Phase 2 Trial of Anti-PD1 and 8 Gy in 1 Fraction for Relapse/Refractory Myeloma

Abstract

Relapsed, refractory multiple myeloma is associated with poor outcome. Role of radiotherapy is mainly for palliation. Anti-PD1 inhibitors have failed to show efficacy in relapsed refractory myeloma patients. A phase 2 trial (NCT03267888) was conducted to see if radiotherapy (8 Gy in 1 fraction) and anti-PD1 (Pembrolizumab) could provide early signals of safety and response. A prospective single-center phase 2 trial involving patients >18 years of age with ECOG 0-1 was conducted after obtaining IRB approval. Patients had to have ISS stage I-III multiple myeloma that was either relapsed or refractory, an osseous and/or extraosseous lesion that could be radiated, and who were candidates for pembrolizumab. Patients had to have either measurable disease per the International Myeloma Working Group Criteria (IMWG) and/or had to have progressive disease on imaging. Radiotherapy was given on day 0, cycle 1 followed by pembrolizumab (200 mg/kg iv on day 2 or 3, then every 3 weeks +/- 7 days) on day 2-3 for at least 2 years or until progression. Primary endpoint was toxicity. Secondary endpoints were IMWG response, abscopal response, overall survival, and immunological changes in patient's blood. Patients were assessed at 3 months, 6 months, and 12 months IMWG criteria as well as serial PET/CT based imaging. Patients with stable disease or better were continued on the trial. Patients that progressive were removed. Standard statistical analysis was performed, and included Kaplan-Meier to estimate OS and PFS. From June, 2018 until October, 2021, 32 patients were screened and 25 were enrolled. Of the enrolled patients, 76% were Caucasian, 64% had ECOG 1, and the mean age was 60 years. Prior to enrollment, the mean number of prior lines of therapy that the patients had failed was 5.20 (range: 2 - 11), suggesting a cohort with poor expected outcome. These cohort also had limited alternative options. Toxicity, as its primary endpoint, was acceptable. There were no grade 2 or higher radiation related toxicity within the irradiated volume. Only one case of grade 3 or higher pembrolizumab-related toxicity was noted amongst the 25 patients. Abscopal response was noted in 5 of 25 patients (20% patients). Several patients showed robust reductions in the paraproteins and other myeloma labs, suggesting response to radiotherapy and anti-PD1 combination. These patients were also associated to have a robust CD 8 T cell activation and an abscopal response. The secondary outcomes were better than expected for this cohort. Combination therapy of single-fraction, low-dose radiation therapy with pembrolizumab in patients with relapsed or refractory multiple myeloma is worth assessing in future trials.