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Relationship Between Quality of Response to Velcade and Clinical Benefit
By Ruben Niesvizky, MD
12.17.06





This analysis of the APEX (Vel vs. dex) and SUMMIT (Vel alone) trials in patients with relapsed/refractory MM indicates that patients who achieved CR/VGPR had longer treatment-free and overall survival. Thus depth of response to Velcade can be used as a surrogate marker for survival.

ABSTRACT:

Relationship between Quality of Response to Bortezomib (btz) and Clinical Benefit in Multiple Myeloma (MM) in the APEX and SUMMIT Studies. Session Type: Poster Session, Board #758-III

Ruben Niesvizky, P.G. Richardson, P. Sonneveld, M.W. Schuster, M. Coleman, D. Irwin, E.A. Stadtmauer, T. Facon, J. Harousseau, A. Boral, K.C. Anderson Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, USA; Dana-Farber Cancer Center, Boston, USA; Erasmus MC, Rotterdam, Netherlands; Alta Bates Cancer Center, Berkeley, USA; University of Pennsylvania Cancer Center, Philadelphia, USA; Hospital Claude Huriez, Lille, France; Hotel Dieu Hospital, Nantes, France; Millennium Pharmaceuticals, Inc, Cambridge, USA

BACKGROUND: The phase 2 SUMMIT trial of patients (pts) with relapsed and refractory MM showed that btz (VELCADE) is active, with a response rate of 27% (CR/PR) as a single agent, median TTP of 7 months, and median OS of 17 months. The phase 3 APEX trial in pts with relapsed MM following 13 prior therapies showed btz to be superior to high-dose dexamethasone (dex) in terms of response rate, TTP, and OS. Updated APEX data show a CR/PR rate of 43%, median TTP of 6.2 months, and median OS of 29.8 months. This analysis evaluated the relationship between quality of response to btz (CR/nCR versus PR; PR does not include nCR in this analysis) in these trials and clinical benefit, as defined by treatment-free interval and time-to-alternative-therapy (TFI and TTAT; time from last and first dose of btz, respectively, to first dose of alternative antineoplastic therapy), OS, and TTP. METHODS: In SUMMIT, 202 pts received btz 1.3mg/m2 on days 1, 4, 8, and 11 for up to eight 21-day cycles (median # of cycles: 6). Dex 20mg was added on the day of and day after each btz dose in pts with suboptimal responses to btz alone. In one arm of APEX, 333 pts received btz 1.3mg/m2 on days 1, 4, 8, and 11 for eight 3-week cycles and then on days 1, 8, 15, and 22 for three 5-week maintenance cycles (median # of cycles: 6). Responses in both trials were assessed according to EBMT criteria (modified to include nCR, a CR with positive immunofixation test). RESULTS: Data are shown in the Table. Median TFI appeared longer in pts with CR/nCR vs PR (SUMMIT, 9.8 vs 3.1 months; APEX, 17.5 vs 6.7 months). Similarly, TTAT appeared longer in pts with CR/nCR vs PR (SUMMIT, 15.4 vs 8.5; APEX, 21.2 vs 14.0). Median OS in all response groups has not yet been reached after a median follow-up of 22 months. TTP tended to be longer with CR/nCR vs PR in both studies (SUMMIT, 16.4 vs 9.2; APEX, 12.2 vs 8.3). CONCLUSIONS: Increasing quality of response to btz is associated with greater clinical benefit assessed by extended TFI ,TTAT, and TTP. Long un-maintained remissions can be attained with btz by achieving maximum tumor mass reduction (CR/nCR), even in pts with relapsed/refractory MM. Updated APEX data show that despite rapid initial response, many pts showed continued improvement in terms of M-protein reduction, and an increasing proportion of pts achieved CR with continued therapy. These data, together with the findings of this analysis, support maximizing tumor mass reduction to CR/nCR with btz to achieve greater clinical benefit.

Clinical benefit of btz by response
Kaplan-Meier median (95% CI) CR/nCR PR*
SUMMIT, n 19 34
TFI, mo 9.8 (2.7,14.3) 3.1 (2.0,8.7)
TTAT, mo 15.4 (7.9,17.6) 8.5 (7.3,14.0)
TTP, mo 16.4 (10.6,NE) 9.2 (7.2,NE)
Median cycles, n 8 8
APEX, n 48 87
TFI, mo 17.5 (6.7,24.1) 6.7(4.4,10.0)
TTAT, mo 21.2 (14.0,27.1) 14.0 (12.6,16.1)
TTP, mo 12.2 (8.8,NE) 8.3 (7.6,10.3)
Median cycles, n 9 10
*PR does not include nCR in this analysis; Includes 8 cycles of protocol-specified therapy plus maintenance cycles


Abstract #3529 appears in Blood, Volume 108, issue 11, November 16, 2006


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