Natural History of Multiple Myeloma Relapsing After Therapy with IMiDs and Bortezomib: A Multicenter International Myeloma Working Group Study
Shaji Kumar, John Crowley, Jae-Hoon Lee, Juan J. Lahuerta, Gareth Morgan, Antje Hoering, Paul Richardson, Jacob Laubach, Philippe Moreau, Xavier LeLeu, Cyrille Hullin, Saskia Klein,
David Siegel, Hartmut Goldschmidt, Sundar Jagannath, Robert Orlowski, Antonio Palumbo, Orhan Sezer, Jackie Szymonifka, Joan Blade, S. Vincent Rajkumar, Brian Durie on behalf of the
International Myeloma Working Group
Background!
Results!
· Significant advances have been made in the treatment of myeloma
Table 1: Baseline features
Features At time zero
with the introduction of thalidomide, lenalidomide, and bortezomib.
Factor
n/N (%)
Median time to Time zero
32 months
· While these new drugs have improved the outcome of patients with
Male
167/270 (62%)
Age > 65 yr

109/265 (41%)
myeloma, the disease still remains incurable.
· Effectiveness of upcoming new therapies will need to be assessed
Race
3 or More Regimens Prior to Time Zero
61/192 (32%)
in the context of anticipated outcome with the currently available
White
169/252 (67%)
At Least 1 Transplant Prior to Time Zero
161/270 (60%)
therapies.
Black
4/252 (2%)
·
>=2 Transplants Prior to Time Zero
36/270 (13%)
However, given the rapid pace of development over the past
Asian
76/252 (30%)
decade, outcome of patients relapsing on the new therapies remain
Features At Diagnosis
Last treatment prior to Time zero contained (n):
unclear.
·
Median age at diagnosis
Bortezomib
106
Hence, we undertook a study of patients relapsing after or are
refractory to either thalidomide or lenalidomide) as well as
Age > 65 yr
67/265 (25%)
Thalidomide
20
bortezomib
ISS stage at Diagnosis
Lenalidomide
29
Figure 1: Overall (OS) and Event-Free Survival (EFS)
Stage 1
56/202 (28%)
Dexamethasone
91
from Time Zero Kaplan-Meier (KM) Plots
Objectives!
Stage 2
84/202 (42%)
Alkylator
39
In contrast, the median OS and EFS excluding patients
Primary objective: Determine the overall survival of patients
Stage 3
62/202 (31%)
who had their first SCT after time zero was 7 and 4
Doxorubicin
10
refractory to bortezomib and one of the IMiDs, from the time they
months respectively.
Cytogenetics: del 13
15/128 (13%)
become refractory.
192 patients (71%) received at least one regimen following
FISH: t(4;14), t(14, 16) or del 17p
21/93 (23%)
Secondary objectives:
time zero. The distribution of the drugs are as in table 2
· To determine the duration of responses to subsequent treatments
Table 2: Regimen Number (Following Time Zero)
following development of bortezomib/ IMiD refractoriness.
Drug
1
2
3
4
5
6
7
Multivariate analysis
· To determine the time to progression/ time to next therapy
Patients (N)
158
61
34
19
9
6
2
· Age < 60 years and at least one
following subsequent salvage therapies
Bortezomib
52
20
19
5
8
3
1
SCT after time zero best predicted
Cisplatin
23
6
2
0
2
1
0
for >= PR following time zero.
Patients and Methods!
· Normal creatinine and albumin at
Cyclophosphamide
62
21
7
6
2
1
1
time zero best predicted for a
· A total of 270 cases from 8 sites in the US, 5 sites in Europe and
Single agent steroid
15
6
2
1
0
0
0
superior OS following time zero
one site in Asia were identified for this study.
Doxorubicin
40
11
4
1
2
1
0
· B2M < 3.5 mg/dL at diagnosis
· Enrolled patients had relapsed and refractory multiple myeloma,
Etoposide
26
4
2
0
2
1
0
predicted for a better EFS
per the EBMT or IMWG response criteria, after at least 2 prior
Figure 2: Cumulative Incidence of Response Following
following time zero
treatments.
Thalidomide
27
14
6
2
2
1
1
Time Zero
· Patients were refractory to bortezomib, defined as having no
Lenalidomide
35
10
6
5
3
2
1
Summary and Conclusion!
response on a prior bortezomib-containing regimen or
Melphalan
29
11
7
6
0
2
0
experiencing disease progression within 60 days of a
Median time to next
3.85
4.57
3.32
4.27
2.62
2.79
3.38
· The median time to satisfy the inclusion criteria for this study was 32 months from
bortezomib-containing regimen.
regimen (months)
diagnosis
· Patients also should have relapsed, refractory, intolerant, and/or
·Patients who have become refractory to or ineligible for treatment with novel agents have a
ineligible in the opinion of the investigator, to an IMiD
Response
1
2
3
4
5
6
7
poor outcome with median overall survival of 8 months from that time point.
(thalidomide or lenalidomide).
PR or higher
47/158 11/61
10/34
4/19
1/9
2/6
1/2
·Excluding patients with first time SCT after they become refractory to novel agents, the
· Clinical and laboratory data pertaining to the time of diagnosis and
response
(30%) (18%) (29%) (21%) (11%) (33%) (50%)
median OS is only 7 months and reflects patients most likely to benefit from new drugs.
from the time of individual relapses were obtained from the
Minor response/
70/158 26/61
11/34
11/19
6/9
4/6
0/2
·Conventional prognostic factors are still important for survival outcomes in this population
clinical records.
Stable disease
(30%) (33%) (27%) (37%) (55%) (67%)
(0%)
·The preserved time to next therapy with each regimen following time zero likely reflects
· The date patients satisfied the above entry criteria was defined as
Progression
41/158 24/61 13/34
4/19
2/9
0/6
1/2
selection of patients with better biology and better performance status for inclusion in trials
time zero.
(26%) (39%) (38%) (21%) (22%)
(0%)
(50%)

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