Incidental finding of monoclonal gammopathy in blood donors: a follow-up study

Abstract

Background.

The incidental finding of monoclonal immunoglobulin in the sera of healthy blood donors is a relatively frequent event and in such cases the subjects are commonly deferred permanently from donating blood. However, no follow-up studies of these cases have been published so far.

Materials and methods.

Since 2000, all regular blood donors at Trieste Blood Bank have undergone annual screening by serum protein electrophoresis. Cases presenting with monoclonal gammopathy between January 2000 and December 2008 were registered and follow-up was performed until December 2010.

Results.

Out of 8,197 regular blood donors, monoclonal gammopathy was detected in 104 subjects (1.3%). The median age at detection was 53 years, the median monoclonal protein concentration was 0.2 g/dL and the cumulative follow-up of these cases amounted to 763 person/years. In two cases asymptomatic multiple myeloma was diagnosed within 6 months of detection of the gammopathy and in 14 cases, the monoclonal gammopathy was transient. The remaining 88 cases were classified as having monoclonal gammopathy of undetermined significance (MGUS). Out of these, two events related to monoclonal gammopathy were observed during the follow up: one lymphoma and one light chain deposition nephropathy.

Discussion.

According to current prognostic staging systems, the majority of blood donors with monoclonal gammopathy were classified as having low-risk MGUS and had a very low incidence of lymphoproliferative diseases. Permanent deferral of blood donors with stable MGUS causes about a 1% loss of potential blood donations and it represents a “precautionary measure” that needs to be substantiated and validated.

Introduction

The incidental finding of monoclonal immunoglobulin (M-protein) during routine serum protein electrophoresis in healthy adults is a relatively frequent event. Its frequency increases with age reaching a prevalence rate of 1.7% in subjects 50–59 years of age and over 5% among people older than 70 years¹. The presence of M-protein in the serum may occasionally be the first manifestation of a concomitant lymphoproliferative disease such as multiple myeloma (MM), Waldestrom’s macroglobulinaemia, lymphoma or AL amyloidosis.

In the great majority of cases, however, monoclonal gammopathy is not accompanied by any physical sign or laboratory abnormality. These cases are defined as monoclonal gammopathy of undetermined significance (MGUS). However, subjects with MGUS do have, on average, a 1% per year lifelong risk of progression to MM or other lymphoproliferative disease².

Since January 2000 all regular blood donors at Trieste Blood Bank have been periodically tested by serum protein electrophoresis. Starting from 2005 this test was introduced by Italian law among the standard annual tests for all regular blood donors. This universal screening resulted in the not uncommon incidental detection of monoclonal gammopathy in healthy, relatively young subjects. The management and counselling of these cases has, therefore, become routine in blood collection centres. It has been suggested that all monoclonal gammopathy carriers should be permanently deferred from blood donation^3,4. This policy is widely applied in Italy⁵ and elsewhere in Europe⁶, and was also adopted in Trieste Blood Bank in mid 2010 following an expert panel meeting at a regional level.

After 11 years of observations we retrospectively analysed the incidence and follow-up data of our blood donors with an incidental finding of monoclonal gammopathy in order to assess the risk of evolution to MM or to other lymphoproliferative diseases in this selected population.

Materials and methods

All regular, whole blood donors at Trieste Blood Bank who underwent serum protein electrophoresis between January 2000 and December 2008 were included in this study.

The method used for the serum protein electrophoresis was cellulose acetate electrophoresis (Jookoo CTE 5000, Chemetron, Tokyo, Japan) until mid 2003 and capillary electrophoresis thereafter (Capillarys, Sebia, Norcross, GA, USA). The immunofixation assay for the identification of gammopathies was the Paragon system (Beckman Instruments Inc., Fullerton, CA, USA) until mid 2003 and Hydrasys (Sebia, Norcross, GA, USA) thereafter.

All donors who had an M-protein or other haematological abnormality were routinely followed up by the Blood Bank’s haematology consultants and any relevant clinical information recorded up to December 2010. All data were extracted retrospectively from the Blood Bank’s database and then entered into Epi info 2000 (CDC Atlanta) for further analysis.

Cases of MGUS, MM and other related monoclonal gammopathies were diagnosed in accordance with diagnostic criteria presented in detail elsewhere⁷. In brief, MGUS was defined as a monoclonal gammopathy with M-protein concentration <3 g/dL, and no “CRAB” sign. “CRAB” is an acronym that encompasses the presence of any of the following: calcium elevation (>2.75 mmol/L), renal dysfunction (creatinine >173 mmol/L), anaemia (haemoglobin <10 g/dL), bone disease (lytic lesions or pathological fracture). The diagnosis of MGUS also requires the absence of any B-cell lymphoproliferative disorder and, in the case that a bone biopsy is performed, that plasma cells account for <10% of bone marrow cells.

Results

Incident cases

From 1 January 2000 to 31 December 2008, serum electrophoresis was conducted on 28,211 serum samples from 8,197 regular whole blood donors attending Trieste Blood Bank. Out of these donors, 5,535 were male (67.5%), with a mean age of 45 years, and 2,662 were female (32.5%), with a mean age of 41 years. The age range of all tested subjects was 18–67 years. A monoclonal gammopathy was detected at some point of the study in 104 donors, of whom 86 (82.7%) were males. In 61 (58.7%) donors the monoclonal gammopathy was detected at the first available serum electrophoresis, whereas in the other 43 (41.3%) it was detected during following investigations, for a cumulative prevalence of 1.3% among all tested donors. Most of the M-proteins were IgG type (73.1%), followed by IgM (14.4%) and IgA (11.5%), with only one case of IgD. In two cases the gammopathy was biclonal, one with both IgG κ and λ and the other with both IgM κ and λ. Overall, M-proteins presented κ light chains in 66 (63.5%) cases and λ light chains in 38 (36.5%) cases. The M-protein concentration was available for 95 cases; in the remaining 9 cases, including five with IgA monoclonal gammopathy, accurate dosage was not possible because of the overlapping of other serum protein fractions.

The median concentration of the M-protein was 0.2 g/dL at first detection (mean 0.3 g/dL; range 0.1–1.4 g/dL). Information on Bence-Jones protein in the urine was available for 85 donors out of whom eight (9.4%) were positive.

Follow up

The median clinical follow up for all monoclonal gammopathy carriers since first M-protein detection was 92 months (mean 88, range 24–131) for a cumulative observation of 763 person-years. Fourteen (13.5%) subjects found to have monoclonal gammopathy became definitely negative in subsequent follow-up tests. These subjects were classified as having “transient” monoclonal gammopathies and were excluded from further analysis. They were all healthy at the end of follow up and they were readmitted to blood donation after 1 year of suspension if not deferred for other reasons.

Two asymptomatic blood donors were diagnosed as having “smouldering” MM on the basis of bone biopsies performed 4 and 6 months after the incidental detection of the M-protein. One was a 57-year old man who had IgA κ M-protein monoclonal gammopathy. The serum concentration of the M-protein was not available because of overlapping of other serum proteins but a significant increase of the IgA fraction (1,290 mg/dL) was noted. The other case, a male donor aged 60, presented with IgG κ M-protein in the serum and with Bence-Jones protein in the urine. Also in this case serum M-protein concentration was not available because of overlapping of other serum proteins but total IgG were in the normal range. Both these subjects progressed from having asymptomatic to overt MM and both underwent autologous stem cell transplantation after 6 and 8 years respectively. They were both alive at the end of the follow up.

The remaining 88 subjects with a monoclonal gammopathy fulfilled the clinical diagnostic criteria for MGUS. Of these 88 subjects diagnosed with MGUS, one developed a marginal zone B-cell lymphoma 3 years after detection of the monoclonal gammopathy. This donor was a 50-year old man with an incidentally found IgM M-protein: the initial concentration of 0.3 g/dL increased four-fold up to 1.2 g/dL after 3 years when further investigation revealed a mediastinal lymphomatous mass. Another case of MGUS developed a severe light chain deposition nephropathy that led to renal failure requiring haemodialysis 6 years after the monoclonal gammopathy was first detected. This subject presented at a routine donation control with 1 g/dL IgG serum M-protein and with Bence-Jone proteins in the urine. Further histological investigations in this subject, including bone biopsy, excluded the presence of MM or AL amyloidosis.

In only two other of the 88 MGUS cases were bone biopsies performed and they were both negative for MM (plasma cells <10%) or other malignancy.

During the follow up the M-protein concentration was stable in 48 MGUS cases and increased in the remaining 31 subjects for whom this concentration was known, with a median overall increase of 0.2 g/dL.

Ten (11%) of the subjects with MGUS suffered from major unrelated health adverse events during follow up: two had major ischaemic heart events, requiring coronary by-pass surgery, six developed cancer (3 prostate, 1 colon, 2 bladder) and also underwent surgical treatment, one had severe chronic obstructive pulmonary disease and eventually died of respiratory insufficiency and the fourth subject died in a car accident. Detailed follow-up data on the monoclonal gammopathy carriers are presented in Table I.

Table I.

Follow-up information of blood donors with M-protein in their sera.

All cases of MG n=104
Median follow up	92 months
Median age (range) at the end of follow up	60 years (36–74)
Alive at the end of follow up (%)	102 (98%)
Transient MG n=14
Median age (range) at diagnosis	54 (30–66)
Ig subtype	IgG 13/IgM 1
Median M-protein concentration (range)	0.1 g/dL (0.1–0.4)
Detection at first test	3/14 (21%)
Early detected* MG-related diseases n=2 Smouldering MM
Ig Subtype	IgA, IgG
Age at diagnosis	57–60
Concentration of M-protein	N.A.
Detection at first test	2/2
MGUS n. 88
No evidence of MG-related disease	86
Occurrence of MG-related malignancy	1 (lymphoma)
Occurrence of other MG-related disease	1 (light chain deposition nephropathy)
Median age (range) at diagnosis	53 (28–67)
Ig Subtype	IgG 60 (69%)
	IgM 15 (17.2%)
	IgA11 (12.6%)
	IgD 1 (1%)
Median M-protein concentration at diagnosis (range)	0.2 g/dL (0.1–1.4)
Median M-protein concentration at the end of follow-up (range)	0.4 g/dL (0.1–2.5)
Detection at first test	55/88 (63.2%)
Cumulative person-years of observation	648

Legend: MG: monoclonal gammopathy;

^*Early detected MG-related diseases are considered those occurring during the follow-up within 12 months of the first detection of MG.

Discussion

To our knowledge this is the first detailed follow-up study of healthy whole blood donors with an incidental finding of monoclonal gammopathy.

In two cases the investigations that followed the incidental detection of the M-protein revealed an asymptomatic or “smouldering” MM. Of the remaining 102 cases, one case evolved to a lymphoproliferative disease, and another case progressed to a light chain deposition disease with nephropathy that resulted in renal failure. These observations show that stable MGUS diagnosed in healthy blood donors carries a low risk of malignant progression to MM or other lymphoproliferative diseases. In fact, based on the general rule of, on average, a 1% per year progression rate² we would have expected at least six incident cases of MM or other B-cell or lymphoid neoplasia after the 648 person/years of follow up. Comparing our observations with findings of other, larger studies, our cohort of donors had a significantly lower incidence of MM or other lymphoproliferative diseases compared to cohorts with MGUS diagnosed in clinical settings, i.e. cases of monoclonal gammopathy occasionally detected among subjects tested in clinical laboratory networks. The difference is smaller and not statistically significant when our findings are compared to those in a population-based study (Table II), i.e. cases of monoclonal gammopathy detected during an universal unselected population screening.

Table II.

Characteristics of MGUS cohorts and incidence of multiple myeloma (MM) or other lymphoid cancers (LC) in different studies.

Study	Reference population	N. of subjects	Age at diagnosis	M-protein (g/dL) at diagnosis	Incident MM/LC cases	Person-years of observation	Incidence rate/100 person-years	Difference in incidence from Trieste cohort*
Trieste cohort	blood donors	88	53 median 51 mean	0.2 median 0.3 mean	1	648	0.15	——
Van de Donk 2001 (15)	clinical setting	88	56 median	1.1 median	12	686	1.75	P=0.006
Kyle 2004 (12)	clinical setting	241	64 mean	1.8 mean	64	3,579	1.79	P=0.001
Gregersen 2001 (13)	clinical setting	1,247	68 mean	0.7–1.5 median	107	6,802	1.57	P=0.002
Kyle 2002 (2)	clinical setting	1,384	72 median	1.2 median	115	11,009	1.04	P=0.03
Rossi 2009 (16)	clinical setting	905	63 median	32% >1.5	77	6,467	1.19	P=0.01
Bida 2009 (9)	population based	605	70 mean	0.5 median	77	14,373	0.54	P=0.26

Legend:

^*Mid-P exact (2 tailed).

In general, it can be said that blood donors are a positively “selected” population, younger and healthier at the time of diagnosis compared to the MGUS cohorts described in other studies. This may also explain the lower average M-protein concentration observed in our study compared to those in previous studies^2,8,9–15.

As mentioned above, we excluded the two cases of smouldering MM, whose diagnoses based on bone biopsy were confirmed 4 and 6 months after the first detection of the M-protein, from the analysis of incident monoclonal gammopathy-related diseases. In accordance with other study case definitions^8,10,16, cases of MM diagnosed within 12 months of first detection of M-protein are considered MM since the beginning and not the result of progression.

The fact that the monoclonal gammopathy disappears in 13.5% of cases during the follow up is compatible with the recognised phenomenon of “transient” monoclonal gammopathies^11,17,18, which are possibly associated with a variety of viral infections and drug treatments.

Given the low proportion of bone biopsies performed on our confirmed cases of monoclonal gammopathy (6 out of 88) we cannot exclude that some of our cases of “stable” MGUS may have met the histological criteria for smouldering myeloma, i.e. >10% plasma cells in the bone marrow. However, in accordance with current clinical practice^2,19,20, this invasive procedure should be motivated by the presence of either suspicious clinical findings, such as “CRAB” signs, or a high-risk profile, such as an M-protein value higher than 1.5 g/dL. This was not the case in the great majority of the blood donors included in our study.

Several factors have been found to be useful in the risk stratification of MGUS patients. Non-IgG M-protein, higher M-protein concentration (>1.5 g/dL), altered ratio of κ/λ free light chains, progressively increasing M-protein value, presence of light chain proteinuria, reduced serum polyclonal immunoglobulin level, and greater than 5% marrow plasmacytosis have been independently associated with a higher risk of progression to MM or other lymphoproliferative disease^{10,13,14,16,19,21–23}.

Our study shows that, in the great majority of cases, an incidental finding of MGUS in a selected and relatively young population, such as blood donors, is associated with a low-risk profile and, therefore, a very low rate of progression to lymphoproliferative disease.

In our experience permanent deferral of regular blood donors with MGUS is likely to cause a reduction of about 1% of blood donations. This should be justified by evidence of potential harm to the donor or to the blood component recipient. To our knowledge there is no study that either prospectively or retrospectively shows that either of the two, harm to the donor or to the recipient, does occur. The permanent deferral of blood donors with stable MGUS is, therefore, a “precautionary measure” that waits to be substantiated and validated.