Cox regression analyses of baseline and time-dependent variables (PMDD of V, T, and D) in relationship to phase of protocol
| Variable . | n/N (%) . | OS . | EFS . | ||
|---|---|---|---|---|---|
| HR (95% CI) . | P (Wald χ2 test in Cox regression) . | HR (95% CI) . | P (Wald χ2 test in Cox regression) . | ||
| Univariate analysis | |||||
| β2M ≥ 3.5 mg/L | 136/303 (45) | 2.26 (1.42, 3.59) | < .001 | 2.02 (1.33, 3.09) | .001 |
| β2M > 5.5 mg/L | 65/303 (21) | 3.67 (2.33, 5.78) | < .001 | 3.45 (2.26, 5.26) | < .001 |
| Creatinine ≥ 2 mg/dL | 23/303 (8) | 2.88 (1.58, 5.23) | < .001 | 3.31 (1.92, 5.69) | < .001 |
| CRP ≥ 8 mg/L | 100/302 (33) | 1.53 (0.97, 2.42) | .069 | 1.77 (1.16, 2.69) | .008 |
| Hb < 10 g/dL | 94/303 (31) | 2.26 (1.44, 3.56) | < .001 | 2.33 (1.54, 3.54) | < .001 |
| LDH ≥ 190 U/L | 81/303 (27) | 3.12 (1.98, 4.89) | < .001 | 3.25 (2.14, 4.93) | < .001 |
| Cytogenetic abnormalities | 100/302 (33) | 2.80 (1.78, 4.41) | < .001 | 2.32 (1.53, 3.53) | < .001 |
| GEP high-risk | 40/275 (15) | 4.66 (2.83, 7.66) | < .001 | 4.50 (2.83, 7.16) | < .001 |
| GEP MAF/MAFB subgroup | 22/275 (8) | 2.41 (1.26, 4.59) | .008 | 2.09 (1.11, 3.95) | .023 |
| GEP proliferation subgroup | 27/275 (10) | 2.73 (1.49, 5.02) | .001 | 2.64 (1.50, 4.63) | < .001 |
| GEP NR3C1 bottom tertile | 91/274 (33) | 1.57 (0.97, 2.54) | .068 | 1.83 (1.18, 2.83) | .007 |
| GEP NR3C1 top tertile | 91/274 (33) | 0.56 (0.32, 0.99) | .046 | 0.52 (0.31, 0.88) | .015 |
| Completed transplantation 2* | — | 0.37 (0.21, 0.62) | < .001 | 0.35 (0.21, 0.59) | < .001 |
| Completed consolidation 1* | — | 0.38 (0.22, 0.67) | < .001 | 0.49 (0.29, 0.83) | .008 |
| Completed consolidation 2* | — | 0.45 (0.26, 0.78) | .005 | 0.57 (0.34, 0.98) | .043 |
| Bortezomib during induction (mg)* | — | 0.88 (0.81, 0.96) | .003 | 0.90 (0.83, 0.97) | .008 |
| Bortezomib during consolidation (mg)* | — | 0.94 (0.90, 0.99) | .008 | 0.96 (0.92, 1.00) | .039 |
| Bortezomib during maintenance (mg)* | — | 0.99 (0.98, 1.00) | .083 | 1.00 (0.99, 1.00) | .286 |
| Dexamethasone during induction (dg)* | — | 0.71 (0.56, 0.89) | .004 | 0.75 (0.60, 0.94) | .011 |
| Dexamethasone during transplantation (dg)* | — | 0.94 (0.84, 1.04) | .210 | 0.92 (0.83, 1.01) | .078 |
| Dexamethasone during consolidation (dg)* | — | 0.85 (0.77, 0.93) | < .001 | 0.89 (0.81, 0.97) | .007 |
| Dexamethasone during maintenance (dg)* | — | 0.93 (0.89, 0.97) | < .001 | 0.97 (0.93, 1.00) | .047 |
| Thalidomide during induction (g)* | — | 0.63 (0.44, 0.90) | .011 | 0.68 (0.50, 0.95) | .021 |
| Thalidomide during transplantation (g)* | — | 0.94 (0.87, 1.02) | .118 | 0.94 (0.87, 1.01) | .071 |
| Thalidomide during consolidation (g)* | — | 0.94 (0.89, 1.00) | .048 | 0.97 (0.92, 1.02) | .220 |
| Thalidomide during maintenance (g)* | — | 0.98 (0.97, 1.00) | .094 | 1.00 (0.98, 1.01) | .824 |
| Premature bortezomib discontinuation* | — | 8.08 (4.41, 14.81) | < .001 | 1.96 (1.19, 3.25) | .009 |
| Premature dexamethasone discontinuation* | — | 7.17 (3.91, 13.15) | < .001 | 1.53 (0.91, 2.58) | .106 |
| Premature thalidomide discontinuation* | — | 7.19 (3.89, 13.29) | < .001 | 1.58 (0.96, 2.60) | .074 |
| Achieved CR* | — | 0.32 (0.19, 0.53) | < .001 | 0.35 (0.22, 0.56) | < .001 |
| Multivariate analysis | |||||
| Creatinine ≥ 2 mg/dL | 21/275 (8%) | 2.09 (1.13, 3.87) | .019 | 2.48 (1.42, 4.34) | .001 |
| LDH ≥ 190 U/L | 74/275 (27%) | 1.98 (1.20, 3.26) | .007 | 2.40 (1.52, 3.79) | < .001 |
| Cytogenetic abnormalities | 95/275 (35%) | 2.28 (1.37, 3.79) | .001 | 1.85 (1.16, 2.95) | .010 |
| GEP high-risk | 40/275 (15%) | 2.85 (1.69, 4.79) | < .001 | 3.01 (1.84, 4.94) | < .001 |
| Premature bortezomib discontinuation* | — | 6.44 (3.30, 12.57) | < .001 | 1.59 (0.93, 2.72) | .087 |
| Achieved CR* | — | 0.41 (0.23, 0.72) | .002 | 0.35 (0.21, 0.59) | < .001 |
| Variable . | n/N (%) . | OS . | EFS . | ||
|---|---|---|---|---|---|
| HR (95% CI) . | P (Wald χ2 test in Cox regression) . | HR (95% CI) . | P (Wald χ2 test in Cox regression) . | ||
| Univariate analysis | |||||
| β2M ≥ 3.5 mg/L | 136/303 (45) | 2.26 (1.42, 3.59) | < .001 | 2.02 (1.33, 3.09) | .001 |
| β2M > 5.5 mg/L | 65/303 (21) | 3.67 (2.33, 5.78) | < .001 | 3.45 (2.26, 5.26) | < .001 |
| Creatinine ≥ 2 mg/dL | 23/303 (8) | 2.88 (1.58, 5.23) | < .001 | 3.31 (1.92, 5.69) | < .001 |
| CRP ≥ 8 mg/L | 100/302 (33) | 1.53 (0.97, 2.42) | .069 | 1.77 (1.16, 2.69) | .008 |
| Hb < 10 g/dL | 94/303 (31) | 2.26 (1.44, 3.56) | < .001 | 2.33 (1.54, 3.54) | < .001 |
| LDH ≥ 190 U/L | 81/303 (27) | 3.12 (1.98, 4.89) | < .001 | 3.25 (2.14, 4.93) | < .001 |
| Cytogenetic abnormalities | 100/302 (33) | 2.80 (1.78, 4.41) | < .001 | 2.32 (1.53, 3.53) | < .001 |
| GEP high-risk | 40/275 (15) | 4.66 (2.83, 7.66) | < .001 | 4.50 (2.83, 7.16) | < .001 |
| GEP MAF/MAFB subgroup | 22/275 (8) | 2.41 (1.26, 4.59) | .008 | 2.09 (1.11, 3.95) | .023 |
| GEP proliferation subgroup | 27/275 (10) | 2.73 (1.49, 5.02) | .001 | 2.64 (1.50, 4.63) | < .001 |
| GEP NR3C1 bottom tertile | 91/274 (33) | 1.57 (0.97, 2.54) | .068 | 1.83 (1.18, 2.83) | .007 |
| GEP NR3C1 top tertile | 91/274 (33) | 0.56 (0.32, 0.99) | .046 | 0.52 (0.31, 0.88) | .015 |
| Completed transplantation 2* | — | 0.37 (0.21, 0.62) | < .001 | 0.35 (0.21, 0.59) | < .001 |
| Completed consolidation 1* | — | 0.38 (0.22, 0.67) | < .001 | 0.49 (0.29, 0.83) | .008 |
| Completed consolidation 2* | — | 0.45 (0.26, 0.78) | .005 | 0.57 (0.34, 0.98) | .043 |
| Bortezomib during induction (mg)* | — | 0.88 (0.81, 0.96) | .003 | 0.90 (0.83, 0.97) | .008 |
| Bortezomib during consolidation (mg)* | — | 0.94 (0.90, 0.99) | .008 | 0.96 (0.92, 1.00) | .039 |
| Bortezomib during maintenance (mg)* | — | 0.99 (0.98, 1.00) | .083 | 1.00 (0.99, 1.00) | .286 |
| Dexamethasone during induction (dg)* | — | 0.71 (0.56, 0.89) | .004 | 0.75 (0.60, 0.94) | .011 |
| Dexamethasone during transplantation (dg)* | — | 0.94 (0.84, 1.04) | .210 | 0.92 (0.83, 1.01) | .078 |
| Dexamethasone during consolidation (dg)* | — | 0.85 (0.77, 0.93) | < .001 | 0.89 (0.81, 0.97) | .007 |
| Dexamethasone during maintenance (dg)* | — | 0.93 (0.89, 0.97) | < .001 | 0.97 (0.93, 1.00) | .047 |
| Thalidomide during induction (g)* | — | 0.63 (0.44, 0.90) | .011 | 0.68 (0.50, 0.95) | .021 |
| Thalidomide during transplantation (g)* | — | 0.94 (0.87, 1.02) | .118 | 0.94 (0.87, 1.01) | .071 |
| Thalidomide during consolidation (g)* | — | 0.94 (0.89, 1.00) | .048 | 0.97 (0.92, 1.02) | .220 |
| Thalidomide during maintenance (g)* | — | 0.98 (0.97, 1.00) | .094 | 1.00 (0.98, 1.01) | .824 |
| Premature bortezomib discontinuation* | — | 8.08 (4.41, 14.81) | < .001 | 1.96 (1.19, 3.25) | .009 |
| Premature dexamethasone discontinuation* | — | 7.17 (3.91, 13.15) | < .001 | 1.53 (0.91, 2.58) | .106 |
| Premature thalidomide discontinuation* | — | 7.19 (3.89, 13.29) | < .001 | 1.58 (0.96, 2.60) | .074 |
| Achieved CR* | — | 0.32 (0.19, 0.53) | < .001 | 0.35 (0.22, 0.56) | < .001 |
| Multivariate analysis | |||||
| Creatinine ≥ 2 mg/dL | 21/275 (8%) | 2.09 (1.13, 3.87) | .019 | 2.48 (1.42, 4.34) | .001 |
| LDH ≥ 190 U/L | 74/275 (27%) | 1.98 (1.20, 3.26) | .007 | 2.40 (1.52, 3.79) | < .001 |
| Cytogenetic abnormalities | 95/275 (35%) | 2.28 (1.37, 3.79) | .001 | 1.85 (1.16, 2.95) | .010 |
| GEP high-risk | 40/275 (15%) | 2.85 (1.69, 4.79) | < .001 | 3.01 (1.84, 4.94) | < .001 |
| Premature bortezomib discontinuation* | — | 6.44 (3.30, 12.57) | < .001 | 1.59 (0.93, 2.72) | .087 |
| Achieved CR* | — | 0.41 (0.23, 0.72) | .002 | 0.35 (0.21, 0.59) | < .001 |
Analyses were performed of cumulative doses per protocol step (induction, peritransplantation, consolidation, and maintenance). The multivariate model uses stepwise selection with entry level of 0.1 and variable remains if it meets the 0.05 level. Variables considered univariately were age ≥ 65 years, female sex, white race, albumin < 3.5 g/dL, B2M ≥ 3.5 mg/L, B2M > 5.5 mg/L, creatinine ≥ 2 mg/dL, CRP ≥ 8 mg/L, Hb < 10 g/dL, LDH ≥ 190 U/L, cytogenetic abnormalities (anytime before enrollment), GEP high-risk, GEP CD-1 subgroup, GEP CD-2 subgroup, GEP hyperdiploidy subgroup, GEP low bone disease subgroup, GEP MAF/MAFB subgroup, GEP MMSET/FGFR3 subgroup, GEP myeloid subgroup, GEP proliferation subgroup, GEP TP53 deletion, GEP NR3C1 bottom tertile, GEP NR3C1 top tertile, completed transplantation 2*, completed consolidation 1*, completed consolidation 2*, bortezomib during induction*, bortezomib during consolidation*, bortezomib during maintenance*, dexamethasone during induction*, dexamethasone during transplantation*, dexamethasone during consolidation*, dexamethasone during maintenance*, thalidomide during induction*, thalidomide during transplantation*, thalidomide during consolidation*, thalidomide during maintenance*, premature bortezomib discontinuation*, premature dexamethasone discontinuation*, premature thalidomide discontinuation*, achieved CR*, and achieved CR before Tx2*. Variables considered for the multivariate model were B2M > 5.5 mg/L, creatinine ≥ 2 mg/dL, CRP ≥ 8 mg/L, Hb < 10 g/dL, LDH ≥ 190 U/L, cytogenetic abnormalities (anytime before enrollment), GEP high-risk, GEP MAF/MAFB subgroup, GEP proliferation subgroup, GEP NR3C1 top tertile, completed transplantation 2*, completed consolidation 1*, completed consolidation 2*, bortezomib during induction*, bortezomib during consolidation*, dexamethasone during induction*, dexamethasone during consolidation*, dexamethasone during maintenance*, thalidomide during induction*, achieved CR*, achieved CR before Tx2*, premature bortezomib discontinuation*, premature dexamethasone discontinuation*, and premature thalidomide discontinuation*.
B2M indicates B2-microglobulin; CRP, C-reactive protein; Hb, hemoglobin; and —, not applicaple.
Variable was treated as a time-dependent variable.