Nonsecretory multiple myeloma (NSMM)

A 38-year-old woman, presented with a fractured rib following mild trauma. Over the following months, the pain subsided but non-specific symptoms including breathlessness, vague chest pains and tiredness persisted. During this time, full blood counts, erythrocyte sedimentation rate (ESR) and biochemistry were all normal as were chest X-rays and lung function tests. In the absence of a diagnosis, the general practitioner considered a psychiatric assessment.

Seven months after the initial presentation, she remained symptomatic and was reinvestigated, whereupon bone scans and X-rays showed extensive osseous lesions. Immunoglobulin measurements showed immune paresis, but no serum monoclonal protein was detected. She was noted to have hypercalcaemia (2.85 mmol/L - NR: 2.08- 2.67) but had normal renal function. In view of the absence of monoclonal immunoglobulins, MM was still considered unlikely. However, a skull X-ray and CT scan showed osteolytic lesions (Figure 9.5) so a skull biopsy was performed which was reported as ‘plasmacytoma/NSMM’. She was given chemotherapy comprising ABCM for the following 8 months that resulted in clinical remission.

Seven months later and over 2 years after the initial presentation, she re-attended hospital because of chest pains and breathlessness. Again, clinical examination was normal, as were routine biochemistry and haematology tests. Immunology tests showed reduced immunoglobulins but no monoclonal spike. A bone marrow biopsy showed 5% plasma cells that were morphologically normal. Chest X-ray, a ventilation perfusion scan and lung function tests revealed no evidence of pulmonary disease. Blood tests were requested for FLCs, the results of which were: κ 330mg/L, λ 6.5mg/L and κ/λ ratio 51, suggesting recurrence of NSMM (Figure 9.1 and Figure 9.6 at week 67). Doubt was expressed regarding the validity of the results so FLC measurements were repeated 2 and 3 weeks later and showed κ increases to 470mg/L and then 525mg/L with a rising κ/λ ratio, confirming recurrence of the disease.

FLC concentrations were assessed retrospectively from archived samples and then the patient was monitored prospectively. Figure 9.6 shows that the κ FLC concentrations had increased rapidly during the tumour recurrence, with an apparent doubling time of 30 days as indicated by the κ/λ ratio. Serum κ concentrations subsequently reduced during VAD chemotherapy prior to high dose melphalan and PBSC rescue. During the period of relapse, the alternate FLC increased in concentration suggesting deteriorating renal clearance of FLCs from impaired glomerular filtration. Serum κ and λ concentrations and the κ/λ ratio returned towards normal, post-transplant, as the patient went into clinical remission. For 2 years following the transplant the patient remained completely well.

Discussion: NSMM is rare so it is not normally considered when a patient first presents with symptoms but rather when other diseases have been excluded. Even then, normal serum and urine tests for monoclonal proteins tend to deceive the diagnostician. When MM is finally thought of, the patient is subjected to a painful bone marrow biopsy, which is not undertaken lightly. Clearly, since sFLC measurements are important they should be requested when the diagnosis of MM is first considered.

While monitoring these patients, repeated serum tests should generally replace other forms of investigation. At present, skeletal surveys using X-rays, MRI or positron emission tomography may be used, together with repeated bone marrow biopsies. None of these tests is likely to provide results that are as representative of the changing total tumour burden as sFLC tests. sFLC concentrations assess FLC production from all of the bone marrow and extramedullary sites. They are likely to be a better reflection of overall tumour activity than bone marrow aspirations or skeletal surveys.

Of additional interest in these patients is the κ/λ ratio. This is a more accurate measure of changing monoclonal FLC production than individual FLC concentrations since the alternate FLC compensates for alterations in glomerular filtration rate. This was apparent during the relapse phase in this patient. After week 40, the alternate FLC gradually increased which suggested impaired renal function from renal deposition of tumour-produced FLCs.

It is also of note that normalisation of the κ/λ ratio had not occurred even 2 years after treatment. This suggests either that the clone of tumour cells persists or that bone marrow function has not completely returned to normal. It is likely that the patient has residual disease (Chapter 12).

Figure 9.5 X-ray and CT scans of the skull in nonsecretory multiple myeloma.

Figure 9.6 Serum FLC concentrations in Patient No 3 during the course of the disease. The changing κ/λ ratio is related to the tumour growth.

A 37-year-old man with pelvic pain was found to have a solitary plasmacytoma located in the right iliac crest. Bone marrow biopsy of the opposite iliac crest was normal and no monoclonal protein was identified in serum or urine. Treatment comprised surgical resection followed by irradiation (5,000Gy). Subsequently, he remained asymptomatic, but 5 years later a routine skeletal survey showed a thoracic spine lesion at T-2 that was irradiated. Over the following 7 years further painful lesions developed. These were identified using different scanning techniques (particularly PET) and were treated with irradiation or melphalan and prednisolone.

Throughout this period, and in spite of repeated testing, no monoclonal protein was identified by SPE and UPE. Finally, 12 years after the initial presentation FLC immunoassays became available and showed; κ 7.5mg/L, λ 632mg/L and a κ/λ ratio 0.01. These results identified a λ producing tumour with no associated suppression of the κ FLC (Figure 9.7). One month later, λ concentrations had increased to 700mg/L, prompting treatment with thalidomide (50mg/day) and dexamethasone (40mg weekly). Over the subsequent 7 months, serum λ gradually fell to 33mg/L and the κ/λ ratio began to normalise. Based on the FLC results, dexamethasone was reduced to 12 mg per week and he remained well and in complete remission.

Figure 9.7 shows the changes in sFLC concentrations over a 12 month period. The effectiveness of the drugs and the doses required can all be monitored during this period of therapy. This has produced clear benefits for the patient and avoided costly scans and painful bone marrow biopsies. Furthermore, the patient can be entered into clinical trials of new treatments when absence of a disease marker had previously led to his exclusion. The patient has been monitored successfully using sFLC assays for many years since the original tests were performed.

Figure 9.7 Serum FLC concentrations in Patient No. 4 during treatment.