Approximately 20% of patients with multiple myeloma do not produce an entire immunoglobulin molecule, but only the light chain, either "kappa" or "lambda". Typically, these patients do not have an M spike in their blood, but only in their urine. The best tumor markers in light chain myeloma are the serum free light chains and the urine M component.
Light-chain only multiple myeloma is due to
the absence of functional (productive) rearrangement of the IgH gene at the DNA
Blood. 2004 May 15;103(10):3869-75.
Magrangeas F, Cormier ML, Descamps G, Gouy N, Lodé L, Mellerin MP, Harousseau JL, Bataille R, Minvielle S, Avet-Loiseau H.
Myeloma cells secreting heavy chains have a legitimate functional IgH rearrangement. Using fiber-fluorescent in situ hybridization, these authors demonstrated that malignant plasma cells of light chain myeloma do not have a functional IgH recombination. One IgH allele has a germline configuration (including the DJ region), and the other allele is involved in an illegitimate recombination. Interestingly, most translocations occurred at or close to the switch regions. Plasma cells of light chain myeloma do not have a legitimate IgH rearrangement at the DNA level, presumably because of an abnormal IgH gene recombination during B-cell maturation.
Serum free light
chains, not urine specimens, should be used to evaluate response in light-chain
Blood. 2016 Dec 22;128(25):2941-2948.
Dejoie T, Corre J, Caillon H, Hulin C, Perrot A, Caillot D, Boyle E, Chretien ML, Fontan J, Belhadj K, Brechignac S, Decaux O, Voillat L, Rodon P, Fitoussi O, Araujo C, Benboubker L, Fontan C, Tiab M, Godmer P, Luycx O, Allangba O, Pignon JM, Fuzibet JG, Legros L, Stoppa AM, Dib M, Pegourie B, Orsini-Piocelle F, Karlin L, Arnulf B, Roussel M, Garderet L, Mohty M, Meuleman N, Doyen C, Lenain P, Macro M, Leleu X, Facon T, Moreau P, Attal M, Avet-Loiseau H.
This is a study that prospectively compared results of serum and urine specimen in the context of the 2009 IFM myeloma trial. The authors showed that in 113 patients with light chain myeloma, serum free light chains (FLC) were superior to urine methods (UPEP and uIFE) in the monitoring the response to therapy. Serum FLC had superior sensitivity and prognostic value. At baseline, FLC were abnormal in 100% of patients, whereas a measurable urine M component (>200 mg/24 hours) by UPEP was observed in only 64% of cases. After 3 cycles of chemotherapy, serum FLC remained elevated in 46% of patients, and urine M only in 18% (and all patients with positive UPEP had elevated serum FLC). The authors concluded that urine tests underestimated the amount of FLC production, and overestimated the response to chemotherapy. Progression-free survival after 3 cycles of chemotherapy was shorter in patients with elevated serum FLC, but not with positive UPEP or uIFE. Serum FLC levels are preferred over urine FLC, which are more erratic, presumably because of the variable urine excretion rate of the FLC among different individuals.
IgD myeloma accounts for 3% of myeloma subtypes.
It has a higher incidence of complications, and outcome is poorer than that observed in other myeloma types.
Immunoglobulin D multiple myeloma: presenting
features, response to therapy, and survival in a series of 53 cases.
J Clin Oncol. 1994 Nov;12(11):2398-404.
Bladé J, Lust JA, Kyle RA.
This study evaluates the clinical and laboratory features of 53 patients with IgD multiple myeloma.
Presenting features included:
- Bone pain (72%)
- Extramedullary plasmacytomas (19%)
- Amyloidosis (19%)
- Renal insufficiency (33%)
- Hypercalcemia (22%)
SPEP showed an M spike in only 60% of cases.
Bence Jones proteinuria was present in 96% of cases.
The type of light chain was:
- Lambda (60%)
- Kappa (38%)
- Indeterminate (2%)
Response to therapy did not differ from that observed in other myeloma types, but the median survival was shorter.
IgD multiple myeloma - a clinical profile and
outcome with chemotherapy and autologous stem cell transplantation.
Ann Hematol. 2005 Feb;84(2):115-7.
Wechalekar A, Amato D, Chen C, Keith Stewart A, Reece D.
This study evaluates the clinical features and outcomes of 25 patients with IgD multiple myeloma.
Associated disorders: 1 patient has B-CLL and another patient had hairy cell leukemia.
Cytogenetics: 3 of 9 patients had monosomy 13 (1 by cytogenetics and 2 by FISH), and 2 patients had a complex karyotype.
Outcome was worse than that observed in historical controls with other myeloma types.
Poor outcomes for IgD multiple myeloma patients following
high-dose melphalan and autologous stem cell transplantation: a single center
J Korean Med Sci. 2008 Oct;23(5):819-24.
Chong YP, Kim S, Ko OB, Koo JE, Lee D, Park SH, Park SJ, Lee D, Kim SW, Suh C.
This is a small study comparing outcomes of 8 patients with IgD myeloma vs 69 patients with other types of myeloma. Outcomes after autologous stem cell transplant were inferior among patients with IgD MM:
- The median event-free survival was 6.9 months in IgD MM vs 11.5 months in other types of MM
- The median overall survival was 12 months vs 55.5 months in other types of MM
Immunoglobulin D multiple myeloma: response to therapy,
survival, and prognostic factors in 75 patients.
Ann Oncol. 2011 Feb;22(2):411-6.
Kim MK, Suh C, Lee DH, Min CK, Kim SJ, Kim K, Moon JH, Yoon SS, Lee GW, Kang HJ, Kim SH, Choi CW, Eom HS, Kwak JY, Kim HJ, Mun YC, Bang SM, Lee K, Shin HJ, Lee JH; Korean Multiple Myeloma Working Party.
This is a retrospective analysis of 75 patients with IgD myeloma. Renal insufficiency was present in 53% of them, and hypercalcemia in 27%. Prognosis was relatively poor. At a median follow-up of 29 months, median overall survival was 18.5 months.
Extremely rare (about 0.01% of MM
A characteristic feature of IgE MM is the t(11;14)(q13;q32) translocation.
Skin involvement in immunoglobulin E multiple myeloma.
J Clin Oncol. 2009 Feb 1;27(4):637-8.
Wozney JL, Ahmed F, Bayerl MG, Ehmann WC, Talamo G.
Cases with IgM monoclonal
gammopathy usually develop lymphoplasmacytic lymphoma (Waldenström's
IgM myeloma is very rare, accounting for <0.5% of myeloma subtypes.
IgM myeloma has similar clinical features and outcomes to those seen with the more common subtypes.
The hallmark of Waldenström's macroglobulinemia is the MYD88 mutation (= Myeloid differentiation factor 88). The MYD88 L265P exon 5 mutation promotes the NF-kB signaling through IRAK (interleukin-1 receptor-associated kinase). The mutational status may be useful for discriminating between WM and IgM-MM.
IgM MM can be differentiated from Waldenström's macroglobulinemia based on:
- Presence of lytic bone lesions
- Presence of t(11;14)
- Absence of MYD88 mutation
IgM myeloma: a report of four cases.
Ann Hematol. 2002 Mar;81(3):136-9.
Dierlamm T, Laack E, Dierlamm J, Fiedler W, Hossfeld DK.
14q32 Translocations discriminate IgM multiple myeloma from
Semin Oncol. 2003 Apr;30(2):153-5.
Avet-Loiseau H, Garand R, Lodé L, Robillard N, Bataille R.
This study found the t(11;14) in 7 of 8 cases of IgM myeloma, whereas no case of t(11;14) was found in 17 cases of WM. Therefore, the presence of t(11;14) can be useful in the differential diagnosis of IgM myeloma vs Waldenstrom's macroglobulinemia.
Long-term follow-up of IgM monoclonal gammopathy of
Blood. 2003 Nov 15;102(10):3759-64.
Kyle RA, Therneau TM, Rajkumar SV, Remstein ED, Offord JR, Larson DR, Plevak MF, Melton LJ 3rd.
In this study, no cases of IgM myeloma were observed after following the evolution of IgM MGUS.
After a median follow-up of 6.3 years, 213 patients with IgM MGUS developed:
- Lymphoma (17 patients)
- Waldenström macroglobulinemia (6 patients)
- Primary amyloidosis (3 patients)
- CLL (3 patients)
Cumulative incidence of progression was:
- 10% at 5 years
- 18% at 10 years
- 24% at 15 years
The average risk of progression was 1.5% per year.
IgM myeloma and Waldenstrom's
macroglobulinemia: a distinct clinical feature, histology, immunophenotype, and
Clin Lab Haematol. 2003 Jun;25(3):187-90.
Chehal A, Taher A, Shamseddine A.
Case report of a patient with IgM myeloma.
IgM myeloma: a rare entity characterized by a
CD20-CD56-CD117- immunophenotype and the t(11;14).
Br J Haematol. 2008 Mar;140(5):547-51.
Feyler S, O'Connor SJ, Rawstron AC, Subash C, Ross FM, Pratt G, Drayson MT, Ashcroft J, Cook G, Owen RG.
These authors report 10 cases of IgM myeloma. They conclude that IgM myeloma is characterized by a CD20-, CD56-, CD117- phenotype and the t(11;14) translocation.
Phenotype: 70% had an aberrant phenotype CD19+, CD45+, CD27+ and Cyclin D1+, but all cases were CD56- and CD117-.
FISH: 50% had deletion 13, and 5/8 cases had the t(11;14) translocation. Despite the high incidence of the t(11;14) translocation, CD20 was positive in only 1 of 9 cases.
IgM multiple myeloma: disease definition, prognosis, and
differentiation from Waldenstrom's macroglobulinemia.
Am J Hematol. 2010 Nov;85(11):853-5.
Schuster SR, Rajkumar SV, Dispenzieri A, Morice W, Aspitia AM, Ansell S, Kyle R, Mikhael J.
At the time of its publication, this was the largest series of patients with IgM myeloma (21 patients). The translocation t(11;14) was present in 38% of cases.
of discrimination between IgM Multiple Myeloma and Waldenström
Macroglobulinaemia by testing for MYD88 L265P mutations.
Br J Haematol. 2013 Jun;161(6):902-4.
Willenbacher W, Willenbacher E, Brunner A, Manzl C.
The authors report the presence of typical MYD88 L265P exon 5 mutations in 6 of 7 patients with Waldenstrom macroglobulinemia, and in 0 of 4 patients with IgM myeloma. They conclude that the MYD88 mutational status may be useful for discriminating between WM and IgM-MM.
IgM myeloma: A multicenter retrospective study of 134
Am J Hematol. 2017 Aug;92(8):746-751.
Castillo JJ, Jurczyszyn A, Brozova L, Crusoe E, Czepiel J, Davila J, Dispenzieri A, Eveillard M, Fiala MA, Ghobrial IM, Gozzetti A, Gustine JN, Hajek R, Hungria V, Jarkovsky J, Jayabalan D, Laubach JP, Lewicka B, Maisnar V, Manasanch EE, Moreau P, Morgan EA, Nahi H, Niesvizky R, Paba-Prada C, Pika T, Pour L, Reagan JL, Richardson PG, Shah J, Spicka I, Vij R, Waszczuk-Gajda A, Gertz MA.
The clinical aspects of biclonal gammopathies.
Review of 57 cases.
Am J Med. 1981 Dec;71(6):999-1008.
Kyle RA, Robinson RA, Katzmann JA.
Review of 57 patients with biclonal gammopathy differentiated 3 groups of patients:
1) Biclonal gammopathy of undetermined significance (37 cases, 65%)
Symptomatic myeloma developed after 2 years in 1 case, the others remained stable
2) Lymphoproliferative disease with biclonal gammopathy (11 cases, 19%)
- Waldenström's macroglobulinemia
- Unclassified lymphoproliferative disorders
3) Multiple myeloma with biclonal gammopathy, (9 cases, 16%)
1 patient had osteosclerotic myeloma and sensorimotor peripheral neuropathy
1 patient had plasma cell leukemia
Response to therapy and survival were similar to myeloma with monoclonal proteins.
In many cases, the biclonal gammopathy was recognized only with immunoelectrophoresis, and SPEP produced only a single band on the acetate strip.
Type of biclonal gammopathy:
- IgG + IgA (30 cases, 53%)
- IgG + IgM (15 cases, 26%)
- IgG-kappa + IgG-lambda (6 cases)
- IgA + IgM (3 cases)
- IgA-kappa + IgA-lambda (1 case)
- IgA + IgE (1 case)
-Triclonal gammopathy (1 case)
Immunoglobulin class switch from IgG to IgA in
a patient with smoldering multiple myeloma.
Blood. 1986 Jun;67(6):1710-3.
Takahashi M, Tsukada T, Kojima M, Koide T, Koike T, Takahashi H, Sakai C, Kashimura M, Shibata A.
A patient with smoldering myeloma contained both monoclonal IgG and monoclonal IgA. During the initial 7 months, the monoclonal IgG were predominantly elevated, but during the next 20 months the monoclonal IgA increased and the IgG decreased. The authors analyzed the N-terminal amino acid sequences of heavy and light chains of the monoclonal IgG and IgA. They found that both light chains were lambda proteins with identical amino acid sequences of variable regions, and also that the heavy chains ofIgG and IgA had the same N-terminal amino acid sequence. Therefore, in this patient, IgG and IgA were produced by the same clone of B lymphocytes, and during the course of the disease cells underwent a class switch from IgG to IgA in immunoglobulin production, as seen during B cell differentiation.
Multiple myeloma with serum IgM kappa and
Bence Jones lambda biclonal gammopathy.
Clin Chem. 1986 Dec;32(12):2220-1.
Graziani MS, Lippi U.
The synthesis of the different light chains seemed to occur in separate cellular clones.
Multiple myeloma with serum IgG kappa and
Bence Jones lambda biclonal gammopathy.
Clin Chem. 1987 Jul;33(7):1305-6.
Finco B, Schiavon R.
Clinical characteristics and outcomes in biclonal
Am J Hematol. 2016 May;91(5):473-5.
Mullikin TC, Rajkumar SV, Dispenzieri A, Buadi FK, Lacy MQ, Lin Y, Dingli D, Go RS, Hayman SR, Zeldenrust SR, Russell SJ, Lust JA, Leung N, Kapoor P, Kyle RA, Gertz MA, Kumar SK.
These authors identified 539 patients with biclonal gammopathies. Of these, 393 had BGUS (biclonal gammopathy of undertermined significance), and 22 of this subset of patients progressed to a hematologic malignancy: symptomatic myeloma (11), smoldering myeloma (6), primary amyloidosis (3), or lymphoplasmacytic lymphoma (2). The rate of progression to hematologic malignancy was approximately 1% per year, which is similar to the rate of progression with MGUS. According to this study, the overall clinical significance of a BGUS is very similar to that of MGUS.
Non-secretory myeloma accounts for
approximately 1% of myeloma subtypes.
It is characterized by the absence of detectable monoclonal protein in both serum and urine. The introduction of the serum free light chain assay has allowed to document secretion of light chains in many cases of myeloma previously considered non-secretory, and it is estimated that only about 25% of those cases are truly non-secretory.
Because of the absence of tumor markers, the diagnosis and follow-up of a truly non-secretory myeloma are more difficult than in secretory myeloma. In these cases, PET scan may be the only useful test in establishing the extent of active disease and response to therapy.
A molecular basis for nonsecretory myeloma.
Blood. 2004 Aug 1;104(3):829-31.
Coriu D, Weaver K, Schell M, Eulitz M, Murphy CL, Weiss DT, Solomon A.
This is the first study which proved that the pathogenesis of non-secretory myeloma is related to the synthesis of of an aberrant immunoglobulin polypeptide. In a patient with non-secretory myeloma, the kappa light chain sequence was altered by a frameshift mutation in nucleotides encoding the constant region of the peptide. Because of a 2-base deletion in codon 187 and loss of the normal stop codon, the kappa chain was composed of 128 amino acids instead of the expected 106. The amino acid sequence was completely altered, and the cysteines required for intrachain and interchain disulfide bonds were absent.
Nonsecretory plasma cell myeloma - becoming
even more rare with serum free light-chain assay: a brief review.
Arch Pathol Lab Med. 2006 Aug;130(8):1212-5.
Efficacy and outcome of autologous transplantation in rare
Haematologica. 2010 Dec;95(12):2126-33.
Morris C, Drake M, Apperley J, Iacobelli S, van Biezen A, Bjorkstrand B, Goldschmidt H, Harousseau JL, Morgan G, de Witte T, Niederwieser D, Gahrton G; Myeloma Subcommittee of Chronic Leukaemia Working Party of EBMT.
This is a retrospective analysis from the European Group for Blood and Marrow Transplantation Myeloma Database. The outcome of 976 patients with non-secretory myeloma was similar to that of patients with IgG, IgA, and light chain myeloma. Of note, the outcome of patients with other rare forms of myeloma was poor (the study included 379 patients with IgD, 13 patients with IgE, and 72 patients with IgM).
Clinical course and prognosis of non-secretory multiple
Eur J Haematol. 2015 Jul;95(1):57-64.
Chawla SS, Kumar SK, Dispenzieri A, Greenberg AJ, Larson DR, Kyle RA, Lacy MQ, Gertz MA, Rajkumar SV.
This is an analysis of 124 patients with non-secretory myeloma. Their outcomes were compared to those of 6953 other myeloma patients. Interestingly, for the cohort of 36 patients diagnosed after 2001, the median overall survival of non-secretory myeloma was superior to that in patients with secretory myeloma (8.3 vs. 5.4 years, with a p=0.03).
LIGHT-CHAIN ESCAPE AND NONSECRETORY ESCAPE
In rare cases, myeloma cells stop secreting the entire immunoglobulin molecule, and produce only light chains (= light-chain escape), or stop producing paraproteins (= nonsecretory escape). In these circumstances, the results of the tumor markers may be falsely reassuring to patients and their treating physicians, because they seem to indicate disease remission where, instead, the disease is progressing.
Extramedullary relapse of multiple myeloma associated with a
shift in secretion from intact immunoglobulin to light chains.
Haematologica. 2007 Jan;92(1):143-4.
Dawson MA, Patil S, Spencer A.
'Light-chain escape-multiple myeloma'-an escape phenomenon
from plateau phase: report of the largest patient series using LC-monitoring.
J Cancer Res Clin Oncol. 2009 Mar;135(3):477-84.
Kühnemund A, Liebisch P, Bauchmüller K, zur Hausen A, Veelken H, Wäsch R, Engelhardt M.
Serum free immunoglobulin light chain evaluation as a marker
of impact from intraclonal heterogeneity on myeloma outcome.
Blood. 2014 May 29;123(22):3414-9.
Brioli A, Giles H, Pawlyn C, Campbell JP, Kaiser MF, Melchor L, Jackson GH, Gregory WM, Owen RG, Child JA, Davies FE, Cavo M, Drayson MT, Morgan GJ.
This is a prospective study that observed a "light-chain escape" in 54 of 520 patients with multiple myeloma in progression. Light chain escape occurs when a growing subclone of malignant plasma cells secretes only light chains instead of the entire immunoglobulin molecule. This phenomenon underscores the importance of monitoring light chains during the routine assessment of the response to therapy.
Giampaolo Talamo, M.D.