Harrison Ogbewe

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Discuss how multiple myeloma is diagnosed and monitored from all aspects of the clinical laboratory

Describe the etiology and pathogenesis of multiple myeloma

Become familiar with various methods of treatment for multiple myeloma

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75 yo. male presents with acute onset of severe left lateral lower side and back pain

Past Medical History◦ Hypertension◦ Emphysema◦ Benign prostatic

hyperplasia◦ Pacemaker for history of

bradycardia◦ Gout◦ Patient is a former smoker

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Image courtesy of: http://www.epainassist.com/back-pain/left-back-pain

Chest X-ray shows serious left lateral thickening in right chest

Chest CT: ◦ Soft tissue mass around

right 8th rib◦ Fracturing with oval lytic

lesion at right 7th rib

Multiple small lucencieswithin the thoracic spike of T10.

Legions found on both sides of kidney

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Images courtesy of: http://www.pleuralthickening.org.uk/causes-of-pleural-

thickening

Physician suspected malignancy

Initial Laboratory Findings:◦ Low RBC count, HB, and HCT

◦ Serum Protein Electrophoresis:

Normal IgM, IgA, IgG

Gamma M spike present

◦ Immunofixation

Monoclonal gammopathy with free Kappa paraprotein

◦ Extremely High Free Kappa Chain count

Patient presented with diagnosis of Kappa Multiple Myeloma

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According to the American Cancer Society, the etiology of multiple has not yet been determined.

Scientific Opinion: Problem adaptive immunity?

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Image courtesy of: http://www.politicspa.com/if-corbett-didnt-run-who-might-republicans-nominate/49473/silhouette-question-mark-3/

Somatic Recombination (T-Cell Independent):◦ (V), (D), (J) segment

recombination at DNA level

◦ B – Cell Maturation

◦ IgM production

◦ Enzymatically Driven by IgH and IgK/L genes

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Image courtesy of:, https://commons.wikimedia.org/w/index.php?curid=4329676

Mature B-cells synthesize antibodies specific to foreign antigens:◦ Somatic

Hypermutation: Produces highly

affinitive antibodies

◦ Class Switching Recombination Heavy chain genes

rearrange to change IgM to IgG, IgE, or IgA

8Image courtesy of: https://i.ytimg.com/vi/ba68cC8h3Eo/maxresdefault.jpg

Anemia (Normocytic, Normochromic)◦ 75% of patients at diagnosis◦ 100% of patients during course

of disease

Bone Disease (Two pronged Attack)◦ Osteoblasts inhibited by rapidly

cloning myeloma cells◦ Osteoclasts put into overdrive

by osteoclastic activating factors produced by myeloma cells

◦ Associated with BONE PAIN

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Image courtesy of: http://www.clinicaloptions.com/Oncology/Treatment%20Updates/Bone%20Complications/Module/Transcript/Pages/~/media/Oncology/Programs/Bone%20Complications/ASCO_BoneTU_Figure1.ashx

Hypercalcemia◦ Kidney dysfunction & impairment of osteoclast-

osteoblast equilibrium leads to bone destruction Large amount of Ca++ released into blood

Renal Disease (Myeloma Kidney)◦ Bence Jones proteins present in huge amounts

overworks kidney’s filtering and reabsorptions ability leading to chronic kidney disease

Amyloidosis◦ Bence Jones proteins deposit themselves into

various tissue causing systemic issues

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11Table 1: Lab Summary

Based on many factors◦ Disease progression rate

Asymptomatic vs. Symptomatic

Bone disease

M protein levels

Bence Jones Protein levels

Age

Scope of Case◦ Patient is considered newly diagnosed elderly

patient not eligible for transplantation

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Melphalan + Prednisone◦ Primary therapy for MM in newly diagnosed elderly

patient

◦ Melphalan = DNA/RNA synthesis inhibitor

◦ Prednisone = Immunosuppression

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Image Courtesy of: https://en.wikipedia.org/wiki/Melphalan#/media/File:Melphalan_ball-and-stick.png

Velcade + dexamethasone◦ Velcade (Bortezomib): Proteasome inhibitor

Proteasomes are cellular complexes that degrade proteins over time

In myeloma cells the proteasomes outlast pro-apoptotic proteins

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Image courtesy of: http://www.velcade.com/Understanding-velcade/About-velcade

Anti-CD38 chemotherapy◦ Developed in 2012◦ Approved for FDA Fast Track Designation and

Breakthrough Therapy designation in 2013

15Image courtesy of http://www.icpoep.com/PDF/TorbenPlesner_ICPOEP2015_PresentationSlides.pdf

Surprise! RBCs weakly express CD38◦ What does this mean?

DARA causes plasma panreactivity in vitro

It invalidates the antibody screen and panel of plasma and eluate

Solution?◦ Treat patient plasma with Dithiothreitol (DTT)

◦ Caveat: DTT denatures Kell antigens. So K negative units must be provided

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5% of patients with multiple myeloma are positive for CD19 and Negative for CD56

Importance:◦ CD19 expression has been correlated with poor

response to chemotherapy

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Daratumumab VS. Patient’s MM◦ Daratumumab is slowing the progression of the

disease, but not at all resolving it

Kappa light chain levels continue to rise◦ Chronic Kidney Disease persists

Patient is almost completely refractory

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Patient’s worsening condition displays resilience of multiple myeloma◦ Clonal plasma cells leads to

Stressed BM Normocytic/Normochromic Anemia

Bone Breakage

◦ Massive amounts of kappa light chains Overwhelmed Kidney Chronic Kidney Disease

In conclusion we have◦ Discussed the Diagnosis of MM◦ Discussed MM etiology and pathophysiology◦ Familiarized ourselves with various treatment for

MM

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1Gonzalez D, Burg M, Garcia-Sanz R. Immunoglobulin gene rearrangements and the pathogenesis of multiple myeloma. J Blood [Internet]. 2007 July [Cited 2016 Feb 22]; 110 (9) 3112-3121.

Available from:http://www.bloodjournal.org/content/bloodjournal/110/9/3112.full.pdf?sso-checked=true

2Stevenson G. CD38 as a Therapeutic Target. Mol Med [Internet]. 2006 [Cited 2016 March 8]; Nov-Dec; 12(11-12): 345-346

Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1829201/

3 S Vincent Rajkumar, MD. Patient information: Multiple myeloma symptoms, diagnosis, and staging (Beyond the Basics) [Internet]. UpToDate; [updated 2015 Nov 5];

Available from: http://www.uptodate.com/contents/multiple-myeloma-symptoms-diagnosis-and-staging-beyond-the-basics

4Papadopoulou E, Batzios S, Dimitriadou M. Multiple myeloma and bone disease: pathogenesis and current therapeutic approaches. Hippokratia [Internet]. 2010 Apr-Jun [Cited 2016 Feb 12]; 14(2): 76-81.

Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2895290/

5Shah D, Seiter K. Multiple Myeloma Clinical Presentation [Internet]. New York (NY): The Medscape Journal of Medicine; c2002 [updated 2016 Feb 5; cited 2016 Feb 12]. Available from: http://emedicine.medscape.com/article/204369-clinical

6Mateo G, Montalban A, Vidriales, M. Prognostic Value of Immunophenotyping in Multiple Myeloma: A Study by the PETHEMA/GEM Cooperative Study groups on Patients Uniformly Treated with High-Dose Therapy. J Clin Onc[Internet]. 2008 Jun [Cited 2016 March 10]; 26(16) 2737-44.

Available from: http://jco.ascopubs.org/content/26/16/2737.full

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7Luiz A, Calheiros L, Kerbauy D. Multiples aberrant phenotypes in multiple myeloma patient expressing CD56-, CD28+, CD19+. Rev Bras Hematol Hemoter [Internet]. 2012 [Cited 2016 Apr 21]; 34(1): 66-67.

Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459618/

8Phillips C, Chen Y, Gopalakrishnan S. Daratumumab and its potential in the treatment of multiple myeloma: overview of the preclinical and clinical development. Ther Adv Hematol[Internet]. 2015 June [Cited 2016 Feb 24]; 6(3): 120-127.

Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480519/

9Lokhorst HM, Plesner T, Laubach JP. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma, N Engl J Med [Internet]. 2015 Sep [Cited 2016 Feb 24]; 373: 1207-1219.

Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa1506348

10Chapuy C, Nicholson R, Aguad M. Resolving the Daratumumab interference with blood compatibility testing. Transfusion [Internet]. 2015 June [Cited 2016 Feb 24]; 55(6 pt 2): 1545-54.

Available from: http://www.ncbi.nlm.nih.gov/pubmed/25764134

11McClure K. Rh, RHAG, and LW Blood Group Systems.

In: Gockel-Blessing EA, Pratt MM, Johns GS, editors. Clinical Laboratory Blood Banking and Transfusion Medicine Principles and Practice. New York:

Pearson; 2015. p. 75-87.

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12E-pain-assist.com [Internet]. Tampa: Painassist Inc.; c2012-16 [updated 2016; cited 2016 April 20]. Available from: http://www.epainassist.com/back-pain/left-back-pain

13Politics-PA.com[Internet]. Pennsylvania: PoliticsPA. 2013 Jul 16 [cited 2016 April 20]. Available from: www.politicspa.com/if-corbett-didnt-run-who-might-republicans-nominate/49473/silhouette-question-mark-3

14Wikimedia.org [Internet]. San Francisco: Gustavo Carra. 2008 Jul 6 – [cited 2016 April 20]. Available from: https://commons.wikimedia.org/w/index.php?curid=4329676

15You-tube.com [Internet]. San Bruno: Alphabet Inc. c2005 [cited 2016 April 20]. Available from: https://i.ytimg.com/vi/ba68cC8h3Eo/maxresdefault.jpg

16Clinical-Options.com[Internet]. Reston: Clinical Options; c2015 [updated 2016 April 20; cited April 20]. Available from: http://www.clinicaloptions.com/Oncology/Treatment%20Updates/Bone%20Complications/Module/Transcript/Pages/~/media/Oncology/Programs/Bone%20Complications/ASCO_BoneTU_Figure1.ashx

17Velcade.com [Internet]. Cambridge: Millennium Pharmaceuticals, Inc c2014 [cited 2016 April 20]: Available from: http://www.velcade.com/Understanding-velcade/About-velcade

18Plesner T. Daratumumab for multiple myeloma: A journey from phase 1 towards approval for marketing. LI KaShing Faculty of Medicine, The University of Hong Kong [Internet]. [Cited 2016 April 24]: Available from: http://www.icpoep.com/PDF/TorbenPlesner_ICPOEP2015_PresentationSlides.pdf

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