The indications for percutaneous kyphoplasty (PKP) and percutaneous vertebroplasty (PVP) are painful vertebral compression fractures. Our study is to assess the risk–benefit ratio of PKP/PVP surgery in the patients with newly diagnosed multiple myeloma (NDMM) without receiving antimyeloma therapy. The clinical data of 426 consecutive patients with NDMM admitted to our center from February 2012 to April 2022 were retrospectively analyzed. The baseline data, postoperative pain relief, the proportion of recurrent vertebral fractures, and survival time were compared between the PKP/PVP surgical group and the nonsurgical group in the NDMM patients. Of the 426 patients with NDMM, 206 patients had vertebral fractures (206/426, 48.4%). Of these, 32 (32/206, 15.5%) underwent PKP/PVP surgery for misdiagnosis of simple osteoporosis prior to diagnosis of MM (surgical group), and the other 174 (174/206, 84.5%) did not undergo surgical treatment prior to definitive diagnosis of MM (non-surgical group). The median age of patients in the surgical and nonsurgical groups was 66 and 62 years, respectively (p= 0.01). The proportion of patients with advanced ISS and RISS stages was higher in the surgical group (ISS stage II + III 96.9% vs. 71.8%,p= 0.03; RISS stage III 96.9% vs. 71%,p= 0.01). Postoperatively, 10 patients (31.3%) never experienced pain relief and 20 patients (62.5%) experienced short-term pain relief with a median duration of relief of 2.6 months (0.2–24.1 months). Postoperative fractures of vertebrae other than the surgical site occurred in 24 patients (75%) in the surgical group, with a median time of 4.4 months postoperatively (0.4–86.8 months). Vertebral fractures other than the fracture site at the first visit occurred in 5 patients (2.9%) in the nonoperative group at the time of diagnosis of MM, with a median time of 11.9 months after the first visit (3.5–12.6 months). The incidence of secondary fractures was significantly higher in the surgical group than in the nonsurgical group (75% vs. 2.9%,p= 0.001). The time interval between the first visit and definitive diagnosis of MM was longer in the surgical group than in the nonsurgical group (6.1 months vs. 1.6 months,p= 0.01). At a median follow-up of 32 months (0.3–123 months), median overall survival (OS) was significantly shorter in the surgical group than in the nonsurgical group (48.2 months vs. 66 months,p= 0.04). Application of PKP/PVP surgery for pain relief in NDMM patients without antimyeloma therapy has a limited effect and a high risk of new vertebral fractures after surgery. Therefore, patients with NDMM may need to have their disease controlled with antimyeloma therapy prior to any consideration for PKP/PVP surgery.