NEW ORLEANSHigh-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, its 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
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. Whats different about this is that its a
way of getting the treatment to sites of disease and avoiding
organs&ldots; that dont 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
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
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
therapieswhich 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.