1. Meletios A. Dimopoulos, MD
Therapy Options for Transplant-Ineligible Patients with Multiple Myeloma
Meletios A. Dimopoulos, MD
Department of Clinical Therapeutics,
National and Kapodistrian University of Athens,
School of Medicine, Athens, Greece

2. What should be the goal of treatment in multiple myeloma?
To search for an appropriate balance between treatment efficacy, toxicity & costs
In fit elderly patients (65-80y) & young ones with severe co-morbidities ……… treatment goal should be to prolong survival and ensure QoL
In very elderly patients (> 80-85y)…….to ensure QoL & avoid additional costs of expensive treatments

3. CR predicts long term outcome Analysis of 1175 elderly patients25 50 75
100 10 20 30 40 60 70 80
PFS OS
100 CR 75 CR
VGPR PR 50
VGPR PR 25 10 20 30 40 50 60 70
months
months
Gay et al. Blood 2011;117: 3 3

4. Approved Treatment Options of Patients
Who Are Not Eligible for HDM and ASCT

5. MP vs. MPT: Meta-analysis of 1,682 individual patient data from 6 randomized clinical trials
Hazard ratio P
Median PFS
14.9 months
20.4 months
0.68 ( )
<0.0001
Median OS
32.7 months
39.3 months
0.83 ( )
0.004
Fayers et al. Blood 2011;118:

6. Myeloma IX: CTDa for elderly patients
Median follow-up: 44 months
ORR significantly higher with CTDa than MP (63.8% vs 32.6%; P < )
Higher rates of CR (13.1% vs 2.4%) and VGPR (16.9% vs 1.7%)
Significantly longer OS for patients with favorable interphase FISH compared with those with adverse interphase FISH (P < 0.001)
PFS OS
Morgan et al. Blood 2011;118(5):

7. VISTA: Final updated OS analysis (31% reduced risk of death with VMP)
Median follow-up 60.1 months
100 90 80 70 60 50 40 30 20 10
Median OS benefit: 13.3 months
5-year OS rates: 46.0% vs. 34.4%
Patients alive (%)
Group N Event Median HR (95% CI) P-value MP
VMP (0.567, 0.852)
Time (months)
San Miguel et al. J Clin Oncol 2013;31:448-55

8. FIRST: Phase 3 trial of Lenalidomide + low-dose Dex vs
FIRST: Phase 3 trial of Lenalidomide + low-dose Dex vs. MPT (IFM 07-01; MM-020)
RANDOMIZATION
Rd (28-day cycle; until disease progression)
Lenalidomide 25 mg/day, days 1–21 Dexamethasone* 40 mg/day, days 1, 8, 15, and 22
Inclusion criteria
N = 1,623
Previously untreated MM
Age  65 years or not eligible for a transplant
No neuropathy of grade > 2
Rd (28-day cycle; up to 18 cycles)
Lenalidomide 25 mg/day, days 1–21 Dexamethasone* 40 mg/day, days 1, 8, 15, and 22
MPT (6-week cycle; up to 12 cycles )
Melphalan* 0.25 mg/kg/day, days 1–4 Prednisone 2.0 mg/kg/day, days 1–4 Thalidomide* 200 mg/day
Primary end-point: PFS
PFS: 28% reduction in the risk of DP/death for Rd (til DP) vs MPT
OS: 22% reduction in the risk of death for Rd (til DP) vs MPT
Len-dex will be a new standard of care for elderly newly diagnosed MM pts, or new backbone
Benboubker L et al. N Engl J Med 2014; 371:906-17 8 8 8

9. FIRST Trial: Response endpoints (IMWG Criteria)Rd
(n = 535)
Rd18
(n = 541)
MPT
(n = 547)
ORR (≥ PR)
75.1
73.4
62.3 CR
15.1
14.2
9.3
VGPR
28.4
28.5
18.8 PR
31.6
30.7
34.2 SD
18.9
20.5
26.5
VGPR or better
43.5
42.7
28.1
Median time to response (mos)
1.8
2.8
Duration of response (mos)
35.5
22.1
22.3
Benboubker L et al. N Engl J Med 2014; 371:906-17

10. FIRST Trial: PFS Continuous Rd reduced the risk of disease progression by 28% vs. MPT
Hazard ratio
Rd vs. MPT: 0.72; P =
Rd vs. Rd18: 0.70; P =
Rd18 vs. MPT: 1.03; P =
Time (months)
Patients (%)
100 80 60 40 20 6 12 18 24 30 36 42 48 54
72 wks
Median PFS
Rd (n= 535)
25.5 mos
Rd18 (n= 541)
20.7 mos
MPT (n= 547)
21.2 mos Rd
535
400
319
265
218
168
105 55 19 2
Rd18
541
391
167
108 56 30 7
MPT
547
380
304
244
170
116 58 28 6 1
mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, Lenalidomide plus low-dose dexamethasone.
Benboubker L et al. N Engl J Med 2014; 371:906-17

11. FIRST Trial: Overall Survival Interim Analysis 574 deaths (35%)
Overall survival (months)
100 80 60 40 20 6 12 18 24 30 36 42 48 54
Hazard ratio
Rd vs. MPT: 0.78; P = ( 22% risk of death with Rd)
Rd vs. Rd18: 0.90; P = 0.307
Rd18 vs. MPT: 0.88; P = 0.184
4-year OS
Rd (n= 535)
59.4%
Rd18 (n= 541)
55.7%
MPT (n= 547)
51.4%
Patients (%) Rd
Rd18
MPT
535
541
547
488
505
484
457
465
448
433
425
418
403
393
375
338
324
312
224
209
205
121
124
106 43 44 30 5 6 3
Benboubker L et al. N Engl J Med 2014; 371:906-17

12. FIRST Trial: OS by Age Stratification
Aged 75 Yrs or Younger
Aged Older Than 75 Yrs
100
3-Yr OS, %
100
3-Yr OS, %
Rd Rd18 MPT
Rd Rd18 MPT 80 80 60 60
Pts (%)
Pts (%) 40 40
HR (95% CI) Rd vs MPT: 0.77 ( ) Rd vs Rd18: 0.88 ( ) Rd18 vs MPT: 0.88 ( )
HR (95% CI) Rd vs MPT: 0.80 ( ) Rd vs Rd18: 0.94 ( ) Rd18 vs MPT: 0.85 ( ) 20 20 6 12 18 24 30 36 42 48 54 60 6 12 18 24 30 36 42 48 54 60
OS (Mos)
OS (Mos)
Hulin C, et al. ASH Abstract 81.

13. FIRST Trial: Safety- Selected Gr3–4 TEAEsRd
(n=535)
Rd 18
(n=541)
MPT
(n=545)
Hematological (%)
Anemia
18.2
15.7
18.9
Neutropenia
27.8
26.5
44.9
Thrombocytopenia
8.3
8.0
11.1
Febrile neutropenia
1.1
0.9
2.6
Non-hematological (%)
Infections
28.9
21.9
17.2
Pneumonia
8.1
5.7
Diarrhea
3.9
3.3
1.5
Constipation
2.3
1.9
5.4
Peripheral sensory neuropathy
0.4
9.4
Rash
8.8
6.7
5.5
Deep vein thrombosis
3.7
Cataract
5.8
0.6
TEAEs: treatment emerging adverse events
Benboubker L et al. N Engl J Med 2014; 371:906-17 13

14. FIRST Trial - Renal Analysis: PFS Per Status
PFS in normal (per IRAC assessment)
PFS in mild RI (per IRAC assessment)
1.0
0.8
0.6
0.4
0.2
0.0 6 12 18 24 30 36 42
PFS (mos) 48 54 60
Survival probability
Cont. Rd vs. MPT HR: 0.71, P = 0.05a
Rd vs. Rd18 HR: 0.67, P = 0.02a
Rd18 vs. MPT HR: 1.06, P = 0.76a
1.0
0.8
0.6
0.4
0.2
0.0 6 12 18 24 30 36 42
PFS (mos) 48 54 60
Survival probability
Cont. Rd vs. MPT HR: 0.74, P = 0.02a
Rd vs. Rd18 HR: 0.72, P < 0.01a
Rd18 vs. MPT HR: 1.04, P = 0.76a
Continuous Rd
Rd18
MPT
Continuous Rd
Rd18
MPT
PFS in moderate RI (per IRAC assessment)
PFS in severe RI (per IRAC assessment)
PFS (mos)
1.0
0.8
0.6
0.4
0.2
0.0 6 12 18 24 30 36 42 48 54 60
Survival probability
Cont. Rd vs. MPT HR: 0.66, P < 0.01a
Rd vs. Rd18 HR: 0.66, P < 0.01a
Rd18 vs. MPT HR: 1.02, P = 0.89a
1.0
0.8
0.6
0.4
0.2
0.0 6 12 18 24 30 36 42
PFS (mos) 48 54 60
Survival probability
Cont. Rd vs. MPT HR: 0.76, P = 0.31a
Rd vs. Rd18 HR: 0.82, P = 0.48a
Rd18 vs. MPT HR: 1.00, P = 1.00a
Continuous Rd
Rd18
MPT
Continuous Rd
Rd18
MPT
aNominal P values are presented for multiplicity assessments which need to be taken into consideration before making clinical interpretations.
HR, hazard ratio; mos, months; MPT, melphalan-prednisone-thalidomide; PFS, progression-free survival; Rd, lenalidomide plus low-dose dexamethasone; Rd18, Rd for 18 cycles; RI, renal impairment; IRAC, Independent Response Adjudication Committee
Dimopoulos MA, et al. ASH 2014, abstract #2112.

15. Studies with Continuous Therapy for Patients
Who Are Not Eligible for HDM and ASCT

16. Continuous Treatment in the non-Transplant Setting: Thalidomide
Median follow-up (months)
Median PFS
(months)
Median OS
Reference
MPT + T vs MP 38
21.8*
14.5
45.0
47.6
Palumbo et al.
Blood 2008; 112(8): 39
13* 9
40* 31
Wijermans et al.
JCO 2010; 28(19):3160-6 42 15 14 29 32
Waage et al.
Blood 2010; 116(9):
CTDa/MP (CTD/CVAD) + T
CTDa/MP (CTD/CVAD) 46
11*
Morgan et al.
Blood 2012; 119(1):7-15
Thal-IFN
IFN† 35
27.7*
13.2
52.6
51.4
Ludwig et al.
Haematologica 2010; 95(9):
†Thal/Dex vs MP induction
*significant difference between arms

17. MM-015: MPR-R vs. MPR vs. MP RANDOMISATION Disease progression MPR-R
Cycles (28-day) 1-9
Cycles 10+
RANDOMISATION
MPR-R
M: 0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
R: 10 mg/day po, days 1-21
Lenalidomide Continued Tx
Disease progression
Lenalidomide
(25 mg/day) +/- dexamethasone
10 mg/day, days 1-21
Primary Comparison
MPR-R vs. MP
MPR
M: 0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
R: 10 mg/day po, days 1-21
Placebo MP
M: 0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
PBO: days 1-21
Secondary Comparison
MPR-R vs. MPR
Addition of MPR arm per EMEA advice
Placebo
Double-Blind Treatment Phase
Open-Label Extension/ Follow-Up Phase
Stratified by age (≤ 75 vs. > 75 years) and stage (ISS 1,2 vs. 3)
Palumbo et al. N Engl J Med 2012;366:

18. MPR-R vs. MPR vs. MP: PFS 58% Reduced Risk of Progression
65-75 Years of Age 2 2 - -
Year PFS
Year PFS
Median PFS
Median PFS 2 2 - -
Year PFS
Year PFS
Median PFS
Median PFS 5 10 15 20 25 30 35 40 50 75
100
100
100
100
100
100
MPR
MPR - - R R
55%
55%
Not reached
Not reached
MPR
MPR - - R R
61%
61%
Not reached
Not reached
MPR
MPR
27%
27%
14.7 months
14.7 months 75 75 75 75 75 MP MP
16%
16%
13.0 months
13.0 months MP MP
10%
10%
12.4 months
12.4 months
HR 0.315
HR 0.423 50 50 50 50 50
Log rank P
< .001
Log rank P
< .001
Patients (%)
Patients (%)
Patients (%)
Patients (%) 25 25 25 25 25
HR 0.675
Log rank P
= .031 5 5 10 10 15 15 20 20 25 25 30 30 35 35 40 40 5 5 5 10 10 10 15 15 15 20 20 20 25 25 25 30 30 30 35 35 35 40 40 40
Time (Months)
Time (Months)
Palumbo et al. N Engl J Med 2012;366:

19. MM-015: PFS & OS update in Patients 65-75 y
Palumbo A, et al. IMW 2013;abstract P-227.

20. Phase III Trial Comparing MPT-T vs
Phase III Trial Comparing MPT-T vs. MPR-R in SCT-Ineligible Patients with NDMM
Joint study of the Dutch-Belgian Cooperative Trial Group for Hematology Oncology and the Nordic Myeloma Study Group
Stratified by center and ISS
Randomization 1:1
MPR
Melphalan 0.18 mg/kg on Days 1-4 +
Prednisone 2 mg/kg on Days 1-4 +
Lenalidomide 10 mg on Days 1-21
(n = 319)
R Maintenance
Lenalidomide 10 mg on Days 1-21 q28d
until PD
28-day cycles x 9
MPT
Melphalan 0.18 mg/kg on Days 1-4 +
Prednisone 2 mg/kg on Days 1-4 +
Thalidomide 200 mg on Days 1-28
(n = 318)
T Maintenance
Thalidomide
100 mg/day
until PD
Granulocyte-colony stimulating factor administered if absolute neutrophil count < 0.5 x 109 cells/L or in event of febrile neutropenia during a cycle.
Zweegman S, et al. ASH Abstract 179.

21. MPT-T vs. MPR-R: Efficacy Analysis
Median follow-up: 33.6 mos
ORR similar between arms: 81% MPT-T vs 83% MPR-R
No significant difference in PFS or OS
Outcome
MPR-R
(n = 319)
MPT-T
(n = 318)
HR (95% CI)
P Value
ORR (on protocol), % 83 81 CR 13 10
VGPR 32 38 PR 39 33
Median PFS, mos 22 20
086 ( )
.12
Median OS, mos NR
0.79 ( )
.08
2-yr OS, % 84 73
3-yr OS, % 69 64
4-yr OS, % 55 52
Zweegman S, et al. ASH Abstract 179.

22. MPT-T vs. MPR-R: Safety Analysis
Treatment Outcome, %
MPR-R
MPT-T
≤ 75 Yrs
> 75 Yrs
Completed 6 induction cycles 68 73 76 77
Initiated maintenance therapy 59 58 57 39
Discontinued maintenance 43 88
Due to AEs* 24 31 67 69
Median duration of maintenance, mos (range)
16 (0-53)
15 (1-52)
5 (0-49)
5 (0-44)
*Primarily due to peripheral neuropathy in thalidomide arm, hematologic toxicity in lenalidomide arm
MPT-T associated with significantly higher rate of grade ≥ 2 neuropathy (45% vs. 8%; P < .0001); higher rate of grade 3/4 hematologic AEs (including neutropenia [63% vs. 27%], thrombocytopenia [28% vs. 8%], and anemia [14% vs. 5%]) vs MPR-R
Zweegman S, et al. ASH Abstract 179.

23. VMPT + VT versus VMP: Study design
Patients (n=511): >65 years old; median age 71 years
VMPT + VT
VMP
9 x 5-wk cycles:*
Bortezomib
Melphalan
Prednisone
Thalidomide
9 x 5-wk cycles:*
Bortezomib
Melphalan
Prednisone
Maintenance (until relapse):
Bortezomib (1.3 mg/m2 d 1, 15)
+ Thalidomide (50 mg continuously)
No maintenance
*Protocol amendment: from twice-weekly bortezomib dosing (d 1,4,8,11,22,25,29,32) to once-weekly bortezomib dosing (d 1,8,15,22); 61 patients in VMP arm and 70 patients in VMPT arm received twice-weekly bortezomib dosing.
Palumbo et al. J Clin Oncol 2010;28:5101-9
Palumbo et al. J Clin Oncol 2014;32:634-40

24. Updated analysis on Survival Data
PFS
TNT OS OS
post relapse
Palumbo et al. J Clin Oncol 2014;32:634-40

25. Updated analysis on OS (advantage only for 65-75 years)
Landmark analysis for OS
Pts years old: VMPT-VT vs VMP, P=0.0001
Pts > 75 years old: VMPT-VT vs VMP, P=0.25
Pts years old
Total
Induction
Maintenance
Disc. for AEs
Bortezomib dose intensity
VMPT-VT
25%
81%
17%
89%
12%
77%
VMP
15% -
Pts > 75 years old
Disc. for Aes
35%
58%
29%
53%
14%
49%
16%
80%
Palumbo et al. IMW 2013 (Abstract P-134), poster presentation

26. Ixazomib Maintenance Following Induction With Ixazomib + Len/Dex in NDMM
Phase I/II trial assessing weekly ixazomib plus lenalidomide/dexamethasone in pts with NDMM
Ixazomib: the first oral proteasome inhibitor to be assessed in clinical trials
Current analysis focused on efficacy and safety of maintenance ixazomib
Maintenance population similar to overall phase II population
Approximately 15% of pts with unfavorable characteristics in each group
Kumar S, et al. Lancet Oncol 2014;15:

27. Ixazomib Maintenance Improves Depth of Response
100 5
n = 2 16 19 19
n = 1 80 19
sCR CR nCR VGPR PR MR SD
n = 5 33 60 8 48
Percent of Patients, % 16
n = 2 10 40 10 31 20 29 29 6 4
Best Response in Overall Population (n = 49)
Best Response to Induction
Best Response Overall
In Pts Receiving Maintenance
(n = 21)
Kumar S, et al. Lancet Oncol 2014;15:

28. Ixazomib Maintenance: PFS
1.0
0.8
0.6
0.4
0.2
Probability of PFS 3 6 9 12 15 18 21 24 27 30 33
Mos
Phase II pts who received maintenance (n = 21)
All phase II pts (n = 50)
(pts who proceeded to ASCT [n = 14] were censored at last response assessment before ASCT)
Median PFS among censored pts who received maintenance: not reached, 10 pts progressed; Estimated 2-yr PFS: 57%
Median PFS among all phase II pts: 28.7 mos; Estimated 2-yr PFS: 50%
Kumar S, et al. Lancet Oncol 2014;15:

29. Ixazomib Maintenance: Efficacy and Safety
Safety in maintenance period similar to induction period
No grade 4 AEs, grade 3 drug-related AEs reported in 62% of pts
52% during induction; 14% during maintenance
Limited new onset AEs during maintenance
New onset AEs ≤ 10% except diarrhea (~ 45%), nausea (~ 20%), and pain in extremities (~ 15%)
Serious AEs were reported in 4 pts during maintenance period but were considered not related to treatment
Grade 3 acute myocardial infarction, grade 3 pneumonia, grade 3 orthostatic hypotension, and grade 2 ventricular extrasystoles
No discontinuations due to AEs; 17 pts required dose reductions due to AEs during induction and 2 required dose reductions due to AEs during maintenance
Kumar S, et al. Lancet Oncol 2014;15:

30. Modified Lenalidomide/Bortezomib/ Dexamethasone in ASCT-Ineligible NDMM
Phase II trial exploring utility of modified RVD (RVD lite); N = 30
Lenalidomide: single daily oral dose of 15 mg Days 1-21
Bortezomib: 1.3 mg/m2 SC once weekly Days 1, 8, 15, 22
Dexamethasone: 20 mg twice weekly if ≤ 75 yrs or once weekly if > 75 yrs
RVD lite resulted in 90% ORR (≥ PR), ≥ VGPR: 53%
3 pts discontinued study after <1 cycle due to worsening adrenal insufficiency; rash attributed to lenalidomide; unrelated
AEs manageable and well tolerated in an older population
Grade 3 AEs in ≥ 5%: hypophosphatemia (32%), rash (12%), mood disorder (9%)
Grade 4 AEs: hypoglycemia (3%), neutropenia (3%), corneal ulcer (3%)
O’Donnell E, et al. ASH Abstract 3454.

31. Weekly Carfilzomib in Combination With Cyclophosphamide/Dex in NDMM
Phase I/II trial to assess feasibility of reduction of carfilzomib dosing from twice weekly to once weekly when used in combination with cyclophosphamide/dexamethasone in elderly pts with NDMM
Carfilzomib given weekly using standard 3+3 phase I dose-escalation (starting at 45 mg/m2, increasing to 56 or 70 mg/m2)
Phase I data (n = 12) identified MTD as 70 mg/m2
3 of 12 pts in phase I portion received MTD
Phase II cohort currently enrolling
18 pts included in current analysis
Similar baseline characteristics across all pts in phase I and II cohorts, with 30% of pts aged ≥ 75 yrs and 33% with unfavorable cytogenetics
Palumbo A, et al. ASH Abstract 175.

32. Weekly Carfilzomib + Cyclophosphamide/ Dex: Preliminary Efficacy
Outcome
Phase I (n = 12)
MTD (n = 19)
Total (N = 28)
Median cycles received, n (range)
9 (1-9)
4 (1-9)
8 (1-9)
ORR (≥ PR), n (%)
11 (92)
15 (79)
24 (86)
≥ VGPR
9 (75)
11 (58)
18 (64)
sCR + CR + nCR
4 (33)
4 (21)
7(25)
At Least nCR
At Least VGPR 47 50
100 89 91 41 77 40 80 30 57 30 24 60
Pts (%)
Pts (%) 20 40 10 20
Cycle 4
Cycle 9
Cycle 4
Cycle 9
Once weekly[1] Twice weekly[2]
1. Palumbo A, et al. ASH Abstract Bringhen S, et al. Blood. 2014;124:63-69.

33. Weekly Carfilzomib + Cyclophosphamide/ Dex: Safety and Tolerability
Outcome,[1] n (%)
Phase I
(n = 12)
MTD
(n = 21)
Total
(N = 30)
Any SAE*
1 (8)
4 (19)
5 (17)
Any drug-related SAE†
4 (13)
Dose reduction due to AE
3 (25)
3 (10)
Discontinuation due to AE
2 (17)
2 (9)
Median cycles, n (range)
9 (1-9)
4 (1-9)
8 (1-9)
Outcome, %
Once-Weekly Carfilzomib[1]
Twice-Weekly Carfilzomib[2]
Grade 3/4 hematologic AEs 23 27
Grade 3/4 nonhematologic AEs 30 29
Median carfilzomib dose, mg
3534
2904
Carfilzomib dose adjustments
Reductions 10 21
Discontinuations 13 14
*AEs graded using NCI-CTCAE v4.02. †Drug-related defined as related to any drug in the combination.
1. Palumbo A, et al. ASH Abstract Bringhen S, et al. Blood. 2014;124:63-69.

34. The elderly patient population – a highly heterogeneous group
Aging – a complex, multifactorial process
Associated with substantial physiological, cognitive and functional changes
Definition of the elderly population complex
 A highly heterogeneous population
Chronological versus
biological age
Fit / independent versus
frail / dependent on help
Disability
Comorbidities ……
Nigam et al. Journal of Aging Research 2012;Article ID
Ludwig et al. J Clin Oncol 2010;28:

35. Age and organ damage correlate with poor OS: Meta-analysis of 4 randomized trials
Bringhen et al. Haematologica 2013;98(6):

36. General considerations when treating the elderly
We cannot treat all elderly patients the same
Importance of assessing comorbidity, frailty ….
Challenge: No formalized assessment recommended, but a range of options available
Activity of Daily Living
Instrumental Activity of Daily Living
Charlson Comorbidity Score ….

37. VP vs. VMP vs. VCP in the elderly (>75 years)
23/11/2018
150 patients (> 75 years) randomized from 3 countries
Patients: Symptomatic disease, organ damage, measurable disease 1° R A N D O M I Z T VP
Nine 35-day courses
Vsc: 1.3 mg/sqm, d 1,8,15,22
P: 50 mg, 3 times wk
MAINTENANCE day course until relpase
Vsc: 1.3 mg/sqm, d 1, 15
P: 25 mg; 3 times wk
VMP
Nine 35-day courses
Vsc: 1.3 mg/sqm, d 1,8,15,22
M: 2 mg, 3 times wk
P: 50 mg, 3 times wk
MAINTENANCE day course until relpase
Vsc: 1.3 mg/sqm, d 1, 15
P: 25 mg; 3 times wk
VCP
Nine 35-day courses
Vsc: 1.3 mg/sqm, d 1,8,15,22
C: 50 mg, 3 times wk
P: 50 mg, 3 times wk
MAINTENANCE day course until relpase
Vsc: 1.3 mg/sqm, d 1, 15
P: 25 mg; 3 times wk
Vsc, subcutaneous bortezomib, cyclophosphamide; M, melphalan; P, prednisone
Larocca et al. Blood 2013;122 (ASH abstracts):539 37

38. VP vs. VMP vs. VCP: Subgroup analysis Fit vs Unfit vs Frail*
Progression-free Survival
Overall Survival
0.00
0.25
0.50
0.75
1.00 5 10 15 20 25
0.00
0.25
0.50
0.75
1.00 5 10 15 20 25
Patients (%)
PFS, Fit versus Frail, p=0.02
PFS , Fit versus Unfit, p=0.2
OS, Fit versus Frail, p=0.001
OS , Fit versus Unfit, p=0.02
Time (months)
Time (months)
*Unfit defined as: ADL 5 or IADL 6-7 or Charlson 1 or fit patient >80 yr
Frail defined as: ADL <4 or IADL <5 or Charlson >2 or unfit patient >80 yr
Larocca et al. Blood 2013;122 (ASH abstracts):539

39. VP vs. VMP vs. VCP: Subgroup analysis Progression-free Survival
Median follow-up 17 months
Overall Survival
0.00
0.25
0.50
0.75
1.00 5 10 15 20 25
0.00
0.25
0.50
0.75
1.00 5 10 15 20 25
Patients (%) VP
VCP
VMP VP
VCP
VMP
OS, VMP versus VP, p=0.29
OS , VCP versus VP, p=0.20
OS, VMP versus VCP, p=0.70
Time (months)
Time (months)
PFS, VMP versus VP, p=0.15
PFS , VCP versus VP, p=0.28
PFS, VMP versus VCP, p=0.69
Larocca et al. Blood 2013;122 (ASH abstracts):539

40. Dose adjustment recommendations for the treatment of frail elderly patients
Agent
Dose level 0
Dose level – 1
Dose level – 2
Bortezomib
1.3 mg/m2 twice / week
d 1,4,8,11 / 3 wks
1.3 mg/m2 once / week
d 1,8,15,22 / 5 weeks
1.0 mg/m2 once / week
Thalidomide
100 mg/d
50 mg/d
50 mg qod
Lenalidomide
25 mg/d
d 1-21 / 4 weeks
15 mg/d
10 mg/d
Dexamethasone
40 mg/d
d 1,8,15,22 / 4 week
20 mg/d
Melphalan
0.25 mg/kg
d 1-4 / 4-6 weeks
0.18 mg/kg
0.13 mg/kg
Prednisone
25 mg qod
12.5 mg qod
Cyclophosphamide
Palumbo et al. N Engl J Med 2011;364:

41. Conclusions for NDMM patients not eligible for HDM
Approved treatment for patients who are not eligible for transplant include: MPT, VMP, CTD and Rd continuous
Continuous treatment with PIs or IMiDs gives promising results in this setting
Novel combinations, i.e. modified VRD, may be also a treatment option in the near future
Caution is needed for frail patients-weekly schedule of bortezomib and dose modifications are necessary

42. Thank you