Incorporation of Bortezomib Into Frontline Treatment of Multiple Myeloma According to Risk Stratification Shifts the Most Significant Prognostic Indicator From Cytogenetics to the Quality of Induction Response

Multiple myeloma (MM) is clinically heterogeneous and risk stratification is vital for prognostication and informing treatment decisions. As bortezomib is able to overcome several adverse features of MM, it has been incorporated into the induction algorithms of high-risk MM. We evaluate the survival data of MM patients managed in a single institution, overall, and with respect to treatment eras before (era 1) and after (era 2) the incorporation of bortezomib as frontline therapy for high-risk MM.

From a comprehensive MM registry maintained in a tertiary institution, we study the survival data of 304 consecutive and previously untreated MM patients managed at our institution from 2000 to 2009. For induction therapy, transplant-eligible patients received.

VAD chemotherapy from 2000 to 2004, and thalidomide/dexamethasone (thal/dex) combination from 2004 to 2009. Transplant-ineligible patients received VAD chemotherapy, thal/dex or melphalan/prednisolone (MP) combination from 2001 to 2004, and thal/dex or MP/thalidomide combination from 2004 to 2009. Patients < 65 years were eligible for high-dose therapy with autologous stem cell transplant (HDT/ASCT). Bortezomib became available for treatment of relapsed disease from 2004 and was incorporated into induction therapy in selected patients with high-risk MM from 2006. High-risk MM is defined by presence any adverse factors including stage III on the International Staging System (ISS), deletion 13, hypodiploidy, pseudo-diploidy or near-tetraploidy on metaphase karyotyping, or presence of deletion 17p, t(4;14) or t(14;16) on interphase florescence in-situ hybridization (FISH). As FISH was only available from 2004, the results of FISH will not be included in the survival analysis. Patient and disease characteristics, and survival data were evaluated overall, and with respect to treatment eras. Disease response was assessed by the IMWG criteria after induction treatment and after HDT/ASCT for transplant ineligible and eligible patients respectively.

We applied multivariate Cox's regression modeling to determine what baseline parameters, along with the eventual induction response, significantly affected the OS in the respective eras.

The median age of all patients was 62 years. Overall, 35%, 40% and 25% of patients presented with ISS stages I, II and III respectively. Conventional karyotyping detected abnormalities in 49% (del 13 [17%], hypodiploidy [18%], hyperdiploidy [22%], pseudodiploidy [7%] and near tetradiploidy [2%]) of patients. Overall, the ISS, conventional cytogenetics, age (≤ or > 60 years), the presenting platelet count (≤ or > 140 × 10⁹/L) and the induction response attained were discriminating of the overall survival (OS) (median= 5.2 yrs) on univariate analyses. Patients and disease characteristic and number of patients undergoing HDT/ASCT were comparable between the 2 eras. 33% of patients in era 1(N=182) were exposed to bortezomib predominantly in the relapse setting, while 52% (41% upfront, 59% during relapse) of patients were exposed to bortezomib (N=123) in era 2. Number of patients attaining ≥ very good partial response (VGPR) were significantly higher in era 2 compared with era 1 (48% vs 26%, p<0.001). The median OS of patients in era 1 and 2 were 5.1 and 6.0 respectively (P=0.06). On multivariate analysis stratified by era, the presence of an abnormal non-hyperdiploid karyotype was the most significant prognostic factor in predicting a worse outcome in era 1(median OS 2.7 years, hazard ratio 3.4, p=0.02), while the attainment of ≥VGPR emerged as the single most significant factor in predicting a favorable outcome in era 2 (median OS 8.1 years, hazard ratio 0.01, p<0.001).

Our study suggests that bortezomib use in the frontline, rather than relapse setting may be better able to overcome the effects of adverse cytogenetics. Superseding the adverse effects of all other presenting clinical and laboratory parameters, the attainment of ≥VGPR emerged as the single most significant predictor of long-term survival in the era of novel therapy.

No relevant conflicts of interest to declare.