A Phase II Study of Consolidation Treatment with Iodione-131 Tositumomab (Bexxar™) in Multiple Myeloma (MM)

Despite the introduction of novel agents and therapies, MM remains incurable. Approximately 15–20% of MM patients have detectable CD20 expression on their malignant cells. Additionally, preclinical studies evaluating the properties of clonogenic MM cells (“MM stem cells”) suggest that these cells express CD20. However, studies with rituximab, an anti-CD20 antibody have not clearly established CD20 as a valid target in MM. I-131 tositumomab is a radiolabeled murine anti-CD20 antibody which is highly effective in the treatment of low-grade B-cell NHL and has a well-characterized toxicity profile. In this study, we evaluated the safety and efficacy of consolidation treatment with I-131 tositumomab in patients with MM who had received ≥1 line of prior treatment.

This was a single arm, phase II, single-center study. All patients had symptomatic MM and had received 1–3 prior treatment regimens. Patients were required to have a stable response to prior therapy of > PR but < CR on at least two evaluations with measurable disease at the time of study entry. Patients were required to have adequate hematologic, hepatic and renal function and ≤ 25% bone marrow involvement of their MM. All patients received I-131 tositumomab in standard fashion, comprised of a dosimetric dose followed within 1–2 weeks by a therapeutic dose of 75cGy of total body radiation. No maintenance therapy was administered. The primary endpoint was the rate of ≥25% reduction in monoclonal proteins (MR). Secondary endpoints included the rate of CR, DOR and PFS.

Between July 2006 and April 2012, sixteen patients were enrolled. Median age was 56 (45–77). Nine were male. The median number of prior treatments was 2. Six patients had CD20 positive MM. In the total population, results were as follows: PD=7, SD=4, MR=1, PR=2, CR=2, for an ORR of 31% (95% CI: 11%-59%). Of the 4 patients with SD, 3 had their data censored at 3 months because they proceeded to transplant, and the other patient has only 3 months of follow up to date. In the CD20 negative population, response rates were PD=6, SD=3, PR=1 for an ORR of 10% (95% CI: <1%-45%). In the CD20 positive population, response rates were PD=1, SD=1, MR=1, PR=1, CR=2 (both stringent CR) for an ORR of 67% (95% CI: 22%–96%), (p=0.036 for comparison between the two). Time to response ranged from 3 months to 2.5 years. With a median follow up of 4 years, none of the responding patients have progressed and all are alive. Both patients who achieved CR were in PR to their prior line of therapy at study entry for 13 months and 9 months respectively, and their duration of CR is 42 months and 25 months respectively. Three patients developed positive human anti-mouse antibodies (HAMA). One of these was the only CD20 positive patient to develop progressive disease. Grade 3 or 4 toxicities included thrombocytopenia (25%), neutropenia (44%) and infection (12.5%).

I-131 tositumomab is well-tolerated in patients with previously treated MM and produces objective responses including CRs. ORR was significantly higher in CD20 positive compared with CD20 negative disease: 67% vs. 10% (p=0.036). Achievement of response is delayed compared to what is observed with standard MM therapy. While we continue to investigate its effects on MM “stem cells,” these results indicate that I-131 tositumomab produces highly durable responses in CD20 positive MM.

Off Label Use: Bexxar (I-131 tositumomab) a radiolabled anti-CD20 antibody. It is approved by the FDA for the treatment of patients with CD20-positive relapsed or refractory, low-grade, follicular, or transformed non-Hodgkin's lymphoma, including patients with Rituximab-refractory non-Hodgkin's lymphoma. In this study, Bexxar is used in the treatment of previously treated multiple myeloma. Kaminski:GlaxoSmithKline: Bexxar, Bexxar Patents & Royalties.