Single Agent Bortezomib Is Associated with a High Response Rate in Patients with High Risk Myeloma. A Phase II Study from the Eastern Cooperative Oncology Group (E2A02).
Angela Dispenzieri, MD1,
Lijung Zhang, M.S.2,*,
Rafael Fonseca, M.D.3,
David H. Vesole, M.D., Ph.D.4 and
Philip R. Greipp, M.D.1
1 Hematology, Mayo Clinic, Rochester, MN, USA; 2 Biostatistics, Dana Farber Cancer Institute, Boston, MA, USA; 3 Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA and 4 Medical Oncology, St. Vincents Comprehensive Cancer Center, New York, NY, USA.
Background: MM is an incurable disease with an anticipated overallsurvival ranging from months to decades. Novel therapies likebortezomib have activity in both the relapsed/refractory andup front settings. There are sparse data on whether novel therapiesmay overcome high risk features.
Methods: Patients with newly diagnosed high-risk myeloma (beta-2microglobulin [B2M] >= 5.5., plasma cell labeling index [PCLI]>= 1, or deletion 13q) were eligible. Patients were treatedwith bortezomib 1.3 mg/m2 day 1, 4, 8, and 11 every 21 daysfor 8 cycles as induction. After induction, patients receivedbortezomib 1.3 mg/m2 every other week indefinitely. Patientsrelapsing on maintenance schedule resumed full induction schedule.Responses were defined by the EBMT criteria. The primary end-pointwas the response rate (90% power to detect a response rate of>=50% ).
Results: Between March 15, 2004 and March 10, 2005, 44 patientsenrolled. Among the 43 eligible patients, median age was 63;51% were male. All had high risk disease: deletion 13q (6/41);PCLI >=1% (17/33); t(4:14) (4/27) and B2M >= 5.5 (34/43).Response data are available for 37 of the 43 eligible patients.The overall response rate was 49% (95% CI: 0.32, 0.66) (0 patientswith CR, 1 VGPR, 15 PR, 2 MR, and 11 inevaluable). The responserate allowing for use of serum monoclonal protein levels whena measurable urine monoclonal protein was unavailable at follow-upwas 59.5% (1 patient with CR, 1 VGPR, 18 PR, 2 MR, and 6 inevaluable).The median progression free survival is 9.4 months. Thirty-threepercent of patients completed the 8 cycles of planned inductiontherapy and moved to maintenance. Reasons for discontinuingtherapy have included progression or death (n=18), adverse events(n=6), and other (n=14). Only 12% of patients remain on activetherapy: 0% of deletion 13q patients; 25% of t(4:14) and 12%each of high B2M and high PCLI patients. Of the 14 patientswho entered the maintenance phase of treatment, 3 have progressed.Of these 3, 2 took re-induction, and neither responded. Mediantime to progression for those entering maintenance was12.4 monthsfrom the time of starting maintenance. The most common adverseevents of grade 3 or higher included neutropenia (33%), diarrhea(31%), hyponatremia (21%), anemia (19%), thrombocytopenia (16%),fatigue (14%). Grade 12 sensory peripheral neuropathyoccurred in 53% of patients, with only 2% having grade 3 sensoryneuropathy. One patient had grade 3 peripheral neuropathy. Onepatient died after receiving 2 doses of protocol treatment dueto heart block and asystole. Updated results on the full studypopulation will be presented at the meeting.
Conclusions: In high risk patients, upfront bortezomib appearsto result in comparable response rates to those reported forunselected cohorts of newly diagnosed myeloma patients. Continuedfollow-up of these patients will provide information about whetherthis will translate into better overall outcomes.