Biological and Clinical Evaluation of Rituximab in the Management of Newly Diagnosed Multiple Myeloma Patients

Multiple myeloma is a neoplastic disease characterized by the expansion of monoclonal plasma cells that seed throughout the bone marrow. Induction regimens for multiple myeloma result in a 60% to 70% response rate. In vitro studies suggest that adding rituximab (Rituxan) to cytotoxic drugs has potential benefit. Pretreatment of DHL-4 cell lines with rituximab resulted in the inhibition of cell proliferation and cell death, as well as a reversal of cell line resistance to several cytotoxic drugs.

A long-standing problem in multiple myeloma treatment has been the absence of cure. The use of rituximab after achieving plateau phase in multiple myeloma could theoretically prevent the proliferative monoclonal B-cell compartment from feeding the nonproliferative myeloma cell compartment, thus prolonging the plateau phase of the disease.

We are conducting a phase II study to evaluate the effects of rituximab in improving the 60% to 70% response rate of MP (melphalan and prednisone), as well as the impact of rituximab on progression-free survival. This theoretical benefit is being correlated with the incidence of monoclonal B cells in the peripheral blood as well as the percentage of CD20-positive or -negative plasma cells at the time of diagnosis using four-color flow cytometry. Response is being evaluated by Eastern Cooperative Oncology Group (ECOG) modified criteria.

Patients receive rituximab, 375 mg/m² intravenously (IV) weekly for 4 weeks q6mo for six cycles. MP (melphalan, 0.25 mg/kg PO on days 1 to 4, and prednisone, 100 mg PO on days 1 to 4) is administered 35 days following the initiation of rituximab, and repeated q4- 6 wk for a minimum of nine cycles and two cycles after best response.

Currently, 28 patients are enrolled; 26 of 28 patients have completed the initial cycle of rituximab and have proceeded to MP therapy, and 25 of 26 are evaluable for response. Patient characteristics include a median age of 56 years (range, 35 to 78 years); mean beta-2-microglobulin of 3.0 mg/L (1.0 to 7.6 mg/L); and disease stage III, II, and I noted in 16, 8, and 4 patients, respectively.

Toxicity associated with rituximab administration was mild. Of 28 patients, 15 experienced grade 1-2 reactions. These reactions consisted of rigors, fevers/chills,arthralgias, and local skin reactions. During MP, 12 of 26 patients experienced grade 3-4 leukopenia and/or thrombocytopenia, resulting in therapy delay, dose reduction, or the use of growth factors. Six of these patients experienced leukopenia alone, and one patient experienced grade 4 thrombocytopenia. The latter patient was diagnosed with immune thrombocytopenia and mild splenomegaly.

During the 5 weeks prior to initiating the first cycle of MP, 2 of 25 patients experienced a major response; 2, a minor response; 18, stable disease; and 3 progressed. (A major response was defined as a > 50% reduction in monoclonal protein levels from baseline, and a minor response, a 25% to 50% reduction from baseline.) Of 25 patients with an adequate number of plasma cells at the time of diagnosis, CD20-positive plasma cells were noted in 5. Four of five patients who responded to rituximab were CD20 positive; the fifth responder had 7% of the plasma cells comarked with CD20. This patient had stable disease while receiving rituximab therapy.

Following a median of four cycles of MP, 13, 3, and 7 patients achieved a major response, minor response, and stable disease, respectively. Two patients progressed while receiving MP therapy.

CONCLUSION: Rituximab as a single agent appears to be active in a subset of multiple myeloma patients, possibly in those with CD20-positive plasma cells. Myelosuppression appears to possibly be more pronounced when rituximab is combined with MP than when MP is used alone. The role of rituximab in improving the response rate to MP and its effects on progression-free survival have yet to be determined.

Click here for Dr. Bruce Cheson’s commentary on this abstract.