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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. Multiple Myeloma: Overview and Objectives. At the end of this presentation, the participant should be able to:
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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
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
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!
Integrated Multidisciplinary Clinical Research Group at the Cleveland Clinic Foundation
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)
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
Distribution of Monoclonal Gammopathies n=1296 SMM, 3.5% (44) Lymphoproliferative2.5% (31) Solitary or extramedullary,1.5% (20) Macro, 3% (41) Amyloidosis(AL) 10% (130) Other, 2.5% (34) Myeloma15% (193) MGUS62% (803) Kyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 2004
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 Pathophysiology: Why do these cells turn malignant? No one Knows! Salmon, S. E., ( Cancer Principals & Practice of Oncology (5th edition). Philadelphia: Lippincott-Raven, pp. 2344-2369.
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.
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.
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.
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.
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
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”.
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?
Laboratory Evaluation General Specific
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
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
B-12 deficiency in plasma cell dyscrasia: Monoclonal proteins like Vitamin B-12! Baz et al; Cancer 101 (4):790-795, 2004.
B-12 deficiency in plasma cell dyscrasia N= 664 patients Baz et al; Cancer 101 (4):790-795, 2004.
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
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
New SWOG staging system ** ** Br.J.Haematol. 122 (3):441-450, 2003
Southwest Oncology Group (SWOG) Stage (All Patients) Overall Survival
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 • 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 • Aspirate and biopsy with karyotyping and plasma cell labeling index
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.
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
Diagnostic Tests • Blood and Urine Tests • Generic blood analysis • Complete blood cell counts (CBC) • Albumin, Beta-2-microglobulin, C-reactive protein, LDH • Calcium, uric acid and creatinine • 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 Kyle (2005). Overview of Multiple Myeloma. On-Line. Available: www.uptodateonline.com
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.
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 KuehlWM. Nat Rev Cancer 2002;3:17,Tricot G. Brit J Hematol 2002;116:211,Facon T. Blood. 2001;97:1566 Fonseca R. Blood. 2002;4:1417, Bergsagel L. Proc Natl Acad Sci USA. 1996;93:13931 Fonseca R. Cancer Res. 2004;64:1546
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
Role of Bone Marrow Microenvironment MM cells IL-6 TNF IL-1 Bone Marrow Stromal Cells ICAM-1 Bone Marrow Vessels VEGF bFGF IL-2 IFN PBMC CD8+ T Cells NK Cells Hideshima et al. Blood 96: 2943, 2000 Davies et al. Blood 98: 210, 2001 Gupta et al. Leukemia 15: 1950, 2001 Mitsiades et al. Blood 99: 4525, 2002 Lentzsch et al Cancer Res 62: 2300, 2002
Angiogenesis in Myeloma CD 34 staining Myeloma Marrow Normal Marrow Rajkumar SV 2004
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.
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!
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
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
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
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. Multiple Myeloma: International Staging System (ISS) for Prognosis 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.
Differential Diagnosis Br.J.Haematol. 121 (5):749-757, 2003 Rajkumar SV. Leukemia 2001;15:1274
MGUS: Risk of Progression Based on Initial M-spike Kyle RA and Rajkumar SV. Immunol Rev. 2003;194:112-139
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
Smoldering (Asymptomatic) MM: Do we need to Treat? Treatment Options Observation Clinical Trial Kyle & Greipp. N Engl J Med 1980; 302:1347-1349 Hjorth et al. Eur J Haematol 1993; 50:95-102 Witzig. Br J Haematol 1994; 87:266-72
Complications of Myeloma • Complications of Myeloma- • Altered Bone Marrow Environment • Infections • Renal • Metabolic • Neurologic (Peripheral Neuropathy) • Hyperviscosity Syndrome • Skeletal
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