1. Update on transplant-ineligible patients: Which regimens are best?
Suzanne Lentzsch MD, PhD
Columbia University, New York

2. Disclosures for Suzanne Lentzsch, MD, PhD
Honoraria
Scientific Advisory Board
Speakers Bureau
No relevant conflicts of interest to declare
Major Stockholder
Consultant
Employee
Celgene
Research Support/P.I.
No relevant conflicts of interest to declare
No relevant conflicts of interest to declare
Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millenium, Onyx

3. Treatment Decision in Older Patients
ADL
IADL
Comorbidities
Hospitalization
Medications
Social Support
Multiple Myeloma
Cytogenetics
Stage
Tumor burden
Optimal Chemo
Supportive meds
Goals of Care (CR vs Disease Control?)
Expectations
Understanding
Life Expectancy

4. Treatment Decision in Transplant Ineligible Patients
Frailty ???
Melphalan based regimens ???
Doublets ???
Triplets ???
Maintenance ???

5. Frailty score Variable HR (CI 95%) P SCORE AGE Age <75 years 1 -
Age years
1.37 ( )
0.114
Age >80 years
2.75 ( )
<0.001 2
CHARLSON INDEX
Charlson <1
Charlson >2
1.6 ( )
0.021
ADL SCORE
ADL >4
ADL<4
1.76 ( )
0.01
IADL SCORE
IADL >5
IADL<5
1.53 ( )
0.036
ADDITIVE TOTAL SCORE
PATIENT STATUS
FIT 1
UNFIT
>2
FRAIL
Slide courtesy of Palumbo, ASH 2013

6. Fit vs. Unfit vs. Frail Overall Survival Multivariate Analysis
Unfit vs Fit
Frail vs Fit
ISS 3 vs ISS 1-2
HR vs SR Fish
ECOG 2-3 vs 0-1
1.24 (0.74, 2.08)
3.11 (1.97, 4.90)
1.77 (1.23, 2.54)
1.83 (1.26, 2.63)
1.19 (0.81, 1.76)
1-yr OS
Fit
96%
Unfit
93%
Frail
78%
Patients (%)
Lower risk Death
FIT
ISS 1-2
FISH neg
Higher risk Death
FRAIL
ISS 3
FISH pos
Unfit vs Fit, HR=1.61 p=0.042
Frail vs Fit, HR=3.57 p<0.001
Fit defined as: score=0 Unfit defined as: score=1 Frail defined as: score>2
Slide courtesy of Palumbo, ASH 2013

7. Slide courtesy of Palumbo, ASH 2013

8. Treatment algorithm for elderly MM
PATIENT STATUS ASSESSMENT
Age (score 0 – 1 – 2) Charlson (score 0 – 1)
ADL (score 0 – 1) IADL (score 0 – 1)
FIT
UNFIT
FRAIL
Additive total score = 0
Additive total score = 1
Additive total score ≥ 2
GO-GO
MODERATE-GO
SLOW-GO
Full-dose
Reduced-dose
Further reduced dose
Dose level 0
Dose level -1
Dose level -2
Lenalidomide
25 mg/d
15 mg/d
10 mg/d
Bortezomib
1.3 mg/m2/wk
1.0 mg/m2/wk
1.3 mg/m2/2wk
Dexamethasone
40 mg/wk
20 mg/wk
10 mg/wk
Cyclophosphamide
300 mg/m2 d 1,8,15
50 mg/d
50 mg/qod
Slide courtesy of Palumbo, ASH 2013

9. Unanswered Question for Transplant Ineligible Patients
Frailty-Adjust Treatment Intensity
Melphalan ???
Doublets ???
Triplets ???
Maintenance ???

10. Progression-free survival
Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials
MP better
MPT better
Progression-free survival
Overall survival
NOTE: weights are from random effects analysis
Overall (I-squared = 61.7%,
p = 0.023)
FR < 75
NMSG
HOVON
Italy
Fr ≥ 75
Turkey
Study
0.67 (0.55– 0.80)
0.50 (0.39– 0.65)
0.89 (0.70–1.13)
0.79 (0.62–1.00)
0.62 (0.48–0.80)
0.61 (0.46–0.82)
0.59 (0.35–0.99)
HR (95% CI) 1
0.5
0.75
1.5
Overall (I-squared = 60.6%, p = 0.026)
Fr ≥ 75
0.82 (0.66–1.02)
1.12 (0.85–1.47)
1.04 (0.75–1.44)
0.61 (0.45– 0.81)
0.75 (0.57–1.00)
0.68 (0.48– 0.96)
0.87 (0.46–1.67)
Fayers P M et al. Blood 2011;118:

11. Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials
MPT MP
mOS
39.3 m
32.7 m
mPFS
20.3 m
14.9 m
Fayers P M et al. Blood 2011;118:

12. Overall survival in patients randomized to bortezomib-melphalan-prednisone (VMP) or melphalan-prednisone (MP) after a median follow-up of 5 years
San Miguel J F et al. JCO 2013;31:

13. Initial Therapy in Older Adults With MM: Randomized Trials of MP With or Without the Addition of Novel Agents
Abbreviations: MM, multiple myeloma; MP, melphalan and prednisone; MPR, melphalan, prednisone, and lenalidomide; MPR-R, melphalan, prednisone, and lenalidomide with lenalidomide maintenance; MPT, melphalan, prednisone, and thalidomide; MPV, melphalan, prednisone, and bortezomib; NR, not reported; OS, overall survival; PFS, progression-free survival; Rd, lenalidomide and low-dose dexamethasone; RD, lenalidomide and high-dose dexamethasone.
↵* Discontinuation rate because of toxicity, specifically during induction where applicable. Global (ie, “any” or “nonhematologic”) toxicity incidence not reported.
↵† Statistically significant for MPR-R v MP and MPR-R v MPR only.
Wildes T M et al. JCO 2014;32:

14. Unanswered Question for Transplant Ineligible Patients
Frailty – Adjust Treatment Intensity
Melphalan or Novel Drugs ???
Doublets or Triplets ???
Maintenance ???

15. Efficacy and Safety of Three Bortezomib-Based Induction and Maintenance Regimens in Previously Untreated, Transplant-Ineligible Multiple Myeloma Patients: Final Results from the Randomized, Phase 3b, US Community-Based UPFRONT Study
Slide Courtesy Niesvizky, R; ASH 2013

16. RESULTS Patients 502 patients were randomized to
VD (n=168),
VTD (n=167),
VMP (n=167)
Baseline characteristics were well balanced across the treatment arms
Median age was 73 years (range 38–91)
48% of patients had comorbidities at baseline
The most common were diabetes mellitus (21%), renal disease (15%), and chronic pulmonary disease (8%)
Slide Courtesy Niesvizky, R; ASH 2013

17. Response*
ORRs after 13 cycles were 73% (VD), 80% (VTD), and 70% (VMP) including:
30%, 40%, and 32% CR/nCR, respectively
37%, 51%, and 41% ≥VGPR, respectively
Best confirmed response after 8 (induction) and 13 (induction + maintenance) cycles
*Response-evaluable population (n=425 patients who received at least one dose of study drug, had measurable disease at baseline, and had at least one post-baseline M-protein measurement)
Slide Courtesy Niesvizky, R; ASH 2013

18. PFS (intent-to-treat population)
After a median follow-up of 42.7 months, 265 (53%) patients had progressed and/or died
Median PFS (95% CI) was 14.7 months (12.0, 18.6), 15.4 months (12.6, 24.2), and 17.3 months (14.8, 20.3), for VD, VTD, and VMP, respectively, with no global difference among arms (p=0.458)
Slide Courtesy Niesvizky, R; ASH 2013

19. OS (intent-to-treat population)
Median OS (95% CI) was 49.8 months (35.7, not estimable [NE]), months (38.5, NE), and 53.1 months (41.1, NE) for VD, VTD, and VMP, respectively, with no global difference among arms (p=0.789)
Slide Courtesy Niesvizky, R; ASH 2013

20. UPFRONT TRIAL CONCLUSIONS
After ~3.5 years’ follow-up, no significant differences in PFS or OS were seen among arms
VTD had the highest toxicity rates and the lowest mean bortezomib dose intensity among the arms
VD doublet therapy may be as effective as VTD or VMP triplet therapy in elderly pat (due less toxicity with higher bortezomib intensity?)
In accordance with:
Recent analysis of VMP data from VISTA suggests that a higher cumulative bortezomib dose, reflecting prolonged treatment duration and/or dose intensity, is associated with superior OS (Mateos MV, et al. ASH 2013, abstract #2155)
Slide Courtesy Niesvizky, R; ASH 2013

21. Unanswered Question for Transplant Ineligible Patients
Frailty – Adjust Treatment Intensity
Melphalan or Novel Drugs!
Doublets! or Triplets
Maintenance ???

22. FIRST Trial: Study Design
Screening
Active Treatment + PFS Follow-up Phase
LT Follow-Up
RANDOMIZATION 1:1:1
LEN + Lo-DEX Continuously
LENALIDOMIDE mg D1-21/28
Lo-DEX mg D1,8,15 & 22/28
PD or Unacceptable Toxicity
Subsequent anti-MM Tx
PD, OS and
Arm A
Continuous Rd
Arm B
Rd18
LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE mg D1-21/28
Lo-DEX mg D1,8,15 & 22/28
MEL + PRED + THAL 12 Cycles1 (72 wks)
MELPHALAN mg/kg D1-4/42
PREDNISONE mg/kg D1-4/42
THALIDOMIDE mg D1-42/42
Arm C
MPT
Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL2 (100 mg D1-42/42); MEL mg/kg D1–4
Stratification: age, country and ISS stage
ISS, International Staging System; LT, long-term; PD, progressive disease; OS, overall survival
1Facon T, et al. Lancet 2007;370: ; 2Hulin C, et al. JCO. 2009;27:
Facon T, et al. Blood. 2013;122:abstract 2.
Benboubker L et al. N Engl J Med 2014;371:

23. FIRST Trial: Final Progression-free Survival
28% reduced risk of disease progression
Median PFS
Rd (n=535)
25.5 mos
Rd18 (n=541)
20.7 mos
MPT (n=547)
21.2 mos
100 80 60 40 20
Hazard ratio
Rd vs. MPT: 0.72; P =
Rd vs. Rd18: 0.70; P =
Rd18 vs. MPT: 1.03; P =
Patients (%)
72 wks 6 12 18 24 30 36 42 48 54 60
Time (months) 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:

24. FIRST Trial: Overall Survival Interim Analysis
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 = 0.02
Rd vs. Rd18: 0.90; P = 0.31
Rd18 vs. MPT: 0.88; P = 0.18
4-year OS
Rd (n= 535)
59%
Rd18 (n= 541)
56%
MPT (n= 547)
51%
Patients (%)
574 deaths (35% of ITT) 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:

25. FIRST Trial: Response Endpoints
Responsea (%)
Continuous Rd
(n=535)
Rd18
(n=541)
MPT
(n=547)
ORR (≥ PR)b 75 73 62 CR 15 14 9
VGPR 28 19 PR 32 31 34 SD 21 27
VGPR or better 43 42
Time to response (median, mos)
1.8
2.8
Duration of response (median, mos)
35.0
22.1
22.3
aIMWG Criteria; CR, complete response; mos, months ORR, overall response rate; PR, partial response; SD, stable disease; VGPR, very good PR.
bResponse assessment for Rd obtained every 4 wks and for MPT every 6 wks; Response and progression rate based on IRAC assessment.
Benboubker L et al. N Engl J Med 2014;371:

26. FIRST Trial: Conclusions
Continuous Rd significantly extended PFS and OS vs. MPT
PFS:
HR= 0.72 (P= )
Consistent benefit across most subgroups
Rd better than Rd18 (HR= 0.70, P= )
3 yr PFS: 42% Rd vs 23% Rd18 and MPT
Planned interim OS: HR= 0.78 (P= )
Rd was superior to MPT across all other efficacy secondary endpoints
Safety profile with continuous Rd was manageable
Hematological and non-hematological AEs were as expected for Rd and MPT
Incidence of hematological SPM was lower with continuous Rd vs. MPT
In NDMM transplant-ineligible patients, the FIRST Trial establishes continuous Rd as a new standard of care
Benboubker L et al. N Engl J Med 2014;371:

27. Unanswered Question for Transplant Ineligible Patients
Frailty – Adjust Treatment Intensity
Melphalan or Novel Drugs !!
Doublets or Triplets !!
Maintenance !!

28. Bortezomib-Melphalan-Prednisone Followed by Maintenance With Bortezomib-Thalidomide (VMP-VT) Compared With Bortezomib-Melphalan-Prednisone (VMP) for Initial Treatment of Multiple Myeloma
N=511
Palumbo A et al. JCO 2014;32:

29. Survival outcomes in the intention-to-treat population, according to study group.
TNT
PFS
OS after Relapse OS
Palumbo A et al. JCO 2014;32:

30. VT-Maintenance for Non-Transplant Patients
VMP vs. VMPT-VT:
3-year PFS: 41% vs 56%
median PFS: vs 35.3 months (P .001)
TNT vs 46.6 months (P .001)
5-year overall survival (OS) was greater with VMPT-VT (61%) than with VMP (51%; HR, 0.70; P .01).
VMPT-VT group, more grade 3 to 4 adverse events including neutropenia (38%), thrombocytopenia (22%), peripheral neuropathy (11%), and cardiologic events (11%).
Conclusion
Bortezomib and thalidomide maintenance significantly improved OS in multiple myeloma patients
Palumbo A et al. JCO 2014;32:

31. UnAnswered Question for Transplant Ineligible Patients?
Frailty
Adjust Treatment Intensity
Determine the goals of care !!
Melphalan or Novel Drugs !!
Doublets or Triplets !!
Less toxic treatment allows longer treatment
Maintenance !!

32. Thank You !!