A Phase II, Safety and Efficacy Study of Fixed Dose Radioimmunotherapy (Zevalin, yttrium-90 ibritumomab tiuxetan) for Patients with Incomplete Response to Chemotherapy Prior to Autologous Stem Cell Transplant (ASCT) for Multiple Myeloma

INTRODUCTION:

Studies suggest that the clonogenic cell in Multiple Myeloma (MM) is a post-germinal center B-cell expressing CD20, which makes it a potential target for antibody therapy.  90Y-Zevalin (ibritumomab tiuxetan) combines an anti-CD20 antibody with the radioisotope yttrium-90, which has the potential to kill not only a targeted CD20+ cell, but also neighboring plasma cells which may not express CD20.  This phase II trial evaluated the safety and efficacy of 90-Zevalin given prior to planned high dose chemotherapy (melphalan 200mg/m2) and ASCT to patients with incomplete response to prior chemotherapy for MM.  

METHODS:

Patients received a cold dose of rituximab 250mg/m2 followed by single dose of 0.4mCi/kg 90Y-Zevalin (max 32mCi) at least 4 weeks following last chemotherapy for MM, corresponding to day -14 prior to ASCT. 111In-Zevalin was given one week prior for imaging to confirm expected biodistribution. At least 14 days separated the outpatient administration of 90Y-Zevalin and reinfusion of autologous stem cells to allow for sufficient 90Y decay. Response was assessed and melphalan administered on day -2 prior to ASCT and again 90 days after ASCT. This non-randomized study employed a Simon two-stage, minmax design. All patients who received the therapeutic dose of 90Y-Zevalin were included in the analysis. Response was scored according to the criteria of Blade J, et al. (1998)

RESULTS:

Six patients received 90Y-Zevalin followed by melphalan and ASCT (5 were male, age range 53-68, 2 were second transplants). Median time to engraftment was 12 days (range 8-21). Four patients had measurable disease at entry and were strictly evaluable for response. One patient achieved partial response (PR) after 90Y-Zevalin and very good PR after ASCT. Two patients achieved stable disease (SD) after 90Y-Zevalin; and PR and complete response respectively after ASCT. The fourth patient had progressive disease (PD) after 90Y-Zevalin and SD after ASCT. A seventh patient received 90Y-Zevalin with delayed ASCT in an initial iteration of the protocol, with PD documented at >10 weeks. Seven patients were evaluable for toxicity. There was no infusion related toxicity. Four patients had peri-transplant bacterial infections: line associated septic thrombosis, bacteremia without source x 2, and peri-rectal abscess associated with delayed engraftment prompting infusion of back-up stem cells on day +19 and granulocytes.

CONCLUSION:

Although the pre-specified response threshold was reached in stage I; the modest response rate associated with the high expense of radioimmunotherapy and concern for a possible increase in peri-ASCT bacterial infections limits enthusiasm for further study.