Radiation Therapy in a New Era of Multiple Myeloma Management: Trends of Engagement and Radiologic, Biochemical, and Cytogenetic Correlates of Outcomes and Response

Background: Systemic therapies for MM have advanced considerably. Yet, the use of RT has remained stagnant due to heterogeneous integration into modern treatments. Here we report on three cohorts of MM RT patients treated at a large cancer center over 10 years, assessing trends of RT engagement, radiographic and biochemical outcomes, and potential correlates of RT response.

Methods: 466 MM patients who received RT to 1165 sites between 2000 - 2022 were identified. 80 consecutive RT courses delivered during 3 periods - 2013-2016, 2019, and 2022 - were analyzed. Cohorts were compared using the Wilcoxon rank-sum test and Chi-squared test with Rao & Scott's second order correction. Biomarkers changes were evaluated with a paired sample t-test and associations with local failure were assessed with Gray's test.

Results: From 2000-2022, the number of RT courses for MM increased to a greater extent than that of MM diagnoses (compounded annual growth rate of 20% vs 10%). Among the 3 groups of 80 RT courses, most common RT indications were palliation (89% in 2013-2016, 73% in 2019, and 69% in 2022), but non-palliative indications including peri-operative RT (3% to 10%), salvage/consolidative RT (9% to 16%), and bridging RT prior to chimeric antigen receptor T-cell therapy (0% to 4%) significantly increased over time (p=0.070). Positron emission tomography-computed tomography (PETCT) performed within 3 months of RT start increased from 76% to 94% (p=0.031). Compared to 2013-2016, the 2019 and 2022 cohorts received more lines of therapy prior to RT (median 6 (0-14) vs. 3 (0-11), p=0.005) and had more lesions on imaging (p=0.013) with more frequent extramedullary disease (EMD) (55% vs 28%, p=0.011). Biologic effective dose (BED) decreased over time (30.0 Gy to 28.0 Gy, p<0.001) and use of concurrent systemic therapy increased (41.3% vs 68.0%, p=0.001), with excellent radiologic response rates of 72% in 2013-2016, and 88% in both 2019 and 2022 (p=0.400). Interestingly, local failure (failure in RT field) was low at 12% despite distant progression occurring in 83%. Still, sustained local control through last follow up or death was observed in 86% of these patients, and all local failures occurred at or after distant progression (7.9 months, 0.0-39.1). Prior to RT, high risk cytogenetics (t(4:14), del(1p), del(17p), or 1q gain/amplification) were present in 72% of patients who had local failure compared to 44% of patients who did not (p=0.067). Other factors associated with local failure were the presence of any EMD on pre-RT imaging (p=0.003), radiating an extramedullary lesion, (p<0.001), lesion SUV≥9 (0.040), or not achieving a complete response on first post-RT imaging (p<0.001). Notably, BED was not significantly associated with local control (p=0.900). Lastly, following the use of RT, significant decreases were seen in total plasma protein (3%, p<0.001), lesion size (33%, p<0.001), and lesion SUV (69%, p<0.001).

Conclusion: Analysis of three cohorts of RT-treated MM revealed increasing incorporation of RT into the care of MM patients with significant changes in use over time. We documented the radiographic and biochemical impact of RT, and identified cytogenetic and clinical features that may indicate relative radio-resistance and inform RT approaches. While sustained local control of irradiated lesions was surprisingly high, further analyses to inform more optimal incorporation of RT into current treatments are ongoing.

Usmani:Pharmacyclics: Research Funding; Bristol-Myers Squibb - Celgene:: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Array Biopharma: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy; Gracell: Consultancy; Oncopeptides: Consultancy; GSK: Consultancy, Research Funding; EdoPharma: Consultancy; Merck: Research Funding; Pfizer: Consultancy; Sanofi: Consultancy, Research Funding; Gilead: Research Funding; SeaGen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; SecuraBio: Consultancy; Takeda: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; TeneoBio: Consultancy; Bristol-Myers Squibb - Celgene: Consultancy, Research Funding; Johnson & Johnson - Janssen: Consultancy, Research Funding. Mailankody:BMS, J&J, GSK, Springworks Therapeutics: Research Funding. Imber:Novartis: Research Funding; AstraZeneca: Research Funding; GT Medical Technologies: Consultancy, Honoraria, Research Funding; Bayer: Research Funding. Yahalom:Convergent RNR: Consultancy.