Objective To investigate the correlation between serum lactate dehydrogenase (LDH) and interleukin-6 (IL-6) and early treatment response in newly diagnosed multiple myeloma (MM) patients. Methods A total of 109 newly diagnosed MM patients in Nanyang Central Hospital from January 2021 to December 2023 were enrolled. All patients received bortezomib-based first-line chemotherapy for 1 to 5 consecutive courses, and treatment response was evaluated at one week post-treatment. The 109 patients were divided into two groups: response group (n=80) and non-response group (n=29), the data between the two groups were compared, and the correlation between serum LDH, IL-6 and treatment response was analyzed. Results Compared with the response group, the non-response group had a significantly higher proportion of patients with age ≥ 65 years, disease stage Ⅲ , and levels of β2-MG, LDH, and IL-6 at diagnosis (P<0.05). Logistic regression analysis showed that age, disease stage, abnormal levels of β2-MG, LDH and IL-6 at diagnosis were related to early treatment non-response in newly diagnosed MM patients (P<0.05). Restricted cubic spline analysis and interaction test showed that there was a non-linear dose-response relationship between the no-response risk of early treatment and serum LDH and IL-6 levels in newly diagnosed MM patients (P<0.05). When the serum LDH and IL-6 levels were greater than 237.95U/L and 113.59pg/mL, respectively, the no-response risk of to treatment increases with the increase of LDH and IL-6 levels, and there is a positive interaction between LDH and IL-6 on the treatment response of patients. Conclusion The early treatment response of newly diagnosed MM patients may be related to the levels of serum LDH and IL-6, which may interact with each other and increase the risk of non-response to treatment.