Targeted Therapy Against Clonogenic Myeloma Cells with Iodine I-131 Tositumomab (Bexxar™).

Abstract

It has been proposed that treatment failures in multiple myeloma (MM) may be related to chemoresistance of malignant myeloma clonogenic cells (myeloma stem cells). Studies suggest that these cells are CD138− and express CD20, which is usually absent in more differentiated malignant plasma cells (Matsui et al, Blood 2004,15:2332). These findings provided a rationale for a treatment strategy to eliminate clonogenic myeloma cells using anti-CD20 antibodies. We conducted preclinical studies in vitro with tositumomab, the unlabeled anti-CD20 antibody in Bexxar. Bone marrow aspirates from MM patients were depleted of CD138 and CD34 to obtain CD138−CD34− cell populations by MACS separation using antibodies coupled to magnetic microbeads. These cells were treated with tositumomab for 24 hrs and plated in methylcellulose media. After 3 weeks of incubation, tositumomab inhibited colony formation of clonogenic myeloma cells. To evaluate the clinical effects of anti-CD20 treatment we developed a phase II trial with Bexxar as a consolidation treatment of MM. We hypothesized that Bexxar would be more efficacious than unlabeled antibody in eradication of highly radiosensitive myeloma cells by direct and cross-fire effects. To be eligible for Bexxar treatment, patients must have completed at least 4 cycles of therapy (1st to 3rd line) and have measurable disease in a plateau of at least partial response (PR) lasting at least 6 weeks. Patients undergoing first line therapy who are eligible for transplant are required to collect stem cells prior to Bexxar and have a second stem cell collection 3 months after Bexxar treatment. Samples for clonogenic studies are collected prior to Bexxar treatment, and at 3 months and 1 year post treatment. To date, 7 of 30 patients have been enrolled, 3 after completion of first line therapy with Velcade, Doxil, Dexamethasone (VDD) and prior to autologous stem cell transplant (ASCT), 4 in a plateau of PR after ASCT. Bexxar treatment was tolerated well in all patients with expected toxicities. Hematologic toxicities were mild. Two patients developed grade 3, and 4 grade 2 neutropenia, 4 patients grade 2 thrombocytopenia, and 1 grade 2 anemia. One patient (post ASCT) developed symptomatic HAMA requiring admission and 3 other patients (1 post ASCT, 2 prior to ASCT) developed HAMA titers without symptoms. Three patients who proceeded to ASCT collected stem cells prior to and after Bexxar treatment and all used post-Bexxar stem cell collections for ASCT. There were no difficulties encountered with stem cell collection. All engrafted at 11–12 days and had no unexpected toxicities with ASCT. Patients who proceeded to ASCT had stable disease (SD) at the end of 3-month period of Bexxar treatment. All remain in remission 6–9 months post Bexxar treatment (all in VGPR). Of patients who were treated with Bexxar post ASCT, 1 achieved a minor response (> 25%), 2 have SD with a followup of 1–12 months, and 1 had progressive disease at 3 months with subsequent 9 months of SD without intervention. The effects of Bexxar treatment on clonogenic myeloma cells are under evaluation and will be presented. We conclude that anti-CD20 consolidation treatment of myeloma patients with Bexxar used as targeted therapy against clonogenic myeloma cells is feasible and well tolerated. Clinical outcomes to date are encouraging, since clonogenic myeloma cells represent <5% of malignant plasma cells and the positive effects of treatment may require longer followup to be fully appreciated.