Maintenance Therapy in Multiple MyelomaThe Role of Other Agents
(Besides Lenalidomide)
James Berenson, MDInstitute for Myeloma and Bone Cancer Research
Los Angeles, CA
Maintenance Therapy in Myeloma
Maintain response achieved following a new treatment with administration of drugs for a prolonged time period
Therapy must be Convenient Safe and well tolerated LONGTERM NOT prevent use or reduce efficacy of other future
treatments
GoalsReduce the risk of relapse
Extend PFS and OS
Maintenance Therapy in Myeloma
In what setting- frontline or > 2nd line Most of the data is in the frontline setting
How long to “maintain” maintenance therapy Until relapse or for a fixed length of time Trials have employed both approaches BUT no randomized trials
comparing the two w/i a trial Which agents
How many to use? Doses? Schedule(s)? Very little data from randomized trials comparing different
maintenance regimens as the only randomization
Maintenance Therapy in Myeloma: Steroids and -Interferon
1. -Interferon: a. 929 patients in 8 trials had prolongation of remission duration and survival by 6 and 5 months Ludwig H. Ann Oncol 1995;467
b. Twist analysis: IFN gained 9.8 months without relapse and 5.8 months survival, but with 4.1 months of toxicityTherefore, benefits must be balanced against toxicity Ludwig H. 1997;1672
2. Prednisone 50 mg qod prolongs overall and event-free survival after VAD induction therapy Berenson J. Blood 2002;99:3163
NInitial
dose, mg/d
Maintenance versus no maintenance
CR, % EFS or PFS, % OS, %
Attal et al.1 597400 w/ PAM
67 vs 55*3-year EFS
52 vs 364-year OS87 vs 77
Barlogie et al.2 668 400 62 vs 435-year EFS
56 vs 448-year OS57 vs 44
Spencer et al.3 243200 w/ steroid
vs steroid alone
63 vs 40* 3-year PFS42 vs 23
3-year OS86 vs 75
Lokhorst et al.4 535 50 24 vs 66*Median
22 m vs 34 mMedian
60 m vs 73 m
Thalidomide: Maintenance Therapy after Autologous Stem Cell Transplant
*CR + VGPR rates.1. Attal M, et al. Blood. 2006 2. Barlogie B, et al. Blood 2008 3. Spencer A, et al. J clin Oncol. 2009 4. Lokhorst et al . Blood 2010
vs PAM or none
Bisphosphonates: Anti-Tumor Effects in MM Direct
Induces apoptosisPrevents prenylation of GTPases
IndirectReduces anti-apoptotic and growth factorsAnti-angiogenic
Decreases angiogenic factorsPrevents endothelial cell developmentInhibits angioattraction
M2 to M1 reversion of TAMsPrevents adhesion of MM cells to stroma
Synergizes w/ other anti-MM drugsImmune stimulatory effects-
Increases Vg9d2 T cells
• Intergroupe Francophone du Myeloma (IFM) 99 02– Large, randomized, prospective study
Attal M et al Blood 2006; 108: 3289.
VAD regimen
3-4 cycles
No maintenance
therapy
(n = 200)
Pts with untreated
Stage I - III MM < 65 yrs old
(N = 780)
Melphalan 140 mg/m2
and autologous stem-cell transplant
Melphalan 200 mg/m2 and second autologous stem-cell transplant
Pamidronate (90 mg/mo)
(n = 196)
Pamidronate (90 mg/mo) + Thalidomide (100 mg/day)
(n = 201)
Pts who did not progress after 2 mos
(n = 597)
VAD; vincristine, doxorubicin, and dexamethasone
Pamidronate With or Without Thalidomide as Post-transplantation Maintenance Therapy
Survival benefit in the combination PAM + Thal arm and not in the single agent PAM armSurvival benefit in the combination PAM + Thal arm and not in the single agent PAM arm
MRC Myeloma IX: Trial Design for Monthly IV Zoledronic Acid vs Daily Oral Clodronate for Newly Diagnosed MM
• Endpoints (ZOL vs CLO)– Primary: PFS, OS, and ORR– Secondary: Time to first SRE, SRE incidence, and safety
N = 1,960Patients with newly
diagnosed MM (stage I, II, III)
Clodronate (1600 mg/d PO) + intensive or non-intensive chemotherapy
(n = 979)
Zoledronic acid (4 mga IV q 3-4 wk) + intensive or non-intensive chemotherapy
(n = 981)
Treatment continued at least until disease progression
Abbreviations: CLO, clodronate; IV, intravenous; MM, multiple myeloma; ORR, overall response rate; OS, overall survival, PFS, progression-free survival; PO, oral; SRE, skeletal-related event; ZOL, zoledronic acid.a Dose-adjusted for patients with impaired renal function, per the prescribing information.
Morgan G, et al. Lancet. 2010;376:1989-1999.
MRC Myeloma IX: ZOL Improved OS and PFS vs CLOa
a Cox model adjusted for chemotherapy, and minimization factors.
Riskreduction
Hazard ratio (ZOL versus CLO)0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2
P value
.01180.842
16%
In favor of ZOL In favor of CLO
OS
.017912%0.883
PFS
• ZOL significantly reduced the relative risk of death by 16% vs CLO (HR = 0.842; 95% CI = 0.736, 0.963; P = .0118)
Morgan G, et al. Lancet. 2010;376:1989-1999.
Bortezomib as Maintenance Therapy VMPT-VT vs VMP: Study
Design
Endpoints:– Primary: PFS– Secondary: RR, OS, and grade ≥3 AEs
Palumbo A, et al. Presented at: ASH. 2012 (abstr 200).
VMPT (n=254)Induction: 9 courses Weekly BORT (4 doses; 1.3 mg/m2) Melphalan 9 mg/m2
Prednisone 60 mg/m2 once daily on days 1-4 of each course Thalidomide 50 mg/day continuously
VMP (n=257)9 courses Weekly BORT (4 doses; 1.3 mg/m2) Melphalan 9 mg/m2
Prednisone 60 mg/m2 once daily on days 1-4 of each course
RANDOMIZE
NDMM(N=511)SCT-ineligibleMeasurable diseaseKarnofsky PS ≥60%
VT (n=254)Maintenance: 2 yearsBORT 1.3 mg/m2 or maximum dose tolerated q2wThalidomide 50 mg/day continuously
10
No Maintenance Therapy(N=257)
VMPT-VT vs VMP: PFS and Time to Next Therapy (TTNT)
1.00
0.75
0.50
0.25
0.000 10 20 30 40 50 60 70 80
Median PFS, Months Median TTNT, Months
VMPT-VT 35.3 46.6
VMP 24.8 27.8
Reduced risk, % 42 (of progression) 48 (of next therapy)
TTNTHR: 0.52 (95% CI, 0.42-0.66); P<0.0001
1.00
0.75
0.50
0.25
0.000 10 20 30 40 50 60 70 80
PFSHR: 0.58 (95% CI, 0.47-0.71); P<0.0001
Time, Months Time, Months
Median follow-up 54 months
11TTNT=time to next therapy.Palumbo A, et al. Presented at: ASH. 2012 (abstr 200).
VMPT-VT VMPT-VT
VMP VMP
VMPT-VT vs VMP: Overall Survival
Palumbo A, et al. Presented at: ASH. 2012 (abstr 200).
Efficacy, % VcMPT-VcT VcMP P Value
5-yr PFS 29 13 <0.0001
5-yr TTNT 41 19 <0.0001
5-yr OS 61 51 0.01
3-yr OS from relapse
47 46 0.63
VMPT-VT
VMP
Induction Maintenance1.00
0.75
0.50
0.25
0.000 10 20 30 40 50 60 70 80
Time, Months
HR: 0.74 (95% CI, 0.55-0.99); P=0.04
12
Impact of Maintenance Therapy: VMPT-VT vs VMP
VMPT-VT
Hematologic 2%
DVT 1%
Sensory neuropathy 6%
Infection 1%
Cardiologic 1%
Discont. due to AE 11%
Grade 3/4 AE’s during maintenance
Landmark analysis after finishing 9 cycles of induction VMPT or VMP
•52% reduced risk of progression with VMPT-VT (HR 0.48, P<0.0001)
– Irrespective of response (CR or PR)
– In pts <75 yrs old, but not ≥75 yrs
•Prognostic factors: response, age, ISS, cytogenetic abnormalities
Palumbo et al. ASH 2010 (Abstract 620)
HOVON-65/GMMG-HD4: Study Design
• Primary endpoint: PFS
• Secondary endpoints: response, OS, toxicity
PAD × 3 cyclesBORT 1.3 mg/m2 days 1, 4, 8, 11doxorubicin 9 mg/m2days 1-4dexamethasone 40 mg days 1-4, 9-12, 17-20(n=371)
VAD × 3 cyclesVincristine 0.4 mg days 1-4 Doxorubicin 9 mg/m2 days 1-4Dexamethasone 40 mg days 1-4, 9-12, 17-20(n=373)
BORT1.3 mg/m2
every 2 weeks
Stem cellcollection
andtransplantation*
Thalidomide50 mg/day
Stem cellcollection
andtransplantation*
2 years
Patients 18-65 years of age with
newly diagnosed
stage II/III MM(N=744)
Multicenter, International, Phase III
Trial
*ASCT + melphalan 200 mg/m2; allogeneic SCT with no maintenance offered when possible; German patients enrolled through GMMG underwent 2 ASCTs.German centers performed double SCT; Dutch centers performed single SCT.Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955
HOVON-65/GMMG-HD4: Response, PFS & OS
ResponseVAD Arm: Thalidomide, %
(n=414)PAD Arm: BORT, %
(n=413)Pand t Value
CR≥ nCR≥ VGPR≥ PR
24345683
36497690
<0.001<0.001<0.0010.002
PADVAD
0 12 24 36 48 60
100
80
60
40
0
20
Time, Months0 12 24 36 48 60
100
80
60
40
0
20
Time, Months
PFS OS
PADVAD
P=0.002 P=0.07
Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955
Improved PFS and OS in pts w/ del 17p13 and those w/ creatinine > 2 mg/dL
Phase III PETHEMA/GEM Trial: Bortezomib as Maintenance Therapy in Previously Untreated MM1,2
• Endpoints: Primary: PFS; Secondary: response rate, OS, safety• Patients: 266 pts <65 yrs of age with previously untreated MM randomized to
maintenance therapy; median age 56–58 yrs across arms; 53–59% ISS stage II/III across arms
• Dose and schedule: Induction: thalidomide/Dex (6 cycles) vs VTD (6 cycles) vs VBMCP/VBAD (4 cycles) +
bortezomib (2 cycles); followed by ASCT with MEL-200; then second randomization to: Maintenance: 3 arms
• bortezomib 1.3 mg/m2 days 1, 4, 8, 11 every 3 mos + thalidomide 100 mg/day (VT)• thalidomide 100 mg/day• interferon-α2b 3 MU 3 times/week; for 3 yrs
• Response:
Rosiñol L, et al. ASH 2012, abstract #334; Induction phase publication: Rosiñol L, et al. Blood 2012;120:1589-1596; Maintenance therapy previous publication: Rosiñol L, et al. ASH 2011, abstract #3962
Maintenance
VT (n=89)
Maintenance thalidomide (n=87)
Maintenance interferon (n=90)
Response before maintenance, %
CR
VGPR
PR
53
12
33
49
11
37
53
13
33
Response improvement with maintenance, %
CR post-maintenance
Increase in CR74
21
63
15
69
15
Phase III PETHEMA/GEM Trial: Bortezomib as Maintenance Therapy for Previously Untreated MM1,2
•Outcomes: Median follow-up of 34.9 mos; from onset of maintenance therapy: PFS: addition of bortezomib to thalidomide (VT) maintenance
resulted in significantly longer PFS vs thalidomide or interferon (p=0.0009)
OS: No difference between arms (p=0.47) Bortezomib-containing (VT) maintenance conferred a significant
PFS advantage in pts with low-risk (p=0.002) but not high-risk (p=0.5) cytogenetics
•Safety: Gr 3/4 thrombocytopenia for VT vs. thalidomide: 10% vs. 2%; p=0.01 Gr 3/4 neutropenia: Approximately 13% for VT, 16% for thalidomide,
and 17% for interferon
Rosiñol L, et al. ASH 2012, abstract #334
*p=0.02 vs thalidomide; #p=0.06 vs thalidomide; †discontinued thalidomide but remained on bortezomib
Phase III: VMP vs VTP in Newly Diagnosed Elderly Pts with MM (PETHEMA/GEM Study)
• Pts (n=260), >65 yrs old (median age 73 yrs)
• Multicenter, two-stage randomized trial
VMP VTPvs
VT VP VT VP
Induction Randomization step 1
Maintenance Randomization
step 2
vs vs
Induction (max. 6 cycles)
• One 6-wk cycle, bortezomib 2x wkly
• Five 5-wk cycles, bortezomib 1x wkly
Maintenance (up to 3 yrs)
Bortezomib: 1.3 mg/m2 (d 1, 4, 8, 11), every 3 mos
+ Thal: 50 mg daily (VT)
or Pred: 50 mg every 48 hrs (VP)
Mateos et al. Lancet Oncol 2010; 11(10): 934-941
PFS and OS
• No significant difference in PFS and OS between VMP and VTP groups and not significantly different for VT or VP maintenance
p=0.1 p=0.3
OSPFS
VMP 34 mos
VTP 25 mos
VMP 3-yr OS 74%
VTP 3-yr OS 65%
Mateos et al. Lancet Oncol 2010; 11(10): 934-941
The role of maintenance therapy with novel agents has not been clearly defined (limitations in trial designs)
Long term use appears to be safe w/ bortezomib and steroids
Better trial designs are required to clarify the role of maintenance therapy in myeloma
Specific drugs Single agent vs combination Doses and schedules Length of therapy- fixed vs to progression Endpoints- PFS vs OS
Summary
Maintenance therapy is used for all patients responding in both the frontline and salvage settings
Drugs are continued until progressive disease; however, doses may have to be reduced or discontinued due to toxicity
Drugs are continued that were part of the treatment regimen EXCEPT chemotherapy
New agents are NOT introduced during maintenance (i.e. the devil you know is better (and shown to be effective) than the one you don’t)- if so, this is NEW treatment
Steroids at equivalent dose intensity (160 mg Dex)/month as oral methylprednisolone qod alone or w/ IV Dex qow
Bortezomib 1.3 mg/m2 sc qow IMiD drugs- Lenalidomide 10 mg for 14 or 21 days
depending on regimen; THAL 50-100 mg daily and tapered w/ neuropathy
Zoledronic acid is continued monthly
In Our Clinical Practice
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