Unmeasurable Serum M-Protein Multiple Myeloma Benefit Less from Bortezomib Than Measurable Myeloma

Background: According to international uniform response criteria for multiple myeloma(MM), unmeasurable disease is defined as serum M-protein level of less than 1 g/dl and urine M-protein level less than 200 mg/d. The anti-tumor activity of bortezomib partly depended on degradation of misfolded or unfolded proteins through ubiquitin-proteasome pathway. We postulate that bortezomib may not able to induce sufficient apoptosis in unmeasurable serum M-protein myeloma comparing with measurable group. The goal of this study is to determine whether the level of serumM-protein expression act as a validated surrogate marker to predict the prognosis in the bortezomib-based therapy.

Materials and Methods: Between 2004 and 2013, a retrospective study was carried out of 630 patients with new diagnosis MM (NDMM) excluding light chain MM, who underwent bortezomib-based therapy or thalidomide-based therapy and for whom had complete data on clinical characteristics, molecular cytogenetics variety, treatment and overall survival (OS) time. According to the level of M-protein, they were devided into two groups: unmeasurable (serum M-protein<1g/dl) and measurable (serum M-protein>1g/dl) M-protein MM.

Results: 1) 92 patients were defined asunmeasurable M-protein MM and were 14.60% of the 630 cases cohort. 2) Compared with measurable M-protein MM, unmeasurable M-protein MM were characterized by younger age(54.89 vs.58.85, p<0.001), lower frequency of IgG and IgA M-protein type (IgG, 14.13% vs. 68.96%; IgA, 21.74% vs. 30.86%; p<0.001), higher incidence of IgD M-protein type (IgD, 36.96% vs. 0.19%; p<0.001), lower frequency of kappa light chain involved (kappa, 26.09% vs. 53.72% p<0.001), higher level of albumin (44.44 vs.32.34, p<0.001) and higher median of LDH (265.29 vs.168.99, p<0.001), higher incidence of renal dysfunction (33.70% vs 16.54%, p<0.001 ) and less advanced ISS stage (Ⅰ, 34.09% vs. 17.30%; Ⅱ, 21.69% vs. 42.54%; Ⅲ, 44.32% vs.40.16%; p<0.001). In addition, unmeasurable M-protein patients had higher incidence of del(17p) ( 15.49% vs. 5.45%; p=0.001) and t(11;14) ( 35.85% vs. 13.99%; p<0.001). However, the incidence of del(13q), 1q21 gains and t(4;14), t(14;16) had no statistically significance (p>0.05). 3) Furthermore, we analyzed OS in these two groups with thalidomide-based or bortezomib-based chemotherapy. In thalidomide-based therapy, the median OS of unmeasurable and measurable M-protein MM were 32.0 (95% CI: 14.3-49.7) and 40.0 (95% CI: 34.3-45.7) months respectively (p=0.124).In bortezomib-based group, the median OS of unmeasurable and measurable M-protein MM were 29.5 (95% CI: 15.4-43.6) and 58.0 (95% CI: 46.1-70.0) months respectively. The unmeasurable M-protein MM had a remarkably shorter OS (P=0.034). Secondly, patients were stratified according to level of M-protein (unmeasurable and measurable), then compared according to treatment. In unmeasurable M-protein MM, the median OS of bortezomib group and thalidomide groupwere 29.5 (95% CI: 15.4-43.6) and 32.0 (95% CI: 14.3-49.7) months respectively(p=0.498). In measurable M-protein MM with bortezomib and thalidomide-based chemotherapy, the median OS were 58.0 (95% CI: 46.1-70.0) and 40.0 (95% CI: 34.3-45.7) months respectively (p=0.004).

Conclusion: In conclusion, unmeasurable serum M-protein myeloma had shorter OS than measurable group, especially in the bortezomib-based therapy. In unmeasurable group, the difference of OS was not significant between thalidomide-based and bortezomib-based therapy. Our findings suggested that the level of serum M-protein was capable of predicting different survival groups to bortezomib and unmeasurable myeloma might benefit less than measurable group from bortezomib.