Multiple myeloma (MM) is an incurable hematological malignancy with increasing incidence and mortality rates, with a worldwide incidence of 160,000 cases per year. Currently approved treatments, including bortezomib treatment, have adverse effects that ultimately lead to the development of resistance. Inadequate vitamin D (VD) levels are frequently observed in patients with MM, and its supplementation has anti-proliferative effects on different MM phenotypes. However, the risk of hypercalcemia restricts the application of VD in cancer therapy; therefore, we analyzed truncated VD analogs with anticancer effects but no calcemic activity. We previously identified a derivative of the C/D ring fragment of vitamin D2 (VD2) against cervical cancer, lung cancer, and MM. Herein, we conducted a structure–activity relationship study by introducing more derivatives and testing them against different MM cells, including bortezomib-sensitive and bortezomibresistant phenotypes. VDF-4 exhibited remarkable toxicity against all tested cells, with less of an effect on normal blood cells; this reflects its potentially high selectivity. VDF-4 IC50 values against KMS-12-PE, KMS-11, and KMS-11/BTZ were 19.1 ± 1.0, 19.8 ± 2.5, and 23.3 ± 1.9 μM, respectively. Notably, the KMS-11/BTZ cells were insensitive to VD2. Furthermore, VDF-4 demonstrated moderate activity against other leukemic cell lines, including Jurkat and M8166 cells. Although its mechanism of action has not yet been elucidated, VDF-4 is a promising compound and warrants further investigation.