To the editor:

We were interested to read the communication from Singhal et al.1  However, there is a misconception that serum free light chain (sFLC) measurement should provide the most sensitive measure of residual disease in all multiple myeloma patients. This appears to have arisen because normalization of the sFLC ratio has been included as one of the criteria necessary for achieving a “stringent complete response” in the proposed international response criteria.2 

In fact, sFLC measurement provides a more sensitive measure of residual disease in some, but not all, myeloma patients. For patients whose tumors produce monoclonal light chains only (LCO), sFLC measurement will generally be more sensitive because (1) serum protein electrophoresis and immunofixation electrophoresis (IFE) are poor at detecting FLC, and (2) the sensitivity of urinalysis is restricted by the kidneys' capacity for reabsorbing and catabolizing FLC.3  Retrospective studies showed sFLC measurement could have aided diagnosis and monitoring in 19 of 28 nonsecretory myeloma patients4  and 224 of 224 LCO myeloma patients.3  Twenty-six of 82 non-intensively treated LCO patients became IFE-negative in the urine, but 17 of these 26 patients had abnormal sFLC, indicating their maximum response was a partial response (PR) rather than complete response (CR).3  Prospective study of 223 LCO patients in the MRC Myeloma IX trial showed 16 of 69 patients who had a PR by sFLC were IFE-negative in the urine. Furthermore, in 12 of 42 LCO patients, progression was detected by sFLC before their urine became IFE-positive.5  In the same prospective study, light chain escape occurred in 5.3% IgG patients and 14.8% IgA patients.

However, for patients producing monoclonal intact immunoglobulins, the relative sensitivity of IFE and sFLC measurement will depend upon the quantities of protein being produced. It has previously been reported that approximately 5% of myeloma patients with monoclonal intact immunoglobulin produce no detectable monoclonal sFLC at presentation.6,7  FLC ratios are only likely to be the more sensitive marker of residual disease in patients who have a relatively high production of FLC and certainly not in the approximately 5% of patients who apparently produce none.

A preliminary study by Kumar et al8  has indicated that normalization of the sFLC ratio is a meaningful measure, associated with superior overall survival in myeloma patients achieving an IFE-negative response. For myeloma patients with monoclonal intact immunoglobulin and FLC, the persistence of abnormal sFLC, after becoming negative by IFE, could indicate the presence of tumor cells producing more FLC than intact immunoglobulin. Alternatively, it could result from the presence of a subclone of tumor cells producing FLCs only.9  This latter phenomenon is more familiar when it is manifested at relapse as light chain escape.

Singhal and colleagues were right to highlight the more rapid falls shown by sFLC in response to successful therapy, which is due to the much shorter serum half-life of FLC (4-6 hours) compared with intact immunoglobulin (∼ 6 days IgA, ∼ 21 days IgG). However, it is wrong to conclude that normalization of the sFLC ratio will invariably predict an IFE-negative response.

Authorship

Conflict-of-interest disclosure: G.P.M. is an employee of The Binding Site, who manufacture assays for free light chain measurement. M.T.D. declares no competing financial interests.

Correspondence: Graham Peter Mead, University of Birmingham and The Binding Site, PO Box 11712, Birmingham, United Kingdom; e-mail: g.p.mead@bham.ac.uk.

References

References
1
Singhal
 
S
Vickrey
 
E
Krishnamurthy
 
J
Singh
 
V
Allen
 
S
Mehta
 
J
The relationship between the serum free light chain assay and serum immunofixation electrophoresis, and the definition of concordant and discordant free light chain ratios.
Blood
2009
, vol. 
114
 
1
(pg. 
38
-
39
)
2
Durie
 
BGM
Harousseau
 
JL
Miguel
 
JS
, et al. 
International uniform response criteria for multiple myeloma.
Leukemia
2006
, vol. 
20
 
9
(pg. 
1467
-
1473
)
3
Bradwell
 
AR
Carr-Smith
 
HD
Mead
 
GP
Harvey
 
TC
Drayson
 
MT
Serum test for assessment of patients with Bence Jones myeloma.
Lancet
2003
, vol. 
361
 (pg. 
489
-
491
)
4
Drayson
 
M
Tang
 
LX
Drew
 
R
Mead
 
GP
Carr-Smith
 
H
Bradwell
 
AR
Serum free light chain measurements for identifying and monitoring patients with nonsecretory multiple myeloma.
Blood
2002
, vol. 
97
 
9
(pg. 
2900
-
2902
)
5
Drayson
 
MT
Morgan
 
GJ
Jackson
 
GH
, et al. 
Prospective study of serum FLC and other M-protein assays: when and how to measure response? [abstract].
Clin Lymphoma Myeloma
2009
, vol. 
9
 
S1
 
Abstract 346
6
Mead
 
GP
Carr-Smith
 
HD
Drayson
 
MT
Morgan
 
GT
Child
 
JA
Bradwell
 
AR
Serum free light chains for monitoring multiple myeloma.
Br J Haematol
2004
, vol. 
126
 (pg. 
348
-
354
)
7
Snozek
 
CLH
Katzmann
 
JA
Kyle
 
RA
, et al. 
Prognostic value of the serum free light chain ratio in newly diagnosed myeloma: proposed incorporation into the international staging system.
Leukemia
2008
, vol. 
22
 (pg. 
1933
-
1937
)
8
Kumar
 
S
Dispenzieri
 
A
Larson
 
D
, et al. 
Normalization of the serum free light chain (FLC) ratio is associated with superior overall survival among myeloma patients achieving immunofixation negative state: results support incorporation of serum FLC ratio in stringent CR definition [abstract].
Blood
2008
, vol. 
112
  
Abstract 1692
9
Ayliffe
 
MJ
Davies
 
FE
de Castro
 
D
Morgan
 
GM
Demonstration of changes in plasma cell subsets in multiple myeloma.
Haematologica
2007
, vol. 
92
 
8
(pg. 
1135
-
1138
)