April 19, 2011 — Treating relapsed multiple myeloma with subcutaneous rather than intravenous (IV) bortezomib (Velcade) cuts the risk for peripheral neuropathy without sacrificing response or survival, according data published online today in the Lancet Oncology.
The study provides proof of principal that subcutaneous bortezomib is not inferior to IV bortezomib in relapsed multiple myeloma, lead author Philippe Moreau, MD, from University Hospital, Nantes, France, told Medscape Medical News.
He also said that clinicians should start using subcutaneous dosing as standard treatment in patients like the ones in the study.
However, another expert disagreed with this recommendation.
In an accompanying editorial, Maria-Victoria Mateos, MD, from the Haematology Department, University Hospital of Salamanca, Spain, warns clinicians not to be too quick to switch to subcutaneous bortezomib dosing.
"This should not be implemented in routine practice until it has been approved. Above all, patient education and dose-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," Dr. Mateos writes.
Study Details
The randomized phase 3 trial enrolled adult patients with measurable secretory multiple myeloma after 1 to 3 previous lines of therapy and evidence of disease progression since last therapy. Patients excluded were those with previous bortezomib treatment, grade 2 or higher peripheral neuropathy or neuropathic pain, antineoplastic or experimental therapy, or who were taking more than 10 mg/day of prednisone.
Patients in the nonblinded study were randomized in a 2:1 ratio to bortezomib 1 to 3 mg/m2 on days 1, 4, 8, and 11 by subcutaneous (n = 148) or IV injection (n = 74), with the goal of showing that 4 cycles of the 2 treatment approaches produced a similar overall response rate (comprised of complete response, complete response plus partial response, or partial response).
Secondary end points included complete response, near complete response, "very good partial response," overall response rate after 8 cycles, effect of adding dexamethasone, time to response, duration of response, time to progression, progression-free survival, and 1-year overall survival.
Dr. Moreau reported that after 4 cycles, overall response rate was 42% in both groups. After a median follow-up of 11.8 months for the subcutaneous bortezomib group and 12.0 months for the IV bortezomib group, there were no differences in either time to progression (10.4 vs 9.4 months) or 1-year survival (72.6% vs 76.7%; P = .54). Median time to first response was 3.5 months in both groups.
However, there was one notable difference: peripheral neuropathy dropped from 53% with IV dosing to 38% with subcutaneous dosing (P = .044). Grade 2 peripheral neuropathy dropped from 41% to 24%, and grade 3 or worse peripheral neuropathy dropped from 16% to 6%.
"Reduction of neurotoxicity is an important finding," Dr. Moreau said. He also noted that overall rates of gastrointestinal disorders; respiratory, thoracic, and mediastinal disorders; and nervous system disorders were 10% or lower in the subcutaneous group.
Subcutaneous injections were generally well tolerated. Injection sites were the thighs or abdomen and were rotated for successive injections.
The authors point out that subcutaneous bortezomib "was noninferior in terms of efficacy compared with intravenous administration" and that this reflects the fact that pharmacokinetic and pharmacodynamic analyses show equivalent systemic exposure.
"Overall, subcutaneous administration 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," they write.
They conclude that "subcutaneous administration . . . in conjunction with dosing or schedule modifications could further reduce neuropathy side effects to a level such that potential peripheral neuropathy risk factors no longer constitute a limiting factor for selection of bortezomib treatment."
They also note that subcutaneous bortezomib might permit home administration of the drug.
The study was supported by Johnson & Johnson and Millennium Pharmaceuticals. Dr. Moreau reports relationships with Janssen and Millennium. Some of Dr. Moreau's coauthors are employees of Johnson & Johnson and Millennium. Dr. Mateos reports relationships with Millennium, Janssen, Celgene, and Novartis.
Lancet Oncol. Published online April 19, 2011. Moreau abstract, Mateos abstract
The study provides proof of principal that subcutaneous bortezomib is not inferior to IV bortezomib in relapsed multiple myeloma, lead author Philippe Moreau, MD, from University Hospital, Nantes, France, told Medscape Medical News.
He also said that clinicians should start using subcutaneous dosing as standard treatment in patients like the ones in the study.
However, another expert disagreed with this recommendation.
In an accompanying editorial, Maria-Victoria Mateos, MD, from the Haematology Department, University Hospital of Salamanca, Spain, warns clinicians not to be too quick to switch to subcutaneous bortezomib dosing.
"This should not be implemented in routine practice until it has been approved. Above all, patient education and dose-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," Dr. Mateos writes.
Study Details
The randomized phase 3 trial enrolled adult patients with measurable secretory multiple myeloma after 1 to 3 previous lines of therapy and evidence of disease progression since last therapy. Patients excluded were those with previous bortezomib treatment, grade 2 or higher peripheral neuropathy or neuropathic pain, antineoplastic or experimental therapy, or who were taking more than 10 mg/day of prednisone.
Patients in the nonblinded study were randomized in a 2:1 ratio to bortezomib 1 to 3 mg/m2 on days 1, 4, 8, and 11 by subcutaneous (n = 148) or IV injection (n = 74), with the goal of showing that 4 cycles of the 2 treatment approaches produced a similar overall response rate (comprised of complete response, complete response plus partial response, or partial response).
Secondary end points included complete response, near complete response, "very good partial response," overall response rate after 8 cycles, effect of adding dexamethasone, time to response, duration of response, time to progression, progression-free survival, and 1-year overall survival.
Dr. Moreau reported that after 4 cycles, overall response rate was 42% in both groups. After a median follow-up of 11.8 months for the subcutaneous bortezomib group and 12.0 months for the IV bortezomib group, there were no differences in either time to progression (10.4 vs 9.4 months) or 1-year survival (72.6% vs 76.7%; P = .54). Median time to first response was 3.5 months in both groups.
However, there was one notable difference: peripheral neuropathy dropped from 53% with IV dosing to 38% with subcutaneous dosing (P = .044). Grade 2 peripheral neuropathy dropped from 41% to 24%, and grade 3 or worse peripheral neuropathy dropped from 16% to 6%.
"Reduction of neurotoxicity is an important finding," Dr. Moreau said. He also noted that overall rates of gastrointestinal disorders; respiratory, thoracic, and mediastinal disorders; and nervous system disorders were 10% or lower in the subcutaneous group.
Subcutaneous injections were generally well tolerated. Injection sites were the thighs or abdomen and were rotated for successive injections.
The authors point out that subcutaneous bortezomib "was noninferior in terms of efficacy compared with intravenous administration" and that this reflects the fact that pharmacokinetic and pharmacodynamic analyses show equivalent systemic exposure.
"Overall, subcutaneous administration 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," they write.
They conclude that "subcutaneous administration . . . in conjunction with dosing or schedule modifications could further reduce neuropathy side effects to a level such that potential peripheral neuropathy risk factors no longer constitute a limiting factor for selection of bortezomib treatment."
They also note that subcutaneous bortezomib might permit home administration of the drug.
The study was supported by Johnson & Johnson and Millennium Pharmaceuticals. Dr. Moreau reports relationships with Janssen and Millennium. Some of Dr. Moreau's coauthors are employees of Johnson & Johnson and Millennium. Dr. Mateos reports relationships with Millennium, Janssen, Celgene, and Novartis.
Lancet Oncol. Published online April 19, 2011. Moreau abstract, Mateos abstract
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