Zhang, Lijun

Abstract Background: The free light chain (FLC) assay allows a nephelometric measurement of this free kappa and lambda light chains that circulate as monomers or dimers, not bound to the immunoglobulin heavy chain. Estimation of the free light chain levels and their ratio has utility in screening, prognostication and treatment response assessment in multiple myeloma, and is particularly useful in light chain myeloma. Previous studies have suggested that absence of a functional rearrangement on at least one of the IgH allele is the basis of light chain myeloma. Translocations involving the immunoglobulin heavy chain (IgH) locus on chromosome 14 can be detected using FISH in over half of the patients with myeloma. We hypothesized that presence of an IgH translocation may be associated with compromised production of heavy chains and leads to unbalanced, excess production of clonal light chain. Methods: From February 1988 to May 1992, 653 patients with previously untreated multiple myeloma were enrolled on the phase III clinical trial E9486. Serum free light chains were run on stored sera obtained at baseline in 495 patients as part of a previous study. Among these patients, 314 patients were previously studied using FISH for presence or absence of IgH translocations, p53 abnormalities and deletion 13 and were included in the current analysis. Results: The median difference between the involved and uninvolved FLC (FLCdiff) was higher among the group of patients with any IgH translocation abnormality compared to those with none (Figure 1). This was particularly evident among the patients with a t(14;16) who had the highest FLCdiff. In a multivariate analysis, we examined if the prognostic value seen with FLCdiff was independent of the presence of IgH translocations t(4:14) and t(14;16), which are associated with a worse outcome. The presence of t(4;14) or t(14;16) was associated with FLCdiff groups using a cutoff point of 185, with 13% of those with FLCd ≤185 and 27% of those with FLCd > 185 having the translocations (P= 0.008). At the cutoff value of 185, the prognostic value of the FLC-diff on progression free and overall survival appears to be independent of these high risk IgH translocations (P-value=0.03 and 0.003, respectively for PFS and OS) We then examined the prognostic value of the FLC-diff in the group of patients without these two high risk abnormalities and were able to confirm that they remained prognostic for PFS (P=0.009) and OS (p=0.005). However, among the group of patients with either of the two high risk IgH abnormalities, FLCdiff estimate added little to assessment of their outcome (P=0.97 and 0.20, respectively for PFS and OS). Conclusion: Elevated free light chain levels are associated with presence of IgH translocations and these patients are more likely to harbor the high risk genetic abnormalities. Routine FISH testing for patients with newly diagnosed myeloma will allow us to confirm these and allow better risk stratification of the patients. Additional work needs to be done to help us better understand the molecular basis for unbalanced light chain excretion by myeloma cells and the current finding of the association with IgH translocation abnormalities should form the basis for this work. Figure 1. Distribution of FLC ratio (inv vs. uninv) and FLC difference (inv − uninv) among patients. Solid squares represent patients with t(4;14) or t(14;16) or t(11;14) or other 14q32 translocation; open circles represent patients without t(4;14), t(14;16), t(11;14) and any other 14q32 translocations. The horizontal dashed lines refer to FLC ratio original values of 100 and 1000, and vertical dashed lines refer to FLC difference original values of 10 and 100. Solid line indicates significant association (P<=0.05) between the dichotomized FLC groups and translocation status. Figure 1. Distribution of FLC ratio (inv vs. uninv) and FLC difference (inv − uninv) among patients. Solid squares represent patients with t(4;14) or t(14;16) or t(11;14) or other 14q32 translocation; open circles represent patients without t(4;14), t(14;16), t(11;14) and any other 14q32 translocations. The horizontal dashed lines refer to FLC ratio original values of 100 and 1000, and vertical dashed lines refer to FLC difference original values of 10 and 100. Solid line indicates significant association (P<=0.05) between the dichotomized FLC groups and translocation status.

Abstract Background: Outcome of patients with Multiple Myeloma (MM) is influenced by a variety of baseline prognostic factors, most importantly presence of chromosomal abnormalities. Nevertheless, these biologically determined risk-factors do not account for a significant subset of patients whose outcome varies greatly from what one expects based on the underlying prognostic characteristics. We have previously demonstrated that outcome in myeloma is dictated not only by baseline risk-factors but also response to therapy (R2, risk and response dependent outcome). We studied response duration following initial therapy as a prognostic factor for long-term overall survival in myeloma in three ECOG clinical trials that enrolled patients with newly diagnosed myeloma. Methods: Data from three studies with long-term, mature follow up were analyzed: E9486, E5A93, and E1A00. The regimens used in these studies included Thalidomide/Dex, Dex, VBMCP, VBMCP + alpha-IFN, and VBMCP + Cyclophosphamide. Among progressed/relapsed patients, the association between time to progression and overall survival since relapse was explored using Cox proportional hazards model, in which time to progression was analyzed as a continuous variable. In addition, the association between response duration and overall survival since relapse was explored similarly among relapsed responders. Treatment effect and calendar time of diagnosis have been adjusted in the model. Also, to determine the best cut off point associated with the best differentiation of patients with short OS after relapse, an outcome-oriented method using log likelihood value was applied. Results: Among the 1136 patients enrolled in the three studies, 625 patients who have documented disease relapse have been included in the current study. Of these, 471 patients had responded to the treatment before relapse. Only 33 patients are alive as of Dec., 2007. For all 625 patients, the time to progression (continuous variable) was significantly associated with overall survival from the time of relapse/progression (P<0.0001), with hazard ratio of 0.77 (95%CI: 0.72~0.81) at time to progression increasing by 1 year (i.e., the later the progression/relapse, the lower the risk). The best cutoff point of the time to progression is 3 yrs (the 75th percentile). The hazard ratio of patients progressing within 3 yrs since randomization vs. after 3 yrs is 2.4 (95% CI: 1.9 ~ 2.9) and P-value<0.0001. The median OS from relapse was 0.96 years for the former vs. 2.43 years in the latter group (Figure). Among the 471 relapsed responders, the response duration (continuous variable) was also significantly associated with overall survival since relapse (P<0.0001), with hazard ratio of 0.76 (95%CI: 0.70~0.81) at response duration increasing by 1 year (i.e., the longer the response duration, the lower the risk). The effects seen with each regimen are detailed in the table. The best cutoff point of the response duration is 2 yrs (median). The hazard ratio of patients with response duration less than or equal to 2 yrs vs. more than 2 yrs is 2.1 (95% CI: 1.7 ~ 2.6) and P-value<0.0001. Conclusions: Among patients treated with alkylator based therapy, the duration of response from the initial therapy is an important predictor of the subsequent outcome among patients with myeloma. Given the heterogeneity of the disease and imprecise predictive ability of the known baseline prognostic factors, the duration of response to initial therapy should be taken into account, to deliver risk and response-adapted therapy. The prognostic value of this feature across different clinical trials, points towards the role of underlying disease biology, both disease aggressiveness and ability to rapidly develop resistance to therapies as two important determinants of outcome. Table 1: Hazard ratio of overall survival since relapse for patients progressed within 3 yrs since randomization vs. after 3 yrs in each treatment arm Treatment arm Treatment arm HR (95% CI) P-value TTP<=3yrs vs. >3 yrs Thal/Dex N/A N/A Dex 0.4 (0.05, 3.9) 0.46 VBMCP(E5A93+ E9486) 1.9 (1.4, 2.7) 0.0001 VBMCP+alpha2IFN (E5A93+ E9486) 3.0 (2.2, 4.1) <0.0001 VBMCP+CYCLOPHOSPHAMIDE 2.3 (1.5, 3.6) 0.0001 Response duration <=2 yrs vs. >2 yrs Thal/Dex 0.2 (0.003, 18.5) 0.51 Dex 0.15 (0.02, 0.98) 0.048 VBMCP(E5A93+ E9486) 1.7 (1.2, 2.3) 0.0009 VBMCP+alpha2IFN (E5A93+ E9486) 3.0(2.1, 4.3) <0.0001 VBMCP+CYCLOPHOSPHAMIDE 2.1 (1.4, 3.3) 0.006 Figure 1: Overall survival since relapse between patients progressed within 3 yrs since randomization vs. after 3 yrs. Figure 1:. Overall survival since relapse between patients progressed within 3 yrs since randomization vs. after 3 yrs.