ORLANDO – A subcutaneous form of bortezomib appears to be a therapeutic chip off the old intravenous bortezomib block, but with better safety than the parent compound, investigators reported at the annual meeting of the American Society of Hematology.
In a randomized phase III study link in patients with relapsed multiple myeloma, the overall response rates (ORR) after four cycles in patients treated with either IV bortezomib (Velcade) or subcutaneous (SC) bortezomib were identical, at 42%. Complete responses occurred in 8% of patients treated with the IV drug and 6% with the SC drug; partial responses occurred in 34% and 36%, respectively, said Dr. Philippe Moreau from University Hospital in Nantes, France.
[Bortezomib-Based Regimens Help Older Patients With Multiple Myeloma]
"So we do have now similar efficacy with sub-Q, a more convenient route of administration for patients, especially those with poor venous access, we don’t require IV lines or central lines, and we do have, most importantly, a reduction of toxicity. In my opinion, these findings are really important for our patients," Dr. Moreau said.
Although patient exposure to the drug (as measured by area-under-the curve mean plasma concentrations) were virtually identical between the two routes of administration, the time to maximum plasma concentration (Tmax) was shorter with the IV formulation, at a median 0.03 hours, than with the SC version, at a median 0.50 hours.
In addition, maximum plasma concentrations (Cmax) of bortezomib were considerably higher with the IV formulation, at a mean 223 ng/mL, than with 20.4 ng/mL for SC. These differences may account for the lower toxicity with the SC formulation, Dr. Moreau said.
The investigators compared the ORR after four cycles of SC or IV bortezomib in previously treated patients with multiple myeloma. Secondary outcomes were complete response, near–complete response, and very good partial response rates after four cycles, ORR after eight cycles with or without dexamethasone, time-to-progression, progression-free survival, 1-year survival, time to response, and duration of response, as well as pharmacokinetics and pharmacodynamics and safety.
Patients with 1 to 3 previous lines of therapy for multiple myeloma were randomly assigned to receive IV bortezomib 1 mg/mL as a 3-5 second IV push (74 patients) or SC injections 2.5 mg/mL in the thigh or abdomen with rotation of injections within each cycle (148 patients). All of the study participants received a median of eight treatment cycles and remained on study for a median of 22.57 weeks.
The median cumulative dose was 31.46 mg/m2 in patients on the IV drug, and 33.76 mg/m2 in patients on the SC form. Slightly more than half of the patients in each group received dexamethasone (53% and 56%, respectively), at a median dose intensity in each group of 160 mg per cycle.
As with the primary end point, the ORR after 8 cycles of bortezomib with or without dexamethasone were identical in the two groups, at 52%. Of these responses, 12% were complete and 40% were partial in the IV group, compared with 10% and 42%, respectively, in the SC group.
The time to first response was also identical, at a median of 1.4 months in each group. Time to best response was a median 1.5 months in the IV group and 1.6 months in the SC group; the median duration of response was 8.8 months and 9.7 months, respectively. Median time to disease progression was 9.4 and 10.4 months, respectively, a difference that was not statistically significant.
The 1-year survival rates were 76.7% for patients who received IV bortezomib, and 72.6% of patients who received the drug subcutaneously.
An analysis of proteasome inhibition measured as the area under the effect-time curve showed that the subcutaneous formulation was comparable to IV push.
Grade 3 or 4 adverse events occurred in 70% of patients in the IV group and 57% of those in the SC group. Bortezomib dose reductions or discontinuations due to adverse events were higher among patients who received the IV form, at 43% and 27%, compared with 31% and 22% for those who received SC injections. Grade 3 or greater hematologic abnormalities were similar between groups, except for white blood cells counts, which were abnormally low in 18% of patients on IV, vs. 8% of those in the SC group.
Peripheral neuropathy of any grade was seen in 53% of IV patients, compared with 38% of SC patients (P =. 04). Also higher in the IV group were grade 2 or greater peripheral neuropathy events (41% vs 24%, P = .01) and grade 3 or greater events (16% vs. 6%, P = .03). Risk factors for peripheral neuropathy, including grade 1 neuropathy or diabetes at baseline or prior exposure to neurotoxic drugs, were similar between groups, however.