GROUP 4 Gadin, Gonzales, Ignacio, Jumawan, Malihan, Manango, Mendoza, Morales, Oliva, Olivar.

GROUP 4 Gadin, Gonzales, Ignacio, Jumawan,

Malihan, Manango, Mendoza, Morales, Oliva, Olivar

42-year-old malebilateral extremity edema (+) history ofcystic lesion in the

jaw with a benign diagnosis eight years ago (see slide S-94-01)

bone pains, easy fatigability, occasional dizziness, polyuria and frequent cough and colds

URINALYSIS Protein: +++ Glucose: + Blood: +

(intact) Ketone: negative Bilirubin:

negative Urobilinogen: trace Leukocytes: +

RBC: 2.2 x 106/ul

Hgb: 4.5 g/dl Hct: 17.1% MCV: 55 fl MCH: 15.7 pg MCHC: 28 g/dl RDW: 23.6 %

WBC: 29.65

Neutrophil: 26 Lymphocytes:6

1 Monocytes 05 Plasma cells 05 Eosinophils 03

COMPLETE BLOOD COUNT

NORMAL CONTROL

PATIENT SERUM

λ β α albumin

0.8% of all cancer diagnoses (86,000 new cases) and 0.9% of cancer deaths worldwide in 2002

Bray, et al. Global Cancer Statistics, 2002

high in North America, Australia/ New Zealand, northern Europe, and western Europe compared with Asian countries

Incidence rate including Lymphomas is 479 per 1,000

WHO statistics, 2004

incidence were higher among males which is 50% higher than rates in

women for all racial/ethnic groups for FILIPINOS, the rate of incidence in

men is 80% higher than women

National Cancer Institute, SEER Program. 1988-1992. retrieved from http://seer.cancer.gov/publications/ethnicity/myeloma.pdf on November 8, 2009.

National Cancer Institute, SEER Program. 1988-1992. retrieved from http://seer.cancer.gov/publications/ethnicity/myeloma.pdf on November 8, 2009

Multiple myeloma rarely occurs in the 30-54 year age group. It is commonly seen on both men and women ages 70 and above.

Adam, Alexander, Cole, P., Hans-Olov, A., Mink, P., Oken, M. and Trichopoulo, D. Multiple myeloma: A review of the epidemiologic literature. 2007. Int. J. Cancer: 120, 40–61

Rates are "average annual" per 100,000 population, age-adjusted to 1970 U.S. standard; N/A = information not available

* = rate not calculated when fewer than 25 cases.

There are currently no reliable or consistent predictors of risk for developing multiple myeloma, beyond race, age and sex.

Other risk factors that are being mentioned warrants further research.

Adam, Alexander, Cole, P., Hans-Olov, A., Mink, P., Oken, M. and Trichopoulo, D. Multiple myeloma: A review of the epidemiologic literature. 2007. Int. J. Cancer: 120, 40–61

Obesity has been associated with an elevated risk of multiple myeloma while high dietary intake of green vegetables and fish has been reported to be associated with decreased risk of the disease

Adam, Alexander, Cole, P., Hans-Olov, A., Mink, P., Oken, M. and Trichopoulo, D. Multiple myeloma: A review of the epidemiologic literature. 2007. Int. J. Cancer: 120, 40–61

Exposure to ionizing radiation is the only well-established risk factor for multiple myeloma, although some chemicals and occupational exposures have been reported to be associated with an increased risk

Bray, F., Ferlay, J., Parkin, M., and Pisani, P. 2005. Global Cancer Statistics, 2002. CA Cancer J Clin 2005; 55:74-108

Adam, Alexander, Cole, P., Hans-Olov, A., Mink, P., Oken, M. and Trichopoulo, D. Multiple myeloma: A review of the epidemiologic literature. 2007. Int. J. Cancer: 120, 40–61

Clinical Findings consistent with the Patient

Underlying Cause and Pathogenetic Mechanism

Lytic bone lesions, bone pain Tumor expansion, production of osteoclast activating factor by tumor cells, osteoblast inhibitory factors

Renal failure Hypercalcemia, light chain deposition, amyloidosis, urate nephropathy, contrast dye

Easy fatigue—anemia Bone marrow infiltration, production of inhibitory factors, hemolysis, decreased red cell production, decreased erythropoietin levels

Recurrent infections Hypogammaglobulinemia, low CD4 count, decreased neutrophil migration

Bone pain, lytic bone lesions Factors produced by neoplastic plasma

cells mediate bone destruction, the major pathologic feature of multiple myeloma.

A variety of cytokines produced by the tumor cells, particularly MIP1α and the receptor activator of NF-κB ligand (RANKL), serve as osteoclast-activating factors

Kumar, et al. 2005.

Lytic bone lesions The bony lysis results in substantial

mobilization of calcium from bone, and serious acute and chronic complications of hypercalcemia may dominate the clinical picture

Braunwald et al., 2008.

Renal Symptoms tubular damage associated with the

excretion of light chains is almost always present

Normally, light chains are filtered, reabsorbed in the tubules, and catabolized.

With the increase in the amount of light chains presented to the tubule, the tubular cells become overloaded with these proteins, and tubular damage results either directly from light chain toxic effects or indirectly from the release of intracellular lysosomal enzymes

CBC (WBC differential count) and Urinalysis

Electrophoresis (serum and urine) Detection of the presence of tumor

marker for plasma cell myeloma (Braunwald et al, 2008).

ImmunoelectrophoresisBone marrow smear

Suspected multiple myeloma, Waldenström's macroglobulinemia, primary amyloidosis, or related disorder

Unexplained peripheral neuropathy (not attributed to longstanding diabetes mellitus, toxin exposure, chemotherapy, etc.)

New-onset anemia associated with renal failure or insufficiency and bone pain

Back pain in which multiple myeloma is suspected Hypercalcemia attributed to possible malignancy (e.g.,

associated weight loss, fatigue, bone pain, abnormal bleeding)

Rouleaux formations noted on peripheral blood smear Renal insufficiency with associated serum protein

elevation Unexplained pathologic fracture or lytic lesion

identified on radiograph Bence Jones proteinuria

If the examination is normal but multiple myeloma, Waldenström's macroglobulinemia, primary amyloidosis, or a related disorder still is suspected, immunofixation should then be performed. This technique may be more sensitive in identifying a small monoclonal (M) protein (Kyle, 1994).

some plasma cell proliferative disorders synthesize and secrete monoclonal free light and heavy chain fragments

These fragments are of relatively small molecular weight and may be readily cleared from blood

To detect these abnormalities, it may be necesssary to test urine samples (Roden et al., 2008).

• is used to detect monoclonal and other proteins in the urine

• monoclonal protein in serum is > 1.5 g/dL

• monoclonnal free light chains are detected in serum

• hypogammaglobulinemia is present in serum

• serum electrophoresis shows nephrotic pattern (Brants, 2009).

Decreased Albumin:malnutrition and malabsorptionkidney diseaseliver disease inflammatory conditions protein-losing syndromeschronic cachectic or wasting diseases

Increased Albumin:dehydration

Decreased α1 globulin:a1-antitrypsin deficiencysevere liver disease

Increased α1 globulin:inflammatory diseases pregnancy

Decreased α2 globulin:hyperthyroidismsevere liver diseaseMegaloblastic anemiaWilson's disease

Increased α2 globulin:kidney disease (nephrotic syndrome)Adrenal insufficiencyAdrenocorticosteroid therapyAdvanced diabetes mellitus

Decreased β globulin: malnutrition cirrhosis

Increased β globulin:hypercholesterolemia some cases of multiple myeloma or MGUS iron deficiency anemia Nephrosis Obstructive jaundice

Decreased Gamma globulin:secondary immune deficiencymultiple myelomaagammaglobulinemiahypogammaglobulinemia

Increased:Rheumatoid and collagen diseasesAmyloidosis Chronic infections (granulomatous diseasesMalignant lymphomaWaldenström's macroglobulinemiaHodgkin's disease

Increased Monoclonal:Waldenstrom’s macroglobulinemiamultiple myelomamonoclonal gammopathies of undetermined significance (MGUS)

also called gamma globulin electrophoresis, or immunoglobulin electrophoresis

a method of determining the blood levels of three major immunoglobulins:

immunoglobulin M (IgM)

immunoglobulin G (IgG) immunoglobulin A (IgA).

a powerful analytical technique with high resolving power as it combines separation of antigens by electrophoresis with immunodiffusion against an antiserum

aids in the diagnosis and evaluation of the therapeutic response in many disease states affecting the immune system

SOURCE: Fauci, 2008

SOURCE: Multiple Myeloma Research Foundation [MMRF]. (2009). Newly diagnosed patients: what is multiple myeloma.

Other studies on serum β2-microglobulin (β2-m) level and plasma cell labeling index (PCLI) shows that β2-m >4ng/μL and PCLI >0.4% were associated with shorter survival than β2-m <1ng/μl and PCLI of 0

(Facon et al., 2001; Gertz et al., 1989)

Deletion of chromosome13q14, 17p13 is associated with poor response to conventional induction therapy and short median overall survival

(Konigsberg et al., 2000) Recurrent translocations involving chromosome

14q32 correlate with survival as a result of intensive chemotherapy: t(4;14) is associated with short event-free and overall survival. t(11;14) associated with a longer overall survival

(Moreau, et al., 2002) Hypodiploidy (pseudodiploid, hypodiploid, near

tetraploid) are adverse prognostic factors(Smadja et al., 2001)

More mature type (i.e. plasmacytic) and <20% marrow replacement are favorable, and more immature or poorly differentiated (i.e. plasmablastic) and >50% marrow replacement are unfavorable prognostic factors

(Bartl et al., 1982)

Dexamethasone (40 mg every 4 days for 2 weeks)

Dexamethasone + VAD combination therapy (Vincristine, 0.4 mg/d in a 4-day continuous infusion; doxorubicin, 9 mg/m2 per day in a 4-day continuous infusion; dexamethasone, 40 mg/d for 4 days per week for 3 weeks)

Alkylating agents such as melphalan should be avoided since they damage the stem cells (Braunwald, 2008).

L-phenylalanine mustard (L-PAM, melphalan) 8 mg/m2 per day

prednisone, 25–60 mg/m2 per day for 4 days.

Courses of therapy are repeated at 4-6 week intervals for at least one year.

Good clinical response is a 50% reduction in the measured M protein levels.

Complete remission is said to occur when the M protein cannot be identified by immunofixation and the bone marrow appears normal on biopsy (Boccadoro M, Pileri A. Diagnosis, prognosis, and standard treatment of multiple myeloma. Hematol Oncol Clin North Am 1997;11:111-31.)

Bone resorption Bisphophonates (pamidronate 90 mg or

zoledronate 4 mg once a month) Fluoride, vitamin D with or without

androgen to strengthen the boneHypercalcemia

Bisphosphonates, glucocoticoids, hydration, natriuresis

Anemia Erythropoetin with hemanitics (iron,

folate, cobalamin)

Eligibility criteria: Less than 60 years of age Durie–Salmon stage I, II, III

Exclusion criteria: Prior treatment to myeloma Another cancer Abnormal cardiac function (systolic

ejection fraction of <50%) Chronic respiratory disease (VC <50% of

predicted) Abnormal liver function (serum bilirubin

>2mg/dL, ALT or AST >4x upper limit of normal

Psychiatric illness

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