Patient characteristics
Among 720 patients who achieved at least stable disease after induction therapy with or without subsequent ASCT, 161 patients of the maintenance group and another 161 patients of the no maintenance group were identified by propensity-score matching and studied. The follow-up periods from the time of diagnosis of these patients ranged from 0.2 to 78.4 months (median, 31.7 months).
Baseline characteristics of each patient group at diagnosis are summarized in Table 1. The median age was 65 years old (range, 33–89). There were 166 males and 156 females. Patient baseline features including age, gender, performance status (PS), M protein isotype, and the percentages of patients with abnormal laboratory parameters such as hemoglobin, calcium, creatinine, albumin, β2-microglobulin, lactate dehydrogenase (LDH), high risk by FISH, and adverse karyotype were not significantly different between the patient groups. The R-ISS stages I, II, and III were distributed in 65 patients (20.2%), 223 (69.2%), and 34 (10.6%), respectively, without significant difference between the groups.
Table 1
Patient characteristics at diagnosis
Characteristics
|
Maintenance
(n = 161)
|
No maintenance
(n = 161)
|
Total
(n = 322)
|
P value
|
Median age (range)
|
65 (35–89) yr
|
65 (33–88) yr
|
65 (33–89) yr
|
0.88
|
Gender (M/F)
|
84/77
|
82/79
|
166/156
|
0.91
|
Performance status
0
1
2
3
4
|
66 (46.5%)
44 (31.0%)
18 (12.7%)
9 (6.3%)
5 (3.5%)
|
46 (31.1%)
60 (40.4%)
18 (12.2%)
18 (12.2%)
6 (4.1%)
|
112 (38.6%)
104 (35.9%)
36 (12.4%)
27 (9.3%)
11 (3.8%)
|
0.06
|
M protein
IgG
IgA
IgD
BJP
Others
|
97 (60.2%)
22 (13.7%)
1 (0.6%)
36 (22.4%)
5 (3.1%)
|
89 (55.3%)
33 (20.5%)
5 (3.1%)
32 (19.9%)
2 (1.2%)
|
186 (57.7%)
55 (17.1%)
6 (1.9%)
68 (21.1%)
7 (2.2%)
|
0.16
|
Hemoglobin
≥10 g/dl
<10g/dl
|
86 (53.4%)
75 (46.6%)
|
85 (52.8%)
76 (47.2%)
|
171 (53.1%)
151 (46.9%)
|
1.0
|
Calcium
>11 mg/dl
≤11 mg/dl
|
12 (7.5%)
149 (92.5%)
|
11 (6.8%)
150 (93.2%)
|
23 (7.1%)
299 (92.9%)
|
1.0
|
Creatinine
>2 mg/dl
≤2 mg/dl
|
18 (11.2%)
143 (88.8%)
|
23 (14.3%)
138 (85.7%)
|
41 (12.7%)
281 (87.3%)
|
0.51
|
Albumin
≥3.5 g/dl
<3.5 g/dl
|
85 (52.8%)
76 (47.2%)
|
96 (59.6%)
65 (40.4%)
|
181 (56.2%)
141 (47.8%)
|
0.26
|
β2-microglobulin
<3.5 mg/l
3.5–5.5 mg/l
>5.5 mg/l
|
72 (44.7%)
41 (25.5%)
48 (29.8%)
|
65 (40.4%)
48 (29.8%)
48 (29.8%)
|
137 (42.6%)
89 (27.6%)
96 (29.8%)
|
0.66
|
LDH
Normal
Abnormal
|
126 (78.3%)
35 (21.7%)
|
131 (81.4%)
30 (18.6%)
|
257 (79.8%)
65 (20.2%)
|
0.58
|
FISH
Standard risk
High risk
|
104 (77.6%)
30 (22.4%)
|
88 (80.0%)
22 (20.0%)
|
192 (78.7%)
52 (21.3%)
|
0.75
|
Karyotype
Normal
Abnormal
|
113 (73.9%)
40 (26.1%)
|
121 (79.6%)
31 (20.4%)
|
234 (76.7%)
71 (23.3%)
|
0.28
|
R-ISS stage
I
II
III
|
31 (19.3%)
113 (70.2%)
17 (10.6%)
|
34 (21.1%)
110 (68.3%)
17 (10.6%)
|
65 (20.2%)
223 (69.2%)
34 (10.6%)
|
0.91
|
Response at front therapy
≥CR
≤VGPR
|
65 (40.4%)
96 (59.6%)
|
51 (31.7%)
110 (68.3%)
|
116 (36.0%)
206 (64.0%)
|
0.13
|
ASCT
Yes
No
|
87 (54.0%)
74 (46.0%)
|
87 (54.0%)
74 (46.0%)
|
174 (54.0%)
148 (46.0%)
|
1.0
|
LDH: lactate dehydrogenase; FISH: fluorescence in situ hybridization |
R-ISS: revised International Staging System; CR: complete response; VGPR: very good partial response; ASCT: autologous stem cell transplantation |
Treatment
As for induction therapy, most patients were treated with bortezomib-based therapy including bortezomib + cyclophosphamide + dexamethasone (DEX) (n = 111, 34.4%), bortezomib + DEX (n = 85, 26.4%), bortezomib + melphalan + prednisolone (n = 53, 16.5%), and bortezomib + doxorubicin + DEX (n = 8, 2.5%), and also with a combination with lenalidomide such as bortezomib + lenalidomide + DEX (n = 29, 9.0%). In contrast, induction with lenalidomide-based therapy was less used and included lenalidomide + DEX (n = 16, 5.0%) and a combination with bortezomib (n = 29, 9.0%). Other regimens included melphalan + prednisolone, high-dose DEX, and vincristine + doxorubicin + DEX (Table 2). Between the maintenance and no maintenance groups, the percentages of induction regimen containing bortezomib, lenalidomide, and both were 93.8% vs 83.8% (p = 0.0073), 14.9% vs 13.0% (p = 0.75), and 12.4% vs 5.6% (p = 0.05), respectively.
Table 2
Induction regimen
|
Maintenance
(n = 161)
|
No maintenance
(n = 161)
|
Total
(n = 322)
|
VCD
|
66 (41.0%)
|
45 (28.0%)
|
111 (34.4%)
|
VD
|
36 (22.4%)
|
49 (30.4%)
|
85 (26.4%)
|
VMP
|
28 (17.4%)
|
25 (15.5%)
|
53 (16.5%)
|
VRD or VRd lite
|
20 (12.4%)
|
9 (5.6%)
|
29 (9.0%)
|
PAD
|
1 (0.6%)
|
7 (4.3%)
|
8 (2.5%)
|
Rd
|
4 (2.5%)
|
12 (7.5%)
|
16 (5.0%)
|
Others
|
6 (3.7%)
|
14 (8.7%)
|
20 (6.2%)
|
VCD: bortezomib + cyclophosphamide + dexamethasone; VD: bortezomib + dexamethasone; VMP: bortezomib + melphalan + prednisolone; VRD: bortezomib + lenalidomide + dexamethasone; PAD: bortezomib + doxorubicin + dexamethasone; Rd: lenalidomide + dexamethasone; others included melphalan + prednisolone, high-dose dexamethasone, and vincristine + doxorubicin + dexamethasone. |
As for the best response obtained after front-line therapy, 116 patients (36.0%) achieved complete response (CR) or better, and 206 patients (64.0%) achieved very good partial response (VGPR) or below. The response rate of CR or better was higher in the maintenance group (40.4% vs 31.7%), but there was no significant difference between the groups (p = 0.13). ASCT was performed in 87 patients in each group (54.0%).
Maintenance/continuous therapy
Maintenance/continuous regimens were heterogeneous and included IMiDs-based [lenalidomide + DEX (n = 38), lenalidomide alone (n = 34), elotuzumab + lenalidomide + DEX (n = 6), and thalidomide alone (n = 5)]; PI-based [bortezomib + DEX (n = 18), bortezomib alone (n = 17), panobinostat + bortezomib + DEX (n = 1), ixazomib alone (n = 9), carfilzomib + DEX (n = 2), and bortezomib + melphalan + prednisolone (n = 1)]; combination of IMiDs and PI-based [bortezomib + lenalidomide + DEX (n = 10), bortezomib + thalidomide + DEX (n = 6), carfilzomib + lenalidomide + DEX (n = 6), ixazomib + lenalidomide + DEX (n = 6), and bortezomib + thalidomide (n = 1)]; and DEX alone (n = 1).
Progression-free survival according to maintenance therapy
We first compared PFS between the maintenance group and the matched no maintenance group. PFS was significantly prolonged in the maintenance group compared with the no maintenance group (median, 37.7 and 21.9 months, respectively, p = 0.0002, Fig. 1A). In terms of risk stratification by cytogenetic abnormalities by FISH, the median PFS was 39.7 and 21.1 months in standard-risk patients (p < 0.00001, Fig. 1B), and was 25.7 and 18.8 months in high-risk patients (p = 0.42, Fig. 1C), respectively. According to the R-ISS stage, significant difference in PFS was observed in patients with stage I (p = 0.037, Fig. 1D) and II (p = 0.00094, Fig. 1E) by maintenance therapy, but not in patients with stage III disease (p = 0.37, Fig. 1F). As for the response status before maintenance therapy, PFS was longer in patients who achieved CR or better than that in those who did not achieve CR, but significant difference in PFS by maintenance was observed only in ≤ VGPR patients (p = 0.0018, Fig. 1H) but not in ≥ CR patients (p = 0.27, Fig. 1G). As for ASCT, prolongation of PFS was observed in both non-transplanted (p = 0.0008, Fig. 1I) and transplanted patients (p = 0.017, Fig. 1J).
According to different maintenance of the PI-based, IMiDs-based, and combination of PI + IMiDs-based regimens, the median PFS were 23.4, 37.7, and 48.3 months, respectively, and was longer in the combination with PI + IMiDs-based than PI or IMiDs alone groups in the whole maintenance cohort (p = 0.021, Fig. 1K). In terms of cytogenetic risk groups by FISH, the median PFS were 22.9 months, 39.0 months, and not reached in standard-risk patients (p = 0.16, Supplementary Fig. 1A), and 15.0, 18.4, and 48.3 months in high-risk patients (p = 0.088, Supplementary Fig. 1B) according to maintenance therapy with PI-based, IMiDs-based, or the combination of PI + IMiDs-based, respectively. In comparison of the PI- or IMiDs-based vs PI + IMiDs-based regimens, the median PFS was 39.0 months and not reached in standard-risk patients (p = 0.094), and 18.4 and 48.3 months in high-risk patients (p = 0.030), respectively. Thus, maintenance with combination of PI and IMiD is likely to prolong PFS regardless of risk category by FISH. As for the effect of ASCT, the median PFS of non-transplanted patients were 18.0 months, 35.4 months, and not reached (p = 0.077, Supplementary Fig. 1C) and those of transplanted patients were not reached, 38.7 months, and 48.3 months (p = 0.69, Supplementary Fig. 1D) according to maintenance therapy with PI, IMiDs, or the combination of PI + IMiDs, respectively. In comparison of the PI- or IMiDs-based vs PI + IMiDs-based regimens, the median PFS was 24.1 months and not reached in non-transplanted patients (p = 0.063), and 39.7 and 48.3 months in transplanted patients (p = 0.55), respectively. Thus, maintenance therapy with combination of PI + IMiDs is likely to extend the PFS in non-transplanted patients although there was no statistically significant difference.
Overall survival according to maintenance therapy
The median OS was not reached in either group and there was no significant difference in OS by maintenance/continuous therapy (p = 0.19, Fig. 2A). In terms of cytogenetic risk by FISH, OS was not different between the maintenance vs no maintenance groups irrespective of risk status [standard risk (p = 0.36, Fig. 2B) and high risk (p = 0.21, Fig. 2C)]. Lack of OS difference between maintenance vs no maintenance was also noted in each of the R-ISS stages [stage I (p = 0.14, Fig. 2D); stage II (p = 0.17, Fig. 2E); and stage III (p = 0.30, Fig. 2F)]. As for the response status before maintenance/continuous therapy, OS appeared to be better in the maintenance group when response was ≤ VGPR, but maintenance therapy did not provide statistically significant benefit irrespective of response status before maintenance/continuous therapy [≥ CR patients (p = 0.28, Fig. 2G) and ≤ VGPR patients (p = 0.053, Fig. 2H)]. As for ASCT, OS appeared to be better in non-transplanted patients by continuous therapy, but there was no significant difference in non-transplanted patients (p = 0.13, Fig. 2I) and transplanted patients (p = 0.57, Fig. 2J).
According to the different maintenance regimens, OS was better in both PI-based and combination of PI + IMiDs-based groups, but the difference in OS between 3 maintenance groups was not statistically significant (p = 0.35, Fig. 2K). We compared the differences in OS in terms of cytogenetic risk or implementation of ASCT, but there was no significant difference between 3 maintenance groups (Supplementary Fig. 2).
Univariate and multivariate analysis
Next, the statistical significance of risk factors related to PFS and OS was evaluated by univariate and multivariate analysis. As shown in Table 3, age (≥ 65 years old), R-ISS stage III, and non-CR response after initial therapy were significant poor prognostic factors for PFS, whereas implementation of ASCT as well as maintenance/continuous therapy were significant favorable factors for PFS. In multivariate analysis, non-CR response after initial therapy, and implementation of ASCT, as well as maintenance therapy were significant independent prognostic factors for PFS.
Table 3
Univariate and multivariate analysis for progression-free survival
Variable
|
Univariate
|
Multivariate*
|
HR
|
95% CI
|
P value
|
HR
|
95%CI
|
P value
|
Age [≥ 65 years]
|
1.542
|
1.128–2.109
|
0.0067
|
0.850
|
0.563–1.284
|
0.44
|
Gender [Male]
|
1.028
|
0.756–1.399
|
0.86
|
-
|
-
|
-
|
R-ISS [stage III]
|
1.718
|
1.085–2.719
|
0.021
|
1.468
|
0.923–2.336
|
0.11
|
Response [non-CR]
|
2.376
|
1.650–3.421
|
< 0.0001
|
1.914
|
1.313–2.788
|
0.00073
|
ASCT
|
0.445
|
0.325–0.607
|
< 0.0001
|
0.428
|
0.282–0.648
|
< 0.0001
|
Maintenance
|
0.562
|
0.413–0.766
|
0.00026
|
0.529
|
0.386–0.725
|
< 0.0001
|
*Variables significance at p < 0.1 in the univariate model were entered in the multivariate model. |
R-ISS: revised International Staging System; Response: response at front line therapy; ASCT: autologous stem cell transplantation; Maintenance: maintenance or continuous therapy |
As for OS, age (≥ 65 years old), R-ISS stage III, and non-CR response after initial therapy were significant unfavorable prognostic factors for OS. Implementation of ASCT was a significant favorable factor for OS but administration of maintenance/continuous therapy was not (Table 4). In multivariate analysis, R-ISS stage III, non-CR response after initial therapy, and implementation of ASCT were significant independent prognosis factors for OS (Table 4).
Table 4
Univariate and multivariate analysis for overall survival
Variable
|
Univariate
|
Multivariate
|
HR
|
95% CI
|
P value
|
HR
|
95%CI
|
P value
|
Age [≥ 65 years]
|
2.237
|
1.362–3.675
|
0.0015
|
1.223
|
0.647–2.313
|
0.53
|
Gender [Male]
|
0.847
|
0.531–1.351
|
0.49
|
-
|
-
|
-
|
R-ISS [stage III]
|
2.774
|
1.541–4.994
|
0.00067
|
2.699
|
1.495–4.871
|
0.00098
|
Response [non-CR]
|
2.775
|
1.543–4.990
|
0.00065
|
2.120
|
1.160–3.876
|
0.015
|
ASCT
|
0.348
|
0.212–0.571
|
< 0.0001
|
0.475
|
0.250–0.903
|
0.023
|
Maintenance
|
0.731
|
0.458–1.165
|
0.19
|
-
|
-
|
-
|
*Variables significance at p < 0.1 in the univariate model were entered in the multivariate model. |
R-ISS: revised International Staging System; Response: response at front line therapy; ASCT: autologous stem cell transplantation; Maintenance: maintenance or continuous therapy |