Serum Immunoglobulin Free Light Chain (sFLC) Measurement as a New Marker of Response to Therapy and Survival in Waldenstrom Macroglobulinemia (WM).

Measurement of serum M-spike is used to determine response to therapy and treatment free survival in Waldenstrom Macroglobulinemia (WM). However, there are many limitations to the use of M-spike level and new markers are needed. We previously showed that involved sFLC values accurately diagnosed patients with WM, correlated with markers of poor prognosis, and especially beta-2 microglobulin. We sought to determine whether involved sFLC value can be used as a reliable marker for response to therapy in WM compared to the M-spike measurement and to assess treatment free and overall survivals.

We prospectively studied involved sFLC (sFLC) in 72 WM patients, at diagnosis (N=15) and with relapsed/refractory disease (N=57). Patients were treated with either perifosine (N=30; given 150mg oral daily for 6 monthly cycles) or bortezomib-rituximab (N=42; given IV bortezomib 1.6mg/m² at days 1, 8, 15 q 28 days x 6 cycles and rituxan 375 mg/m² at days 1, 8, 15, 22 on cycles 1 and 4) phase II clinical trials. Responses were assessed after cycle 3, confirmed at 2 consecutive values and included minor response (MR) or better. Time to response was determined from start of therapy to time needed to reach at least PR, and was calculated only in patients who reached a response. Overall survival (OS) and treatment free survival (TFS) were calculated from start of therapy to date of last follow-up and time of next treatment, respectively.

The median age of the overall population was 64.5 years (range, 43-83), Male/Female ratio 2.25, and WM-International Staging score breakdown was 36% low, 32% intermediate, and 32% high. Serum M-spike was 2.5g/L (range, 0.41-4.62) with 8.3% patients >= 4.0 g/L, involved sFLC 88.3mg/L (range 4.92-3740) with 51.4% patients >= 80mg/L. The overall response rate was 68%, with minor response in 27 pts, major response in 22 pts. The ORR using involved sFLC level was 71%, including a minor response in 19 pts and major response in 32 pts. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for sFLC in predicting ORR and MR were 85.7%, 60.8%, 82.3%, 66.6% and 73%, 68%, 50%, 85%, respectively. With a median (+/-se) follow-up of 17 months (+/-1.33), death occurred in 8 patients, and the median OS was not reached with a 3-year probability of survival of 75%. The median TFS was 20 months (+/-1.80). The 3-year probability of survival estimate were 57.5% and 96.8% for WM patients with elevated values of sFLC higher (number of death/number of patients in the group: O/N=7/37) and patients with values lower than 80mg/L (O/N=1/35), respectively [p=0.05; OR=6.08, 95%CI 0.75-49.45]. However, none of the studied markers impacted TFS. Interestingly, involved sFLC measurement impacted OS while IgM M-spike did not (p=0.68) and WM-ISS slightly (p=0.08) on univariate analysis.

Involved sFLC is a new and reliable marker for monitoring response to therapy in WM. To strengthen our study, measurements were done prospectively in different clinical trials. Study of involved sFLC level to monitor response to therapy should be performed in future prospective clinical trials to validate these results.

Ghobrial:Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.