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Evangelos Terpos, MD, PhD

Clinical Case Study Discussion:

Maintenance in MM

Disclosure of Conflict of Interest (List)

Honoraria Celgene, Janssen-Cilag

National & Kapodistrian University of Athens,

School of Medicine, Athens, Greece

61-year-old female presents with acute

back pain that has persisted for 1 month

• Evaluations in the

orthopedics clinic revealed

– A fracture in L4

– DXA-scan T-score of the

lumbar spine: -2.8

– hemoglobin 10.5 g/dL

– serum protein

electrophoresis: 25 g/L

IgG-kappa

• Referral to the hematology

clinic

Patient diagnosed with multiple myeloma, IgGk, ISS-2

Patient workup and diagnosis

• Evaluations in the hematology clinic revealed

– skeletal survey (WBXR): no osteolytic lesions, only

diffuse osteoporosis, L4 fracture

– WBC 2.7 x 109/L

– hemoglobin 10.6 g/dL

– platelets 175 x 109/L

– creatinine 101 µmol/L (1.1 mg/dL)

– albumin 2.8 g/dL

– Kappa/lambda ratio: 8.4

– Electrophoresis of the urine: 95% of k-light chains

– FISH analyses revealed t(4;14) translocation

– BM plasma cells: 35% plasma cells

– β2M 3.2 mg/L

At this point would you treat the patient?

A. The patient has asymptomatic myeloma (no CRAB)

criteria and needs close follow-up

B. The patients has symptomatic myeloma and

requires immediate treatment

C. The patient has an osteoporotic fracture and needs

only bisphosphonate administration

D. The patient has high-risk asymptomatic myeloma

and needs treatment with RD (lenalidomide and

dexamethasone)

Case continue

An MRI of the spine was performed: several focal

lesions were revealed

Hillengass et al. J Clin Oncol 2010;28:1606-10

149 patients

Focal lesions: 28%

The presence of

focal lesions was

the strongest

adverse prognostic

factor for

progression into

symptomatic

disease (p<0.001)

Algorithm for Imaging in our Center

Suspected plasmacytoma or

myeloma Soft tissue mass

Suspected spinal cord

compression

CT scan

and consider biopsy Radiological

Skeletal Survey and WBCT

Urgent MRI/CT scan

and appropriate

medical management

Lytic Lesions Present?

Yes No

Whole Body CT/LS & pelvis MRI Risk for fracture?

Yes No

Urgent orthodedic review;

consider radiotherapy Systemic Therapy

Lytic Lesions >1

Diffuse pattern

0-1 Focal Lesions

0-1 Lytic Lesions

No Diffuse pattern

Observation

?

Case continue

• The patients was treated with VTD x 4, high dose

melphalan with ASCT

• Zoledronica acid was also given

• She achieved a vgPR post-induction and CR post-

ASCT: the M-component was present only in

serum immunofixation

• Grade 2 painful peripheral neuropathy was

present post-ASCT

Would you continue the treatment at this

point?

A. No, the patient has achieved a CR and does not

need further anti-myeloma treatment; I will follow-up

him every month with zoledronic acid

administration only

B. The patient has high-risk myeloma and I will give

maintenance with thalidomide

C. The patient has high-risk myeloma and I will give

lenalidomide maintenance

D. The patient has shown significant improvement with

the given therapy and I will continue on VTD

consolidation plus zoledronic acid with no

maintenance afterwards

E. The patient needs a second auto-transplant

Answer E: Single versus double ASCT in MM IFM94 trial

VGPR after first ASCT Absence of VGPR after first ASCT

P<0.001

P=0.7

Attal et al. N Engl J Med 2003;349:2495-502

Double vs single ASCT after bortezomib-based

induction: Integrated analysis of phase European 3 studies

• Pts (n=606)

– Bortezomib-based induction

– Single (n=254) or double (n=352) ASCT

• Differentiation of 4 groups based on adverse prognostic variables:

– ISS 3, high-risk cytogenetics, failure to achieve CR after induction

therapy

• Group 0 (13%): ISS 1-2, lack of high-risk cytogenetics, CR after induction

• Group 1 (61%): one adverse variable

• Group 2 (23%): two adverse variables

• Group 3 (3%): all three adverse variables

Cavo et al. ASH 2013 (Abstract 767), oral presentation

Double vs single ASCT after bortezomib-based

induction: Integrated analysis of phase European 3 studies

Group 0

(no adverse

variable)

Group 1

(1 adverse

variable)

Group 2

(2 adverse

variables)

Group 3

(3 adverse

variables)

Median PFS 61 months 56 months 36 months 26 months

• Presence of 2 (P<0.001) or 3 (P<0.001) adverse prognostic

variables associated with progressively shorter OS compared to lack

of all 3 adverse variables

Adverse variables: ISS 3, high-risk cytogenetics, failure to achieve CR after induction therapy

Cavo et al. ASH 2013 (Abstract 767), oral presentation

Double vs single ASCT after bortezomib-

based induction PFS and OS in patients with 2 adverse variables

Cavo et al. ASH 2013 (Abstract 767), oral presentation

PFS and OS for pts with high-risk cytogenetics and who failed CR

after bortezomib-based induction regimens

Double ASCT Single ASCT P

PFS 41 months 20 months 0.003

OS 67 months 31.5 months <0.001

PFS OS

Randomization

Induction (three 21-day cycles)

• Bortezomib-Thal-Dex (VTD)

V 1.3 mg/m2 d1, 4, 8, 11

T 200 mg daily

D 320 mg/cycle

Double ASCT

Consolidation (two 35-day cycles)

• Bortezomib-Thal-Dex (VTD)

V 1.3 mg/m2 once-weekly

T 100 mg/d through d 1 to 70

D 320 mg/cycle

Induction (three 21-day cycles)

• Thal-Dex (TD)

T 200 mg daily

D 320 mg/cycle

Consolidation (two 35-day cycles)

• Thal-Dex

T 100 mg/d through d 1 to 70

D 320 mg/cycle

Answer D: VTD consolidation

Study design (Gimema-MMY-3006)

n=236 n=238

Maintenance: Dex

Cavo et al. Lancet 2010;376(9758):2075-85

Cavo et al. Blood 2012;120(1):9-19

Cavo et al. ASH 2013 (Abstract 2090), poster presentation

PFS PFS for pts with

t(4;14) and/or del(17p)

PFS for pts with or

without t(4;14)

PFS from starting

consolidation

Cavo et al. ASH 2013 (Abstract 2090), poster presentation

VTD vs TD incorporated into double ASCT: Updated analysis of Phase 3 Gimema-MMY-3006 study

Do we need a bisphosphonate together

with VTD consolidation?

• VTD started on day 100 post-

ASCT

• patients received 4 cycles of

VTD (1st block), were followed

without treatment for 100

days and then received

another 4 VTD cycles (2nd

block)

• during this 12-month period,

BPs were not administered.

• only one patient with PD

developed a skeletal-related

event (i.e. radiation to bone)

N=42

• Best response:

CR 36%, CR 31%,

vgPR 16.5%, PR 9.5%, PD 7%

• 33% and 47% of patients

improved their status of

response after the 1st and 2nd

VTD block, respectively

• median TTP after ASCT was 34

months

• median TtNT was 40 months

Terpos et al. Leukemia 2014;28:928-34

Phase 3 trial: Bortezomib monotherapy

as consolidation (Nordic Myeloma Study Group [NMSG 15/05] trial)

Induction (no bortezomib) + single or double ASCT (n=403)

Randomization (3 months post-ASCT) (n=370)

Bortezomib (n=187)

1.3 mg/m2 IV

Two 3-week cycles: days 1, 4, 8, 11

+

Four 4-week cycles: days 1, 8, 15

(total 20 injections over 21 weeks)

Observation (n=183)

Primary objective: PFS

Mellqvist et al. Blood 2013;121:4647-4654

Bortezomib Control p value

Improvement of response from

PR to ≥ VGPR 57% 36% 0.007

Median PFS 27 months 20 months 0.05

Incidence of neuropathy CTC ≥ III

Neuropathic pain > grade 2 6% 1% < 0.006

Sensory neuropathy > grade 2 5% 1% < 0.04

Bortezomib Monotherapy as Consolidation:

Results

• Median follow-up: 38 months

• Beneficial effect of bortezomib consolidation on PFS only seen

in patients not achieving at least VGPR after ASCT

Mellqvist et al. Blood 2013;121:4647-4654

Bortezomib Control p value

Improvement of response from

PR to ≥ VGPR 57% 36% 0.007

Median PFS 27 months 20 months 0.05

Incidence of neuropathy CTC ≥ III

Neuropathic pain > grade 2 6% 1% < 0.006

Sensory neuropathy > grade 2 5% 1% < 0.04

Bortezomib Monotherapy as Consolidation:

Results

• Median follow-up: 38 months

• Beneficial effect of bortezomib consolidation on PFS only seen

in patients not achieving at least VGPR after ASCT

Mellqvist et al. Blood 2013;121:4647-4654

VAD/HDM/Thalidomide PAD/HDM/Bortezomib

N PFS at

36 Mos, %

OS at

36 Mos, %

N PFS at

36 Mos, %

OS at

36 Mos, %

All 305 42 71 308 48 78

-13/13q- 126 29 59 112 44 82

t(4;14) 28 22 43 26 32 65

17p- 32 16 19 15 27 60

P < .01 in univariate analysis

All data FISH, -13/13q- also karyotype if available

Bortezomib maintenance therapy Phase 3 HOVON/GMMG trial

Sonneveld et al. J Clin Oncol 2012;30:3654

VAD PAD

goodintermediatepoor

N468330

D6

3724

good

intermediatepoor

At risk:468330

447322

436818

41549

39488

31355

19132

531

good

intermediate

poor

0

25

50

75

100

months0 12 24 36 48 60 72 84

Cum

ula

tive p

erc

enta

ge

goodintermediatepoor

N567327

D122815

good

intermediatepoor

At risk:567327

506723

496019

475516

444616

383810

27114

1030

good

intermediate

poor

0

25

50

75

100

months0 12 24 36 48 60 72 84

Cum

ula

tive p

erc

enta

ge

Bortezomib improves outcome in patients

with intermediate/poor risk based on FISH/ISS

Good Risk: no t(4;14)/del17p/add1q and ISS 1

Intermediate Risk: either t(4;14)/del17p/add1q and ISS 1

or no t(4;14)/del17p/add1q and ISS 2/3

Poor Risk: t(4;14)/del17p/add1q and ISS 2/3

Sonneveld et al. ASH 2013 (Abstract 404), oral presentation; Neben et al. Blood 2012;119(4):940-8.

Overall survival by risk group (FISH + ISS)

Significant improvement in

PFS with maintenance

therapy

Significant improvement in

OS with maintenance

therapy

Survival after

relapse

Spencer Yes Yes

(3 years follow up) Similar in all groups

Attal Yes

Yes (@ 39 m),

but OS advantage

disappeared with longer

follow-up (5.7 years)

Similar in all groups

Barlogie Yes Yes

(7.2 years follow-up)

Reduced OS after

thal exposure

Lokhorst Yes No Reduced OS after

thal exposure

Morgan Yes No Reduced OS after

thal exposure

Stewart Yes No Reduced OS after

thal exposure

Answer 3: Thalidomide maintenance therapy

Spencer et al. J Clin Oncol 2009;27:1788-93; Attal et al. Blood 2006;108:3289-94;

Barlogie et al. N Engl J Med 2006;354:1021-30; Blood 2008;112:3115-21;J Clin Oncol 2010;28:1209-14; Lokhorst et al. Blood

2010; 115: 1113-20; Morgan et al. Clin Cancer Res 2013;19:6030-8; Stewart et al. Blood 2013;121:1517-23

ALLG MM6 study Updated results

TP versus P: Survival benefit is durable

5yr PFS: 27% vs 15%

HR 0.16; 95% CI 0.044 to 0.582

5yr OS: 66% vs 47%

HR 0.12; 95% CI 0.028 to 0.558

Progression Free Survival Overall Survival

TA

CA

TA

CA

Kalff et al. HSANZ 2013 (oral presentation)

Median follow-up: 5.4 years

Pts (n=243), newly diagnosed MM

Treatment: Single ASCT

Randomization: Thal/Pred (n=114) vs Pred (n=129)

At least 8 months of thalidomide is

required for PFS and OS benefit

8-12m vs CA p<0.001

8-12m vs <8m p=0.032

8-12m vs CA p<0.001

8-12m vs <8m p=0.013

Progression Free Survival Overall Survival

TA <8m

TA 8-12m

CA

TA <8m

TA 8-12m

CA

Kalff et al. HSANZ 2013 (oral presentation)

Answer B: Lenalidomide maintenance (IFM 2005-02)

Arm A=

Placebo

(n=307)

until relapse

Patients < 65 years, with non-progressive disease,

6 months after ASCT in first line

Arm B=

Lenalidomide

(n=307)

10-15 mg/d until relapse

Primary end-point: PFS. Secondary end-points: CR rate, TTP, OS, feasibility of long-term lenalidomide

Phase 3 randomized, placebo-controlled trial n= 614 patients, from 78 centers, enrolled between 7/2006 and 8/2008

Consolidation:

Lenalidomide alone 25 mg/day p.o.

days 1-21 of every 28 days for 2 months

Randomization: stratified according to Beta-2m, del13, VGPR

Attal et al. N Engl J Med 2012;366(19):1782-91.

PFS and OS data IFM 2005-02: Lenalidomide maintenance

• Median follow-up: 67 months (from randomization)

Lenalidomide

n=307

Placebo

n=307 P

PFS 46 months 24 months 0.001

OS 82 months 81 months 0.8

Attal et al. ASH 2013 (Abstract 406), oral presentation

0.0

00

.25

0.5

00

.75

1.0

0

0 6 12 18 24 30 36 42

Placebo Revlimid

0.0

00

.25

0.5

00

.75

1.0

0

0 6 12 18 24 30 36 42

Placebo Revlimid

PFS according to Response Post-ASCT

HR= 0.31 - CI 95% [0.14-0.68] HR= 0.50- CI 95% [0.38-0.65]

CR Not in CR

p=0.021 p<0.0001

Rev

Placebo

Rev

Placebo

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

Lenalidomide maintenance in high-risk

cytogenetics

• Patients treated in 2005-01 trial: Vel/dex vs VAD

• Patients achieving ≥ PR post-transplantation enrolled in 2005-02 trial:

2 months consolidation with lenalidomide followed by lenalidomide

maintenance or placebo

• Chromosomal data available for 488 patients:

– t(4;14) in 13.3%

– del(17p) in 6.6%

• Within lenalidomide arm, PFS comparison for patients with or without

t(4;14) or del(17p) showed significant difference, in favor of ‘no

abnormality’ group: The median PFS of the total group of Len treated

patients was 42m

Lenalidomide maintenance Placebo

Median PFS for pts with t(4;14) 27 months 15 months

Median PFS for pts with del(17p) 29 months 14 months

Avet-Loiseau et al. ASH 2010 (Abstract 1944)

Lenalidomide maintenance therapy: CALGB 100104 Update at IMW 2013

• Cumulative incidence of second primary cancers greater in

lenalidomide group (P=0.034)

• Cumulative incidence of risk of PD (P=0.004) and death

(P<0.001) greater in placebo group

Lenalidomide arm Placebo arm P

Median EFS 47 months 27 months <0.001

Events: PD, death, SPM

McCarthy P. IMW 2013, oral presentation (S15 Consolidation / Maintenance)

Phase 3: MPR vs tandem ASCT,

Len maintenance vs no treatment

• Pts (n=402) with newly diagnosed MM <65 years

Gay et al. ASH 2013 (Abstract 2089), poster presentation

PFS and OS: Len maintenance vs no

treatment

Gay et al. ASH 2013 (Abstract 2089), poster presentation

4-year OS:

Len maintenance 80%

No maintenance 62%

Median PFS:

Len maintenance 42.7 mos

No maintenance 17.5 mos

PFS

OS

No maintenance

No

maintenance

R maintenance

R maintenance

Lenalidomide maintenance:

Meta-analysis of randomized trials

• 4 phase 3 trials (3 publications and 1 abstract) (n= 1935):

– IFM 05-02, CALGB 100104, RV-MM-PI209 (transplant setting)

– MM-015 (non-transplant setting)

– Analysis of entire treatment package (not only maintenance)

• Findings

– Len maintenance is associated with

• improvement in PFS

• trend towards improved OS

• increased risk of grade 3-4 AEs and SPMs

– Subset of pts benefiting from Len maintenance not yet defined

– Careful discussion with patient required

Singh et al. ASH 2013 (Abstract 407), oral presentation

Who might benefit from continued

therapy?

Implications of continued response after ASCT Retrospective analysis

• Pts (n=430) who underwent ASCT within 12 months of diagnosis

– Excluded: pts in CR at day 100 or who had received maintenance

• Comparison of patients with and without continued response after day 100

without additional therapy

• Results

• Multivariate analysis: lack of continued response predicted for worse PFS

and OS

• Conclusions

– Continued response post-ASCT is prognostic

– Possible clinical implications on the use of post-transplant therapy

Continued response

(n=167)

No continued response

(n=263) P

PFS 35 months 13 months <0.001

TTNT 43 months 16 months <0.001

OS 96 months 57 months <0.001

Gonsalves et al. Blood 2013;122(10):1746-1749

Who might benefit from post-ASCT

therapy?

• High-risk disease by FISH and GEP associated with poor OS Chng et al. Leukemia 2013 Aug 26 [Epub ahead of print]

Avet-Loiseau et al, Blood 2007;109: 3489-3495

Shaughnessy et al. Blood 2007;109: 2276-2284

Decaux et al. J Clin Oncol 2008;26:4798-4805

Dickens et al. Clin Cancer Res 2010;16(6);1856–64

Moreaux et al. Haematologica 2011;96(4):574-582

Broyl et al. Blood 2010;116(14):2543-53

• ISS 3, high LDH and t(4;14) and/or del(17p) as a prognostic index

for OS

– Scoring system to identify pts with very high-risk disease and

short survival due to PD Moreau et al. IMW 2013 (Abstract O-13), oral presentation

Who might benefit from post-ASCT

therapy?

• High serum-free light chain levels and their rapid reduction in

response to therapy define an aggressive MM subtype with poor

prognosis

– SFLC baseline levels higher than 75 mg/dL identified pts with

higher nCR to induction therapy, yet inferior EFS and OS Van Rhee et al. Blood. 2007; 110:827-832

• Early responder myeloma: kinetic studies identify patient subgroup

characterized by poor prognosis

– Early response associated with high plasma cell proliferative

activity is a poor prognostic factor Boccadoro et al. J Clin Oncol 1989;7(1):119-25

– Shorter remission duration and OS in pts who had an initially

rapid response to therapy Belch et al. Br J Cancer 1988;57(1):94-9

Who might benefit from post-ASCT

therapy?

• Sustained CR independent favorable post-treatment variable

associated with prolonged OS

– Loss of CR associated with adverse prognosis

Barlogie et al. Cancer 2008;113:355–9

Hoering et al. Blood 2009; 114(7): 1299–1305

• Long-term survival despite absence of CR

– Persistent small levels of M-protein and minimal marrow

plasmacytosis (likely regression to an MGUS phase)

Fassas et al. Bone Marrow Transplant 2005;35(3):215-24

Study case continue….

• The patient received lenalidomide maintenance for 5

years

• Achieve sCR

• Suddenly a dramatic reduction in FBC values

• RAEB-II was diagnosed

• Currently on Vidaza (acatydidine) 75 mg/m2 seven

days per month

• MDS in PR

Summary / Conclusions

• Consolidated data confirm PFS and OS benefit of

bortezomib-based induction therapy

• Consolidation with VTD improves depth of response and

PFS

• Maintenance therapy:

– Thalidomide: improvement in PFS and OS

– Lenalidomide: improvement in PFS (2 studies) and OS

(1 study), but reduced OS post-relapse (1 study)

– Bortezomib: improvement in OS

• We need further studies to better define the subgroups of

patients who will be benefited for a post-ASCT

continuous therapy strategy