Objective: To investigate the relationship between the Bcl-2 and survivin expression and the different regimens therapeutic efficacy newly diagnosed multiple myeloma (NDMM). Methods: We retrospectively assessed the association of Bcl-2 and survivin expression with chemotherapeutic efficacy and prognosis in 59 NDMM patients in a single center. Results: The positive expression rate for survivin and Bcl-2 was 35% and 74%, respectively. Survivin and Bcl-2 protein expression were not associated with clinical stage, suggesting that they are not related to tumor burden in NDMM. Bortezomib-based regimens were more effective in reducing tumor burden and achieving therapeutic (complete and partial) response compared with non-bortezomib-based regimens irrespective of Bcl-2 or survivin expression (P < 0.05). In cases with both negative Bcl-2 and survivin expression (Bcl-2(-)survivin(-)), the response to bortezomib and non-bortezomib-based regimens was similar (p = 0.429). Bcl-2 and survivin expression were not correlated with overall survival (OS); however, Bcl-2(-)survivin(-) cases showed a trend towards a longer OS (P = 0.078). Conclusion: We recommend bortezomib-containing regimens for NDMM with single or double-positive Bcl-2 and survivin expression.