CCF Multiple Myeloma: An Overview of the Disease and It’s Complications Beth Faiman RN, MSN, CNP, AOCN Cleveland Clinic Myeloma Program

CCF

Multiple Myeloma: An Overview of the Disease and

It’s Complications

Beth Faiman RN, MSN, CNP, AOCN

Cleveland Clinic Myeloma Program http://www.clevelandclinic.org/myeloma

CCF

Multiple Myeloma: Overview and Objectives

At the end of this presentation, the participant should be able to: Describe the Pathobiology of Multiple

Myeloma, Identify criteria for diagnosis of Multiple

Myeloma, Describe complications of Myeloma and

identify appropriate interventions, Discuss supportive care measures for patients

and families with Myeloma

CCF

Multiple Myeloma: It’s Like a Puzzle.

There are many different factors that go into the diagnosis and management of this disease

Interdisciplinary and aggressive symptom management for our patients is key to their success!

CCF

Integrated Multidisciplinary Clinical Research Group at the Cleveland Clinic Foundation

Phoresis Unit

RadiationOncology

Renal

Neurology

Cardiolology

Radiology &Neuro-Radiology

Orthopedics

Palliative Medicine

Multiple Myeloma

CCF

Did you know?

The first case described in 1844 – Sarah Newbury

Spontaneous fractures of her femurs, rt. humerus

Skeletal evidence of Myeloma obtained from Egyptian Mummies

1850 – Dr. Henry Bence Jones detected heat properties of urinary light chains

Kyle in Malpas (1998), Salmon (1995) and Hussein (1994)

CCF

Plasma Cell Disorders

Multiple Myeloma Other Disorders

Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Solitary Plasmacytoma

Bone Extramedullary

Waldenström’s Macroglobulinemia Primary Amyloidosis (AL) Heavy chain disease POEMS syndrome Type I and II cryoglobulinemia

CCF

MGUS62% (803)

Myeloma15% (193)

Amyloidosis(AL) 10% (130)Amyloidosis

(AL) 10% (130)

Lymphoproliferative2.5% (31)

Lymphoproliferative2.5% (31)

SMM, 3.5% (44)SMM, 3.5% (44)

Solitary or extramedullary,1.5% (20)

Solitary or extramedullary,1.5% (20)

Macro, 3% (41)Macro, 3% (41)

Other, 2.5% (34)Other, 2.5% (34)

n=1296n=1296

Distribution of Monoclonal Gammopathies

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

CCF

Pathophysiology: Why do these cells turn malignant? No one Knows!

Chromosomal changes and abnormalities present in 80-90% patients on Fluorescent in Situ Hybridization (FISH) analysis

FISH – molecular cytogenetic technique describes genes, chromosomes and their aberrations

Salmon, S. E., ( Cancer Principals & Practice of Oncology (5th edition). Philadelphia: Lippincott-Raven, pp. 2344-2369.

CCF

Etiology/Risk factors

Radiation – chronic, low level Industrial – farming, herbicide exposure,

Agent Orange First degree relatives- Study by Brown et. al

(1999) provides data consistent with a familial risk, yet did not illustrate race-related differences

Cytogenetic abnormalities Are there more?

Brown, L.M, et. Al. (1999) Multiple myeloma and family history of cancer among blacks and whites in the U. S. Cancer, 85, 2385-2390.

CCF

Pathobiology/Pathogenesis

Cytokines have been implicated in myeloma cell growth, especially Interleukin-6 (IL-6)

In vivo and in vitro studies – a major autocrine and paracrine growth factor – bone marrow stromal cells compose the microenvironment for cells to secrete large amounts of IL-6

Elevated IL-6 levels linked to higher c-reactive protein levels, lower serum albumin levels and a poorer prognosis

Pelliniemi, T.T. (1995). Immunoreactive interleukin-6 and neopterin in patients with multiple myeloma. Blood, 85, 765-771.

Salmon, S. E., (1997). Plasma cell neoplasms. In V.T DeVita, S. Hellman, & S.A Rosenberg, (Eds). Cancer Principals & Practice of Oncology (5th edition). Philadelphia: Lippincott-Raven, pp. 2344-2369.

CCF

Pathophysiology: The Pluripotent Stem Cell

Myeloid stem cell

Lymphoid stem cell – the earliest cell – can self-replicate or differentiate into: T- Lymphocytes regulate immune

response, cell mediated immunity B- Lymphocytes – mature into plasma

cells, responsible for humoral immunity

Sheridan, C.A and Serrano, M. (2000). Multiple myelomaCancer nursing principles and practice (5th edition). Boston: Jones and Bartlett, pp. 1354-1370.

CCF

Pathophysiology: Remember the Immunoglobulins?

Five classes: IgG, IgA, IgM, IgD, IgE

Comprised of 4 polypeptide chains, 2 heavy and 2 light

Heavy: Take their name from their class: IgG = gamma, IgA = alpha, IgM = Mu.

Light: Kappa (κ) and Lambda (λ)

Sheridan, C.A and Serrano, M. (2000). Multiple myeloma.. Cancer nursing principles and practice (5th edition).

Boston: Jones and Bartlett, pp. 1354-1370.

CCF

Pathophysiology: So what happens?

Abnormal, overproduction of one immunoglobulin, it makes a “clone” of itself;

Referred to as the “M” protein (monoclonal), or “M- Spike”, normal plasma cells turn malignant

This “M” Protein is present in 80-90% patients These excess amounts of abnormal proteins

interfere with humoral immunity

CCF

Case Presentation

Mr. Peterson is a 62-year-old gentleman with a past medical history of hypertension, hyperlipidemia and osteoarthritis, who presented first to his Primary Care Physician (PCP) after experiencing severe 8/10 back pain while working in his yard. He had complained of intermittent lower back pain for “many years”, and a prior CT scan 8 months ago of the lumbar spine showed arthritic changes. He had also been complaining of some fatigue, and had noticed some new right hip pain, however this was attributed to increasing his work schedule, and “old age”.

CCF

Case Presentation

Where do you go from here?

What do you suspect to be part of the diagnosis?

What tests can you anticipate that the Practitioner would perform?

CCF

Laboratory Evaluation

General

Specific

CCF

Diagnostic Tests Blood and Urine Tests

Generic blood analysis Complete blood cell counts (CBC) Calcium, uric acid and creatinine Albumin, Beta-2-microglobulin, C-reactive protein, LDH

M proteins Blood—Serum protein electrophoresis and Immunofixation Urine protein electrophoresis and immunofixation Quantitative Immunoglobulins, serum free light chain assay

Radiological Skeletal survey; MRI/computerized tomography (CT)

scanning if needed Bone Marrow

Aspirate and biopsy with karyotyping and plasma cell labeling index

CCF

MULTIPLE MYELOMACBC

CBC Anemia (60%)

Cytokine mediated, or from Crowded Bone Marrow Blunted Erythropoeisis and shortened red cell survival Increased blood volume Chronic Renal Disease Macrocytic anemia

B12 and Folate levels Neuropathy Count recovery Quality of life

MDS Leukopenia Thrombocytopenia

Beckmann MJ et al Low Serum Vitamin B12 in Patients with Plasma Cell Myeloma Is Associated with True Functional Cobalamin Deficiency. American Journal of Clinical Pathology, 1995, 104:350

Baz R et al The Prevalence of Vitamin B-12 Deficiency in Plasma Cell Dyscrasias: A Retrospective Analysis. Blood 2002, 2368 a

CCF

B-12 deficiency in plasma cell dyscrasia: Monoclonal proteins like Vitamin B-12!

B-12 deficiency•B-12 < 200 pg/ml•B-12 >200<300pg/ml& Elevated MMA

Probable B-12 deficiency

•B-12 >200<300pg/ml& normal MMA•B-12 > 300pg/ml& elevated MMA

Baz et al; Cancer 101 (4):790-795, 2004.

CCF

B-12 deficiency in plasma cell dyscrasia

Myeloma Amyloid MGUS

B-12 Deficiency

14.2% 3.6% 5.8%

Probable B-12 deficiency

10.7% 7.1% 4.1%

Total 24.9% 10.7% 9.9%

N= 664 patients

Baz et al; Cancer 101 (4):790-795, 2004.

CCF

B-12 deficiency in plasma cell dyscrasia

15% of MM are B-12 deficient B-12 deficiency appears more prevalent in

IgA subtype 80% of B12 deficient patients have normal

MCV 35% of MM are B-12 or folate deficient B-12 influences

BM activity Neuropathy Endothelial health

Baz et al; Cancer 101 (4):790-795, 2004

CCF

Diagnostic Tests: Metabolic Panel

Hypercalcemia in 25% of the patients Hyperuricemia and Renal failure in 25-40%

Renal insufficiency – present in 20-25% patients at diagnosis – does not necessarily mean poor prognosis – present at one time or another in 50% Usually caused by Kappa or Lambda Light chains -

Some may have myeloma kidney or amyloidosis Albumin, Beta-2-microglobulin is now known to be an

EXCELLENT indicator of prognosis

Malpas, J. S. Et al. (1998). Myeloma Biology and Management: Second edition. New York: Oxford university press.

** Br.J.Haematol. 122 (3):441-450, 2003

CCF

New SWOG staging system **

Beta 2 M

Beta 2M< 5.5

Beta 2M> 5.5

Stage 1

Beta 2M<2.5

Beta 2M>2.5 < 5.5

Stage 2

Albumin> 3.0

Albumin< 3.0

Stage 3 Stage 4

** Br.J.Haematol. 122 (3):441-450, 2003

CCF

0%

20%

40%

60%

80%

100%

0 5 10 15 20Years After Registration

Stage IStage IIStage IIIStage IV

N197614447152

Deaths158563421149

Medianin Months

53402416

P < .0001

Southwest Oncology Group (SWOG)Stage (All Patients)

Overall Survival

CCF



Monoclonal proteins Blood—Serum protein electrophoresis and Immunofixation Urine protein electrophoresis and immunofixation Quantitative Immunoglobulins, serum free light chain assay

Radiological Skeletal survey; MRI/computerized tomography (CT) scanning

if needed Bone Marrow


CCF

MULTIPLE MYELOMADiagnosis SPEP/UPEP Immunofixation of the serum and the urine- This is

where heavy and light chains are determined Serum protein electrophoresis – presence of M-

protein - could miss 15% of the patients with MGUS Immunofixation- investigates abnormal bands Not performing a urine evaluation could miss 10% of

the patients with hypogammaglobulinemia where the M-Spike is ‘hiding’ under the gamma region and is undetected.

Malpas, J. S. Et al. (1998). Myeloma Biology and Management: Second edition. New York: Oxford university press.

CCF

Multiple Myeloma:Serum Protein Electrophoresis

CCF

Multiple Myeloma:Serum Protein Electrophoresis

CCF







CCF

Multiple Myeloma, spine

CCF


Generic blood analysis Complete blood cell counts (CBC) Albumin, Beta-2-microglobulin, C-reactive protein, LDH Calcium, uric acid and creatinine





Kyle (2005). Overview of Multiple Myeloma. On-Line. Available: www.uptodateonline.com

CCF

MULTIPLE MYELOMA: Diagnosis

Bone marrow (BM) aspirate and biopsy Suggested at baseline, end of therapy Cytogenetics and plasma cell labeling index

are helpful with prognosis; especially at baseline, but aren’t essential

As Myeloma disease may be assessed with serum and urine testing, BM does not need to be repeated unless clinically indicated

Vescio, R. A & Berenson, J.R. (2000). Myeloma, macroglobulinemia and heavy chain disease. In C.M Haskell (Ed). Cancer Treatment, 5th edition. Philadelphia: Saunders, pp. 1503-1539.

CCF

Chromosomal Alterations in Myeloma Chromosome anomalies: incidence

Conventional G-banding: 30-50% of patients Interphase FISH: > 90% of cases SKY: ? ~ 100%

Specific chromosome changes IgH translocations (14q32): 60% of cases

11q13 (cyclin D1 locus, 15-20%) 4p16 (FGFR3, MMSET, 12%) 6p21 (cyclin D3) 16q23 (c-maf, 1%) 20q11 (mafB)

Others: 13 deletion (10-20% of patients using conventional cytogenetics and 50% using FISH), c-myc translocations, 17p-, hypodiploidy, Ras mutations

Kuehl WM. Nat Rev Cancer 2002;3:17,Tricot G. Brit J Hematol 2002;116:211,Facon T. Blood. 2001;97:1566Fonseca R. Blood. 2002;4:1417, Bergsagel L. Proc Natl Acad Sci USA. 1996;93:13931 Fonseca R. Cancer Res. 2004;64:1546

CCF

Plasma Cells Differentiated

CCF

Plasmablastic Morphology

CCF

Plasma Cells are Immune Cells

Plasma cells are “immune Cells”, and meant to survive.

While most regimens for treatment of Myeloma include Dexamethasone or Prednisone as the basis of therapy, the goal with treatment is to attack the bone marrow microenvironment in different ways.

Steroids interfere with IL-6, and induce apoptosis of the plasma cell

CCF

MM cells

Bone Marrow Stromal Cells

PBMC

IL-6

TNF

IL-1

IL-2

IFN

CD8+ T Cells

Bone Marrow Vessels

ICAM-1

VEGF

bFGF

NK Cells

Role of Bone Marrow Microenvironment

Hideshima et al. Blood 96: 2943, 2000Davies et al. Blood 98: 210, 2001Gupta et al. Leukemia 15: 1950, 2001

Mitsiades et al. Blood 99: 4525, 2002Lentzsch et al Cancer Res 62: 2300, 2002

CCF

Angiogenesis in Myeloma

Normal Marrow Myeloma Marrow

CD 34 staining

Rajkumar SV 2004

CCF

Case Presentation I

Review of systems is positive for mild constipation, increased fatigue over the last few weeks, and shortness of breath on exertion. Pain is currently controlled with Tylenol #3 every 6 hrs as needed, prescribed by his PCP.

Physical Examination is normal, except he appears to be pale. The Musculoskeletal exam reveals point-tenderness to Thoracic spine, and bilateral hip joints.

CCF

Clinical Presentation

Subjective: Not all inclusive - everyone is different. General:

Back/bony pains- #1 presenting symptom Generalized weakness and fatigue Flu-like symptoms, nausea and vomiting

(electrolytes) Easy bruisability, recurrent infections (low plts) Neuro: Headaches, blurred vision, ataxia, vertigo 20% of patients will be diagnosed based on

routine laboratory examination, and are asymptomatic!

CCF

Clinical Presentation

Objective: Pallor Tenderness over affected bony areas Altered mental status Incontinence, loss of sphincter tone, lower

extremity weakness with pain may signify an Oncologic emergency – Spinal cord compression must be ruled out

Tachycardia/ arrhythmias due to electrolyte imbalance and associated renal impairment

CCF

Multiple Myeloma: Diagnosis According to Durie/Salmon Staging

Does Not: Take into account prognostic variables such as:

Inherent biology, cytogenetics, or proliferative rate of tumor

Chemosensitivity

Does provide us with a standardized tool for diagnosing and classifying Myeloma

CCF

Multiple Myeloma: Diagnosis According to Durie/Salmon Staging

* all of the following: *one or more of following:

Stage I Stage III Hgb >10g/dl <8.5 g/dl Serum Ca <12 mg/dl >12 g/dl Bone survey nml, solitary Lytic lesions

plasmacytoma Low M component High M component

A= Creat < 2.0 B = Creat > 2.0

CCF

Multiple Myeloma: International Staging System (ISS) for Prognosis

• B2M = Serum Beta-2 microglobulin• ALB = Serum Albumin in g/dL

Good and Poor risk groups: Age is the only significant risk

factor that impacts outcome Survival >5 years is

associated w/ age < 60 yrs Survival <2 yrs is correlated w/

age >60, plts <130,000 mm3, elevated LDH

Cytogenetics do influence outcome, however chromosome 13 deletion and presence of complex chromosome abnormalities do not add to the impact of age, B2M and ALB.

Stage 1 B2M < 3.5

ALB > 3.5

Stage 2 B2M < 3.5 ALB < 3.5

Stage 3 B2M > 5.5

Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003; 121:749.

CCF

Classification Characteristics Management

Monoclonal gammopathy of undetermined significance (MGUS)

Serum M protein <3 g/dL

Bone marrow plasma cells <10% if done

Absence of anemia, renal failure, hypercalcemia, and lytic bone lesions

Observation, with treatment beginning at disease progression

Smoldering multiple myeloma (SMM)

Serum M protein <3 g/dLand/or

Bone marrow plasma cells <10% if done

Absence of anemia, renal failure, hypercalcemia, and lytic bone lesions

Observation, with treatment beginning at disease progression

Indolent multiple myeloma (IMM) Presence of serum/urine M protein

Bone marrow plasmacytosis

Mild anemia or few small lytic bone lesions

Absence of symptoms

Monitoring every 3 months, with treatment beginning at disease progression

Multiple myeloma (MM) Presence of serum/urine M protein

Bone marrow plasmacytosis

Anemia, renal failure, hypercalcemia, or lytic bone lesions

Patients with primary systematic amyloidosis and bone marrow plasma cells ≥30% are considered to have both MM and amyloidosis

Immediate treatment

Differential Diagnosis

Rajkumar SV. Leukemia 2001;15:1274

Br.J.Haematol. 121 (5):749-757, 2003

CCF

Kyle RA and Rajkumar SV. Immunol Rev. 2003;194:112-139

MGUS: Risk of Progression Based on Initial M-spike

CCF

Multiple Myeloma: Diagnosis

Plasmacytosis –Bone Marrow Biopsy Serum and urine electrophoresis Beta 2 Microglobulin Lytic lesions With or without renal failure – ANY SIGN OF

ORGAN DYSFUNCTION Especially if patient is symptomatic Treat ASAP

CCF

Smoldering (Asymptomatic) MM: Do we need to Treat?

Treatment Options

Observation Clinical Trial

Kyle & Greipp. N Engl J Med 1980; 302:1347-1349Hjorth et al. Eur J Haematol 1993; 50:95-102Witzig. Br J Haematol 1994; 87:266-72

CCF

Complications of Myeloma

Complications of Myeloma- Altered Bone Marrow Environment Infections RenalMetabolicNeurologic (Peripheral Neuropathy)Hyperviscosity SyndromeSkeletal

CCF

Newly diagnosed and relapsed patient with MM. What are our goals?

Administer antineoplastic therapy and management of complications Chemosensitive; response – 50-75%; survival 24-40

mos. Vs. no treatment, survival 12 months Address concerns at diagnosis

hair loss, loss of appetite, nausea and GI side effects and provide appropriate interventions. reassurance

Negotiate short term and long term goals important to maintaining an optimal level of functioning, optimal health, assist patients in achieving them

CCF

Complications of Myeloma- Altered Bone Marrow Environment

Bone marrow involvement – normocytic, normochromic anemia manifested by weakness is present 60% at diagnosis Iron, B12 and folate Vitamin Deficiencies

Concerns at diagnosis and through chemotherapy: Neutropenia/Granulocytopenia Thrombocytopenia

CCF

Complications of Myeloma- Altered Bone Marrow Environment

Educate regarding: Fatigue –Erythropoeitin/Darbopoeitin

Blood transfusions, negotiate activities, treatment

Safety precautions - thrombocytopenia Infections – Avoid people with colds, report to

practitioner if patient notes signs and symptoms of illness

CCF

Complications of Myeloma- Infections

Infections: The main cause of death for patients with hematologic malignancies.

Patients with MM have serious abnormalities of humoral immunity, consisting of impaired antibody formation after antigenic stimulation and depressed polyclonal immunoglobulin levels in serum

*Flu vaccine not always effective

Paradisi, F., et. Al. (2001). Infections in multiple myeloma. Infectious Disease Clinics of North America, 15(2).

CCF


Most infections are in urinary/respiratory tracts, with Streptococcus pneumoniae and Gram negative bacilli (GNB) the most likely causitive organisms.

These can occur at any time during therapy – whether in a plateau phase or during treatment

23-Valent Pneumococcal Vaccine is indicated

Paradisi, F., et. Al. (2001). Infections in multiple myeloma. Infectious Disease Clinics of North America, 15(2).

CCF


What can nurses do? Provide non-pharmacologic and

pharmacologic interventions related to related to disease prevention

Non-pharmacologic: Target to UTI/Respiratory, or if at Nadir, must be individualized to each patient- education is the key!

Pharmacologic: IVIG, antibiotic prophylaxis, vaccines, growth factors

Malpas, J. S. (1998). Myeloma Biology and Management: Second edition. New York: Oxford university press. Gautier, M. (1994). Multiple myeloma in the elderly. American Geriatric Society, 42, 653-664.

CCF

Complications of Myeloma- Renal

Renal insufficiency –present at one time or another in 50%

Cause: Dehydration or medications such as NSAIDs May be implicated, but more likely due to Kappa or Lambda Light chains

Some may have “myeloma kidney” as the kidney has trouble filtering the light chains and through the glomerulus and proximal tubule

Malpas, J. S. (1998). Myeloma Biology and Management: Second edition. New York: Oxford university press.

CCF

Complications of Myeloma- Renal

Nursing: Avoid nephrotoxic agents (IV dyes, non-steroidals (NSAIDS), aminoglycosides especially), monitor electrolytes, serum creatinine.

Educate patients on ways to maintain hydration, assess fluid status, urine character

Renal failure may be corrected if damaging cause is corrected (I.e hypercalcemia, hyperuricemia, dehydration, disease)

PLASMAPHERESIS

Malpas, J. S. (1998). Myeloma Biology and Management: Second edition. New York: Oxford university press.

CCF

Complications of Myeloma: Metabolic

Metabolic Syndromes:

hypercalcemia

hyperuricemia

Treat the suspected, underlying cause

CCF

Complications of Myeloma: Hyperviscosity Serum

Hyperviscosity syndrome – increased vascular sludging can occur in individuals with IgM, IgG, or IgA myeloma.

Uncommon, found in less than 5% patients Symptoms of easy fatigability, blurred vision,

drowsiness, headaches, confusion Treated with Plasmapheresis Nursing: Rare; but be aware!

CCF

Complications of Myeloma: Neurologic (Peripheral Neuropathy)

Due to Myeloma disease or Drug Induced Often Heavy chain IgM or related to amyloid if no

diabetes, heart disease or if never treated with chemotherapy

If previously treated with Vincristine, Thalidomide, or Bortezomib

Adjunct medicines (Neurontin, check for vitamin deficiency, LGlutamine) - Neurology referral

Nursing: emotional support, comfortable shoes, ongoing research

CCF

Complications of Myeloma- Skeletal

Bone Involvement = Pain!

70% an up to 100% in some series

Plasmacytoma with significant bone

destruction could be elicited clinically and

radiologically (MRI, PET scanning)

Analgesia- pain assessment, BTCP,

persistent and incident pain – discuss barriers

to good pain control Body JJ, et al. J Clin Oncol. 1998.

CCF

Complications of Myeloma- Skeletal

Radiology

Plain-film radiography- sensitivity is low, some use to screen - Bone survey more reliable

Magnetic resonance imaging – highly sensitive to bone metastases, spinal mets, soft tissue tumors

Computed tomography scan – confirm suspicious findings raised on bone survey

More to be addressed later!

CCF

Complications of Myeloma: Skeletal

Chemotherapy for disease progression, bisphosphonates

Analgesia - Avoid NSAID’s, but be liberal, closely obtaining pain scores and altering the dosages if necessary

Radiotherapy Only for identified lesions – relieves pain from local tumor in 60-80 % patients

CCF

Management of Myeloma: Supportive Care is Key! Multiple Myeloma is a complex disease! Although it comprises only a small

percentage of the population, it remains imperative that Nurses be aware of the disease, and management of symptoms

Be aware of local and national support groups for patients and their families to participate – provide education materials, handouts according to learning needs

Documents

CCF Multiple Myeloma: An Overview of the Disease and It’s Complications Beth Faiman RN, MSN, CNP, AOCN Cleveland Clinic Myeloma Program