The evidence supporting continuous therapy in multiple myeloma

Sergio Giralt, MD

Chief, Adult Bone Marrow Transplant Service

Memorial Sloan Kettering Cancer Center

New York, New York

Why Maintenance Therapy?

• Induction therapy followed by autologous SCT alone will cytoreduce but not cure most Multiple Myeloma patients

• Can maintenance therapy:– prevent or delay disease progression?– convert partial responses to complete responses?– improve overall survival?

• Problems with maintenance therapy– Everybody gets the drug not everybody gets the benefit.– You “burn” an effective drug.– Treatment fatigue

• What defines an ideal maintenance strategy?– Significantly improved outcomes with minimal side effects and

preservation of response to salvage.

Maintenance TherapyPhilosophical Perspective

• Pros

• Increases remission duration.

• Maintains minimal disease burden preventing end organ damage.

• Targets “tumor cells” that leave “dormancy phase”.

• May further decrease tumor burden post primary therapy.

• Cons

• Exposes all patients to the side effects of prolonged treatment.

• Can result in resistant clones.

• Late effects of long-term therapy.

• Cost

Common wisdom dictates that PFS by itself may not justify continuous therapy for all patients with a specific disease. Either a survival or QOL benefit needs to be garnered when comparing continuous therapy to therapy upon progression. The question is made even more difficult if the issue of pre-emptive (i.e. early intervention) is included.

Rationale for continuous treatment in the era of IMID’s and Proteosome Inhibitors

• Primary therapy even with high dose therapy results in CR in less than 50% of patients.

• Longer treatment can result in better disease control and may be associated with

– prolonged duration of response

– increased depth of response

• Survival benefit???

• Use of different mechanisms of action (MoAs) of novel agents

• Tolerability of novel agents allows for longer-term treatment

Potential risks of continuous treatment in the era of IMID’s and Proteosome Inhibitors

• Adverse events related to long-term treatment

– reduced quality of life

– impact on subsequent therapeutic options

– second primary malignancies?

• Reduced survival after relapse

– selection of resistant clones

– availability of non-cross-reacting agents

Historical Perspective

• Long term alkylator therapy associated with higher risk of 2ry MDS/AML

• Interferon maintenance multiple randomized trials marginal benefit in PFS no survival benefit. Poor compliance.

• Long term steroid therapy potentially beneficial

Upgrade in MRD negativity with consolidation: GIMEMA study

• VTD compared with TD consolidation (x 2 cycles starting within 3 months post ASCT) on minimal residual disease (MRD) in MM patients treated in the phase III GIMEMA trial

• Results (VTD, n = 35; TD, n = 32)– upgrade in MRD-negativity from 43% to 67% for VTD vs

upgrade from 38% to 52% with TD (p = 0.05 for 67% vs 52%)

– PCR bone marrow analysis showed a median 5 log reduction in tumour burden with VTD vs a 1 log reduction with TD (p = 0.05)

Terragna, et al. Blood. 2010;116:[abstract 861].

Patients (N)

Duration of treatment CR + VGPR (%) EFS or PFS (%) OS (%)

TT21,2 668 Double ASCTThal vs no maintenance

until progression

64 vs 43*(CR only)p < 0.001

52 vs 41 (5 years)

p = 0.0005

57 vs 44 (8 year) p = 0.09

Sign in cyto abnormalities

IFM 99-023 597 Double ASCTPam + Thal vs Pam vs none

until progression

67 vs 57 vs 55

p = 0.03

52 vs 37 vs 36 (3 years)p < 0.009

87 vs 74 vs 77 (4 years)p < 0.04

Spencer4 243 Single ASCTPred + Thal vs Pred,

12 months

63 vs 40 42 vs 23(3 years)p < 0.001

86 vs 75 (3 years)p = 0.004

Morgan5 820 Thal vs no maintenanceuntil progression

NA HR: 1.36; 95% CI: 1.15–1.61p < 0.001

NS

Lokhorst6 556 Double or single ASCTThal vs alpha-interferon

until progression

66 vs 54p = 0.005

34 vs 22p < 0.001

73 vs 60p = 0.77

Stewart7 332 Single ASCTThal + Pred vs observation

until progression

Not reported 28 months vs 17 months

p < 0.0001

Median not reached vs 5 yearsP = 0.18

Impact of thalidomide based maintenance post-ASCT

1. Barlogie B, et al. Blood. 2008;112:3115-21. 2. Barlogie B, et al. J Clin Oncol. 2010;28:3023-7. 3. Attal M, et al. Blood. 2006;108:3289-94. 4. Spencer A, et al. J Clin Oncol. 2009;27:1788-93. 5. Morgan GJ, et al. Blood. 2010;116:[623].

6. Lokhorst HM, et al. Blood. 2010;115:1113-20. 7. Stewart AK, et al. Blood. 2010;116:[39].

• 6/6 trials showed a significant benefit on PFS

• 2/6 trials showed a significant benefit on OS + 1/6 showed a significant OS benefit in patients with cytogenetic abnormalities

Impact of bortezomib and thalidomide maintenance post-ASCT

16

3842

71

30

50 48

78

0

20

40

60

80

100

CR/nCR pre-maintenance

CR/nCR post-maintenance

PFS at 3 years OS at 3 years

VAD-thalidomidePAD-bortezomib

Sonneveld P, et al. Blood. 2010;116:[abstract 40].

* Patients received one (HOVON) or two (GMMG) treatments with high-dose melphalan (HDM) with ASCT.

Yea

rs (

%)

HOVON-65/GMMG-HD4 trial

Tales of Two Cases

Case 1

• 55 yo female presents with asymptomatic anemia of 10 gm/dl and total serum protein 10 gm/lt

• Work up reveals

– 30 % plasma cells

– Cytogenetic diploid

– IgA kappa peak of 3.2

– Beta 2 microglobulin of 3.0

• Receives 4 cycles of Bortezomib /Thal/Dex

• Followed by Auto SCT on Day 60 documented stringent CR

Case 2

• 55 yo female presents with asymptomatic anemia of 10 gm/dl and total serum protein 10 gm/lt

• Work up reveals

– 30 % plasma cells

– Cytogenetic t 4,14

– IgA kappa peak of 3.2

– Beta 2 microglobulin of 3.0

• Receives 4 cycles of Bortezomib /Thal/Dex

• Followed by Auto SCT on Day 60 documented paraprotein peak of 0.4 gm/dl

Phase III IFM 2005-02: Lenalidomide as Phase III IFM 2005-02: Lenalidomide as Consolidation/Maintenance Post-ASCTConsolidation/Maintenance Post-ASCT

First-line

ASCT < 65 years

Lenalidomide: 25 mg/d Days 1–21/month2 months

Primary end point: PFS

≤ 6 monthsNo PD

N = 614

Lenalidomide: 10–15 mg/duntil relapse

Lenalidomide: 25 mg/d Days 1–21/month2 months

Placebo until relapse

Consolidation

Attal et al, 2009.

IFM 2005-02 : PFS from randomization

. Arm A

N=307

Arm B

N=307P

Progression or Death 143 (47%) 77 (25%)

Median PFS (m) 24 (21-27) NA

3-year post rando PFS 34% 68%

Hazard Ratio 1 0.46 < 10-

7

PFS according to Response Pre-Consolidation

HR= 0.37 - CI 95% [0.25-0.58] HR= 0.54 - CI 95% [0.37-0.78]

PR or SD VGPR or CR

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36

Placebo Revlimid

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36

Placebo Revlimid

p<10-5 p=0.001

Placebo

Placebo

Len

Len

IFM 2005 02 : Prognostic factors for PFS

Univariate analysisUnivariate analysis pp

AgeAge NSNS

ISS (I / II + III)ISS (I / II + III) NSNS

Beta-2 m (<=3 / >3)Beta-2 m (<=3 / >3) 0.010.01

Del 13 (Yes / No)Del 13 (Yes / No) 0.060.06

Induction (VAD / Vel-Dex / Others)Induction (VAD / Vel-Dex / Others) 0.040.04

Response after ASCT (VGPR / no)Response after ASCT (VGPR / no) 0.0090.009

Response after consolidation (VGPR / no)Response after consolidation (VGPR / no) 0.00040.0004

Treatment Arm (A / B)Treatment Arm (A / B) < 10< 10-7-7

Multivariate analysisMultivariate analysis pp

Treatment Arm (A / B)Treatment Arm (A / B) 0.000010.00001

Response after consolidation (VGPR / no)Response after consolidation (VGPR / no) 0.0040.004

Grade 3-4 Adverse Events during Maintenance

AEs (grade 4) Arm A Arm B

Anemia 0% 3% (2%)

Thrombocytopenia 3% 8% (3%)

Neutropenia 6% (1%) 31% (7%)

Febrile Neutropenia 0% 0.1%

Infections 4% 8%

DVT 0.3% 0.6%

Skin disorders 1% 4%

Fatigue 0.6% 2%

Peripheral Neuropathy 0.3% 0.4%

Neoplasia 0.9% 1%

Overall discontinuation due to AEs: XX % placebo versus XX % lenalidomide

D-S Stage 1-3, < 70 years> 2 cycles of induction Attained SD or better 1 yr from start of therapy> 2 x 106 CD34 cells/kg

Placebo

Lenalidomide*10 mg/d with

↑↓ (5–15 mg)

Lenalidomide*10 mg/d with

↑↓ (5–15 mg)

RestagingRestagingDays 90Days 90––100100

RegistrationRegistration

CALGB 100104 SchemaCALGB 100104 Schema

CRPRSD

Stratification based on registration -2M level and prior thalidomide and lenalidomide use during Induction. Primary Endpoint: powered to determine a prolongation of TTP from 24 months to 33.6 months (9.6 months)

Mel 200Mel 200

ASCTASCT

* provided by Celgene Corp, Summit, NJ

Randomization

ITT Analysis with a median follow-up from transplant of 34 months. P < 0.001 Estimated HR=0.48 (95% CI = 0.36 to 0.63), Median TTP: 46 months versus 27 months.

CALGB 100104, NEJM 2012follow up to 10/31/2011

86 of 128 placebo patients crossed over to lenalidomide

CALGB 100104, NEJM 2012follow up to 10/31/2011

35 deaths in the lenalidomide arm and 53 deaths in the placebo arm. P = 0.028, 3 yr OS 88 vs 80%, HR 0.62 or a 40% reduction in death with the cross over

Median follow-up of 34 months

The cumulative incidence risk of second primary cancers was greater in the lenalidomide group (P=0.0008). The cumulative incidence risks ofprogressive disease (P<0.001)and death (P=0.002) were greater in the placebo group

CALGB 100104, NEJM 2012follow up to 10/31/2011

CALGB 100104, NEJM 2012

After cross over,most placebo patientswere on lenalidomide

100104: NEJM 2012

CALGB 100104, NEJM 2012

CALGB 100104, NEJM 2012

Tales of Two Cases

Case 1• 55 yo female presents with asymptomatic

anemia of 10 gm/dl and total serum protein 10 gm/lt

• Work up reveals

– 30 % plasma cells

– Cytogenetic diploid

– IgA kappa peak of 3.2

– Beta 2 microglobulin of 3.0

• Receives 4 cycles of Bortezomib /Thal/Dex

• Followed by Auto SCT on Day 60 documented stringent CR

Case 2• 55 yo female presents with asymptomatic

anemia of 10 gm/dl and total serum protein 10 gm/lt

• Work up reveals

– 30 % plasma cells

– Cytogenetic t 4,14

– IgA kappa peak of 3.2

– Beta 2 microglobulin of 3.0

• Receives 4 cycles of Bortezomib /Thal/Dex

• Followed by Auto SCT on Day 60 documented paraprotein peak of 0.4 gm/dl

THEY BOTH ASK1)Should they get consolidation?2)Should they get a 2nd SCT?3)Should they receive post transplant lenalidomide?

BMT CTN 0702 StAMINA TRIAL: A Trial of Single Autologous Transplant with or without RVD Consolidation versus Tandem

Transplant and Maintenance Therapy.

BMT CTN 0702: SCHEMA

Register and

Randomize

MEL 200mg/m2 VRD x 4* Lenalidomide

Maintenance**

Lenalidomide Maintenance**

Lenalidomide Maintenance

MEL 200mg/m

2

**Lenalidomide 15 mg daily x **Lenalidomide 15 mg daily x 3years3years

* Bortezomib 1.3mg /m2 days 1, 4, 8,11

Lenalidomide 15mg days 1-15 Dexamethasone 40mg days 1,

8, 15

*

Monitoring DiseaseCR Definition Does Matter With Regards to Depth of

Remission

Rate of molecular CR with HDT is 5%

At diagnosis

Partial response – 50% reduction in M protein

Near complete remission – immunofixation positive only

Complete remission – immunofixation negative

Nonquantitative ASO-PCR

Quantitative ASO-PCRflow cytometryMRD

1 × 104

1 × 106

1 × 108

1 × 1012N

um

ber

of

Mye

lom

aC

ells

Common Sense Scenarios

• We may never have randomized data to guide us for all possible scenarios so clinical judgement is paramount.– Low risk patient in CR – maintain or watch?

– High risk patient NOT in CR – continued triple therapy?

• What role for newer agents?

Conclusions

• Continuous treatment strategies are being evaluated in all phases of myeloma disease from smouldering myeloma to relapsed/refractory myeloma

• Continuous therapy appeared to– improve response rates

– prolong PFS/EFS, impact on OS still to be determined

• All novel agents appear to have benefits in longer term use. Management of adverse events is crucial

• Impact of second primary malignancies not yet fully understood and should be monitored carefully