Overall survival, portrayed in , is characterized by slope segments with progressively decreasing steepness, herein modeled for OS by two such segments with a change-point at 52 months, justifying the analyses of serial LM. Univariately significant laboratory variables associated with OS varied with the LM examined (). Of 12 baseline parameters examined, 10 affected survival significantly in the context of LM-0, with only trends observed for albumin (constituting ISS stage together with B2M) and osteolytic bone lesions (component of the Durie–Salmon staging system). B2M impacted survival from all LM while the prognostic implications of CRP, platelet count, hemoglobin, calcium, and performance status were restricted to LM-0. Age affected prognosis from LM-0, LM-3, LM-4, and LM-7 and LDH from LM-0 and LM-5. In the multivariate model (), B2M’s consistent survival impact across all LM was confirmed while, of the seven LM-0-significant baseline variables, five did not extend beyond LM-0; older age appeared significant for LM-3 and LM-7 with a strong trend for LM-4. According to R2 statistics, values of nearly 18% and 19%, respectively, for LM-0 and LM-7 suggest that almost 20% of variability in survival outcome can be accounted for. In the case of the other intervening LM analyses, R2 values of less than 10% reflect a relatively poor performance of the multivariate models pertaining to these time segments. Similar conclusions were reached using continuous as opposed to dichotomized cut-points for prognostic factors (data not shown).
Overall survival from registration to start of protocol therapy. Overall survival fit with two exponentials with a cut-point at 52 months
Univariate analysis: results of parameters associated with overall survival applying landmarks at baseline (LM-0) and at 3, 4, 5, and 7 years after treatment start (LM-3, LM-4, LM-5, LM-7)
Multivariate analysis: results of parameters associated with overall survival applying landmarks at baseline (LM-0) and at 3, 4, 5, and 7 years after treatment start (LM-3, LM-4, LM-5, LM-7)
To illustrate the impact of the LM variable, portrays hazard ratio (HR) estimates over time. With the exception of age, HR values declined over time, especially for PS and platelet count. The consistently significant adverse impact of B2M across all LM considered was also reflected in the shallower decline of its HR values. portrays Kaplan–Meier plots dated from early to later LM relevant to the presence of two variables shown to govern all segments of survival history (B2M, age) or LM-0 only (calcium, LDH). In the case of B2M and age, the risk factor number-dependent progressively shorter survival pertained across LM (left panels) whereas, for calcium and LDH, such prognostic discrimination was lost beyond LM-0 (right panels).
Hazard ratio (HR) values of the significant prognostic factors (PF) are portrayed over time
Fig. 3 Kaplan–Meier plots from treatment initiation according to two variables affecting different segments of survival: Left panels serum B2M and age affected survival independently across all landmarks (LM) examined; the best outcome was observed when (more ...)