Augmented conditioning with targeted molecular radiotherapy prior to autologous stem cell transplantation in myeloma: Results of a phase II randomised control trial with improved CR rate post ASCT

Background: Autologous stem cell transplantation (ASCT) remains important as consolidation therapy for patients with myeloma, improving rate and duration of response. The standard conditioning treatment with high dose melphalan has remained unchanged for 3 decades, further increase in the intensity of therapy is limited by toxicity to non-haematopoietic organs. We developed TMRT with a radiolabelled monoclonal antiCD66 that targets bone marrow, plasma cells and lymphoid tissue as a vector for delivering high dose radiation to sites of disease. We report the results of a Phase II RCT demonstrating improved sCR/CR responses using the radiolabelled mAb. Aims: Trial Design: A randomised, multi-centre, non-blinded Phase II study comparing two treatment conditioning schedules prior to ASCT. Arm A TMRT plus high dose melphalan vs Arm B high dose melphalan alone. Primary objective: To determine the efficacy of TMRT delivered by an Yttrium-90 (90Y)-radiolabelled murine antiCD66 monoclonal antibody given in addition to high dose melphalan (200mg/m2) in terms of disease response in patients undergoing ASCT for multiple myeloma. Secondary objectives: Engraftment, time to disease progression, time to next treatment, overall survival, HAMA formation. Methods: Twenty-five patients were recruited out of a planned 90. All patients had confirmed multiple myeloma, were in PR/vgPR following chemotherapy and were scheduled to receive autologous stem cell transplantation. Randomisation was stratified by disease risk (low/high). Patients randomised to receive TMRT received an infusion of indium-111 labelled antiCD66 to allow imaging and organ dosimetry calculation. Patients with favourable dosimetry received an infusion of 90Y-labelled antiCD66, at an activity of 37.5MBq/kg lean body weight as outpatients 14 days prior to scheduled ASCT. Patients in both arms were admitted two days before ASCT and given high does melphalan. All patients were managed post ASCT as per centre protocols. Disease response was assessed pre-ASCT and at 3, 6, 9 and 12 months using EBMT response criteria. Logistic regression, adjusting for risk group, was used to analyse the primary endpoint (alpha 15% 1-sided). Results: Twenty-five patients were randomised: 12 to Arm A; 13 to Arm B. Twelve patients in each arm were available for analysis. Myeloma sub-type, gender, patient's age and risk group numbers were similar in each arm. Median infused 90Y-activity 2.31GBq, range 1.61-2.74GBq. Median radiation doses to organs BM 32.10Gy (17.2-34.7), liver 4.70Gy (1.7-12.0), spleen 28.55Gy (7.4- 34.0), renal 2.90Gy (2.1-3.6), pulmonary 3.45Gy (1.2-4.0), whole body 0.85Gy (0.8-1.2). Toxicities were similar in each arm. All Arm A patients showed a response improvement, 3 Arm B patients had stable disease with no change (2 PR, 1 vgPR). Summary and Conclusions: The study achieved its primary endpoint demonstrating a statistically significant improvement in the complete response rate for patients in Arm A compared to Arm B (50% vs 25%, odds ratio [85% 1- sided CI]: 0.277 [0.102, 0.753]). This is the first demonstration in an RCT of effective augmentation of the conditioning prior to ASCT that improves the response rate post transplant without additional toxicity. (Figure Presented).