Clonal Evolution In Two Multiple Myeloma Patients and a Biclonal MGUS Patient

Multiple myeloma (MM) and its benign precursor monoclonal gammopathy of undetermined significance (MGUS) are diseases characterised by the production of monoclonal immunoglobulins. Clonal heterogeneity in MM has become a well-accepted phenomenon; however dogma would suggest the proteins produced by these clones remain consistent. Free light chain (FLC) escape is one exception to this rule, but is comparatively poorly documented and to our knowledge has not been identified in MGUS patients. Here we report 2 cases of MM patients with intact immunoglobulin and FLC producing clones that have different sensitivities to treatment leading to escape. In addition we report an MGUS patient whose routine corticosteroid treatment for polymyalgia rheumatica (PMR) impacted on the intact immunoglobulin but not the FLC producing clones and led to an escaping FLC clone which was subsequently diagnosed as myelomic.

Serum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE) were performed using Hydrasys 2 apparatus (SEBIA).  Serum free light chain (FLC) levels were measured nephelometrically on a Siemens BN^TM  II using polyclonal antisera assays, Freelite^®(The Binding Site Group Limited, Birmingham, UK).

Two intact immunoglobulin MM patients (Patient 1 IgAκ: 14.4g/L, κ FLC: 1320 mg/L, age: 65, sex: male; Patient 2 IgAλ: 8g/L, λ FLC: 9510 mg/L, age: 48, sex: male) were monitored through the course of their disease for 762 and 1330 days respectively. Following cyclophosphamide, thalidomide and dexamethasone (CTD) treatment Patient 1 achieved a VGPR (∼90% reduction in IgAk and 65% reduction in FLC) which was stable for 270 days. Subsequently whilst only a trace of IgAκ was present, dFLC levels increased from 460mg/L to 15194mg/L. Patient 2 achieved a CR following treatment with vincristine, doxorubicin and dexamethasone (VAD) and autologous stem cell transplant (ASCT) which was stable for 330 days. As with Patient 1 relapse was characterised by a substantial increase in dFLC from 8.61mg/L to 3168mg/L. In both patients the velocity of change and sensitivity to treatment of the intact immunoglobulin and FLC suggested the presence of heterogeneous clones.

A rare biclonal MGUS patient, IgGκ (3.9g/L) and λ FLC (316mg/L), was identified during routine laboratory investigations (age: 71, sex: female) and followed annually in accordance with local guidelines (low/moderate risk MGUS). 16 months following MGUS diagnosis the patient was started on oral methylprednisolone for PMR. The treatment resolved the PMR and coincidently caused a reduction in the IgGκ serum concentration (trace quantities) and a normalisation of the FLC κ/λ ratio. A year post steroidal treatment whilst the IgGκ monoclonal protein concentration remained stable, dFLC levels increased from 9.6 mg/L to 1052 mg/L (κ/λ ratio: 0.008), indicating the emergence of a λ FLC clone although the patient remained asymptomatic. 4 months later and almost 4 years following diagnosis, the patient progressed to symptomatic disease with severe renal impairment (creatinine 6.19 mg/dL; eGFR 7.03 ml/min/1.73m²) anemia (Hb 9.0g/dL) and 70% clonal plasma cells present in the bone marrow. The dFLC concentration had further increased to 9726 mg/L however the IgGκ monoclonal protein was no longer detectable by IFE indicating the biclonal MGUS had progressed to a λ light chain multiple myeloma.

Routine monitoring of MM patients to detect FLC escape is recommended by international guidelines, in light of the MGUS patient FLC escape leading to MM, we suggest routine evaluation of FLC levels in MGUS may also be beneficial.

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