Serum Free Light Chain Escape In Progression and Treatment Resistance In Multiple Myeloma: A Marker For The Impact Of Intra-Clonal Heterogeneity

Intra-clonal heterogeneity has recently been described in Multiple Myeloma (MM), but as yet its clinical impact on disease progression and relapse has not been fully explored. The immunoglobulin type produced by the plasma cells provides an excellent marker, which can be used to address this issue by allowing us to follow clonal sub-structure over time and we have previously noted sub-clonal differences in heavy and light chain production within the predominant myeloma clones. Relapses characterized by an increase in FLC without a correspondent increase in paraprotein level have also been described, a phenomenon that has been termed “serum free light chain escape” (FLC escape).

As FLC escape can serve as a marker of sub-clonal evolution and intra-clonal heterogeneity and, to better understand the extent of sub-clonal evolution over time as well as its impact on outcomes following relapse, we have prospectively evaluated serial FLC and paraprotein measurements on a large population of newly diagnosed MM patients treated within the Myeloma IX clinical trial.

The trial comprised an intensive and a non-intensive pathway based on patient eligibility for autologous transplantation. Patients were randomized to receive conventional treatment or thalidomide containing induction. A randomization between maintenance thalidomide versus no maintenance was also performed. The International Myeloma Working Group uniform response criteria were used to assess response based on central laboratory analysis of serial blood and urine samples. FLC escape at relapse was defined as an increase of FLC with a paraprotein value either undetectable or stable compared to the best response. Median follow up was 5.9 years.

A complete FLC dataset for diagnosis, response and relapse was available in 647 patients with IgG or IgA myeloma; 29% achieved a complete response (CR), of which 66% were in stringent CR (sCR). To date 520 of these 647 patients have relapsed (80%) and of these 96% (503/520) had abnormal FLC levels at relapse. In 6% of patients (N=31, 4.4% of IgG and 9.8% of IgA paraprotein MM patients) relapse was characterised by FLC escape.

The median OS of patients with FLC escape was approximately 12 months shorter compared to patients relapsing with a whole paraprotein. This was mostly attributable to a significantly shorter survival from relapse (19.2 vs 32 months, p=0.013). When looking at FLC escape according to the isotype of paraprotein at diagnosis, we found that IgG patients had the worse survival from relapse (median survival 9.9 vs 33.6 months for FLC escape and normal relapse respectively, p=0.019). In contrast the outcome of IgA patients was not significantly influenced by the presence of FLC escape (median survival post relapse 20.3 vs 28.7 respectively, p=0.425). A Cox regression analysis including maximum response, age, paraprotein isotype, treatment pathway, thalidomide therapy and the type of relapse identified a maximum response <VGPR, an IgA paraprotein, non intensive treatment and a relapse with FLC escape as variables independently associated with a reduced OS (Table 1).

Monitoring for light chain escape at relapse provides an excellent tool to study the global impact of intra-clonal heterogeneity. Our observations fit with a model in which different clones have a different secretory behaviour. One clone is able to produce a complete antibody, while the other secretes only FLC. In such a model FLC escape is a marker of a heterogeneous disease and represents the outgrowth of the clone producing only light chains, which is more resistant to therapy. The results presented here provide evidence to support the idea that intra-clonal heterogeneity and clonal evolution is a general feature associated with disease progression and treatment resistance in myeloma. These results also illustrate the importance of disease monitoring using FLC analysis when there is a suspicion of clinical relapse.

Cavo:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Morgan:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millenium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Johnson and Johnson: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.