1. GEM2005MAS65 Trial: Bortezomib-Based Maintenance Increases CR Rate and PFS in Elderly Patients With Newly Diagnosed Multiple Myeloma
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Mateos MV, Oriol A, Martínez-López J, et al. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012;120:
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2. Background
Maintenance therapy with novel agents an important challenge in elderly patients with MM
Thalidomide: in data from MP vs MPT trials, thalidomide maintenance upgraded response and improved PFS but provided only a marginal improvement in OS
Lenalidomide: maintenance improved PFS but not OS in the ongoing MM-015 trial[1]
Bortezomib: improved 3-yr PFS (but no OS benefit) for VMP plus thalidomide induction followed by VT maintenance vs VMP induction with no maintenance[2]
MM, multiple myeloma; MP, melphalan/prednisone; MPT, melphalan/prednisone/thalidomide; OS, overall survival; PFS, progression-free survival; VMP, bortezomib/melphalan/prednisone; VP, bortezomib/prednisone; VT, bortezomib/thalidomide; VTP, bortezomib/thalidomide/prednisone
Palumbo A, et al. N Engl J Med. 2012;366: Palumbo A, et al. J Clin Oncol. 2010;28:

3. Rationale
GEM2005MAS65: randomized study VMP or VTP induction followed by VT or VP maintenance in 260 elderly patients with untreated MM
Previously reported from this trial: bortezomib-based induction followed by maintenance safe and effective in elderly patients with MM[1]
Current analysis: compare efficacy and toxicity of VT maintenance therapy vs VP in elderly patients with newly diagnosed MM enrolled in GEM2005MAS65[2]
MM, multiple myeloma; MP, melphalan/prednisone; MPT, melphalan/prednisone/thalidomide; OS, overall survival; PFS, progression-free survival; VMP, bortezomib/melphalan/prednisone; VP, bortezomib/prednisone; VT, bortezomib/thalidomide; VTP, bortezomib/thalidomide/prednisone
1. Mateos MV, et al. Lancet Oncol. 2010;11: Mateos MV, et al. Blood. 2012;120:

4. GEM2005MAS65: Study Design Induction: 6 wks Maintenance: up to 3 yrsVP
Bortezomib 1.3 mg/m2 twice/wk
(Days 1, 4, 8, 11) every 3 mos
Prednisone 50 mg every 48 hrs
(n = 44)
VMP
6 cycles of
Bortezomib 1.3 mg/m2 twice/wk*
Melphalan 9 mg/m2 on Days 1-4
Prednisone 60 mg/m2 on Days 1-4
(n = 130) VT
Bortezomib 1.3 mg/m2 twice/wk (Days 1, 4, 8, 11) every 3 mos
Thalidomide 50 mg/day
(n = 47)
Elderly patients (≥ 65 yrs) with newly diagnosed MM
(N = 260) VP
Bortezomib 1.3 mg/m2 twice/wk
(Days 1, 4, 8, 11) every 3 mos
Prednisone 50 mg every 48 hrs
(n = 43)
MM, multiple myeloma; VMP, bortezomib/melphalan/prednisone; VP, bortezomib/prednisone; VT, bortezomib/thalidomide , VTP, bortezomib/thalidomide/prednisone
VTP
6 cycles of
Bortezomib 1.3 mg/m2 twice/wk* Thalidomide 100 mg/day
Prednisone 60 mg/m2 on Days 1-4
(n = 130) VT
Bortezomib 1.3 mg/m2 twice/wk (Days 1, 4, 8, 11) every 3 mos
Thalidomide 50 mg/day
(n = 44)
*Days 1, 4, 8, 11, 22, 25, 29, 32 for one 6-wk course, then on Days 1, 8, 15, 22 for five 5-wk courses
Mateos MV, et al. Blood. 2012;120:

5. Description of Current Analysis
Assessment of safety and efficacy in randomized comparison of maintenance therapy with VT or VP
FISH studies conducted in CD138-purified plasma cells
Response assessment according to EBMT criteria
Standard CR; IF-negative CR; IF-positive near CR
Assessments performed monthly during maintenance
Median follow-up: 38 mos from maintenance therapy initiation (range: 8-58)
CR, complete response; FISH, fluorescence in-situ hybridization; IF, immunofixation; nCR, near-complete response; VMP, bortezomib/melphalan/prednisone; VP, bortezomib/prednisone; VT, bortezomib/thalidomide , VTP, bortezomib/thalidomide/prednisone
Mateos MV, et al. Blood. 2012;120:

6. Eligibility Inclusion criteria 65 yrs of age or older
Transplantation ineligible
Newly diagnosed symptomatic MM
Measurable disease
No previous treatment
MM, multiple myeloma
Mateos MV, et al. Blood. 2012;120:

7. Baseline Characteristics
178 patients randomized for maintenance and evaluable for response
Characteristic
VT (n = 91)
VP (n = 87)
Male, % 53 47
Mean age, yrs (range)
71 (66-82)
72 (65-84)
ISS stage, % I 30 28 II 41
III 29
IgG/IgA/light chain, %
62/28/9
55/32/12
Mean β2-microglobulin, mg/L
3.7
3.8
Mean creatinine, mg/dL
1.0
Mean plasma cell bone marrow infiltration 38 44
Induction regimen, %
VMP 52 51
VTP 48 49
High-risk cytogenetics by FISH,* % 17 15
FISH, fluorescence in-situ hybridization; ISS, international staging system; IgA, immunoglobulin A; IgG, immunoglobulin G; VMP, bortezomib/melphalan/prednisone; VP, bortezomib/prednisone; VT, bortezomib/thalidomide , VTP, bortezomib/thalidomide/prednisone
*t(4;14), t(14;16), or del17p.
Mateos MV, et al. Blood. 2012;120:

8. CR Rate After Induction
Response, %
Premaintenance VT
(n = 91) VP
(n = 87)
P Value
IF-negative CR 24 46 39 NS
IF-positive CR 10 11 PR 47 MR 8 3 1 SD
CR, complete response; IF, immunofixation; MR, minor response; NS, not significant; PR, partial response; SD, stable disease
Mateos MV, et al. Blood. 2012;120:

9. Proportion of Patients Proportion of Patients
PFS and OS
Median PFS and 5-yr OS superior among patients randomized to VT vs VP maintenance, but the differences did not reach statistical significance
PFS OS
1.0
1.0
YT: not reached
5-yr OS: 69%
0.8
0.8
VT: 39 mos
0.6
0.6
VT: 60 mos
Proportion of Patients
Proportion of Patients
OS, overall survival; PFS, progression-free survival; VP, bortezomib/prednisone; VT, bortezomib/thalidomide
VT: 39 mos
0.4
0.4
0.2
0.2
P = .1
P = .1
0.0
0.0 10 20 30 40 50 60 10 20 30 40 50 60
Months
Months
Mateos MV, et al. Blood. 2012;120:

10. PFS and OS According to Response
Achievement of CR significantly associated with longer PFS and 5-yr OS (P < .001)
PFS OS
1.0
1.0 CR
0.8
0.8 CR PR
0.6
0.6
Proportion of Patients
Near CR
Proportion of Patients
Near CR
CI, confidence interval; CR, complete response; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; VP, bortezomib/prednisone; VT, bortezomib/thalidomide
0.4 PR
0.4
0.2
0.2
P > (HR: 1.73; 95% Cl: )
P >
(HR: 1.5; 95% Cl: )
0.0
0.0 10 20 30 40 50 60 70 10 20 30 40 50 60 70
Months
Months
Mateos MV, et al. Blood. 2012;120:

11. Depth of Response
Patients with improved depth of response during maintenance had better outcomes vs patients who only maintained response
Median PFS: 47 vs 32 mos, respectively (HR: 0.56; 95% CI: ; P = .02)
5-yr OS: 81% vs 54%, respectively (HR: 0.4; 95% CI: ; P = .02)
These outcomes not influenced by the type of maintenance regimen
FISH analysis completed for 160 (89%) of patients randomized to receive maintenance
Distribution by treatment arms balanced across both risk subgroups
CI, confidence interval; CR, complete response; FISH, fluorescence in-situ hybridization; HR, hazard ratio; OS, overall survival; PFS, progression-free survival;
Mateos MV, et al. Blood. 2012;120:

12. Response According to Patient Risk
Type of maintenance regimen did not influence response in high-risk or standard-risk patients
Response, %
Standard Risk
(n = 111)
High Risk
(n = 28)
P Value VT VP
IF-negative CR 48 41 47 39 NS
IF-positive CR 10 11 7 8 PR 37 45 40 54 MR 3 2
CR, complete response; IF, immunofixation; MR, minor response; NS, not significant; PR, partial response
Mateos MV, et al. Blood. 2012;120:

13. PFS and OS According to Patient Risk
Differences in PFS and OS by risk minimal and did not reach statistical significance
High-risk subgroup for VT vs VP
Median PFS: 28 vs 27 mos, respectively (P = .6)
4-yr OS: 55% vs 53%, respectively (P = .2)
Standard-risk subgroup
Median PFS: slightly higher with VT (47 vs 36 mos; P = .1)
4-yr OS: 79% vs 69% for VT vs VP (P = .1)
OS, overall survival; PFS, progression-free survival; VP, bortezomib/prednisone; VT, bortezomib/thalidomide
Mateos MV, et al. Blood. 2012;120:

14. Hematologic Toxicity AEs, % VT (n = 91) VP (n = 87 ) P Value
Grade 3/4 AEs
All 17 5
.009
Peripheral neuropathy 9 3
Asthenia 2
Gastrointestinal symptoms 4 1*
Cardiac events
Discontinuations 57 59
Reason for discontinuation
Disease progression 35 46
Toxicity 13
Development of SPM
Deaths 26 21 30
Development of AEs 6
AEs, adverse events; SPM, second primary malignancies
*Gastrointestinal symptomatology and other cardiac events.
Mateos MV, et al. Blood. 2012;120:

15. Hematologic Toxicity Second primary malignancies encountered: AEs:
Lung, colorectal, prostate, and lung and liver metastases of unknown origin
AEs:
Heart attack, stroke, hepatic/lung metastasis, lung cancer, septic shock in VT arm; sepsis, colorectal neoplasm, progressive cognitive impairment, intracerebral hemorrhage in VP arm
AE, adverse event; VP, bortezomib/prednisone; VT, bortezomib/thalidomide
Mateos MV, et al. Blood. 2012;120:

16. Summary
Bortezomib-based maintenance increases CR rate and PFS in elderly patients with newly diagnosed MM
Achievement of CR associated with significantly longer PFS (P < ) and 5-yr OS (P < .001)
Median PFS and OS higher with VT vs VP but differences did not reach statistical significance
Overall acceptable toxicity profile with bortezomib-based maintenance
More grade 3/4 peripheral neuropathy with VT vs VP
Maintenance with VT or VP does not overcome the adverse prognosis associated with high-risk cytogenetic features
CR, complete response; OS, overall survival; PFS, progression-free survival; VP, bortezomib/prednisone; VT, bortezomib/thalidomide
Mateos MV, et al. Blood. 2012;120: