Light chain multiple myeloma (LCMM)

From Wikilite

8.1. Diagnosis of LCMM using serum free light chains

Figure 8.1 Serum and urine IFE from a patient with λ LCMM compared with FLC immunoassay results. SPE and IFE of (A) serum with no abnormality visible and (B) urine showing a λ FLC band.

Figure 8.2 Serum FLC concentrations in normal individuals, patients with LCMM and patients with renal impairment but no plasma cell dyscrasia (Chapter 20). The diagonal lines separate monoclonal from polyclonal diseases. • Clinical case No 1.

Figure 8.3 Relationship between serum and urine FLCs in 224 patients with LCMM at the time of diagnosis. (A) κ: r=0.29; p=0.0012. (B) λ: r=0.13; p=0.183. Urine FLCs were measured by immunoassay and corrected for urine dilution using creatinine concentrations.

Figure 8.4 Comparison of 24-hour urinary monoclonal protein concentrations and serum FLCs in 2 patients with LCMM, measured at different times after chemotherapy. (Courtesy of RA Kyle and JA Katzmann).

Figure 8.5 Correlation between changes in serum and urine FLCs during the evolution of their disease in 71 patients with LCMM. Initial measurement values were changed to zero and transformed logarithmically for comparison purposes (P=0.0001). (Courtesy of JA Katzmann).

Figure 8.6 Serum and urine FLC levels in a patient with κ LCMM during treatment.

Figure 8.7 Serum and urine FLC levels in a patient with λ LCMM during treatment.

The typical clinical features of LCMM, such as bone pain, fractures, renal failure and anaemia alert the physician to the diagnosis. Bence Jones protein in the urine, in the absence of intact monoclonal immunoglobulins in the serum, alongside a positive bone marrow biopsy, confirm the diagnosis. On occasions, symptoms and signs can be obscure so that urine tests for LCMM are not considered for some time. This leads to delays in diagnosis as indicated by the occasional published case report ^[1][2] illustrating the difficulties facing the clinicians (see Clinical Case Histories 1 and 2).

Commonly, the initial screening test for LCMM is SPE. This demonstrates a monoclonal FLC band in approximately 50% of patients and others may show hypogammaglobulinaemia. Serum IFE demonstrates monoclonal bands in most patients but ultimately a urine test is required to identify and quantitate the monoclonal FLCs. Figure 8.1 shows some typical electrophoretic test results.

Since immunoassays for sFLCs are more sensitive than electrophoretic tests (Chapter 6), could urinalysis be stopped when the diagnosis of LCMM is being considered? The answer to this question was published in The Lancet in 2003 ^[3] as a clear, “Yes”. The study was based on archived sera from 224 patients with LCMM entered into the UK MRC Myeloma trials between 1983 and 1999. The clinical diagnosis of MM had been established using bone marrow plasma cell content, the presence of monoclonal FLCs in the serum or urine (without intact monoclonal immunoglobulins) and the presence of lytic bone lesions.

The results showed that at the time of diagnosis, all patients had abnormal concentrations of the appropriate sFLC (Figure 8.2) and abnormal κ/λ ratios. The concentrations were clearly different from FLCs measured in the serum of 282 blood donors (Chapter 5). The non-tumour FLCs, produced by normal plasma cells, were also abnormal in a high proportion of the patients. Some were elevated as a result of renal impairment while others were low because of bone marrow suppression. Comparison of results was made with 31 patients who had renal impairment from causes other than monoclonal gammopathies. Characteristically, they had elevations of both κ and λ FLC types with normal κ/λ ratios (Chapter 20).

Similar results have been found in all studies and have included over 350 patients (Table 8.1). No patient with untreated LCMM has yet been identified who was positive by urine tests but negative by serum FLC tests. These include patients with renal failure when urine samples may be difficult to obtain because of poor urine flow ^[4] (Chapter 13).

Table 8.1. Serum FLC measurements in studies of LCMM. (na: not available).

In The Lancet study mentioned above, all the patients had elevated concentrations of both serum and urine monoclonal FLCs, so it might be expected that the two variables would be highly correlated. In fact, there was only a modest association (Figure 8.3). This may seem rather surprising, at first glance, but it can be explained by the effect of the renal tubular metabolism of FLCs. The amounts of FLCs observed in urine are highly dependent upon renal function. When renal function is normal, the proximal tubules remove 20-30g of protein per day (Chapter 3). Hence, serum and urine FLC concentrations are frequently discordant, with serum being more representative of tumour mass than urine concentrations. The amounts of sFLCs required to produce abnormal urine tests is discussed in (Chapter 24).

Similar results were found in a study of 66 patients with MM by Nowrousian et al ^[6]. Nearly all patients who had uFLCs by IFE had abnormal sFLC κ/λ ratios. Furthermore, more than 60% of patients under treatment, with negative urine tests for Bence Jones protein, had abnormal sFLCs, indicating the additional sensitivity of the serum test. The study concluded that assessment of sFLCs was much more sensitive than urine IFE for identifying Bence Jones protein in patients with MM.

8.2. Monitoring LCMM using serum free light chains

Assays that are useful in disease diagnosis are typically useful for disease monitoring. This is particularly true for FLC assays. Not only are FLC immunoassays inherently quantitative but also their precision is considerably better than measurements of monoclonal bands on electrophoretic gels.

Figure 8.3 shows that there is little correlation between serum and urine FLC concentrations at the time of disease diagnosis. In contrast, changes in serum and urine FLC concentrations observed during the course of the disease show a good correlation. This is illustrated in Figure 8.4 in 2 patients from the Mayo Clinic ^[5]. In both patients the concentrations of FLCs in serum and urine fell following chemotherapy (although in the first patient this was not in parallel, possibly due to inadequate 24-hour urine collections). In an expanded study of 71 patients ^[5], a good correlation was found between changes in serum and urine FLC concentrations (Figure 8.5). The authors concluded that sFLC measurements provided a satisfactory alternative to 24-hour urine collections for monitoring patients with LCMM.

In The Lancet study ^[3], changes in sFLC concentrations were assessed as indicators of responses to treatment. The results showed that 99% of patients (81/82) had reductions in sFLCs compared with 95% (78/82) for the corresponding uFLCs. This indicated a marginally better sensitivity for serum tests when initial responses to chemotherapy were evaluated. However, there were considerable differences when assessing rates of remission. 32% (26/82) of the patients were considered to be in complete remission as assessed by normal uFLC concentrations but this compared with only 11% (9/82) from sFLC levels. In the same clinical trials, 10% of patients with IIMM (117/1189) had complete serological remission. Since the serum responses to chemotherapy were similar in IIMM and LCMM, the results indicated that uFLC measurements were relatively insensitive for assessing residual disease. This has been substantiated in many other studies (Chapter 12).

The discrepancy between serum and urine results is mainly due to renal metabolism of FLCs (Chapter 3). Other factors are the greater sensitivity of the immunoassays and errors in collecting and measuring urine samples (Chapter 24). While changes in serum and urine FLC concentrations generally occur in parallel, sFLCs remain abnormal in many patients when urine is normal. Clinical responses and assessment of residual disease are better judged from sFLC measurements.

Comparisons of serum and urine assays for monitoring LCMM are illustrated for two patients in Figures 8.6 and 8.7. In both patients the uFLC measurements became normal while serum tests remained abnormal.

The results indicate that sFLC measurements have an important role in identifying and managing these patients. FLC tests are included in international diagnosis and response guidelines for MM (Chapter 25) . A detailed comparison of the use of serum versus urine FLC tests is given in Chapter 24.

Clinical Case History No 1

Clinical case history No 1. Unusual clinical features in a patient with light chain multiple myeloma.
A 63-year-old woman attended hospital with severe pain in her right shoulder. An X-ray showed minor erosive changes in the shoulder joint while blood tests were normal apart from a marginally elevated serum calcium at 2.69 mmol/L (NR: 2.08-2.67). An orthopaedic surgeon recommended a hemiarthroplasty. At operation, the head of the humerus was eroded and the glenoid was almost entirely replaced by 'extremely soft bone' suggestive of malignancy or a metabolic cause. The operation was aborted and the tissue was sent for histological examination. Re-examination of the patient failed to identify any additional clinical features. Investigations showed a normal chest X-ray while the serum calcium had increased further to 3.41mmol/L and she was hypophosphataemic at 0.55mmol/L (NR: 0.67-1.54). Other results included a raised alkaline phosphatase at 234 IU/L (NR: 30-115) and an increased parathyroid hormone related peptide at 9.5 pmol/L (NR: 0.7-1.8) while parathyroid hormone levels were low at 9ng/L (NR: 10-60). A metastatic tumour deposit was considered the most likely cause of her shoulder disease. The search for a primary tumour, however, was unsuccessful: CT scans of the abdomen and thorax were normal, as were the serum cancer markers, CA-199, CA-125 and CEA. The possibility of MM was considered. Bone histology from the surgically resected specimen showed osteo-arthritis and osteopenia and there was no excess of plasma cells. A skeletal survey showed only osteoporotic bone with no discrete lytic lesions and no features of MM. Serum and urine electrophoretic tests showed no monoclonal gammopathy but assessment of immunoglobulins by nephelometry revealed hypogammaglobulinaemia: IgG 3.20g/L (NR: 5.3- 16.5), IgA 0.15g/L (NR: 0.8- 4.0) and IgM 0.26g/L (NR: 0.5- 2.0). In view of the diagnostic difficulties, the recently available sFLC measurements were requested, with the following results:- κ 7,840mg/L (NR: 3.3 - 19.4); λ 4.4mg/L (NR: 5.7 - 26.3); κ/λ ratio 1,782 (NR: 0.26-1.65) (Figure 8.8). Urine FLC concentrations by immunoassay were as follows: κ 371mg/L; λ 4.7mg/L; κ/λ ratio 79. Subsequent bone-marrow aspiration of the iliac crest indicated a high concentration of abnormal plasma cells. This established the diagnosis as κ-secreting LCMM with production of excess parathyroid hormone related peptide leading to hypercalcaemia. Several months after her initial clinical presentation, the patient was finally treated with chemotherapy. This resulted in a satisfactory reduction of the serum κ FLC concentrations and normalisation of serum calcium. Since then, her shoulder has remained unstable although pain free. Comment. The diagnosis of LCMM can be difficult. In this patient the clinical features were atypical and did not provide a clear lead to the diagnosis, so tests for MM were not considered for some time. When electrophoretic analysis of serum and urine were eventually performed the results showed no monoclonal proteins. Reassessment of the original urine sample, at a later date, showed a low concentration of monoclonal κ by IFE that had been overlooked on the earlier analysis. The final diagnosis was LCMM with limited plasma cell infiltration of the bone marrow. The response of the tumour to chemotherapy was good. The serum κ FLC concentrations fell for 45 weeks with a half-life of approximately four weeks (Figure 8.8). The patient is likely to have a good clinical course in the medium term.
	Figure 8.8 Case history No 1. Serum FLC concentrations in a patient with κ LCMM and unusual clinical features.

Clinical Case History No 2

Clinical case history No 2. Free light chain breakthrough during relapse of multiple myeloma.
A 56-year-old man was followed for refractory MM grade IIIB (Durie and Salmon classification). The IgGλ monoclonal protein was 69 g/L, at diagnosis, on the scanned SPE gel. Following a bone marrow allograft, SPE and IFE showed a reduction and stabilisation of the IgGλ band at 3.0 g/L. Three months after the allograft the patient was clinically deteriorating with no change in the IgGλ monoclonal protein band (Figure 8.9). SPE showed a peak in the gamma-region while IFE showed a monoclonal IgGλ but no monoclonal FLC band. sFLC analysis showed: κ 1.3mg/L, λ 242mg/L and κ/λ ratio of 0.005, clear evidence of the tumour that was not apparent from the monoclonal IgGλ level. The diagnosis was relapse of the MM with FLC breakthrough. The patient died one month later.
	Figure 8.9 Case history No 2. SPE scan and sIFE of the patient during clinical relapse. (Courtesy of Dr Lucile Musset)

References