friday, april 11, 2014 irene m ghobrial, md dana-farber/harvard cancer center ola landgren, md, phd...

Friday, April 11, 2014

Irene M Ghobrial, MDDana-Farber/Harvard Cancer Center

Ola Landgren, MD, PhDCenter for Cancer ResearchNational Cancer Institute

RTP ON DEMAND: Multiple Myeloma

Case Presentation:

2 versus 3 Drug Pretransplant Induction Therapy

Getting to Minimal Residual Disease (MRD)

S.S. Patient

1×1012

Stringent CR

Molecular/Flow CR

?Cure?

Disease burden

Newly diagnosed

1×108

1×104

0.0

CR

Whole Exome Sequencing of Multiple Myeloma Reveals an Heterogeneous Clonal Architecture and Genomic Evolution

Bolli N et al. Proc ASH 2013;Abstract 399.

Serum Free Light Chain Escape in Progression and Treatment Resistance in Multiple Myeloma: A Marker for the Impact of Intra-Clonal Heterogeneity

Brioli A et al. Proc ASH 2013;Abstract 752.

% of respondents

An otherwise healthy 60-year-old patient presents with fatigue. Workup reveals Hb 9.0 g/dL, normal renal function, an M-spike with an IgG lambda component of 4.9 g/dL and bone marrow consistent with MM (ISS Stage II). Conventional cytogenetics, FISH and skeletal survey are normal. Which induction treatment would you most likely recommend for this patient?

Other

VD

CyBorD

RD/Rd

RVD

0% 10% 20% 30% 40% 50%

8%

13%

15%

18%

46%

Research To Practice Patterns of Care Study 2014 (N = 101 practicing oncologists)

IFM/DFCI 2009: Phase III Study of the Initial Management of Multiple Myeloma in Patients ≤65 Years

R

Eligibility

• Untreated, symptomatic multiple myeloma

RVD for 2 cycles HD cyclophosphamide + SC collection

RVD for 5 cyclesMaintenance lenalidomide x 12+ mo

RVD for 2 cycles HD cyclophosphamide + SC collection

HD melphalan + ASCTRVD for 2 cycles

Maintenance lenalidomide x 12+ mo

www.clinicaltrials.gov, May 2014.

Protocol ID: NCT01191060Target Accrual: 700 (Closed)

Primary Endpoint: PFS

ECOG-E1A11: A Phase III Study of Bortezomib or Carfilzomib with Lenalidomide and Dexamethasone for Newly Diagnosed MM

• Primary endpoint: Overall survival• Select secondary endpoints: Progression-free survival, overall response

rate, duration of response, incidence of Grade ≥2 peripheral neuropathy and cardiac toxicity

R

Eligibility

• Newly diagnosed, symptomatic standard-risk MM

• No prior history of Grade 2 or higher peripheral neuropathy

Carfilzomib + lenalidomide +low-dose dexamethasone

limited OR finite lenalidomide maintenance

Bortezomib + lenalidomide + low-dose dexamethasone

limited OR finitelenalidomide maintenance

www.clinicaltrials.gov; Accessed May 2014

Protocol ID: NCT01863550Target Accrual: 756 (open)

Phase II Clinical and Correlative Study of Carfilzomib, Lenalidomide, and Dexamethasone Followed by Lenalidomide Extended Dosing (CRd-R) Induces High Rates of MRD Negativity in Newly Diagnosed Multiple Myeloma (MM) Patients

Korde N et al.

Proc ASH 2013;Abstract 538.

• Each cycle is 28 days

• Stem cell harvest after ≥4 cycles of CRd for patients <75 years of age

• Cycle 1, day 1, 2: Cfz dose is 20 mg/m2

• Cycles 1-4: Dexamethasone dose is 20 mg; cycles 5-8: Dexamethasone dose is 10 mg

SD = stable disease

8 cycles CRd combination therapy

Cfz 20/36 mg/m2, 30-min infusion Day 1, 2, 8, 9, 15, 16

Lenalidomide 25 mg/day Day 1-21

Dexamethasone 20/10 mg Day 1, 2, 8, 9, 15, 16, 22, 23

SD

or

be

tte

r?

24 cycles extended dosing

Ln 10 mg/day, day 1-21

Korde N et al. Proc ASH 2013;Abstract 538.

Phase II Study Design

Phase II Clinical and Correlative Study of CRd-R in Newly Diagnosed Multiple Myeloma – Patient Characteristics

Characteristic

Patients enrolled (by Nov 2013) n = 45

Evaluable patients who completed 2 cycles n = 43

Median age (range) 60 years (40-88)

Male 26/43 (60%)

Isotype: IgG 28 (65%)

IgA 10 (23%)

Kappa 4 (9%)

Lambda 1 (2%)

Median cycles of CRd R received (range) 12 (2-25)

Median follow-up (range) 12 mo (2-26)

Patients who completed 8 cycles of CRd n = 29


ORR = overall response rate; PR = partial response; VGPR = very good PR; nCR = near complete response; sCR = stringent CR

* Median 12 cycles of CRd Ln maintenance

Response 2 cycles 8 cyclesBest

response*

ORR (≥PR) 98% 97% 98%

≥VGPR 51% 91% 88%

nCR/CR/sCR 16% 73% 67%

CR/sCR 7% 42% 51%

VGPR 35% 18% 21%

PR 47% 6% 9%

SD 2% 3% 2%


Response Rates

• 4 patients have come off study treatment, 3 due to progression and 1 due to

personal reasons. All other patients remain on study treatment.


Time to CR/sCR and PFS

Time to CR/sCR

CR/sCR, n/N (%) 22/43 (51%)

Patients reaching CR/sCR with ≥8 cycles of CRd, n/N (%) 5/22 (23%)

Median time to CR/sCR, months (range) 5 (2-18)

PFS at 12 months 97%

Immunophenotypic Evaluation of the Plasma Cell Compartment in Multiple Myeloma: A Tool for Comparing the Efficacy of Different Treatment Strategies and Predicting Outcome

San Miguel JF et al. Blood 2002;99(5):1853-56.

Martinez-Lopez J et al. Blood 2014;123(20):3073-9.

• None of the 43 evaluable patients developed Grade ≥3 neuropathy


Select Grade 3/4 Nonhematologic Adverse Events (AEs)

Nonhematologic AEs (n = 43)

Electrolyte disturbances 21%

LFT elevation 12%

Skin (rash, pruritus, eye) 12%

Constitutional (fatigue, presyncope, dehydration, adrenal insufficiency)

12%

Lung (dyspnea, respiratory failure) 9%

Cardiac (hypertension, heart failure) 9%

Infection (pneumonia, enterocolitis, febrile neutropenia) 9%

VTE 7%

Predictors of Treatment Outcome with the Combination of Carfilzomib, Lenalidomide, and Low-Dose Dexamethasone (CRd) in Newly Diagnosed Multiple Myeloma (NDMM)

Jasielec J et al.


• All 4 patients with SKY92 high-risk disease relapsed compared to only 2 of 11 patients with SKY92 standard-risk disease.

• Patients who achieved sCR at any time during CRd treatment trended toward a longer estimated 3-year PFS and OS.

Results Summary

Jasielec J et al. Proc ASH 2013;Abstract 3220.

Clinical variableStandard-risk cytogenetics

High-risk cytogenetics p-value

3-year PFS rate 88% 69% 0.081

3-year PFS 100% 88% 0.041

CR 71% 53% 0.233

sCR 62% 41% 0.234

A Phase II Study with Carfilzomib, Cyclophosphamide, and Dexamethasone (CCd) for Newly Diagnosed Multiple Myeloma

Bringhen S et al.


Primary objectives: • Safety: Grade 4 neutropenia (>3 d), Grade 4 thrombocytopenia (>7 d),

Grade ≥3 nonhematologic toxicity • Efficacy: Partial response (PR)

Phase II Study Design

Bringhen S et al. Proc ASH 2013;Abstract 685.

MAINTENANCECYCLE 9CYCLE 2CYCLE 1

CCd inductionCycles 1-9

C maintenanceUntil progression

Carfilzomib

Cyclophosphamide

Dexamethasone

Dose (mg/m2)

300 mg/m2 orally

40 mg orally

Dosing

Cycle day

N = 58

1 2 8 9 15 16 22 1 2 8 9 15 16 22 1 2 8 9 15 16 22 1 2 15 16 1 2 15 16 1 2 15 16

20 36 36 36 36 36 36 36 36 36 36 36 36 36 36

Response assessments

% of respondents

A 60-year-old patient with Stage II MM with normal cytogenetic/FISH receives your induction treatment of choice, undergoes autologous stem cell transplant (ASCT) and achieves a complete response after ASCT. Which post-transplant maintenance treatment, if any, would you most likely recommend for this patient?

Dexamethasone

Bortezomib/dexamethasone

Lenalidomide/bortezomib

Lenalidomide/dexamethasone

Bortezomib

Lenalidomide

I would not use maintenance therapy

0% 10% 20% 30% 40% 50% 60% 70%

1%

3%

3%

5%

9%

64%

15%


N Engl J Med 2012;366:1782-91.

N Engl J Med 2012;366:1770-81.

• Outcome: HR for death or progression; LM vs no maintenance (<1 implies better outcome with LM)

• No heterogeneity for estimate of PFS:

– Cochran Q = 1.51 (p = 0.68), I2 = 0%

Meta-Analysis: Lenalidomide Maintenance (LM) and PFS

Singh PP et al. Proc ASH 2013;Abstract 407.

Study name HR p-value

IFM 2005-02 0.500 <0.001

CALGB-100104 0.480 <0.001

Meta-Analysis: Lenalidomide Maintenance and OS

Singh PP et al. Proc ASH 2013;Abstract 407.

• Outcome: HR for death or progression; LM vs no maintenance (<1 implies better outcome with LM)

• Significant heterogeneity for estimate of OS:

– Cochran Q = 8.11 (p = 0.044), I2 = 63%

Study name HR p-value

IFM 2005-02 1.060 0.664

CALGB-100104 0.610 0.008

Bortezomib Induction and Maintenance Treatment Improves Survival in Patients with Newly Diagnosed Multiple Myeloma: Extended Follow-Up of the HOVON-65/GMMG-HD4 Trial

Sonneveld P et al.


Trial Design

Allogeneic Tx

Newly diagnosed, symptomatic, transplant eligible

Randomization

3 x VAD

CAD + GCSF

3 x PAD

CAD + GCSF

MEL 200 + PBSCT MEL 200 + PBSCT

In GMMG 2nd MEL 200 + PBSCT

In GMMG 2nd MEL 200 + PBSCT

Thalidomidemaintenance 50 mg/day for

2 years

Bortezomib maintenance

1.3 mg/m2/2 weeks for 2 years

Key Features of Ixazomib and Bortezomib

Compound Chemical Binding Adm Status

Bortezomib Boronate Reversible IV/SCFDA

approved

Ixazomib Boronate Reversible Oral/IV Phase I-III

Ixazomib Bortezomib

Adapted from Fostier K et al. OncoTargets and Therapy 2012;5:237-44.

Twice-Weekly Oral MLN9708 (Ixazomib Citrate), an Investigational Proteasome Inhibitor, in Combination with Lenalidomide (Len) and Dexamethasone (Dex) in Patients (Pts) with Newly Diagnosed Multiple Myeloma (MM): Final Phase 1 Results and Phase 2 Data

Richardson PG et al.


• Depth of response increased over the course of treatment– Median time to first response: 0.69 months– Median time to best response to date: 1.96 months

• Median duration of response to date: 13.8 months

Preliminary Response Over the Course of Treatment at RP2D

With permission from Richardson PG et al. Proc ASH 2013;Abstract 535.

21

6

48

20

16

50

24

5

9

52

32

0

sCR

CR

VGPR (incl. nCR)

PR

ORR 93% ORR 95% ORR 95%

sCR/CR27%

≥VGPR75%

sCR/CR21%

≥VGPR71%

sCR/CR29%

≥VGPR61%

%

After 4 cycles (n = 56) After 8 cycles (n = 56) Overall (n = 56)

100

90

80

70

60

50

40

30

20

10

0

Ongoing Phase II Trial of Modified Lenalidomide/Bortezomib/Dexamethasone for Multiple Myeloma (RVD Lite)

* For patients ≤75 years (d1, 2, 8, 9, 15, 16, 22, 23)† For patients >75 years (d1, 8, 15, 22)

• Primary endpoint: Objective response rate

Target accrual (n = 50)

• Newly diagnosed, symptomatic MM

• Transplant-ineligible

• No peripheral neuropathy ≥2

• No known brain metastases

Induction cycles 1-9Lenalidomide (PO), d1-21

Bortezomib (SC), d1, 8, 15, 22

Dexamethasone (PO), biweekly*

or weekly†

Consolidation cycles 10-15Lenalidomide (PO), d1-21

Bortezomib (SC), d1, 15

www.clinicaltrials.gov (Identifier: NCT01782963)

Initial Phase 3 Results of the FIRST (Frontline Investigation of Lenalidomide + Dexamethasone versus Standard Thalidomide) Trial (MM-020/IFM 07 01) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible for Stem Cell Transplantation (SCT)

Facon T et al.


• Primary endpoint: PFS

• Patients were stratified by age, country and ISS stage

1:1:1

R: 25 mg d1-21, every 4 weeks

d: 40 mg d1, 8, 15, 22, every 4 weeks

M: 0.25 mg/kg d1-4, every 6 weeks

P: 2 mg/kg d1-4, every 6 weeks

T: 200 mg d1-42, every 6 weeks

Phase III FIRST Trial Design

Facon T et al. Proc ASH 2013;Abstract 2.

Eligibility (n = 1,623)

• Symptomatic NDMM

• Transplant ineligible or ≥65 years old

• Renal impairment allowed, but patients requiring dialysis excluded

Rd until progression (n = 535)

Rd for 18 cycles (Rd18) (n = 541)R

MPT for 12 cycles (n = 547)

% of respondents

An otherwise healthy 77-year-old patient presents with fatigue. Workup reveals Hb 9.0 g/dL, normal renal function, an M-spike with an IgG lambda component of 4.9 g/dL and bone marrow consistent with MM (ISS Stage II). Conventional cytogenetics, FISH and skeletal survey are normal. The patient is not eligible for transplant. Which induction treatment would you most likely recommend for this patient?

Other

Bortezomib

Lenalidomide

MRP

MVP

CyBorD

VD

RVD

RD/Rd

0% 10% 20% 30% 40%

13%

4%

4%

5%

6%

10%

11%

20%

27%


Any regimen containing melphalan: 22%

Pomalidomide plus Low-Dose Dexamethasone in Relapsed or Refractory Multiple Myeloma (RRMM) with Deletion (del) 17p and/or Translocation t(4;14)

Leleu X et al. Proc ASH 2013;Abstract 689.

• N = 50 patients with a median of 3 prior treatments (range: 1-10)– Del(17p): 40%– t(4;14): 60%

• Prior lenalidomide: 100%• Prior proteasome inhibitor: 96%• Median OS: 12 mo del(17p) and 9.2 mo t(4:14)• Median time to disease progression: 7.3 mo del(17p) and 2.8 mo t(4;14)

Final Analysis, Cytogenetics, Long-Term Treatment, and Long-Term Survival in MM-003, a Phase 3 Study Comparing Pomalidomide + Low-Dose Dexamethasone (POM + LoDEX) vs High-Dose Dexamethasone (HiDEX) in Relapsed/Refractory Multiple Myeloma (RRMM)

Dimopoulos MA et al. Proc ASH 2013;Abstract 408.

• Pomalidomide + LoDex (n = 302) vs HiDex (n = 153)• Del(17p) and/or t(4;14): ~25%• Median prior treatments: 5 (range: 2-17)

• Grade 3/4 AEs: Neutropenia, anemia and infections

Pom/LoDex HiDex p-value

Median PFS 4.0 mo 1.9 mo <0.001

Median OS 13.1 mo 8.1 mo 0.009

Phase I/II Dose Expansion of a Multi-Center Trial of Carfilzomib and Pomalidomide with Dexamethasone (Car-Pom-d) in Patients with Relapsed/Refractory Multiple Myeloma

Shah JJ et al. Proc ASH 2013;Abstract 690.

• N = 79 patients • Median prior treatments: 5 (range 1-12)• Prior bortezomib: 89%, prior lenalidomide: 100%

– ORR: 70%– Median PFS: 9.7 months– Median OS: >18 months

• Intermediate- or high-risk cytogenetics– ORR: 53% (intermediate risk); 78% (high risk)

• Grade ≥3 drug-related AEs: – Fatigue, neutropenia, anemia, thrombocytopenia, diarrhea

New Recommendations for Use of Bisphosphonates in Multiple Myeloma

Factor Recommendation

Patient population Newly diagnosed patients with MM who require antimyeloma treatment (regardless of bone status)

Administration IV

Duration/frequency • Monthly during initial therapy and ongoing in patients who are not in remission

• After 2 years, discontinue if CR/VGPR; continue if ≤ PR

Monitoring Monthly creatinine clearance

Choice • ZOL (first option)• PAM (second option)• CLO (only in patients who cannot come to hospital, those with severe disabilities, and those with contraindications to

ZOL and PAM)

MM = multiple myeloma; IV = intravenous; CR = complete response; VGPR = very good partial response; PR = partial response; ZOL = zoledronic acid; PAM = pamidronate; CLO = clodronate

• Median PFS = 5.4 months• Median OS at 8.3 months median follow-up: Not yet reached

N = 55 n (%)

Overall response (at least partial response) 19 (34.5)

Complete response 0

Near-complete response 1 (1.8)

Partial response 18 (32.7)

Clinical benefit rate (at least minimal response) 29 (52.7)

Minimal response 10 (18.2)

Stable disease 20 (36.4)

Progressive disease 3 (5.5)

Unknown 3 (5.5)

Very good partial response 3 (5.5)

Best Response (Confirmed at 6 Weeks) at the End of 8 Cycles

• Primary endpoint: Progression-free survival

• Select secondary endpoints: Overall survival, overall response rate, time to response, duration of response, health-related quality of life

PANORAMA-1: A Phase III Study of Panobinostat with Bortezomib and Dexamethasone in Relapsed MM


R

Eligibility (n = 769)

• Patients with relapsed multiple myeloma

• No prior deacetylase inhibitor

Panobinostat + Bortezomib

+ Dexamethasone

Placebo+ Bortezomib

+ Dexamethasone

A Phase 2 Study of Elotuzumab (Elo) in Combination with Lenalidomide and Low-Dose Dexamethasone (Ld) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (R/R MM): Updated Results

Richardson PG et al. Proc ASH 2012;Abstract 202.• N = 73 patients• 55% received ≥2 prior treatments

– 60% prior bortezomib, 62% prior thalidomide

• Grade ≥3 AEs in ≥5% of patients: – Lymphopenia, neutropenia, thrombocytopenia, anemia, leukopenia,

hyperglycemia

Len + 10 mg/kg Elo

Len + 20 mg/kg Elo + Len Total

ORR 92% 76% 84%

Median PFS Not reached 18.6 mo —

• Primary Endpoint: Progression-free survival

• Secondary Endpoints: Objective response rate, overall survival

ELOQUENT-1 Phase III Study Schema


R

• Newly diagnosed, symptomatic multiple myeloma

• Ineligible for stem-cell transplant

Lenalidomide + Dexamethasone

Lenalidomide + Dexamethasone +

Elotuzumab

N = 750

Carfilzomib, Rituximab and Dexamethasone (CaRD) Is Highly Active and Offers a Neuropathy Sparing Approach for Proteasome-Inhibitor Based Therapy in Waldenström’s Macroglobulinemia

Treon SP et al.


• For all 31 patients, median serum IgM levels and M-protein declined to 749 mg/dL and 0.7 g/dL, respectively (p < 0.00001).

• Median hematocrit and hemoglobin rose to 40.9% and 13.7 g/dL, respectively (p < 0.00001).

• A total of 30 patients concluded induction therapy with bone marrow tumor involvement reduced to a median of 7.5% (p = 0.0003).

• No Grade 2 or higher peripheral neuropathy was observed.

Study Results

Treon SP et al. Proc ASH 2013;Abstract 757.

* Using criteria adapted from the Third International Workshop on WM

• Median follow-up = 8 cycles

• Median time to response (for MR or better) = 2.1 months

• 22 patients remain on study, including 20 currently on maintenance therapy

n = 31

Best overall response rate,* n (%) 25 (81.0%)

CR 1 (3.2%)

VGPR 8 (25.8%)

Partial response 12 (38.7%)

Minor response (MR) 4 (12.9%)


Response Evaluation

Treon SP et al. NEJM 2012;367(9):826-33.

A Prospective Multicenter Study of the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib in Patients with Relapsed or Refractory Waldenstrom’s Macroglobulinemia


• N = 63 patients with a median of 2 prior treatments (range: 1-6)

n = 63

Best overall response rate (≥minor response) 51 (81.0%)

Very good partial response 4 (6.3%)

Partial response 32 (50.8%)

Minor response 15 (23.8%)

Lohr JG et al. Cancer Cell 2014;25(1):91-101.

Clinical and Correlative Pilot Study of Carfilzomib, Lenalidomide, and Dexamethasone Followed by Lenalidomide Extended Dosing (CRd–R) in High Risk Smoldering Multiple Myeloma Patients

Landgren O et al. Proc ASH 2013;Abstract 1939.

friday, april 11, 2014 irene m ghobrial, md dana-farber/harvard cancer center ola landgren, md, phd...

Documents

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