Pembrolizumab and low-dose, single-fraction radiotherapy for patients with relapsed or refractory multiple myeloma: a prospective, single-centre, single-group, open-label, phase 2 pilot trial in the USA.

BACKGROUND

Currently, the use of radiotherapy alone for people with multiple myeloma is limited to palliation of pain, pending fracture, and control of spinal-cord compression. Single immune-checkpoint inhibitors, such as anti-programmed death-1 (anti-PD1), have not been successful. We aimed to evaluate the activity and safety of the combination of pembrolizumab and low-dose, single-fraction, hypofractionated radiotherapy to treat patients with relapsed or refractory multiple myeloma.

METHODS

For this prospective, single-centre, single-group, open-label, phase 2 trial, we recruited patients with relapsed or refractory multiple myeloma from the Winship Cancer Institute (Emory University, Atlanta, GA, USA). Key inclusion criteria were aged 18 years or older, Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1, relapsed or refractory multiple myeloma as indicated by progression under International Myeloma Working Group (IMWG) criteria, and adequate candidacy for both pembrolizumab and radiotherapy. Baseline and post-treatment assessments were serial bone-marrow biopsy, peripheral blood collections, staging, serial serum and urine paraprotein analysis, serial PET-CT imaging, and a physical examination. On day 1, patients received hypofractionated 8 gray in 1 fraction (8 Gy/1 fx) radiotherapy to either symptomatic or progressing extra-osseous or osseous myeloma sites. Patients also received pembrolizumab (200 mg/kg intravenously) on day 2 or 3, then once every 3 weeks (±7 days) for 2 years or until progressive disease, unacceptable toxicity, withdrawal of consent, loss to follow-up, or death. Dose reduction and interruptions were not allowed. The primary outcome was acute toxicity defined as grade 3 or worse toxicity at 3 months within the radiated site when used in combination with pembrolizumab. All patients were analysed per protocol and included in safety analyses. This trial is registered on ClinicalTrials.gov (NCT03267888); it is completed and closed to accrual.

FINDINGS

32 patients were screened between June 1, 2018, and Sept 2, 2022, and 25 were enrolled in the trial and treated on protocol. Of the 25 treated patients, 11 (44%) were female and 14 (56%) were male. 19 (76%) patients were White and six (24%) were Black or African American. Toxicity, as the primary outcome, was deemed to be acceptable as no grade 4 or 5 adverse events were observed. At 3-month follow-up, eight (32%) of 25 patients had treatment benefit (one had stable disease, three had partial response, two had very good partial response, and two had complete response). There was no grade 3 or worse radiation-related toxicity within irradiated volumes. One (4%) patient of the 25 who received combination treatment had a grade 3 pembrolizumab-related adverse event. There were no treatment-related deaths.

INTERPRETATION

Combination treatment of low-dose, single-fraction radiotherapy with pembrolizumab was safe, with early promise of response activity. Our approach could be an option for patients with relapsed or refractory multiple myeloma who have not responded to previous treatment. Larger trials to substantiate our findings are needed.

FUNDING

Merck Sharp & Dohme.

Informations de copyright

Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

Déclaration de conflit d'intérêts

Declaration of interests MKK received funding for this research, paid to their institution, from Merck Pharmaceutical. JMS received a grant for this research from the US National Institutes of Health. JLK has received contracts from Janssen, AbbVie, Genentech, Bristol Myers Squibb, Fortis, Takeda, and Amgen; has received consulting fees from AbbVie, Bristol Myers Squibb, Sebia, and Sanofi; has received support for attending meetings from Bristol Myers Squibb and Sanofi; and has participated on a data safety monitoring board and an advisory board for Incyte. AJN has been on advisory boards for and received honorarium from Adaptive Biotechnologies, Amgen, AstraZeneca, Bristol Myers Squibb, Cellectar Biosciences, GlaxoSmithKline, Janssen, K36 Therapeutics, ONK Therapeutics, Pfizer, Sanofi, Sebia, and Takeda; has received research support, paid to their institution, from Aduro Biotech, Amgen, Arch Oncology, Bristol Myers Squibb, Cellectis, Genentech, GlaxoSmithKline, Janssen, Karyopharm, Kite Pharma, Merck, Pfizer, and Takeda; and has received research support for investigator-initiated studies from Amgen, GlaxoSmithKline, Janssen, Merck, and Takeda. SL has received contracts from Merck, Novartis, Bristol Myers Squibb, and Janssen; has received consulting fees from Janssen, Bristol Myers Squibb, GlaxoSmithKline, Regeneron, Novartis, AbbVie, Genentech, Pfizer, Takeda, and Celsene; has been on the board of directors for TG Therapeutics; and holds stock in TG therapeutics. All other authors declare no competing interests.