Topics:
body surface area, bortezomib, dexamethasone, follow-up, thalidomide, transplantation, progression-free survival

To the editor:

In response to requests from readers1  we are providing additional analyses regarding whether taking patient size into account changes the conclusions from our paper in Blood.2  We performed time-dependent analyses of cumulative dosing of velcade, thalidomide, and dexamethasone (VTD) components with and without adjustment for baseline body surface area (BSA) both per date of publication and per follow-up as of April 20, 2012. Adjustments for BSA were performed by dividing the cumulative dose by BSA. These additional analyses allow a side-by-side comparison of the univariate models presented in our original publication2  with identical models adjusted for BSA, and clearly indicates that our conclusions regarding the importance of cumulative dosing stand, even when BSA is accounted for. Table 1 shows univariate analyses for overall survival and Table 2 for progression-free survival (PFS). Supplemental Tables 1, 2, and 3 (available on the Blood Web site; see the Supplemental Materials link at the top of the letter) present these data in the context of glucocorticoid receptor NR3C1 tertile expression levels.

Table 1

OS from enrollment, showing bortezomib, dexamethasone, and thalidomide by protocol step

OS with BSA-adjusted dosages
OS without BSA-adjusted dosages
Factorn/N (%)HR (95% CI)PHR (95% CI)*P*FactorHR (95% CI)PHR (95% CI)*P*
Bortezomib during induction (mg/m2) 303/303 (100) 0.78 (0.66, 0.91) .002 0.84 (0.72, 0.98) .032 Bortezomib during induction (mg) 0.88 (0.81, 0.96) .003 0.90 (0.84, 0.98) .013 
Bortezomib during consolidation (mg/m2) 232/303 (77) 0.90 (0.83, 0.97) .005 0.91 (0.85, 0.97) .004 Bortezomib during consolidation (mg) 0.94 (0.90, 0.99) .008 0.95 (0.91, 0.98) .003 
Bortezomib during maintenance (mg/m2) 215/303 (71) 0.99 (0.97, 1.00) .071 0.99 (0.97, 1.00) .050 Bortezomib during maintenance (mg) 0.99 (0.98, 1.00) .083 0.99 (0.98, 1.00) .030 
Dexamethasone during induction (dg/m2) 303/303 (100) 0.62 (0.42, 0.92) .017 0.71 (0.50, 1.02) .066 Dexamethasone during induction (dg) 0.71 (0.56, 0.89) .004 0.75 (0.60, 0.93) .009 
Dexamethasone during transplant (dg/m2) 260/303 (86) 0.89 (0.74, 1.07) .206 0.87 (0.74, 1.02) .090 Dexamethasone during transplant (dg) 0.94 (0.84, 1.04) .210 0.91 (0.83, 1.00) .051 
Dexamethasone during consolidation (dg/m2) 233/303 (77) 0.75 (0.63, 0.89) < .001 0.94 (0.83, 1.06) .307 Dexamethasone during consolidation (dg) 0.85 (0.77, 0.93) < .001 0.95 (0.89, 1.03) .212 
Dexamethasone during maintenance (dg/m2) 211/303 (70) 0.88 (0.82, 0.94) < .001 0.91 (0.86, 0.96) .001 Dexamethasone during maintenance (dg) 0.93 (0.89, 0.97) < .001 0.95 (0.92, 0.98) .001 
Thalidomide during induction (g/m2) 301/303 (99) 0.52 (0.29, 0.94) .031 0.62 (0.37, 1.05) .075 Thalidomide during induction (g) 0.63 (0.44, 0.90) .011 0.69 (0.50, 0.95) .022 
Thalidomide during transplant (g/m2) 253/303 (84) 0.88 (0.77, 1.02) .080 0.89 (0.79, 1.00) .055 Thalidomide during transplant (g) 0.94 (0.87, 1.02) .118 0.93 (0.87, 1.00) .053 
Thalidomide during consolidation (g/m2) 230/303 (76) 0.89 (0.80, 0.99) .036 0.95 (0.88, 1.03) .231 Thalidomide during consolidation (g) 0.94 (0.89, 1.00) .048 0.96 0.91, 1.00) .073 
Thalidomide during maintenance (g/m2) 195/303 (64) 0.97 (0.94, 1.01) .101 0.98 (0.96, 1.01) .179 Thalidomide during maintenance (g) 0.98 (0.97, 1.00) .094 0.99 (0.98, 1.00) .155 
OS with BSA-adjusted dosages
OS without BSA-adjusted dosages
Factorn/N (%)HR (95% CI)PHR (95% CI)*P*FactorHR (95% CI)PHR (95% CI)*P*
Bortezomib during induction (mg/m2) 303/303 (100) 0.78 (0.66, 0.91) .002 0.84 (0.72, 0.98) .032 Bortezomib during induction (mg) 0.88 (0.81, 0.96) .003 0.90 (0.84, 0.98) .013 
Bortezomib during consolidation (mg/m2) 232/303 (77) 0.90 (0.83, 0.97) .005 0.91 (0.85, 0.97) .004 Bortezomib during consolidation (mg) 0.94 (0.90, 0.99) .008 0.95 (0.91, 0.98) .003 
Bortezomib during maintenance (mg/m2) 215/303 (71) 0.99 (0.97, 1.00) .071 0.99 (0.97, 1.00) .050 Bortezomib during maintenance (mg) 0.99 (0.98, 1.00) .083 0.99 (0.98, 1.00) .030 
Dexamethasone during induction (dg/m2) 303/303 (100) 0.62 (0.42, 0.92) .017 0.71 (0.50, 1.02) .066 Dexamethasone during induction (dg) 0.71 (0.56, 0.89) .004 0.75 (0.60, 0.93) .009 
Dexamethasone during transplant (dg/m2) 260/303 (86) 0.89 (0.74, 1.07) .206 0.87 (0.74, 1.02) .090 Dexamethasone during transplant (dg) 0.94 (0.84, 1.04) .210 0.91 (0.83, 1.00) .051 
Dexamethasone during consolidation (dg/m2) 233/303 (77) 0.75 (0.63, 0.89) < .001 0.94 (0.83, 1.06) .307 Dexamethasone during consolidation (dg) 0.85 (0.77, 0.93) < .001 0.95 (0.89, 1.03) .212 
Dexamethasone during maintenance (dg/m2) 211/303 (70) 0.88 (0.82, 0.94) < .001 0.91 (0.86, 0.96) .001 Dexamethasone during maintenance (dg) 0.93 (0.89, 0.97) < .001 0.95 (0.92, 0.98) .001 
Thalidomide during induction (g/m2) 301/303 (99) 0.52 (0.29, 0.94) .031 0.62 (0.37, 1.05) .075 Thalidomide during induction (g) 0.63 (0.44, 0.90) .011 0.69 (0.50, 0.95) .022 
Thalidomide during transplant (g/m2) 253/303 (84) 0.88 (0.77, 1.02) .080 0.89 (0.79, 1.00) .055 Thalidomide during transplant (g) 0.94 (0.87, 1.02) .118 0.93 (0.87, 1.00) .053 
Thalidomide during consolidation (g/m2) 230/303 (76) 0.89 (0.80, 0.99) .036 0.95 (0.88, 1.03) .231 Thalidomide during consolidation (g) 0.94 (0.89, 1.00) .048 0.96 0.91, 1.00) .073 
Thalidomide during maintenance (g/m2) 195/303 (64) 0.97 (0.94, 1.01) .101 0.98 (0.96, 1.01) .179 Thalidomide during maintenance (g) 0.98 (0.97, 1.00) .094 0.99 (0.98, 1.00) .155 

The univariate time-dependent models for OS fail to show a confounding effect of BSA on the cumulative dosing of bortezemib, dexamethasone, and thalidomide. Hazard ratio estimates are consistent after accounting for BSA within the original data and the data with updated follow-up.

OS indicates overall survival; n, number receiving a dose during the specified step; N, total number of patients on TT3 (2003-33); HR, hazard ratio; BSA, body surface area; and CI, confidence interval.

*

Data as of April 20, 2012.

View Large
Table 2

PFS from enrollment, showing bortezomib, dexamethasone, and thalidomide by protocol step

PFS with BSA-adjusted dosages
PFS without BSA adjustment
Factorn/N (%)HR (95% CI)PHR (95% CI)*P*FactorHR (95% CI)PHR (95% CI)*P*
Bortezomib during induction (mg/m2) 303/303 (100) 0.81 (0.70, 0.94) .005 0.89 (0.78, 1.02) .106 Bortezomib during induction (mg) 0.90 (0.83, 0.97) .008 0.93 (0.87, 1.00) .055 
Bortezomib during consolidation (mg/m2) 232/303 (77) 0.92 (0.85, 0.99) .019 0.94 (0.89, 1.00) .038 Bortezomib during consolidation (mg) 0.96 (0.92, 1.00) .039 0.97 (0.93, 1.00) .034 
Bortezomib during maintenance (mg/m2) 215/303 (71) 0.99 (0.98, 1.00) .219 0.99 (0.98, 1.00) .165 Bortezomib during maintenance (mg) 1.00 (0.99, 1.00) .286 1.00 (0.99, 1.00) .134 
Dexamethasone during induction (dg/m2) 303/303 (100) 0.66 (0.46, 0.95) .025 0.80 (0.58, 1.09) .161 Dexamethasone during induction (dg) 0.75 (0.60, 0.94) .011 0.82 (0.67, 1.00) .047 
Dexamethasone during transplant (dg/m2) 260/303 (86) 0.85 (0.72, 1.01) .067 0.87 (0.76, 1.01) .060 Dexamethasone during transplant (dg) 0.92 (0.83, 1.01) .078 0.92 (0.85, 0.99) .036 
Dexamethasone during consolidation (dg/m2) 233/303 (77) 0.80 (0.69, 0.94) .005 0.94 (0.84, 1.04) .236 Dexamethasone during consolidation (dg) 0.89 (0.81, 0.97) .007 0.95 (0.89, 1.02) .165 
Dexamethasone during maintenance (dg/m2) 211/303 (70) 0.93 (0.87, 0.99) .029 0.92 (0.88, 0.97) < .001 Dexamethasone during maintenance (dg) 0.97 (0.93, 1.00) .047 0.96 (0.93, 0.98) .001 
Thalidomide during induction (g/m2) 301/303 (99) 0.57 (0.33, 0.97) .039 0.75 (0.48, 1.16) .191 Thalidomide during induction (g) 0.68 (0.50, 0.95) .021 0.80 (0.62, 1.05) .108 
Thalidomide during transplant (g/m2) 253/303 (84) 0.88 (0.77, 1.00) .046 0.91 (0.83, 1.01) .083 Thalidomide during transplant (g) 0.94 (0.87, 1.01) .071 0.95 (0.90, 1.01) .084 
Thalidomide during consolidation (g/m2) 230/303 (76) 0.93 (0.85, 1.02) .142 0.95 (0.89, 1.02) .171 Thalidomide during consolidation (g) 0.97 (0.92, 1.02) .220 0.96 (0.92, 1.00) .069 
Thalidomide during maintenance (g/m2) 195/303 (64) 1.00 (0.97, 1.02) .761 0.98 (0.96, 1.00) .092 Thalidomide during maintenance (g) 1.00 (0.98, 1.01) .824 0.99 (0.98, 1.00) .095 
PFS with BSA-adjusted dosages
PFS without BSA adjustment
Factorn/N (%)HR (95% CI)PHR (95% CI)*P*FactorHR (95% CI)PHR (95% CI)*P*
Bortezomib during induction (mg/m2) 303/303 (100) 0.81 (0.70, 0.94) .005 0.89 (0.78, 1.02) .106 Bortezomib during induction (mg) 0.90 (0.83, 0.97) .008 0.93 (0.87, 1.00) .055 
Bortezomib during consolidation (mg/m2) 232/303 (77) 0.92 (0.85, 0.99) .019 0.94 (0.89, 1.00) .038 Bortezomib during consolidation (mg) 0.96 (0.92, 1.00) .039 0.97 (0.93, 1.00) .034 
Bortezomib during maintenance (mg/m2) 215/303 (71) 0.99 (0.98, 1.00) .219 0.99 (0.98, 1.00) .165 Bortezomib during maintenance (mg) 1.00 (0.99, 1.00) .286 1.00 (0.99, 1.00) .134 
Dexamethasone during induction (dg/m2) 303/303 (100) 0.66 (0.46, 0.95) .025 0.80 (0.58, 1.09) .161 Dexamethasone during induction (dg) 0.75 (0.60, 0.94) .011 0.82 (0.67, 1.00) .047 
Dexamethasone during transplant (dg/m2) 260/303 (86) 0.85 (0.72, 1.01) .067 0.87 (0.76, 1.01) .060 Dexamethasone during transplant (dg) 0.92 (0.83, 1.01) .078 0.92 (0.85, 0.99) .036 
Dexamethasone during consolidation (dg/m2) 233/303 (77) 0.80 (0.69, 0.94) .005 0.94 (0.84, 1.04) .236 Dexamethasone during consolidation (dg) 0.89 (0.81, 0.97) .007 0.95 (0.89, 1.02) .165 
Dexamethasone during maintenance (dg/m2) 211/303 (70) 0.93 (0.87, 0.99) .029 0.92 (0.88, 0.97) < .001 Dexamethasone during maintenance (dg) 0.97 (0.93, 1.00) .047 0.96 (0.93, 0.98) .001 
Thalidomide during induction (g/m2) 301/303 (99) 0.57 (0.33, 0.97) .039 0.75 (0.48, 1.16) .191 Thalidomide during induction (g) 0.68 (0.50, 0.95) .021 0.80 (0.62, 1.05) .108 
Thalidomide during transplant (g/m2) 253/303 (84) 0.88 (0.77, 1.00) .046 0.91 (0.83, 1.01) .083 Thalidomide during transplant (g) 0.94 (0.87, 1.01) .071 0.95 (0.90, 1.01) .084 
Thalidomide during consolidation (g/m2) 230/303 (76) 0.93 (0.85, 1.02) .142 0.95 (0.89, 1.02) .171 Thalidomide during consolidation (g) 0.97 (0.92, 1.02) .220 0.96 (0.92, 1.00) .069 
Thalidomide during maintenance (g/m2) 195/303 (64) 1.00 (0.97, 1.02) .761 0.98 (0.96, 1.00) .092 Thalidomide during maintenance (g) 1.00 (0.98, 1.01) .824 0.99 (0.98, 1.00) .095 

As seen with time-dependent models for OS, the univariate time-dependent models for PFS fail to show a confounding effect of BSA. Estimates of the hazard ratio remain consistent.

PFS indicates progression-free survival; n, number receiving a dose during the specified step; N, total number of patients on TT3 (2003-33); BSA, body surface area; HR, hazard ratio; and CI, confidence interval.

*

Data as of April 20, 2012.

View Large

It is important to note that these analyses using BSA adjustment are completely compatible with those previously published for bortezomib, as well as for dexamethasone and thalidomide. In each of these additional analyses, adjustment for BSA resulted in only minor changes to the hazard ratios. Therefore we believe the relationship between cumulative dosing and outcomes does not simply reflect impact of body size on outcomes.

The online version of this letter contains a data supplement.

Conflict-of-interest disclosure: B.B. has received research funding from Celgene, Novartis. Centocor, Johnson and Johnson, Onyx, and ICON; is a consultant to Celgene, Millenium, and Genzyme; and has received speaking honoraria from Celgene and Millennium. He is a coinventor on patents and patent applications related to the use of GEP in cancer medicine and holds interest in Signal Genetics. The remaining author declares no competing financial interests.

Correspondence: Dr Bart Barlogie, University of Arkansas for Medical Sciences, 4301 W Markham St, Slot 816, Little Rock, AR 72205; e-mail: barlogiebart@uams.edu.

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