010)Sanchorawala, V. (2006)

Treatment of Amyloidosis- AL and AA

• Treat to prevent renal complications - i.e. Steroids such as dexamethasone, melphalan,

cyclophosphamide or lenalidomide- Clin trials with transplant, bortezomib and

lenalidomide

• Secondary AA can lead to renal failure d/t high circulating levels of Serum Amyloid A- Treatment aim is to control primary disease, such as

RA, Chron’s disease, - Colchicine in Familial Mediterranean fever (FMF)

Rajkumar, S. V. and M. A. Gertz (2007).

Treatment of Amyloidosis- ASH 2009

• Lenalidomide in Combination with Melphalan and Dexamethasone in Patients with Newly-Diagnosed Light-Chain (AL)-Amyloidosis: a Multicenter Phase I/II Dose Escalation Study (Moreau et al, 2009)

• Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL-Amyloidosis with Tolerable Neurotoxicity (Zonder et al, 2009)

• A Phase I/II Study of Lenalidomide (R) with Low Dose Dexamethasone (d) and Cyclophosphamide (C) for Patients with Primary Systemic (AL) Amyloidosis (Kastritis, et al 2009)

Kastritis, et al 2009Moreau et al, 2009Zonder et al, 2009

Light chain response vs. PEP in amyloid retrospective

• New response criteria will be discussed in near future

• Currently, protein electrophoresis and serum free light chain assay are the tests used

Dispenzieri, A., R. Kyle, et al. (2008).

Amyloidosis Case Presentation

• 56 year old Caucasian school teacher with chronic renal insufficiency, hypertension and hyperlipidemia

• Presents to PCP with progressive shortness of breath and bilateral LE edema

Physical Examination

• Gen: in no acute distress but visibly dyspneic after ambulating to exam room from lobby

• CV: diastolic murmur but heart rate regular at 98 BPM

• Lungs: Clear

• Abd: No HSM , soft

• Ext: 2+ pitting edema

Labs

• CBC: WBC 9.5, Hgb 11.4, Platelets 152K

• Chemistry: Albumin 2.7, creatinine 1.9, calcium 9.2

• Troponin: <0.01

• NT-pro-BNP: 3600

• Serum free light chains: Kappa 3250, elevated K/L ratio

• 24 hr urine: 86% albumin, 11.2gms/24 hrs, kappa light chain protein on immunofixation

Cardiac

• Echocardiogram shows diastolic dysfunction, thickened IVS (2.1). Endomyocardial biopsy:

Trichrome stain H&E

Used with Permission.

Echocardiogram

• Enlarged wall with motion abnormality

Used with Permission.

Renal

• Baseline creatinine less than 1.6mg/dL

• Renal insufficiency attributed to 10-year history of hypertension

• Kidney biopsy

Satoskar, A. (2007) .

Bone Marrow Biopsy

• 10% plasma cells lambda restricted by flow

• Congo red stain positive for amyloid

Congo Red for Amyloid

Courtesy of Elizabeth Sagatys, MD. Used with permission.

Diagnosis and Treatment

• Started on diuretic and beta-blocker by cardiology

• Bortezomib , lenalidomide and dexamethasone on a clinical trial

• Evaluation for transplant

Summary

• MM and PCDs are incurable, chronic diseases

• Palliation of symptoms and prevention of organ damage is essential to patient quality of life

• Novel agents have demonstrated significant activity in relapsed/refractory MM and amyloidosis and shown improved survival

• Sequential administration of novel therapies can potentially prolong survival