1. Harrison Ogbewe
1

2.  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
2

3.  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
3
Image courtesy of: http://www.epainassist.com/back-pain/left-back-pain

4.  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 lucencies
within the thoracic spike
of T10.
 Legions found on both
sides of kidney
4
Images courtesy of: http://www.pleuralthickening.org.uk/causes-of-pleural-
thickening

5.  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
5

6.  According to the
American Cancer Society,
the etiology of multiple
has not yet been
determined.
 Scientific Opinion:
Problem adaptive
immunity?
6
Image courtesy of: http://www.politicspa.com/if-corbett-didnt-run-who-might-
republicans-nominate/49473/silhouette-question-mark-3/

7.  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
7
Image courtesy of:, https://commons.wikimedia.org/w/index.php?curid=4329676

8.  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

9.  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
9
Image courtesy of:
http://www.clinicaloptions.com/Oncology/Treatment%20Updates/Bone%20Complications/Module/Tra
nscript/Pages/~/media/Oncology/Programs/Bone%20Complications/ASCO_BoneTU_Figure1.ashx

10.  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
10

11. 11
Table 1: Lab Summary

12.  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
12

13.  Melphalan + Prednisone
◦ Primary therapy for MM in newly diagnosed elderly
patient
◦ Melphalan = DNA/RNA synthesis inhibitor
◦ Prednisone = Immunosuppression
13
Image Courtesy of:
https://en.wikipedia.org/wiki/Melphalan#/media/File:Melphalan_ball-and-stick.png

14.  Velcade + dexamethasone
◦ Velcade (Bortezomib): Proteasome inhibitor
 Proteasomes are cellular complexes that degrade
proteins over time
 In myeloma cells the proteasomes outlast pro-
apoptotic proteins
14
Image courtesy of: http://www.velcade.com/Understanding-velcade/About-velcade

15.  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

16.  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
16

17.  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
17

18.  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
18

19.  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
19

20.  1Gonzalez D, Burg M, Garcia-Sanz R. Immunoglobulin gene rearrangements and the pathogenesis of multiple
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 Available from:http://www.bloodjournal.org/content/bloodjournal/110/9/3112.full.pdf?sso-checked=true

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Medicine; c2002 [updated 2016 Feb 5; cited 2016 Feb 12]. Available from:
http://emedicine.medscape.com/article/204369-clinical
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 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.
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21.  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/
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 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
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 Pearson; 2015. p. 75-87.
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22.  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:
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 15You-tube.com [Internet]. San Bruno: Alphabet Inc. c2005 [cited 2016 April 20]. Available from:
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 16Clinical-Options.com[Internet]. Reston: Clinical Options; c2015 [updated 2016 April 20; cited April 20].
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 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 Ka
Shing 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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