Abstract

INTRODUCTION

Botezomib-based induction is widely used and highly effective for the treatment of patients with newly diagnosed multiple myeloma (NDMM), with an overall response rate (ORR) of 75-80%. However, the outcomes of patients who fail to respond to this treatment remain unclear. The goal of this study was to investigate the outcome of patients with NDMM who failed to respond to bortezomib-based induction as compared to induction-responsive patients.

METHODS

We reviewed consecutive patients with NDMM between 1-JAN-2007 and 31-JAN-2014 in three participating centers in Greece and Israel. Inclusion criteria were measurable disease and an induction regimen containing bortezomib in combination with alkylators and/or corticosteroids. Patients who failed to achieve at least partial response in accordance with IMWG criteria after 4 cycles of therapy were classified as non-responsive and their baseline characteristics, next treatment, overall survival and progression following second-line treatment (2ndPFS) were assessed and compared to responsive patients. 2ndPFS was defined as the time from 2nd line treatment to disease progression, death or censoring. In the non-responsive group we limited this analysis to patients advancing to 2nd line within six months of initiation of induction.

RESULTS

Two hundred and ninety five patients met inclusion criteria and 74 (25%) were non-responsive to bortezomib-containing induction. Non-responsive patients were older, more anemic and had more often ISS-3, del17p and ECOG performance status 2-4 (table 1). Notably, these patients received less often a bi-weekly bortezomib schedule, a triple-drug regimen and high dose melphalan treatment at first line.

Of the non-responsive patients 57% (n=42) received salvage treatment immediately following induction non-response, with an ORR of 59% (25/42); 12/31(39%) of those treated with salvage 2nd line and 13/15(87%) of those who underwent HDM at first line, responded.

Failure to respond to bortezomib induction was associated with increased mortality (HR 5.06, 95% CI 2.80 – 9.16) (Fig. a), which remained significant in multivariate analysis. One- and 3-years OS in responsive vs. non-responsive patients were 97% vs 76% and 88% vs 53%, respectively (p<0.0001).

2ndPFS in patients who received salvage second line therapy immediately following induction failure was similar to that measured in bortezomib-responsive patients receiving 2nd-line therapy for disease progression, approaching 14 months. However, survival from time of salvage 2nd-line treatment was significantly lower among patients non-responsive to bortezomib-based induction compared to that measured in responsive patients (25 months vs. not reached, respectively, p=0.024; Fig. b).

CONCLUSIONS

Failure to respond to a bortezomib-based induction was found to be an independent risk factor for mortality. Despite the non-inferior 2ndPFS reported in these patients as compared with their bortezomib-responsive counterparts, survival remained significantly inferior. Possibly this difference is because non-responsive patients are less likely to respond to further proteasome inhibitor therapy at following relapses. Randomized controlled trials are needed to test whether intensification of induction and/or of further treatment may improve the poor prognosis of patients who fail to respond to bortezomib-based induction.

Table 1:
 All patients
n = 295 
Induction non-responsive
n = 74 
Induction
- responsive
n =221 
P value
 
Demographic 
Median Age (yrs) 62.0 66.8 61.0 0.004 
Gender
Male
Female 
148 (50%)
147 (50%) 
42 (55%)
33 (45%) 
107 (48%)
114 (52%) 
0.347 
Patient / Disease 
ECOG
0-1
2-4 
182 (63%)
107 (37%) 
33 (45%)
40 (55%) 
149 (69%)
67 (31%) 
<0.0001 
ISS
I
II
III 
74 (28%)
95 (36%)
95 (36%)  
9 (14%)
20 (33%)
33 (53%)  
65 (32%)
75 (37%)
62 (31%)  
0.002  
High risk Cytogenietics
Del17p
High risk (%)
Elevated LDH (%)
Extramedullary disease (%)
Hb≤ 10 gr%
Creatinine > 2mg% 
23 (14%)
69 (34%)
66 (27%)
23 (9.5%)
114 (43%)
64 (23%) 
10 (26%)
13 (28%)
21 (36%)
5 (8.1%)
35 (54%)
20 (30%) 
13 (10%)
56 (36%)
45 (24%)
18 (9.7%)
79 (39)
44 (21%) 
0.031
0.297
0.091
0.805
0.044
0.094 
Therapy 
Induction regimen
VCD
Vd
VMP
PAD  
204 (69%)
49 (17%)
11 (4%)
19 (6%)  
52 (57%)
18 (24%)
3 (4%)
4 (5%)  
162 (73%)
31 (14%)
8 (4%)
15 (7%)  
0.007  
Any triplet  243 (82%)  55 (74%)  188 (85%)  0.051  
Bortezomib schedule
Bi-weekly
Weekly 
239 (81%)
56 (19%)  
52 (70%)
22 (30%)  
187 (85%)
34 (15%)  
0.010  
HDM at first line 143 (48%) 15 (20%) 128 (58%) <0.0001 
 All patients
n = 295 
Induction non-responsive
n = 74 
Induction
- responsive
n =221 
P value
 
Demographic 
Median Age (yrs) 62.0 66.8 61.0 0.004 
Gender
Male
Female 
148 (50%)
147 (50%) 
42 (55%)
33 (45%) 
107 (48%)
114 (52%) 
0.347 
Patient / Disease 
ECOG
0-1
2-4 
182 (63%)
107 (37%) 
33 (45%)
40 (55%) 
149 (69%)
67 (31%) 
<0.0001 
ISS
I
II
III 
74 (28%)
95 (36%)
95 (36%)  
9 (14%)
20 (33%)
33 (53%)  
65 (32%)
75 (37%)
62 (31%)  
0.002  
High risk Cytogenietics
Del17p
High risk (%)
Elevated LDH (%)
Extramedullary disease (%)
Hb≤ 10 gr%
Creatinine > 2mg% 
23 (14%)
69 (34%)
66 (27%)
23 (9.5%)
114 (43%)
64 (23%) 
10 (26%)
13 (28%)
21 (36%)
5 (8.1%)
35 (54%)
20 (30%) 
13 (10%)
56 (36%)
45 (24%)
18 (9.7%)
79 (39)
44 (21%) 
0.031
0.297
0.091
0.805
0.044
0.094 
Therapy 
Induction regimen
VCD
Vd
VMP
PAD  
204 (69%)
49 (17%)
11 (4%)
19 (6%)  
52 (57%)
18 (24%)
3 (4%)
4 (5%)  
162 (73%)
31 (14%)
8 (4%)
15 (7%)  
0.007  
Any triplet  243 (82%)  55 (74%)  188 (85%)  0.051  
Bortezomib schedule
Bi-weekly
Weekly 
239 (81%)
56 (19%)  
52 (70%)
22 (30%)  
187 (85%)
34 (15%)  
0.010  
HDM at first line 143 (48%) 15 (20%) 128 (58%) <0.0001 

Disclosures

Dimopoulos:Celgene: Consultancy, Honoraria.

Author notes

*

Asterisk with author names denotes non-ASH members.