case studies - camlt.org
TRANSCRIPT
Anne L Sherwood, PhD
Director of Scientific Affairs
The Binding Site, Inc.
Case Studies
Outline
• Multiple Myeloma Overview
• Three case studies (with audience participation)
Multiple Myeloma
• Cancer of the blood (Haematological malignancy)
• Uncontrolled proliferation of plasma cells derived from a single clone (Plasma cell dyscrasia)
• Accumulation of the myeloma cells in the bone marrow results in:• a. Destruction of bone → pain• b. Abnormal bone marrow function → anemia• c. Secretion of monoclonal protein → intact antibody, free light
chains, or both• d. Suppression of normal antibodies → infection
Palumbo, A, Rajkumar SV. Leukemia 23:449 2009; Kyle , RA, Rajkumar SV. N. Engl. J of Med 351:1860 2004
Multiple Myeloma
• 1% of all cancers in the US
• 2nd most common heme malignancy (#1 NHL)
• 10% of all hematologic malignancies in Caucasians
( Incidence is 4.5 per 100,000 per year)
• 20% of all hematologic malignancies in African Americans
(Incidence is 9.3 per 100,000 per year)
Palumbo, A, Rajkumar SV. Leukemia 23:449 2009
Kyle , RA, Rajkumar SV. N. Engl. J of Med 351:1860 2004
Multiple Myeloma
• The ƒ is constantly increasing due to the aging of the population
• 35% of patients are younger than 65 years of age
• 28% are 65 – 74 years of age
• 37% are > 75 years of age
Palumbo, A, Rajkumar SV. Leukemia 23:449 2009
Kyle , RA, Rajkumar SV. N. Engl. J of Med 351:1860 2004
Risk Factors
• Exposure to pesticides• Agricultural workers
• Vietnam era veterans exposed to Agent Orange
• More common in men
• More common in African Americans
• No apparent association with:• Smoking
• Alcohol consumption
• Familial genetics
Dispenzieri, A. Multiple Myeloma. In: Multiple Myeloma and Related Plasma Cell Disorders. M Gertz and P Greipp, Eds. Springer Press 2004
Signs & Symptoms of Multiple MyelomaNONSPECIFIC
• Bone pain (~58%): lower back, ribs• Fatigue: 32%• Weight loss: 24%• Recurrent infections• Anemia: 73%• Nausea• Hypercalcemia: 13%• Serum creatinine ≥ 2.0 mg/dL: 19%• Hyperviscosity: esp Waldenström’s, IgA• Neurologic: peripheral neuropathy• Asymptomatic or minimal symptoms: 11%
Kyle RA. Mayo Clin Proc. 2003;78:21-33.
Diagnostic Criteria for Symptomatic Multiple Myeloma
C Hypercalcemia
R Renal involvement
A Anemia
B Bone Involvement
(I) Infections CANCER – the CRAB
Vertebral fractures due to myeloma
Plasma cell infiltration in bone
marrow
PET Scans in Multiple Myeloma
Osteolytic Lesions
↑ macrophage
inflammatory
protein 1α
↑ receptor
activator of NF-κB
ligand (RANKL)
↓ osteoprotegerin
Osteoblast
Osteoclast activation
with bone resorption
Kyle RA, Rajkumar SV. N Engl J Med. 2004:351:1860-73.
Types of Myeloma
• Intact immunoglobulin myeloma• Production of intact immunoglobulins (M-protein)
• Commonly called myeloma
• Light chain myeloma• Production of only light chains
• Sometimes called light chain disease
• Nonsecretory myeloma*• M-protein is not present on SPEP, IFE, UPEP, or uIFE
* Now usually referred to as Hyposecretory or Oligosecretory MM
Methods to Detect and/or Quantify Immunoglobulins
• Protein electrophoresis
• Serum (SPEP)
• Urine (UPEP)
• Immunofixation electrophoresis (IFE)
• Capillary zone electrophoresis (CZE)
• Nephelometry and turbidimetry
• Quantitative immunoglobulins: measure levels of IgG, IgA, IgM, IgE, IgD
• Serum free light chain assays: measure levels of kappa, lambda, and their ratio
Kyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 2004
Monoclonal
Protein “Spike”
Kyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd
Edition, 2004
Kyle RA and Rajkumar SV. Cecil Textbook of Medicine,
22nd Edition, 2004
Polyclonal Gammopathy
SPEP With:
IFE – Normal Serum IFE – Elevated Polyclonal IgG
Serum Free Light Chains – Normal Ranges
• Kappa ()
• 95% reference interval: 3.3–19.4 mg/L
• Lambda ()
• 95% reference interval: 5.7–26.3 mg/L
• / ratio
• Normal range: 0.26–1.65
• Renal range: 0.37 – 3.10*
Katzmann J, Clin Chem 48: 1437, 2002
*Hutchison C , BMC Nephrol, 2008
Renal Reference Range
• In renal failure, clearance slows for κ and
• Reference range in normal renal function: 0.26–1.651
• Renal reference range for κ/ ratio: 0.37–3.12,3
• Improved specificity from 93% to 99%
1 Katzmann et al. Clin Chem. 2002;48:1437-1444
2 Hutchison et al. BMC Nephrol. Sept. 2008;9:11
3 Wells et al. Clin Chem 2008 C-91.
Renal Ranges for sFLC
Hutchison et al. BMC Nephrol. Sept. 2008;9:11
0.26–1.65
0.37–3.1
normal
MM
RF
Case Studies
Case #1
• PATIENT HISTORY: A 41 year old businessman from San Diego CA, an avid golfer who loves to engage in playful rough-housing with his 8 year old son, experienced sudden excruciating pain in his mid back during a spirited wrestling match. He iced the injury and took to his bed for a couple of days. Noticing no improvement after exhausting his supply of Vioxx (leftover from a prescription 2 years earlier for a golf injury where he threw his back out), he went to see his primary care physician.
• A Skeletal survey revealed a sizable solitary bone lesion in T11 of his thoracic vertebrae.
• A bone marrow biopsy showed 35% plasma cells in the marrow. Other tests gave the following results:
Calcium: 10.0 mmol (nr = 2.25-2.75)Serum creatinine: 1.2 mg/dL (nr = 0.8 to 1.4 mg/dL)Hemoglobin: 13.0 gm/dL (Female: 12.1 to 15.1 gm/dL; Male: 13.8 to 17.2 gm/dL)
Free Kappa () – 7.2 mg/L (nr = 3.3-19.4 mg/L)Free Lambda () – 607.3 mg/L (nr = 5.7-26.3 mg/L)Ratio (/) – 0.012 (nr = 0.26 – 1.65), (normal renal ratio range = 0.37–3.1)
SPEP
sIFE Example (normal sIFE)
Based on the data presented, what do you think is wrong with this patient?
IIMM- IgG-
(Intact Immunoglobulin multiple myeloma; IgG heavy chain; lambda light chain)
Rationale: Bone lesions, Hypercalcemia, 35% plasma cells in marrow. Classic sharp M spike in gamma region on SPEP. Clear banding in IgG and lanes on sIFE. Results confirmed by Freelite testing.
Conclusion
Case #2
• PATIENT HISTORY: A 68 year old woman from Seattle WA, who enjoys bird watching and trips to the wine country with her husband, and has been fit and generally very healthy all her life, presented with a fractured rib following mild trauma. Over the following months, the pain subsided but she reported feeling breathlessness, vague chest pains and tiredness. Full blood counts, blood biochemistry and chest X-rays all appeared normal at this time. Her symptoms persisted and 9 months after initial presentation, bone scans and X-rays revealed extensive osseous lesions. A bone marrow biopsy showed 72% plasma cells in the marrow. Other tests gave the following results:
• Calcium: 4.05 mmol (nr = 2.25-2.75)
• Serum creatinine: 1.0 mg/dL (nr = 0.8 to 1.4 mg/dL)
• Hemoglobin: 10.7 gm/dL (Female: 12.1 to 15.1 gm/dL; Male: 13.8 to 17.2 gm/dL)
• Free Kappa () – 30 mg/L (nr = 3.3-19.4 mg/L)• Free Lambda () – 6.5 mg/L (nr = 5.7-26.3 mg/L)• Ratio (/) – 4.6 (nr = 0.26 – 1.65), (normal renal ratio range
= 0.37–3.1)
Higher risk of malignant plasma cell disorder is associated with more extreme / ratio
0.05 0.26 1.65 5.0 10.0
Very Low LikelyPossiblePossible InconclusiveLikely
/ ratio :
Risk :
Vermeersch Clin Chem Acta 2009 410: 54-58
0.001 0.26 1.65 1000
Lambda secretor Normal Kappa Secretor
/ ratio
Katzmann J, Clin Chem 2002 48: 1437
SPEP – (No evidence of M protein or unusual banding)
sIFE (Example- normal sIFE )
Based on the data presented, what do you think is wrong with this patient?
Hyposecretory (or Oligosecretory) MM
Rationale:
SPEP and sIFE were both negative. Extensive bone lesions with high calcium, 72% plasma cells in marrow. Freelite analysis showed modest elevation of kappa light chains with / ratio of 4.6 (nr= 0.26-1.65)
Conclusion
Case #3• PATIENT HISTORY: A 72 year old Caucasian male went to see his primary care physician with debilitating bone and joint pain. He had been receiving treatment for several years for a number of chronic conditions, including skin rashes, rheumatoid arthritis and osteoporosis. A comprehensive metabolic panel was run and all test results were found to be normal. There was no evidence of renal impairment, although the patient had been previously diagnosed with congenital multiple renal cysts.
Additional testing was ordered including serum immunofixationelectrophoresis (sIFE) and serum protein electrophoresis (SPEP). The sIFEresults showed no abnormality, but the SPEP demonstrated a broad diffuse area in the gamma region that was initially reported by the lab to be suspicious but 'not clearly monoclonal'. The patient was diagnosed with a monoclonal gammopathy based on these laboratory results. The patient’s physician placed a standing order for SPEP testing to occur every month in order to monitor the patient. The laboratory noticed the frequency of orders as well as the ambiguous finding that lead to the diagnosis of monoclonal gammopathy and recommended serum free light chain testing.
Based on all the findings presented, do you think this patient received a correct diagnosis?
Freelite Results
• Free Kappa () – 250.3 mg/L (nr = 3.3-19.4 mg/L)• Free Lambda () – 134.7 mg/L (nr = 5.7-26.3 mg/L)• Ratio (/) - 1.86 (nr = 0.26 – 1.65), (normal renal ratio range
= 0.37–3.1)
Conclusion
Rationale:Osteoporosis can be a presenting sign of MM or related disorder, especially when found in atypical patients such as men and younger pre-menopausal women. However, the sFLC results indicated that this patient had significantly elevated levels of both kappa and lambda light chains and a marginally abnormal κ/ ratio just above the reference range. In polyclonal gammopathy, intact Igs and sFLCs are both elevated, which may explain the presence of the diffuse broad band in the gamma region of the SPEP gel. Based on this patient’s history, this most likely resulted from chronic inflammation. The unique ability of sFLC testing to differentiate between monoclonal and polyclonal gammopathy helped overturn an initial mis-diagnosis in this case amending the final diagnosis to polyclonal hypergammaglobulinemia caused by inflammation.
Initial diagnosis of monoclonal gammopathy was wrong. Freelite testing confirmed this patient had polyclonal (as opposed to monoclonal) gammopathy.
Questions?