Subcutaneous (sc) administration of bortezomib (Bor) has become more common than intravenous (iv) administration in the treatment of multiple myeloma (MM), because scBor results in a lower incidence and severity of peripheral neuropathy and shows efficacy equivalent to ivBor. Bor is an irritant cytotoxic agent when it extravasates from the vasculature. Therefore, it is recommended that sc injections of Bor should be delivered on a rotating basis across eight sites on the abdomen and thighs. Previously, we reported that sc injections of Bor in the abdomen caused fewer grade 2 injection site reactions (ISRs) than those in the thigh. In the present study, we recruited more patients and expanded the scale of our analysis into ISRs following treatment with 300 scBor injections in 20 patients. ISRs of ≥grade 2 were documented in 12 of 109 (11.0 %) thigh injections, but only in three of 191 (1.6 %) abdominal injections (p < 0.001). Interestingly, ISRs of ≥grade 2 occurred more frequently in the first cycle than in the second and subsequent cycles (16.3 vs. 0.91 %, p < 0.001). These results clearly indicate that closer attention should be paid to ISR management, particularly with regard to the first cycle of scBor administration in the thigh. To our knowledge, this is the first report showing that ≥grade 2 ISRs are more common in the first cycle compared with subsequent cycles of scBor in the treatment of MM.