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.