How the
biomarkers Freelite® and Hevylite® can
illuminate what is going on in a myeloma
patient’s bone marrow
Judith A. Finlay, Ph.D.
Director of Scientific Affairs
The Binding Site, Inc.
San Diego, CA
800-633-4484 X335
Some of the subject matter and data contained or addressed in the following
presentation may involve off-label or forward-looking use of Freelite® or Hevylite®
kits, and other Binding Site products. As such, no off-label use of Freelite, Hevylite
or other Binding Site products can be supported by Binding Site Inc.
Immunoglobulin and Free Light Chain
Production by Plasma Cells
Kappa
Lambda
Multiple Myeloma – Diagnosis
1. Monoclonal protein in either serum
or urine (or abnormal FLC ratio)
2. >10% plasma cells in the bone
marrow
3.
End Organ Damage (CRAB)
Calcium elevation in the blood
(hypercalcaemia)
Renal Insufficiency (kidney
damage)
Anaemia (blood disorder)
Bone lesions (bone damage)
MGUS (1 only)
Smoldering
MM
(1 + 2)
MM (1 + 2 + 3)
Involved and uninvolved
FLC
IgAk MM patient
Involved light chain is k
Uninvolved light chain is l
Elevated (NR) involved kappa light chain (and
ratio): clonal process
• Suppressed (NR) lambda light chain:
immunosuppression
• Use of involved/uninvolved allows grouping of
•
•
•
•
o Kappa
o Lambda
New IMWG MM Criteria
Previous IMWG Criteria
New IMWG Criteria
Kyle – Leukemia 2009;
Dimopoulos – Blood 2011
Rajkumar – Lancet Oncology 2014
Clonal bone marrow plasma cells ≥10%
Clonal bone marrow plasma cells ≥10% or biopsyproven bony or extramedullary plasmacytoma
PLUS
Presence of serum and/or urinary monoclonal protein
(except in patients with nonsecretory myeloma)
PLUS
Evidence of end-organ damage that can be attributed
to the underlying plasma cell proliferative disorder:

Hypercalcaemia

Renal insufficiency

Anaemia

Bone lesions
“the requirement for monoclonal protein presence as
part of the diagnostic criteria is not mandatory”
PLUS
Evidence of end-organ damage that can be attributed
to the underlying plasma cell proliferative disorder:

Hypercalcaemia

Renal insufficiency

Anaemia

Bone lesions
OR
One or more biomarkers of malignancy:

Clonal bone marrow plasma cells ≥60%

Involved:uninvolved sFLC ratio ≥100

>1 focal lesion on MRI studies
What is HevyLite?
• Hevylite antibodies
(assays) recognize
conformational
epitopes between
heavy and light chains
• Can distinguish:
o IgAk v. IgAl
o IgGk v. IgGl
o IgMk v. IgMl
Normal ranges for Hevylite
IgG kappa (g/L)
IgG lambda (g/L)
Gk/Gl ratio
3.84 – 12.07
1.91 – 6.74
1.12 – 3.21
IgA kappa (g/L)
IgA lambda (g/L)
Ak/Al ratio
0.57 – 2.08
0.44 – 2.04
0.78 – 1.94
IgM kappa (g/L)
IgM lambda (g/L)
Mk/Ml ratio
0.19 – 1.63
0.12 – 1.01
1.18 – 2.74
Changes in HLC ratio are the result of both involved and uninvolved immunoglobulin
concentrations
Involved vs uninvolved
HLC pair
•
•
•
•
IgAk MM patient
Involved HLC isotype: IgAk
Uninvolved HLC isotype: IgAl
Immunosuppression (NR) can be in:
o Uninvolved HLC isotype: IgAl
o Systemic immunoglobulin suppression: IgG + IgM
o Both
Suppression of Uninvolved
Immunoglobulins is associated with
Reduced Overall Survival
500 patients
One Center
Strictly followed
60 vs 25 months, p<0.001)
independent of other common
prognostic factors
Kastritis - Leukaemia 2014
Uninvolved Heavy-light chain pair suppression is
associated with Reduced Overall Survival
100 IgAk MM
</>0.18 g/L IgAl
P = 0.002
38 vs 54 mo
50% decrease from the
lower limit of normal
57 IgAl MM
</>0.24 g/L IgAk
P = 0.03
35 vs 47 mo
Unanswered question: What is
best?
uninvolved HLC pair
suppression
or systemic
immunosuppression?
Boyle Cancer 2014
HLCR detects relapse 1st
HL+FL
FL
suppressed suppressed
h
l
h
l
l
h
l
h
h
l
h
l
h
l
l
HLR elev
1st relap?
h
l
h
l*
h
l
l
l
l
h
l
h
l
l
5 ½ months
HLC ratio became abnormal indicating relapse when IFE was still normal
Laboratory relapse was confirmed by IFE
Later clinical relapse was noted.
Ludwig Leukemia 2013
l
l
Summary
• Freelite and Hevylite both give information about
o Clonal plasma cells (involved chains)
o Rest of the immune system/marrow (uninvolved chain/pair)
• IMWG: iFLCR>100 is a myeloma defining event
• Immunosuppression: poor prognosis in MM
o Systemic
o FLC
o HLC pair suppression
• Can following immunosuppression lead to better
patient care?