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

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