An ultra-low 4-Gy course of radiation therapy (RT) delivered in just one or two treatments provided pain relief for most patients with uncomplicated painful bone lesions from multiple myeloma, according to a prospective multicenter phase 2 trial.

“Four out of five patients did not need more radiation therapy after the first course, which tells us this strategy can provide effective pain control without interrupting other treatments and with almost no side effects to the patient,” lead investigator Leslie Ballas, MD, professor of radiation oncology at Cedars-Sinai Medical Center, Los Angeles, said in a statement from the American Society for Radiation Oncology (ASTRO) 2026 Annual Meeting, where she presented the results. 

The results are “exciting [and] may help clinicians consider radiotherapy earlier in the course of care for patients with multiple myeloma experiencing painful bone disease,” said ASTRO expert Chelsea Pinnix, MD, PhD, a radiation oncologist at The University of Texas MD Anderson Cancer Center, Houston. 

Bone disease is a common complication of multiple myeloma. RT is effective for palliation, but patients often are referred later in their care after symptoms worsen, in part because of concerns about effects on healthy bone marrow.

Survival in multiple myeloma is improving. That means patients may receive multiple lines of therapy over their lifetime and consequently need to preserve bone marrow function for subsequent treatments. That’s an important rationale for testing an ultra-low dose, Ballas explained.

Another reason to minimize marrow exposure: The volume of bone marrow receiving 10 Gy or more has been shown to independently predict hematologic adverse events.

“This is critical as patients receive more systemic lines of therapy, need transplant, CAR T-cell therapy, and trial eligibility,” Ballas told attendees. “Low initial dose keeps the door open for re-irradiation.”

The prospective, single-arm trial enrolled patients with painful, uncomplicated bone lesions from multiple myeloma from seven institutions. Patients with spinal cord compression, pathologic fracture of a long bone, or skull-base or orbital index lesions were excluded.

Participants received a total radiation dose of 4 Gy, either as a single 4-Gy fraction or 2 Gy in two fractions. Fractionation approach was selected by the treating clinician rather than randomized. Pain was evaluated using the Brief Pain Inventory (BPI), together with oral morphine equivalent dosing (OMED), according to international consensus criteria for palliative RT.

The primary endpoint was pain response at 4 weeks, with additional assessments at 8 weeks and 6 months. Patients with inadequate pain control could receive further radiation to the same site. 

Sixty-nine patients were treated and 63 were evaluable for the primary endpoint. The median age was 66 years, most patients had received prior chemotherapy, and 42% had previously received RT to another site. The pelvis was the most commonly treated index site, followed by the spine. 

Among patients completing pain questionnaires, complete or partial pain responses were reported in 66% at 4 weeks, 64% at 8 weeks, and 86% at 6 months. The median time to pain relief was 36 days, and BPI scores and opioid use declined from baseline and remained lower at 6 months. 

The study, however, did not meet its prespecified primary statistical endpoint. In the primary analysis of all 63 evaluable patients, including two who did not complete the 4-week questionnaire, 40 patients (64%) achieved a response at 4 weeks compared with the prespecified null response rate of 55% (one-sided P = .11).

Ballas explained that the trial was “arbitrarily designed to show a pain response of 70% at 4 weeks, based on very limited data.” Although the primary endpoint was not met, she said, “a pain response of approximately two thirds is potentially clinically meaningful, especially in a risk-adapted approach.” 

Most patients also avoided additional radiation. Overall, 19% underwent re-irradiation of the index lesion, generally about 2 months after the initial course; among those re-irradiated, the pain response rate was 63% at 4 weeks. 

The trial was not powered to compare the two fractionation schedules, but Ballas said there appeared to be no difference in response rates at any time point or in the need for re-irradiation between patients receiving 4 Gy once and those receiving 2 Gy twice. 

Treatment-related toxicity was limited. Four patients experienced grade 1-2 fatigue and one developed grade 1 dermatitis; there were no grade 3 or higher treatment-related adverse events.

Ballas said next steps include determining whether some patients with multiple myeloma might benefit from low-dose RT earlier in the course of bone disease, before pain becomes severe, and identifying which lesions are most likely to respond to this approach.

Ballas said she does anticipate needing to do a phase 3 trial. The prospective phase 2 results compare favorably with historical controls, she said, and 4 Gy — either 2 Gy in two fractions or 4 Gy in one — is “ready for clinical use,” provided patients are counseled that it is a “risk-adapted approach” and that some ultimately may require re-irradiation. 

The study had no specific funding. Ballas has received honoraria from UpToDate and compensation/payment from UroToday. Pinnix reported receiving grant/research funding from Merck.