Subcutaneous bortezomib appears to be as effective as the standard intravenous route for treating relapsed multiple myeloma, but with a lower risk of peripheral neuropathy and the potential for facilitating home administration by a nurse. That was the conclusion of a multicenter Phase II trial conducted at 53 treatment centers in Europe, Asia, and South America, published in the May issue of Lancet Oncology (DOI:10.1016/S1470-204570081-X).
The findings also indicate that subcutaneous treatment could be less costly while helping to improve patient compliance, reducing side effects without jeopardizing efficacy.
Bortezomib is a standard treatment for patients with newly diagnosed and relapsed multiple myeloma. In 2003, it became the first proteasome inhibitor to be approved by the FDA.
The new study involved 222 patients randomly assigned to receive the approved 1.3 mg/m2 dose twice per week, for eight cycles. A total of 145 patients were enrolled in the subcutaneous treatment group, while 73 received bortezomib intravenously.
The primary objective was to evaluate overall and complete response plus partial response after four cycles of treatment. Secondary objectives were to establish complete, near complete, and very good partial response rates after four cycles; overall response after eight cycles, including the effects of adding the glucosteroid dexamethasone; time to response; duration of response; time to progression; progression-free survival; and one-year overall survival.
The researchers also assessed safety and tolerability and the pharmacokinetics and pharmacodynamics of both routes of administration.
After four cycles there was an overall response rate of 42% in both groups, and at a median about one year no significant differences in time to disease progression, progression-free survival, or overall survival were observed. The study found that for 60% of patients, subcutaneous treatment was at least as effective as intravenous delivery.
Subcutaneous patients also reported fewer Grade 3 or worse side effects—57% compared with 70%—and fewer dose reductions and discontinuations due to adverse events. Among subjects in the intravenous group, 35 discontinued treatment, half because of adverse side effects.
The incidence of peripheral neuropathy was significantly lower in the subcutaneous group, 38% to 53%, although potential risk factor rates were similar in patients in both groups. An estimated 30 percent of all patients treated with bor-tezomib had peripheral neuropathy.
About one in four patients who also received dexamethasone plus bortezomib showed improved responses from cycle 4 to cycle 8. Roughly half received dexamethasone after four cycles, while those with poor response after cycle 4 were eligible for 20 mg per day of dexamethasone. Patients who continued to worsen could receive two additional cycles.
“Overall, subcutaneous administration [of bortezomib] seemed to have an improved systemic safety profile compared with intravenous delivery, with lower rates of Grade 3 or worse adverse events and fewer bortezomib dose reductions and discontinuations because of adverse events,” the authors reported.
“Subcutaneous administration seems to provide an additional option to reduce bortezomib-related peripheral neuropathy, and in conjunction with dosing or schedule modifications could further reduce neuropathy side effects to a level such that…peripheral neuropathy risk factors no longer constitute a limiting factor for selection of bortezomib treatment.”
First author Philippe Moreau, MD, PhD, Professor in the Department of Hematology at University Hospital Hôtel-Dieu in Nantes, France, told OT that he does not believe that further study is necessary to demonstrate the benefits found in the trial.
“Larger studies are unnecessary—this is definitely a better approach, but approval from regulatory authorities will be needed. Also, I don't believe self-administration is a valid option at this point. A nurse needs to be there due to the risk of overdose.”
One important limitation of the study—senior author was Jean-Luc Harousseau, MD—was that no patient-reported outcome or health-related quality-of-life data were collected.
“Such data could have been useful to differentiate [between] the administrative approaches in addition to the differing systemic safety profiles, and the increased convenience of subcutaneous administration,” he said.
Patient Education and Close Monitoring Needed
In an accompanying comment in the journal, María-Victoria Mateos, MD, PhD, a consultant physician in the hematology department at University Hospital of Salamanca in Spain, emphasized the importance of ongoing research on transcutaneous bortezomib, and said changing from IV treatment should not be implemented in routine practice until it has been approved.
“Above all, patient education and close monitoring programs must continue, in conjunction with developing dose-modification guidelines that might avoid and reduce side-effects, to avoid converting a step forward into a step back,” she wrote.
Asked for his opinion for this article, Kenneth Anderson, MD, Director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, said the study had several important outcomes.
“I think the major advantage is that subcutaneous therapy is more user-friendly for both the patient and caregiver,” he said in a telephone interview.
The study also offers the opportunity to evaluate subcutaneous bortezomib as a maintenance therapy, he said. “I think eventually self-administered subcutaneous therapy will become an in-home option, but in the meantime it will make outpatient clinic visits shorter.”
Big Advantage: Reduced Peripheral Neuropathy
The Chair of the Myeloma Committee of the Eastern Cooperative Oncology Group, S. Vincent Rajkumar, MD, Professor of Medicine in the Hematology Division of the Mayo Clinic, said that reducing the incidence of peripheral neuropathy—“the number one problem for patients given bortezomib”—should be a major advantage.
The rates of effectiveness were also impressive, he noted.
He called the study's differences between IV and SC administration—6% vs 16%—quite dramatic. “Around 53 percent of IV patients experienced peripheral neuropathy, so this is an important and encouraging finding.”
The potential for patients to eventually be able to self-administer the drug is also significant, with its potential to improve patients' quality of life, he said.
“But this is much further down the road. Bortezomib currently must be diluted before it is given at a clinic or hospital, and it would be unreasonable to expect patients to do this properly at home. The drug will also need to be repackaged, probably as individual syringes similar to those used to self-administer heparin or insulin.”
But all of this will require FDA approval, he noted.
“We have no idea how soon it could become available, but it might be relatively quick—all the manufacturer has to do is show the benefits. With these two important findings, reduced peripheral neuropathy and in-home administration—one is a reality and the other remains a possibility.”