Grand rounds MM

Please note, these are the actual
video-recorded proceedings from the
live CME event and may include the use of trade names and other raw, unedited
content.


Second Opinion: New Agents and
Emerging Trial Data in the Management
of Multiple Myeloma

Noopur Raje, MD
Director, Center for Multiple Myeloma
Massachusetts General Hospital Cancer Center
Associate Professor of Medicine
Harvard Medical School
Boston, Massachusetts


Disclosures

Advisory Committee

Consulting Agreements

Contracted Research

Amgen Inc, Bristol-Myers Squibb Company, Celgene Corporation, Novartis
Pharmaceuticals Corporation, Roche Laboratories Inc, Takeda Oncology

Amgen Inc, Bristol-Myers Squibb Company, Celgene Corporation, Novartis
Pharmaceuticals Corporation, Takeda Oncology

AstraZeneca Pharmaceuticals LP, Lilly


Grand Rounds Program Steering Committee
Morie A Gertz, MD, MACP

Joseph Mikhael, MD, MEd

Roland Seidler Jr Professor of the Art of Medicine

Professor of Medicine

Chair, Department of Medicine

Mayo College of Medicine

Mayo Distinguished Physician Mayo Clinic Rochester

Associate Dean, Mayo School

Rochester, Minnesota

of Graduate Medical Education
Deputy Director – Education
Mayo Clinic Cancer Center
Mayo Clinic in Arizona
Phoenix, Arizona

Jonathan L Kaufman, MD

Nikhil C Munshi, MD

Associate Professor of

Professor of Medicine

Hematology and Medical Oncology

Harvard Medical School

Winship Cancer Institute of

Director of Basic and Correlative Science

Emory University

Associate Director, Jerome Lipper Multiple Myeloma Center

Atlanta, Georgia

Department of Medical Oncology Dana-Farber Cancer Institute
Boston, Massachusetts


Grand Rounds Program Steering Committee
Noopur Raje, MD

Jeffrey A Zonder, MD

Director, Center for Multiple Myeloma, Massachusetts General

Professor of Oncology

Hospital Cancer Center

Karmanos Cancer Institute

Associate Professor of Medicine Harvard Medical School

Wayne State University

Boston, Massachusetts

Detroit, Michigan

Jeffrey L Wolf, MD

Project Chair

Professor of Medicine

Neil Love, MD

Director, Myeloma Program

Research To Practice

Division of Hematology/Oncology

Miami, Florida

Blood and Marrow Transplantation
University of California, San Francisco
San Francisco, California


New Agents and Emerging Trial Data in the Management of Multiple Myeloma

Module 1: Induction and Maintenance Therapy for Newly
Diagnosed MM

Module 2: Management of Relapsed/Refractory Disease

Module 3: Integrating Newly Approved Agents into Clinical Practice

•
•
•
•

Ixazomib (Tourmaline-MM1)
Daratumumab (GEN501, Sirius)
Elotuzumab (ELOQUENT-2)
Panobinostat (PANORAMA1)

Module 4: Investigational Immunotherapy Strategies


An otherwise healthy 60-year-old patient presents with ISS Stage II multiple myeloma (MM). Cytogenetics and FISH reveal no high-risk

features. In general, which induction treatment would you most likely recommend?

What are your thoughts about autologous stem cell transplant (ASCT)?

INDUCTION

ASCT

RVd

Recommend

RVd

Recommend

RVd

Recommend but willing to delay

RVd

Recommend

RVd

Recommend

RVd

Recommend

RVd

Recommend but willing to delay

R = lenalidomide; V = bortezomib; d = dexamethasone


Treatment Sequence in Myeloma
Bortezomib
Lenalidomide
Thalidomide
VD

Now

Rev/Dex
CyBorD

Nothing
SCT

Thalidomide?
Bortezomib

VTD

Lenalidomide

VRD

Carfilzomib
Pomalidomide
Panobinostat
Daratumumab
Ixazomib
Elotuzumab

Front-line treatment

Induction

New

Consolidation

Maintenance

Postconsolidation

Relapsed disease

Rescue

Oprozomib
Carfilzomib combos

“More induction”
Lenalidomide 2 months

? Ixazomib

Isatuximab
Bendamustine
PD/PD-L1 inhibition
++++++++


Autologous Transplantation for Multiple Myeloma in the Era of New Drugs: A
Phase III Study of the Intergroupe Francophone Du Myelome (IFM/DFCI 2009
Trial)

Attal M et al.
Proc ASH 2015;Abstract 391.


IFM/DFCI 2009: A Phase III Study of RVD ± ASCT in Newly Diagnosed Multiple Myeloma
(NDMM)

RVD cycles 2, 3
PBSC collection
Eligibility (N = 700)

•
•
•

Cyclophosphamide + G-CSF
1:1

≤65 years old
Symptomatic NDMM
Treated with 1 cycle of RVD

RVD cycles 4-8

maintenance

R

10-15 mg/d
RVD cycles 2,3
PBSC collection
Cyclophosphamide + G-CSF
ASCT with MEL200
RVD cycles 4, 5

Primary endpoint: Progression-free survival

Attal M et al. Proc ASH 2015;Abstract 391.

Lenalidomide

x 12 mo


IFM/DFCI 2009: Response and Survival Analyses
RVD  ASCT

RVD

(n = 350)

(n = 350)

61%

48%

3-year PFS*

HR = 1.5, p < 0.0002
Complete response (CR)

58%

46%
p < 0.001

* Benefit observed was uniform across all the following subgroups:

•
•
•
•
•
•

Age (≤ or >60 years)

Sex
Ig isotype (IgG or others)
ISS stage (I or II or III)
Cytogenetics (standard or high risk)
Response after the first 3 cycles of RVD (CR or not)

The ongoing Phase III DETERMINATION trial (DFCI 10-106) is the parallel US trial and will continue maintenance lenalidomide until disease
progression.

Attal M et al. Proc ASH 2015;Abstract 391.


Getting to Minimal Residual Disease (MRD)

Newly diagnosed

1×10

S.S. Patient

Disease burden
CR

1×10

Stringent CR

1×10

Molecular/Flow CR

?Cure?

0.0

4

8

12


Predictive Value of MRD by Next-Generation Sequencing (NGS) in the IFM/DFCI 2009 Trial

•

Bone marrow MRD evaluation before and after maintenance therapy in patients with very good partial response (VGPR) or better

•

MRD assessment by flow cytometry (FCM) and NGS

•

Prediction of PFS by MRD status as determined by NGS

•

Comparison of MRD sensitivity of NGS and FCM

−

-4
-6
Sensitivity: FCM = 10 ; NGS = 10

−

Of 163 patients MRD-negative by FCM, 84 (51%) were positive by NGS

Three-year PFS for patients achieving complete response
-6
MRD-negative by NGS (<10 )

-6
MRD-positive by NGS (≥10 )

p-value

Before maintenance

87%

63%

0.0075

After maintenance

92%

64%

<0.0001

Avet-Loiseau H et al. Proc ASH 2015;Abstract 191.


Bortezomib, Lenalidomide and Dexamethasone vs Lenalidomide and
Dexamethasone in Patients with Previously Untreated Multiple Myeloma
without an Intent for Immediate Autologous Stem Cell Transplant: Results of
the Randomized Phase III Trial SWOG S0777

Durie B et al.
Proc ASH 2015;Abstract 25.


SWOG S0777: A Phase III Trial of RVd
versus Rd in NDMM

RVd
8 cycles of 21 days each

Eligibility (N = 525)

•
•

Rd maintenance

Previously untreated NDMM

Immediate ASCT not intended

until toxicity or

R

withdrawal

Rd
6 cycles of 28 days each

Primary endpoint: Progression-free survival

Durie B et al. Proc ASH 2015;Abstract 25.


Survival Analyses
PFS

OS

100%

100%

80%

80%

60%

60%

40%

HR = 0.712 (0.560, 0.906)*

Rd

40%

RVd

20%

RVd

20%

Rd

HR = 0.709 (0.516, 0.973)*
Log-rank P value = 0.0250 (two sided)*

Log-rank P value = 0.0018 (one sided)*

0%

0%
0

24

48

72

96

0

24

Months from Registration

48

72

96

Months from Registration

* Stratified

Median PFS

RVd

Rd

(n = 242)

(n = 229)

HR

p-value

43 mo

30 mo

0.712

0.0018

Durie B et al. Proc ASH 2015;Abstract 25.

One-sided

Median OS

RVd

Rd

Two-sided

(n = 242)

(n = 229)

HR

p-value

75 mo

64 mo

0.709

0.025


ECOG/ACRIN E1A11 (ENDURANCE): A Phase III Trial of Bortezomib or Carfilzomib with
Lenalidomide/Dexamethasone in NDMM

Trial Identifier: NCT01863550
Estimated Enrollment: 756 (Open)
Maintenance lenalidomide
RVd

x
2 years

Eligibility

•

Newly diagnosed, symptomatic
standard-risk MM

R

R
KRd

Maintenance lenalidomide
X
until PD

Primary endpoint: Overall survival for the maintenance analysis

www.clinicaltrials.gov. Accessed March 2016.


A 60-year-old patient with ISS Stage II MM receives RVd induction and ASCT. What would be your choice of
post-transplant maintenance therapy?

No high-risk features, CR after induction/ASCT

Del(17p), VGPR after induction/ASCT

Lenalidomide

Modified RVd

Lenalidomide

Weekly RVd

Lenalidomide

Bortezomib ± lenalidomide

Lenalidomide

Bortezomib ± lenalidomide

Lenalidomide

Bortezomib ± lenalidomide

Lenalidomide

RVd

Lenalidomide

R = lenalidomide; V = bortezomib; d = dexamethasone

Bortezomib ± lenalidomide


You recommend bortezomib/lenalidomide maintenance for the 60-year-old patient with ISS Stage II, high-risk (del 17p) MM in
the previous scenario. However, the patient has a very busy schedule and would like to minimize visits and asks about using
ixazomib.
Cost and reimbursement issues aside, would you use ixazomib as post-transplant maintenance therapy in this patient?

Yes

Yes

Yes, hesitantly

Yes

Yes

Yes

Yes


What is your usual induction regimen for a frail but otherwise healthy 75-year-old, transplant-ineligible
patient with ISS Stage II MM and no high-risk features?
What if the patient were an 85-year-old?

75-YEAR OLD

85-YEAR OLD

Rd

Rd

Rd

Rd

Rd or RVd-lite

Rd

RVd-lite

Rd

RVd-lite

RVd-lite

Rd

Rd

Rd or RVd-lite

Rd or Vd

R = lenalidomide; V = bortezomib; d = dexamethasone


TOURMALINE-MM2: A Phase III Trial
of Ixazomib with Lenalidomide/Dexamethasone in NDMM

Trial Identifier: NCT01850524

Ixazomib + lenalidomide/dexamethasone

Enrollment: 701 (Closed)

Eligibility

•
•

Newly diagnosed MM
Not eligible for stem cell transplant due to:

•
•

Age ≥ 65 years
Age < 65 years but with significant comorbidities

Primary endpoint: Progression-free survival

www.clinicaltrials.gov. Accessed March 2016.

R
Placebo + lenalidomide/dexamethasone


New Agents and Emerging Trial Data in the Management of Multiple Myeloma

Module 1: Induction and Maintenance Therapy for Newly
Diagnosed MM

Module 2: Management of Relapsed/Refractory Disease

Module 3: Integrating Newly Approved Agents into Clinical Practice

•
•
•
•

Ixazomib (Tourmaline-MM1)
Daratumumab (GEN501, Sirius)
Elotuzumab (ELOQUENT-2)
Panobinostat (PANORAMA1)

Module 4: Investigational Immunotherapy Strategies


Treatment Sequence in Myeloma
Bortezomib
Lenalidomide
Thalidomide
VD

Now

Rev/Dex
CyBorD

Nothing

SCT

Thalidomide?
Bortezomib

VTD

Lenalidomide

VRD

Carfilzomib
Pomalidomide
Panobinostat
Daratumumab
Ixazomib
Elotuzumab

Front-line treatment

Induction

New

Consolidation

Maintenance

Postconsolidation

Relapsed disease

Rescue

Oprozomib
Carfilzomib combos

“More induction”
Lenalidomide 2 months

? Ixazomib

Isatuximab
Bendamustine
PD/PD-L1 inhibition
++++++++


A 70-year-old patient who initially received RVD followed by ASCT experiences limited, asymptomatic relapse 18
months after transplant while receiving lenalidomide maintenance at 10 mg daily. Which systemic treatment
would you most likely recommend?

Pomalidomide

Ixazomib-Rd or Elotuzumab-Rd

Carfilzomib-dex + Cyclophosphamide or Pomalidomide

Increase lenalidomide to standard dose and add dex

Pomalidomide-dex or Ixazomib-Rd

Increase lenalidomide dose and add dex or Vd

Elotuzumab-Rd

R = lenalidomide; V = bortezomib; d = dexamethasone


What would be your treatment recommendation for a
70-year-old patient with MM who received RVd followed by transplant and experiences extensive,
symptomatic relapse
18 months after transplant and while receiving maintenance?

Bortezomib-cyclophosphamide-dex

Carfilzomib-Rd or Pomalidomide-dex +
Carfilzomib or Bortezomib or Daratumumab
Carfilzomib-pomalidomide-dex

Bortezomib-cyclophosphamide-dex
Bortezomib-pomalidomide-dex or
Carfilzomib-pomalidomide-dex

Carfilzomib-cyclophosphamide-dex

Ixazomib-Rd or Carfilzomib-Rd

R = lenalidomide; V = bortezomib; d = dexamethasone