Timed sequential chemotherapy of cytoxan-refractory multiple myeloma with cytoxan and adriamycin based on induced tumor proliferation

Malignant plasma cell proliferation and induced humoral stimulatory activity (HSA) occur in vivo at a predictable time following drug administration. Sequential sera from 11 patients with poor-risk multiple myeloma (MM) undergoing treatment with Cytoxan (CY) 2400 mg/sq m were assayed for their in vitro effects on malignant bone marrow plasma cell tritiated thymidine (³HTdR) incorporation. Peak HSA was detected day 9 following CY. Sequential changes in marrow malignant plasma cell :3HTdR-labeling indices (LI) paralleled changes in serum activity, with peak LI occurring at the time of peak HSA. An in vitro model of chemotherapy demonstrated that malignant plasma cell proliferation was enhanced by HSA, as determined by ³HTdR incorporation assay, ³HTdR LI, and tumor cell counts, and that stimulated plasma cells were more sensitive to cytotoxic effects of adriamycin (ADR) than were cells cultured in autologous pretreatment serum. Based on these studies, we designed a clinical trial to treat 12 CY-refractory poor-risk patients with MM in which ADR (60 mg/sq m) was administered at the time of peak HSA and residual tumor cell LI (day 9) following initial CY, 2400 mg/m (CY₁ADR₉). Eight of 12 (67%) responded to timed sequential chemotherapy with a >50% decrement in monoclonal protein marker and a median survival projected to be >8 mo duration (range 4-21⁺ mo). These clinical results using timed sequential CY₁ADR₉ compare favorably with results obtained using ADR in nonsequential chemotherapeutic regimens.