HEM13 MIB slides FINAL

17th Annual International Congress
on Hematologic Malignancies®:
Focus on Leukemias, Lymphomas,
and Myeloma
Meeting in a Box


MULTIPLE MYELOMA


What Can We Learn From Multiple
Myeloma Genomic Analysis?
Nikhil Munshi, MD


Genomic Analysis Takeaways
•

Methods of genomic analysis
– Established techniques: cytogenetics, FISH
– Emerging techniques: RNA- and DNA-based arrays, transcriptprocessing arrays, genomic sequencing, and proteomics

•

Current goals of genomic analysis in myeloma
– Understand the biology of myeloma
– Identify risk categories to improve prognostication
– Identify and validate novel targets
– Develop biologic agents that target the myeloma cell
– Ultimately, develop personalized therapy

•

Currently, gene expression profiling has prognostic value, predicting
survival of patients with different genomic signatures, but it cannot yet
predict response to therapy.


High-Risk Smoldering Myeloma –
Should We Intervene Early?
Ola Landgren, MD, PhD


Smoldering Myeloma
•

Definition of smoldering myeloma1
– Serum monoclonal IgG or IgA ≥ 3 g/dL and/or clonal bone marrow
plasma cells ≥ 10% AND
– Absence of end-organ damage (ie, hypercalcemia, renal
insufficiency, anemia, or bone lesions attributed to plasma cell
proliferative disorder)

•

Overall risk of progression2
– 10% per year in years 0-5
– 3% per year in years 6-10
– 1% per year in years 11-20

•

Risk stratification
– Mayo Clinic analysis3 stratifies patients according to their 5-yr risk of
progression into 3 groups: 25% risk, 51% risk, and 76% risk
– PETHEMA Study Group analysis4 stratifies patients according to their
5-yr risk of progression into 3 groups: 4% risk, 46% risk, and 72%
Kyle RA, et al. Leukemia. 2010;24:1121-7.
risk
1

Kyle RA, et al. N Engl J Med. 2007;356:2582-90.
3
Dispenzieri A, et al. Blood. 2008;111:785-9.
4
Perez-Persona E, et al. Blood. 2007;110:2586-92.
2

e


First Randomized Phase III Trial
for Smoldering Myeloma
Randomization of high-risk smoldering MM patients:
Lenalidomide 25 mg/day,
D1-21
Dexamethasone
20 mg D1-D4 and D12-D15
Lenalidomide 10 mg/day,
D1-21 every 2 months

Induction:
Nine 28-day cycles

Therapeutic abstention

Maintenance:
Until progression

Therapeutic abstention

Primary endpoint: time to progression to symptomatic MM
Secondary endpoints: ORR, DOR, PFS, OS, and safety and tolerability

Median time to symptomatic progression
Len/dex: not yet reached
Observation: 21 months

HR = 5.67; P < .0001

4-year overall survival
Len/dex: 94%
Observation: 85%

HR = 3.5; P < .01
Mateos MV, et al. ASH 2011. Abstract 991.


Smoldering Myeloma Takeaways
•

Current clinical recommendation for smoldering myeloma: no treatment
unless part of a clinical trial1

•

Better understanding of pathogenesis from MGUS to myeloma needed:
– To develop better biological markers
– To predict a patient’s risk of progression
– To develop early intervention strategies

1

Kyle R, et al. Int’l Myeloma Working Group. Leukemia


Current Trends:
Treatment Strategies for Newly
Diagnosed Elderly Patients With
Myeloma
James Berenson, MD


Dexamethasone ± Lenalidomide
SWOG S0232
Len + Dex (n = 97)

Dexamethasone (n = 95)

Len: 25 mg/day, D1-28

Placebo: 25 mg/day, D1-28

Dex: 40 mg/day, D1-4, 9-12, 17-20

Dex: 40 mg/day, D1-4, 9-12, 17-20

Three 35-day cycles

Three 35-day cycles
Disease
progression

Responding/stable
disease

Len + Dex

Dexamethasone

Unblinded Treatment

Len: 25 mg/day, D1-21

Placebo: 25 mg/day, D1-21

Len: 25 mg/day, D1-28

Dex: 40 mg/day, D1-4 and 15-18

Dex: 40 mg/day, D1-21

Dex: 40 mg/day, D1-4, 9-12, 17-20

28-day cycles until progression

28-day cycles until progression

Three 35-day cycles

Objective: to determine the efficacy and safety of Len + Dex
as induction therapy in NDMM patients
Primary endpoint: PFS

Unblinded Len + Dex
Len: 25 mg/day, D1-21
Dex: 40 mg/day, D1-4 and 15-18

Zonder JA, et al. Blood. 2010;116:5838-41.


Patients (%)

Dexamethasone ± Lenalidomide
SWOG S0232
90
80
70

ORR = 78%
15

ORR, P < .0001
VGPR, P < .001

60

ORR = 48%

50
37

PR
VGP
R
CR

40
32

30
20
10

26

4

0

Len + dex

•

12

Placebo + dex

1-yr PFS was significantly improved with the addition of lenalidomide
(78% vs 53%; P = .002)

Zonder JA, et al. Blood. 2010;116:5838-41.


Lenalidomide + High-Dose Dex vs
Lenalidomide + Low-Dose Dex: ECOG
E4A03
Lenalidomide + High-Dose Dexamethasone (RD)
a

Len: 25 mg/day, days 1-21

Transplant-eligible
patients can
proceed to SCT

Dex: 40 mg/day, days 1-4, 9-12, 17-20
(n = 223)
Four 28-day cycles
Lenalidomide + Low-Dose Dexamethasone (Rd)
Len: 25 mg/day, days 1-21

Continue therapy until
disease progression

Dex: 40 mg/day, days 1, 8, 15, 22
(n = 222)

Objective: to assess if a reduced dose of dex decreases toxicity while maintaining efficacy
Primary endpoint: ORR after first 4 cycles
Based on the superiority of the Rd regimen, the study was stopped at a median
follow-up of 12.5 months and patients in the RD arm crossed over to Rd therapy.
a

Arm

1-yr OS

2-yr OS

RD (high-dose)

87%

75%

Rd (low-dose)

96%

87%

Survival significantly improved
with Rd (low-dose) regimen (P = .
0002 at 1 year)

Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.


MP ± Bortezomib: VISTA
► Endpoints: Primary: TTP; Secondary: CR, ORR, TTR, DOR, PFS, TNT, OS, QoL
Previously untreated patients;
not candidates for transplant

► Study Schema:
R
A
N
D
O
M
I
Z
E

ARM A (VMP)

VMP: Four 6-week cycles: Cycles 1-4
Bortezomib 1.3mg/m2 days 1, 4, 8, 11, 22, 25, 29, 32;
Melphalan 9mg/m2 and prednisone 60mg/m2 days 1-4
Followed by five 6-week cycles: Cycles 5-9

Bortezomib 1.3mg/m2 days 1, 8, 22, 29; Melphalan 9mg/m2 and
prednisone 60mg/m2 once daily on days 1–4
Max of 9 cycles (total 54 weeks) in both arms

ARM B (MP)

MP: Nine 6-week cycles: Cycles 1-9
Melphalan 9mg/m2 and prednisone 60mg/m2 days 1-4

Efficacy Parameter

– 682 patients randomized
 151 centers
 22 countries worldwide
– IDMC recommended study stop in
September 2007 based on protocolspecified interim analysis
– VMP was significantly superior for all
efficacy endpoints

Lenalidomide

Placebo

HR

P Value

Median TTP, months

24.0

16.6

0.483

< .000001

Median OS, months

NR

NR

0.61

.008

•

3-yr OS: 72% in VMP arm vs 69.5% in MP arm
San Miguel J, et al. N Engl J Med. 2008;359:906-17.
Mateos MV, et al. J Clin Oncol. 2010;28:2259-66.


Phase II Studies for Newly Diagnosed
Multiple Myeloma
Regimen

Drugs

ORR

CR

Cybor-D1

cyclophosphamide + bortezomib + dex

93%

39%

DVD2

bortezomib + pegylated liposomal doxorubicin + dex

86%

20%

VRD3

bortezomib + lenalidomide + dex

100%

37%

BAM4

bortezomib + ascorbic acid + melphalan →
maintenance bortezomib

74%

13%

BiRD5,6

clarithromycin + lenalidomide + high-dose dex

90%

39%

CRd7

carfilzomib 27 mg/m2 + lenalidomide + dex

100%

85%

CYCLONE8

carfilzomib + cyclophosphamide + thalidomide + dex

96%

29%

CMP9

carfilzomib + melphalan + prednisone

89%

3%

Reeder CB, et al. ASCO 2008. Abstract 8517.
Berenson JR, et al. Br J Haematol. 2011;155:580-7.
3
Richardson PG, et al. Blood. 2009;114:501-2.
4
Berenson JR, et al. Eur J Haematol. 2009;82:433-9.
5Niesvizky R, et al. Blood. 2008;111:1101-9.
6
Rossi A, et al. ASCO 2011. Abstract 8008.
7
Jakubowiak AJ, et al. Blood. 2012;120:1801-9.
8
Mikhael J, et al. ASCO 2012. Abstract 8010.
9
Kolb B, et al. ASCO 2012. Abstract 8009.
1

2


Novel Combinations and New Drugs

for Elderly Patients With Myeloma
•

•

Approved drugs
‒

Novel combinations

‒

Modifications of dose and schedule


Improve efficacy



Better tolerability

Drugs in development
‒

‒

Similar targets


Proteasome inhibitors - carfilzomib (FDA-approved!), ixazomib



IMiDs - pomalidomide (FDA-approved!)

New classes of agents


Monoclonal antibodies - anti-CS-1 (elotuzumab), anti-CD40
(dacetuzumab), anti-CD38



mTOR inhibitors - temsirolimus



PI3K inhibitors - perifosine



HDAC inhibitors - vorinostat, romidepsin, panobinostat


Maintenance Therapy –
Is It for Everyone?
Nikhil Munshi, MD


Maintenance Therapy for Multiple

Myeloma
•

Maintenance therapy:
– Purpose is to prolong remission duration and life expectancy
– Requires periodic follow-up to monitor toxicity and response

•

Patient must have:
– Disease that is in remission (undetectable or at a low level)
– Recovered from all previous toxicities

•

Maintenance agent must have:
– Minimal toxicity or at least not overlapping with the toxicity of the
induction regimen
– Convenient dosing
– Convenient route of administration


Lenalidomide Maintenance After
Transplant: CALGB 100104
Restaging
Days 90–100

Registration

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

Efficacy Parameter
Median TTP, months
3-yr OS

Mel 200
ASCT

Randomization

Placebo
CR
PR
SD

Lenalidomide
10 mg/d with
↑↓ (5–15 mg)

Lenalidomide

Placebo

HR

P Value

46

27

--

< .0001

88%

80%

0.62

.027

McCarthy PL, et al. N Engl J Med. 2012;366:1770-81.


Lenalidomide Maintenance Following
Lenalidomide Consolidation: IFM 200502
Phase III randomized, placebo-controlled trial
N= 614 patients, from 78 centers, enrolled between 7/2006 and 8/2008

Patients age < 65 years, with nonprogressive disease, ≤ 6 months after ASCT in first line
Randomization: stratified according to Beta-2m, del13, VGPR
Consolidation:
Lenalidomide alone 25 mg/day po
days 1-21 of every 28 days for 2 months

Arm A = Placebo
(N=307)
until relapse

Arm B = Lenalidomide
(N=307)
10-15 mg/d until relapse

Primary endpoint: PFS
Secondary endpoints: CR rate, TTP, OS, feasibility of long-term lenalidomide…
•

PFS significantly prolonged with lenalidomide maintenance compared with
placebo (41 vs 24 months; P < 10-9)

•

OS not significantly different between groups (P = .79)
Attal M, et al. Proc International Myeloma Workshop 2011.
McCarthy P, et al. Proc International Myeloma Workshop 2011.


Lenalidomide Maintenance in Patients
Ineligible for Transplant: MM-015
Open- Label
Extension Phase

Double- Blind Treatment Phase

RANDOMIZATION

Cycles (28day) 1-9

MPR-R
M:0.18 mg/kg, days 1-4
P:2 mg/kg, days 1-4
R:10 mg/day po, days 1-21
MPR
M:0.18 mg/kg, days 1-4
P:2 mg/kg, days 1-4
R:10 mg/day po, days 1-21
MP
M:0.18 mg/kg, days 1-4
P:2 mg/kg, days 1-4
PBO: days 1-21

•
•

Cycles 10+

Maintenance
Lenalidomide
10 mg/day
days 1-21

Placebo

Disease
Progression

Lenalidomide
(25 mg/day)
+/Dexamethasone

Placebo

PFS significantly prolonged with the addition of lenalidomide
maintenance following MPR induction therapy (HR = 0.349; P < .001)
PFS benefit maintained across patient subgroups
Palumbo A, et al. N Engl J Med. 2012;366:1759-69.


Maintenance Lenalidomide and
Second Primary Malignancies
•

Both CALGB 100104 and IFM 2005-002 showed increased risk of
second primary malignancies compared with placebo (23 vs 6 and 18
vs 4, respectively)1,2

•

MM-015 also showed increase in frequency of second primary
malignancies with lenalidomide use (n=12, MPR-R; n=10, MPR;
n=4, MP)

Attal M, et al. Proc International Myeloma Workshop 2011.
McCarthy P, et al. Proc International Myeloma Workshop 2011.
3

Palumbo A, et al. N Engl J Med. 2012;366:1759-69.
1

2


PAD + Bortezomib Maintenance vs VAD
+ Thalidomide Maintenance: HOVON
Trial
MM Stage II or III, Age 18–65
Randomization
3 x PAD

3 x VAD
CAD + GCSF

Bortezomib

1.3 mg/m2 IV

Doxorubicin

9 mg/m2

Dexameth

40 mg

CAD + GCSF

MEL 200 + PBSCT

MEL 200 + PBSCT

In GMMG 2nd

In GMMG 2nd

MEL 200 + PBSCT

Allogeneic Tx

Bortezomib maintenance
1.3 mg/m2/2 weeks for 2 yrs

Thalidomide maintenance
50 mg/day for 2 yrs

Efficacy Parameter

MEL 200 + PBSCT

PAD → bortezomib

VAD → thalidomide

P Value

3-yr PFS

48%

42%

.005

3-yr OS

78%

71%

.02

Sonneveld P, et al. ASH 2010. Abstract 40.


Bortezomib + Thalidomide vs Bortezomib
+ Prednisone as Maintenance:
GEM2005MAS65
Series of 260 elderly untreated MM patients included in the GEM2005 Spanish trial
Bort/Mel/Pred
(VMP)

Induction
(6 cycles)

Maintenance

vs

Bort/Thal/Pred
(VTP)

Bort/Thal

Bort/Pred

Bort/Thal

Bort/Pred

(VT)

(VP)

(VT)

(VP)

No significant differences between VMP and VTP in ORR
(80% and 81%) and CR rate (20% and 27%)
Arm

ORR

CR

Median PFS

VT maintenance

95%

46%

39 months

VP maintenance

97%

39%

32 months

Mateos MV, et al. Lancet Oncol. 2010;10:934-41.


Conclusions About Maintenance
Therapy
for Multiple Myeloma

•

Maintenance therapy prolongs PFS.

•

Low-dose oral agents preferable for maintenance therapy.

•

Both bortezomib and lenalidomide are useful maintenance agents and
may need to be combined for patients with high-risk disease.

•

Slight increase in incidence of secondary malignancy after lenalidomide
maintenance.

•

Overall, everyone who meets prerequisites for maintenance therapy
should be considered candidates for treatment.


How to Best Use New Proteasome
Inhibitors and IMiDs in Myeloma
Sundar Jagannath, MD