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H.W. Auner et al.
mosomal abnormalities with melphalan dose were analyzed sep- arately. Chromosomal abnormalities were classified as high-risk [t(4;14), t(14;16), and del(17)] or standard risk (all other cytogenetic findings).
All P-values shown are from two-sided tests, and the reported confidence intervals (CI) refer to 95% boundaries. A P-value <0.05 was regarded as statistically significant. A value up to 0.2 was used to determine the significance of interaction terms.
Results
Patient- and treatment-related characteristics
Patient-related and treatment characteristics are shown in Table 1. Patients in the Mel140 group (n=245, 12.5%) were older than patients in the Mel200 group (n=1719, 87.5%) at the time of ASCT [median 64 years (range, 27- 73) versus 59 years (range, 25-76); P<0.001]. Compared to the Mel200 patients, those in the Mel140 group more often had light chain myeloma, were more often in ISS III, and were less often transplanted within 12 months of diagnosis. The two groups differed significantly in terms of body mass index, with a higher proportion of normal weight patients in the Mel140 group. Mel140 patients had received proteasome inhibitor-containing induction thera- py more often, and a greater proportion had a Karnofsky score of <90. Finally, more Mel140 patients had impaired renal function, defined as a glomerular filtration rate of ≤50 mL/min, and a greater proportion of Mel140 patients underwent ASCT in partial remission or worse.
Efficacy
Overall survival was not significantly different between the two melphalan dose groups (Mel140, median not reached; 95% CI, 70.6 months to indeterminate; Mel200, 78 months; 95% CI, 74.0 months to indeterminate) (Figure 1A). The overall adjusted hazard ratio (HR) for death from all causes was 1.10 (95% CI: 0.79-1.54; P=0.56) for the Mel140 group (Figure 1B). Multivariable analysis of differ- ent subgroups showed that age, renal function, prior pro- teasome inhibitor treatment, gender, or Karnofsky score did not interact with overall survival in the melphalan dose groups (Figure 1B). However, disease status at trans- plant significantly modified the risk of death (P=0.006). In patients transplanted in less than partial response, Mel200 was associated with a significant overall survival advan- tage (adjusted HR 0.5 for Mel200 versus Mel140). In con- trast, transplantation in very good partial response/com- plete response significantly favored Mel140 (adjusted HR 2.02). Transplantation in partial response did not modify the effect of melphalan dose on overall survival (adjusted HR 0.98).
The median progression-free survival was 29 months (95% CI: 24.6-33.7) in the Mel140 group and 26.3 months (95% CI: 24.6-28.1) in the Mel200 group (Figure 2A). The adjusted HR for disease progression or death was 1.0 (95% CI: 0.79-1.25; P=0.98) for the Mel140 group (Figure 2B). The multivariable models with interaction terms indi- cated that the HR of Mel200 versus Mel140 was not signif- icantly modified by age, renal function, prior proteasome inhibitor treatment, gender, or Karnofsky score. However, in line with the overall survival analysis, there was a sta- tistically significant change (P=0.043) according to disease status at transplantation. Among the patients transplanted in partial response or less, Mel200 was associated with a
significant progression-free survival advantage (adjusted HR 0.54 for Mel200 versus Mel140), while Mel140 was linked to a numerically better outcome in those trans-
Table 1. Patient- and transplant-related characteristics. Mel200
P value
0.818
0.001* 0.004*
0.002*
0.001*
0.001*
0.001*
0.979
0.001*
0.022*
0.020*
0.123
Patients’ characteristics
Gender Male
Female
Age at ASCT (median and range) years
n=1719 (87.5%)
997 (58.0%) 722 (42.0%)
59 (25–76)
15 (1.1%) 484 (35.2%) 587 (42.7%) 216 (15.7%) 72 (5.2%)
1117 (71.9%) 436 (28.1%)
1316 (96.3%) 51 (3.7%)
1328 (78.9%) 328 (19.5%) 27 (1.6%)
453 (43.1%) 373 (35.5%) 225 (21.4%)
Mel140 n=245 (12.5%)
144 (58.8%) 101 (41.2%)
64 (27–73)
4 (2.0%) 95 (48.5%) 66 (33.7%) 22 (11.2%) 9 (4.6%)
139 (61.8%) 86 (38.2%)
123 (63.1%) 72 (36.9%)
159 (65.7%) 79 (32.6%) 4 (1.7%)
31 (23.5%) 48 (36.4%) 53 (40.2%)
78 (85.7%) 13 (14.3%)
7 (3.4%) 35 (17.1%)
37 (18.0%) 14 (6.8%)
44 (21.5%) 4 (2.0%) 54 (26.3%) 10 (4.9%)
179 (73.1%) 66 (26.9%)
105 (43.9%) 103 (43.1%) 31 (13.0%)
79 (40.9%) 71 (36.8%) 43 (22.3%)
Body mass index (BMI) Underweight (BMI <18.5) Normal weight (18.5 ≤ BMI < 25) Overweight (25 ≤ BMI < 30) Obese (30 ≤ BMI < 35)
Severely obese (BMI ≥ 35)
Karnofsky score ≥ 90
< 90
Estimated GFR at ASCT >50 mL/min
≤50 mL/min
Myeloma characteristics
Myeloma type Common type Light chain Non-secretory
International Staging System stage I
II III
High-risk chromosomal abnormalities#
No Yes
Treatment-related parameters
Pre-transplant treatment Alkylating agent(s) Alkylating agent(s)
+ proteasome inhibitor Alkalyting agent(s) + IMiD(s) Alkylating agent(s) + proteasome
inhibitor + IMiD(s) Proteasome inhibitor
IMiD(s)
Proteasome inhibitor + IMiD(s) Other
Time from diagnosis to ASCT < 12 months
> 12 months
Disease status at ASCT CR/VGPR
PR
<PR
CD34+ cells infused (per kg) <3x106
3–5x106
>5x106
466 (85.8%) 77 (14.2%)
155 (10.6%) 236 (16,2%)
322 (22.1%) 88 (6.0%)
233 (16.0%) 92 (6.3%) 280 (19.2%) 50 (3.4%)
1366 (79.5%) 353 (20.5%)
765 (45.2%) 797 (47.1%) 130 (7.7%)
405 (33.4%) 508 (41.9%) 299 (24.7%)
516
*Denotes statistically significant P values (<0.05); # includes t(4;14), t(14;16), or del(17p). ASCT: autologous stem cell transplantation; GFR: glomerular filtration rate; IMiD: immunomodulatory drug; CR: complete response;VGPR: very good partial response; PR: partial response.
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