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Clinical Trial
. 2012 Jun;157(5):553-63.
doi: 10.1111/j.1365-2141.2012.09099.x. Epub 2012 Mar 26.

Bortezomib salvage followed by a Phase I/II study of bortezomib plus high-dose melphalan and tandem autologous transplantation for patients with primary resistant myeloma

Taiga Nishihori  1 , Todd J Alekshun, Kenneth Shain, Daniel M Sullivan, Rachid Baz, Lia Perez, Joseph Pidala, Mohamed A Kharfan-Dabaja, Jose L Ochoa-Bayona, Hugo F Fernandez, Danielle N Yarde, Vasco Oliveira, William Fulp, Gang Han, Jongphil Kim, Dung-Tsa Chen, Jyoti Raychaudhuri, William Dalton, Claudio Anasetti, Melissa Alsina
Affiliations
Clinical Trial

Bortezomib salvage followed by a Phase I/II study of bortezomib plus high-dose melphalan and tandem autologous transplantation for patients with primary resistant myeloma

Taiga Nishihori et al. Br J Haematol. 2012 Jun.

Abstract

We conducted a Phase 1/2 study of bortezomib administered in combination with high-dose melphalan followed by tandem autologous transplants in patients with primary resistant multiple myeloma. Thirty patients received two cycles of salvage bortezomib followed by stem cell mobilization with granulocyte colony-stimulating factor and harvest. Melphalan 100 mg/m(2) per day on two consecutive days was administered, immediately followed by one dose of bortezomib (dose escalation) and stem cell infusion. The median beta 2-microglobulin was 4·35 mg/l (range: 1·8-11·4); albumin was 37 g/l (range: 3·1-4·9); high-risk karyotypes were noted in 45% of patients. The maximum planned dose of bortezomib at 1·3 mg/m(2) was well tolerated and a formal maximum tolerated dose was not determined. The peak of best overall response (≥partial response) and complete response rates after tandem transplants were 84% and 36%, respectively. With a median follow-up of 48 months, the median progression-free survival was 15 [95% confidence interval (CI): 11-21] months and the median overall survival was 35 (95% CI: 22-43) months. Correlative studies demonstrated decreased expression of BRCA2 (P = 0·0072) and FANCF (P = 0·0458) mRNA following bortezomib treatment. Bortezomib combined with high-dose melphalan is a well-tolerated conditioning with some activity in patients with resistant myeloma.

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Figures

Figure 1
Figure 1. Study schema
HCT: Hematopoietic cell transplantation Melphalan 200: Melphalan 200 mg/m2 *Bortezomib given on day -3 (dose escalation: 0.7 mg/m2, 1.0 mg/m2, and 1.3 mg/m2)
Figure 2
Figure 2. Responses after treatment
The overall response and complete response rates increased after autologous hematopoiectic cell transplantation. Abbreviations: CR, complete response; HCT, hematopoietic cell transplantation; PR, partial response; VGPR, very good partial response
Figure 3a
Figure 3a. Overall Survival (OS)
Kaplan-Meier probability of overall survival. Vertical tick marks indicate censored patients.
Figure 3b
Figure 3b. Progression-Free Survival (PFS)
Kaplan-Meier probability of progression-free survival. Vertical tick marks indicate censored patients.
Figure 3c
Figure 3c. Overall Survival According to Risk Groups
Kaplan-Meier probability of overall survival based on risk groups. Vertical tick marks indicate censored patients.
Figure 3d
Figure 3d. PFS According to Risk Groups
Kaplan-Meier probability of progression-free survival based on risk groups. Vertical tick marks indicate censored patients.
Figure 3e
Figure 3e. PFS According to Response to Salvage Bortezomib
Kaplan-Meier probability of progression-free survival based on response to salvage bortezomib. Vertical tick marks indicate censored patients.
Figure 4a
Figure 4a. FA/BRCA gene expression by RT-PCR after first dose of bortezomib
FANCD1, also known as BRCA2, and FANCF expressions were significantly lower after first dose of bortezomib (P=0.0072 and P=0.0458, respectively). There was a trend toward decreased expression of 4 other genes including FANCC, FANCD2, RAD51 and BRCA1.
Figure 4b
Figure 4b. FA/BRCA gene expression by RT-PCR after 2 cycles of bortezomib
FANCD1 (=BRCA2) expression remained significant lower after 2 cycles of bortezomib (P = 0.0055).
See this image and copyright information in PMC

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