FLC monitoring in Multiple Myeloma

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FLC monitoring in Multiple Myeloma Dr Guy
Pratt Consultant Haematologist Birmingham Heart
of England NHS Trust Senior Lecturer in
Haematology University of Birmingham
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• Several potential advantages for using FLC
• assays in monitoring multiple myeloma?
• Clear advantages in light chain only,
  non-secretory
• and oligo-secretory multiple myeloma
• Short half-life (hours) compared to intact
  immunoglobulin - allows earlier detection of
  response
• For a minority of patients it can identify
  relapse earlier

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• What to monitor?
• What is the best predictor of response?
• Could look at..
• involved serum FLC alone (iFLC)
• Ratio of involved to uninvolved FLC (rFLC)
• Difference between involved and uninvolved FLC
  (dFLC)
• dFLC also incorporated into response criteria
• (Gertz et al, 2005 Durie et al, 2006) and shown
  to be predictive of response (Dispenzieri et al,
  2008)
• ..probably best to look at all three parameters

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What are the minimal values of FLC to be deemed
evaluable? gt 100mg/l (0.1 g/L) Gertz et al,
2005 gt 100mg/L (0.1g/L) Durie et al, 2006 gt
50mg/L (0.05g/L) with an abnormal FLC ratio
Dispenzieri et al 2008
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Monitoring of Light chain only multiple
myeloma(Bence Jones myeloma)15 of
myelomasWorse prognosisdue to higher levels of
light chain compared with intact immunoglobulin
myeloma and increased renal failure
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FLC levels increase in renal failure and in
polyclonal B cell stimulation seen in a wide
range of conditions
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• Serum FLC assays are more sensitive than urine
• Poor correlation The amount of FLC in the urine
  will depend on renal function. Renal function
  often alters during the course of myeloma. Serum
  FLC ratio will be unaffected by changing renal
  function
• Defining response With normal renal tubular
  absorption the urine may appear negative for FLC
  when serum FLC is still abnormal. In 82 MRC trial
  patients serum FLC normalised in
• 9 patients (11) while urine FLC normalised in
  26 patients (32). Serum FLC incorporated into
  new response criteria (Durie et al, 2006)
• 3) Errors and failure to collect urine
• Still need 24 hour urine to quantify proteinuria

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Nonsecretory multiple myelomaAbsence of
monoclonal paraprotein byconventional serum and
urine electrophoresis1-3 of myelomasOnly
25-35 are truly non-secretory
Blood 2001 97 2900-2902
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Non-secretory myeloma 19/28 (68) had
identifiable tumour FLC, 4/28 (14) had
abnormally low FLC and 5/28 had normal FLC (18)
Blood 2001 97 2900-2902
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Can be use to monitor disease in patients with
non-secretory myeloma
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Oligosecretory multiple myeloma Defined as
myeloma with a paraprotein of lt10g/L (Durie et
al, 2006)
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Poor correlation between the concentration of
tumour FLC and the tumour monoclonal intact
paraprotein
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A minority of myelomas have a paraprotein level
of less than 10g/L (so-called oligosecretory
myeloma)If the serum FLC is gt100mg/L in these
myeloma cases then serum FLC should be used to
monitor disease(Durie et al, 2006)
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What about the monitoring of intact
immunoglobulin multiple myeloma (paraprotein
gt10g/L)?
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• Several potential advantages for using FLC assays
  in monitoring intact immunoglobulin myeloma?
• Specific for tumour, abnormal in gt90 of cases
• Short half-life may allow earlier detection of
  response.
• For a minority of patients it can identify
  relapse earlier

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95 (508/535) of patients with intact Ig
monoclonal proteins had abnormal serum FLC
concentrations Brit J Haem.2004 126, 348-354.
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Theoretical serum half-lifes for immunoglobulin
molecules short half life of kappa and lambda
Acknowledge Keith Godfrey, Ying Hu, Neil Evans,
Michael Chappell
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Recycling of IgG
Fluid phase uptake
Endothelial cell
FcRn binds IgG inside endosome
Bound IgG is recycled
Degradation
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Acknowledge Keith Godfrey, Ying Hu, Neil Evans,
Michael Chappell
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Are there potential BENEFITS of rapid assessment
to chemotherapy in multiple myeloma? HALTING
treatment earlier by identifying plateau phase
earlier Rapidly identifying responding patients
who need to CONTINUE treatment and predicting
their response. Rapidly identifying patients who
need to CHANGE treatment when FLC shows minimal
change. Important with acute renal failure.
Not a new concept McLaughlin and Alexanian 1982
24 hour urine assessments
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Concentrations of free light chains (FLC) after
stem cell transplantation in a patient with
Plasma cell leukaemia (lambda)
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Brit J Haem.2004 126, 348-354.
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Brit J Haem.2004 126, 348-354.
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The serum free light chain ratio after one or two
cycles of treatment is highly predictive of the
magnitude of the final response in patients
undergoing initial treatment for multiple myeloma
Hassoun et al ASH, Atlanta 2005. BJH 2006
Adriamycin Dexamethasone x 1 cycle
CR, PR, SD
Adriamycin Dexamethasone x 2 cycles
Thalidomide Dexamethasone x 2 cycles
PD
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42 patients evaluable 37 with abnormal FLC ratio
at baseline Normalisation of ratio after 1-2
cycles occurred in 7/15 achieving CR compared
with 1/22 achieving PR, SD or PD. Decrease in
M-spike by over 50 after 1-2 cycles was not
significantly associated with a response of CR
or nCR. Suggests that monitoring FLC ratio after
two cycles may identify some, but not all, of the
patients who are going to achieve CR
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Dispenzieri et al 2008- Appraisal of
immunoglobulin free light chain as a marker of
response 653 patients gt50mg/L involved FLC with
an abnormal FLC ratio deemed evaluable FLC
response at 2 months predicted overall response
better than M-protein but did not predict OS or
PFS 40-50 reduction in the derived FLC
(involved FLC minus uninvolved FLC) best
predictor of response Poor correlation between
changes in 24 hour urinary FLC and changes in
serum FLC
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Rapid identification of non-responding patients
using serum FLC assay Avoid unnecessary toxicity
from prolonged ineffective treatment Switching
to a more effective treatment is particular
important in attempting to salvage renal function
in myeloma kidney. Switching to a more effective
treatment earlier likely to benefit patients in
reducing myeloma related morbidity and mortality

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Concentrations of free light chains (FLC) after
stem cell transplantation in a patient with
Bence-Jones myeloma (kappa)
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IgG k monoclonal protein
l free light chain
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Monitoring patients on bortezomib treatment
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Monitoring patients on bortezomib treatment
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• Does serum FLC have an role in detecting relapse
  earlier?
• For the majority of intact immunoglobulin
  multiple myelomas NO
• However for a minority may allow earlier
  detection of relapse if
• Rapidly changing disease when rising IgG
  paraprotein may be obscured by initial falling of
  IgG paraprotein from treatment
• Differences in the relative production of tumour
  intact immunoglobulin and tumour FLC may mean one
  marker is detectable earlier
• Light chain breakthrough ?commoner with newer
  agents

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Dual plasma cell subsets
Stain with
Plasma cell Populations
Ayliffe Haematologica 2007 92 1135 - 1138
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Onkologie 2005 28 (suppl 3) 165.
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Haematologica (2008) 93 Abst 672
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Haematologica 20072(s2)p205, PO1016.
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Haematologica 20072(s2)p205, PO1016.
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Conclusions Serum FLC assays allow better
monitoring of response in light chain only
multiple myeloma, non-secretory multiple myeloma,
AL amyloid and oligo-secretory multiple
myeloma. The involved FLC needs to be
gt50-100mg/L change in the difference between
involved and uninvolved FLC is probably the best
predictor of response Serum FLC following
chemotherapy does allow rapid and earlier
assessment of response probably most useful in
identifying non-responding disease. Serum FLC
may allow earlier detection of relapse in some
patients