Novel Compound Permits High-Dose Radiation to Bone

NEW ORLEANS—High-dose radiation targeted to bone by 166Ho-DOTMP combined with melphalan (Alkeran) with or without total body radiation (TBI) is safe and effective in patients with multiple myeloma, according to clinical trial results presented at the 36th Annual Meeting of the American Society of Clinical Oncology (ASCO).

The toxicity of high-dose radiation is a barrier to effective treatment of multiple myeloma, said William Bensinger, MD, director, autologous bone marrow transplant program, Fred Hutchinson Cancer Research Center, Seattle.

“Ordinarily, it’s not possible to give more intensive therapy because most of the regimens we use in [stem cell] transplants are already at the maximum tolerated doses. If you go higher, patients die of toxicities,” he said. Even with high-dose therapies, Dr. Bensinger noted, malignant cells may regrow.

Generally, he said, treatment of the bone has been reserved for palliation in patients who have bone metastases from breast or prostate cancer.

What enables delivery of higher doses of radiation in the current study is the use of ¹⁶⁶Ho-DOTMP, described by Dr. Bensinger as a high energy, beta-emitting, phosphonate chelate that localizes to bone, produces aplasia in the adjacent marrow with little uptake into other tissues, and has minimal extramedullary toxicity. “What’s different about this is that it’s a way of getting the treatment to sites of disease and avoiding organs&ldots; that don’t have a lot of disease,” he said in an interview with ONI.

In the phase I/II multicenter, open-label, three-arm, dose-escalation study, holmium, a therapeutic isotope, was combined with the bone-seeking compound tetraphosphonate to make the novel compound ¹⁶⁶Ho-DOTMP. It was used in conjunction with one of three dose regimens of melphalan, an agent commonly used to treat patients with multiple myeloma.

¹⁶⁶Ho-DOTMP was administered in escalating doses of 20, 30, and 40 Gy. The three melphalan regimens were 140 mg/m² with or without TBI, or 200 mg/m² alone.

Participating patients (aged 18 to 70; mean, 54) had a diagnosis of advanced multiple myeloma with normal organ function and minimal previous radiotherapy to the marrow or spine. A total of 78 patients were entered into the study (52% male), with 72 eligible for treatment. To date, 66 patients have been evaluated for safety and 40 for efficacy.

Study Protocol

Patients were given 166Ho-DOTMP (dose range, 460 mCi to 4.5 Ci) followed by melphalan and then TBI for those assigned to it. Administered doses varied because patients differed in the amount of radiation their bone absorbed. Subsequently, patients received autologous stem cell transplant.

55% Overall Response Rate

Preliminary data, Dr. Bensinger reported, show a 55% overall response rate, with a 45% complete response across all doses of melphalan. Of the 40 patients evaluated for efficacy, 18 had a complete response, 4 had a partial response, and another 18 were primary refractory. Eight of the complete responses were in the ¹⁶⁶Ho-DOTMP plus melphalan 200 mg/m² group, while 7 were in the ¹⁶⁶Ho-DOTMP plus melphalan 140 mg/m² plus TBI group.

Five patients died during the study period, two of relapse and three of infection or bleeding, but the deaths were not related to the treatment regimen, Dr. Bensinger said.

He characterized the complete response rate as “higher than the complete response rates generally reported with high-dose therapies—which are usually in the 30% range.” He concluded that a targeted dose of up to 40 Gy of ¹⁶⁶Ho-DOTMP can be delivered safely to the marrow with either regimen of melpha-lan, and with TBI/melphalan 140 mg/m².

While cautioning that the findings were preliminary and the follow-up relatively short, Dr. Bensinger added, “We think these data will translate into improved survival.”