Asklepios Klinik Altona, Hamburg, Germany Treatment of ...€¦ · Asklepios Klinik Altona Hamburg,...

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Hans Salwender, MD

Treatment of Younger Myeloma Patients

Induction Therapy

Disclosure of Potential Conflicts of Interest: Honoraria and Consultant

Celgene Binding site

Mundipharma Chugai Pharma

Janssen Cilag

Novartis

Asklepios Klinik Altona, Hamburg, Germany

Sylt Bad Griesbach Barmbek (Hamburg) Falkenstein Ini Hannover

Treatment of Younger Myeloma Patients

Induction Therapy

Hans Salwender, MD

Head of Department of Hematology

Stemcell transplant unit

Asklepios Klinik Altona

Hamburg, Germany

Altona (Hamburg)

Induction of what and when?

MGUS, SMM, symptomatic MM

Barlogie et al., BrJH 2006

IMWG recommendations for global myeloma care

PARAMETERS FOR THE INITIATION OF THERAPY

Treatment should be initiated in all p. with active myeloma fulfilling the CRAB criteria,

…one or more of clinically relevant bone lesions, anemia (Hb 10 g/dl), myeloma induced renal

impairment (creatinine 2.0 mg/ml) and hypercalcemia (11.0 mg/dl),

as well as in those symptomatic owing to the underlying disease.

…

…before results have been confirmed by other trials, starting treatment when patients

become symptomatic because of myeloma and/or fulfill the CRAB criteria is considered

standard,

although initiation of therapy may also be considered for prevention of

imminent disease-related complications such as increasing deterioration of renal

function, but not having reached the cutoff level of 2 mg/dl creatinine.

Ludwig H et al., Leukemia. 2013 Oct 9

Smoldering Myeloma

Dispenzieri A et al, Blood 21. Oct 2013

Survival of patients with renal failure

according to induction treatment (VAD vs. PAD)

Scheid C et al., Haematologica 2014, 99(1)

PFS

OS

Association between response and OS in

patients with newly diagnosed MM treated with HDT

IFM90 CR/VGPR vs. PR vs. Other <0.00001

MRC VII CR vs. PR vs. MR 0.00002

TT1 CR vs. PR 0.2496

TT2 CR vs. PR/NR <0.05

IFM94-02 Maximal response <0.001

IFM99C CR/VGPR vs. PR <0.0000

NMSG 5/94 CR vs. PR/NR 0.38

Bologna VGPR or better vs. Other 0.002

GMA CR/MRD vs. Other 0.22

Combined <0.00001

Modified. Van de Velde et al., Haematologica 2007; 92:1399-1406.

CR/VGPR enough?

Martinez-Lopez J et al., BLOOD, 21 JULY 2011, VOLUME 118

EMN-Recommendations

Modified. Engelhardt M et al., Haematologica 2014, 99(2)

Sonneveld P et al., J Clin Oncol. 2013 Sep 10;31(26):3279-87

Bortezomib-Based Versus Nonbortezomib-Based Induction

Treatment Before Autologous Stem-Cell Transplantation in

Patients With Previously Untreated Multiple Myeloma:

A Meta-Analysis of Phase III Randomized, Controlled Trials

Bortezomib-based induction treatment

Modified. Sonneveld P et al., J Clin Oncol. 2013 Sep 10;31(26):3279-87

Postinduction response rate


Post-transplantation CR plus nCR-rate

Subgroup analysis


Progression-free survival

Median follow up 37 months

Impact of bortezomib on outcome in pts with

high-risk cytogenetics: Results from 3 European trials

Vel-based regimens Non Vel-based

regimens

P

Post-induction CR rate

Overall

Pts with high-risk cytogen.

14.5%

18.6%

4%

0.6%

< 0.001

< 0.001

Median PFS

Overall


Pts without high-risk cytogen.

Pts with t(4;14), but no del17p

Pts with del17p, but no t(4;14)

41.5 mos

32 mos

47 mos

36 mos

27 mos

33 mos

22 mos

38 mos

24 mos

19 mos

< 0.001

< 0.001

0.01

0.001

0.014

• Multivariate analysis: independent variables associated with extended PFS: lack of high-risk

cytogen., thrombocytopenia, high β2-M, anemia, achievement of CR after induction therapy

• Vel-based ASCT not associated with prolonged PFS in pts with both t(4;14) and del(17p)

(ultra high-risk): they had shortest PFS (median: 21 mos); multivariate analysis showed

benefit from double ASCT

Cavo et al. ASH 2012 (Abstract 749), oral presentation

Impact of bortezomib on outcome in pts with

high-risk cytogenetics: Results from 3 European trials

Vel-based regimens Non Vel-based

regimens

P

Median OS

Overall Trend favoring incorporation of Vel 0.58

Pts with high-risk cytogenetics 65 mos 41 mos 0.004

• Conclusion

• Higher CR rates and extended PFS with Vel-based regimens

• PFS benefit retained across pts with and without high-risk cytogenetics

• Vel-based ASCT significantly improved outcome of pts with high-risk cytogenetics,

but did not overcome the adverse prognosis imparted by t(4;14) and/or del(17p)


GMMG-HD4 / HOVON65 -trial

Cooperative trial by the Dutch-Belgium HOVON Myeloma Working Party & the German-speaking Myeloma Multicenter Group GMMG based on a common protocol, study rules, datamanagement, monitoring and analysis.

Accrual period 05/2005 – 06/2008, 835 patients

Presented data based on 835 patients (827 eligible) per final analysis of 20 November 2013.

Median follow-up of 490 patients alive is 74 months

Bortezomib-based treatment consistently improves PFS (median 27 m vs 36 m) and OS (median 84 m vs not reached, p=0.05) in patients with newly diagnosed MM who are transplant eligible

Sonneveld P et al. ASH 2013 abstract 404

Randomization

NDMM, age 18–65 y

CAD + GCSF

3 x VAD

CAD + GCSF

3 x PAD

MEL 200 + PBSCT

In GMMG 2nd

MEL 200 + PBSCT

MEL 200 + PBSCT

In GMMG 2nd

MEL 200 + PBSCT

Thalidomide

maintenance

50 mg/day for

2 years

Bortezomib

Maintenance

1.3 mg/m2 / 2 weeks

for 2 years

Bortezomib 1.3 mg/m2

i.v.

Doxorubicin 9 mg/m2

Dexameth 40 mg

GMMG-HD4 / HOVON65 -trial

Modified. Sonneveld P et al. ASH 2013 abstract 404


according to induction treatment (VAD vs. PAD)

Scheid C et al., Haematologica 2014, 99(1)

GMMG-HD4 / HOVON65 -trial IR and HR groups compared to good risk per treatment arm

Arm Relative risk P value

VAD IR HR 2.26,

CI 1.42-3.58

<0.001

HR HR 5.02,

CI 2.89-8.73

< 0.001

PAD IR HR 1.26

CI 0.82-1.92

0.29

HR HR 2.04

CI 1.20-3.48

0.009

PFS

Sonneveld P et al. ASH 2013 abstract 404

GMMG MM5 Trial In Newly Diagnosed Multiple Myeloma To Evaluate

PAd Vs VCD Induction Prior To High Dose Treatment Followed By

Lenalidomide Consolidation and Maintenance –

Final Analysis On Induction Therapy Hartmut Goldschmidt, MD, Jan Duerig, MD, Uta Bertsch, MD, Christina Kunz, PhD, Thomas

Hielscher, Mathias Haenel, MD, Igor Wolfgang Blau, MD, PhD, Dirk Hose, Dr. med. dipl.-phys.,

Anna Jauch, PhD, Baerbel Schurich, PhD, Kai Neben, MD, Anja Seckinger, MD, Barbara Huegle-

Doerr, PhD, Maximilian Merz, MD, Markus Munder, MD, Walter Lindemann, MD, Matthias Zeis,

MD, Christian Gerecke, MD, Ingo GH Schmidt-Wolf, MD, Katja Weisel, MD, Christof Scheid, MD and

Hans Salwender, MD

n: 502

PAd VCD

≥ VGPR: 34.3% 37.0%

SAEs during induction 32.7% 24.0% p=0.037

Neutropenia 3°/4° 11.3% 35.2% p<0.001

Infections during induction 24.6% 22.4% p=0.60

No. of deaths 6 /251 1/ 251

Goldschmidt H, et al., abstract 3369, ASH 2013

PAd vs VCD Induction

Future ??

Carfilzomib, Lenalidomide, and Dexamethasone Followed By Lenalidomide Extended

Dosing (CRd – R) In High Risk Smoldering MM Pat

8 Zyklen Carfilzomib 20/36mg, Lenalidomide 25, Dex 20/10 --- 24 Zyklen Len 10

Response nach 8 Zyklen CRd: 12/12 Pat mit nCR/CR/sCR, 11/12 MRD neg.

Landgren et al. abstract 1939, ASH 2013

Induction Therapy, Younger Myeloma Patients

Conclusions:

- Start treatment before the onset of severe renal impairment

- Bortezomib significantly improves the long-term outcome

of patients presenting with renal failure

- Bortezomib improves outcome in patients with

intermediate/poor risk based on FISH/ISS

Questions?

RD vs RCD vs VCD

Khan et al., British Journal of Haematology, 156, 326–333, 2011

Richardson et al., Blood, 5 August 2010, Vol 116, No 5

Double Vs Single Autologous Stem Cell Transplantation After Bortezomib-Based

Induction Regimens For Multiple Myeloma: An Integrated Analysis Of Patient-Level

Data From European Phase III Studies

Michele Cavo, MD, Hans Salwender, MD, Laura Rosiñol, MD, Philippe Moreau, MD, Maria Teresa Petrucci,

MD, Igor Wolgang Blau, MD, Joan Bladé, MD, PhD, Michel Attal, MD, Francesca Patriarca, MD, Katja Weisel,

MD, Jesus F San Miguel, MD, PhD, Herve Avet-Loiseau, MD, Nicoletta Testoni, BS, Michael Pfreundschuh,

Prof MD, Juan Jose Lahuerta, MD, Thierry Facon, MD, Lucia Pantani, MD, Christof Scheid, MD, Norma

Gutierrez, PhD, MD, Gerald Marit, MD, Antonio Palumbo, MD, Maria Luisa Martin, PhD, Denis Caillot, MD and

Hartmut Goldschmidt, MD

Cavo M et al., abstract 767, ASH 2013

CR after induction in high-risk patients

https://ash.confex.com/data/abstract/ash/2013/5/1/Paper_58415_abstract_107476_0.jpg

https://ash.confex.com/data/abstract/ash/2013/5/1/Paper_58415_abstract_107475_0.jpg

Smoldering Myeloma

Lenalidomide plus Dexamethasone for High-Risk Smoldering MM

Mateos et al., N Engl J Med 2013; 369:438-447; August 1, 2013

“3-year survival rate was higher in the treatment group (94% vs. 80%; P=0.03).”

CR necessary after induction?

No:

Singhal S et al.:

Response to induction chemotherapy is not essential to obtain survival benefit

from high-dose melphalan and autotransplantationin myeloma.

Br J Haematol. 2002;30(10):673-679.

Yes:

Alvares CL et al.

Longterm outcomes of previously untreated myeloma patients: response to

induction chemotherapy and high-dose melphalan incorporated within a

risk stratification model can help to direct the use of novel treatments.

Br J Haematol. 2005;129(5):607-614.

Impact of bortezomib on outcome in pts with high-

risk cytogenetics: Results from 3 European trials

• Study details:

– Integrated analysis of 4 phase 3 studies conducted by

HOVON/GMMG, IFM, PETHEMA/GEM, GIMEMA:

• Comparison of

– Bortezomib-based (Vel-based) induction regimens (VD or

VTD or PAD)

– vs non bortezomib-based (non Vel-based) treatments (VAD or

TD) before single or double ASCT for newly diagnosed MM

• Analysis of impact of bortezomib in post-ASCT consolidation or

maintenance therapy in 3 trials

– 2169 pts enrolled, data on cytogenetics available for 1894 pts

– Pts followed for median 37 months




Vel-based

regimens

Non Vel-based

regimens

P


Overall


14.5%

18.6%

4%

0.6%

< 0.001

< 0.001

Median PFS

Overall





41.5 mos

32 mos

47 mos

36 mos

27 mos

33 mos

22 mos

38 mos

24 mos

19 mos

< 0.001

< 0.001

0.01

0.001

0.014

• Multivariate analysis: independent variables associated with extended PFS: lack of

high-risk cytogen., thrombocytopenia, high β2-M, anemia, achievement of CR after

induction therapy

• Vel-based ASCT not associated with prolonged PFS in pts with both t(4;14) and

del(17p) (ultra high-risk): they had shortest PFS (median: 21 mos); multivariate

analysis showed benefit from double ASCT




Vel-based

regimens

Non Vel-based

regimens

P

Median OS

Overall Trend favoring incorporation of Vel 0.58

Pts with high-risk cytogenetics 65 mos 41 mos 0.004

• Double ASCT favorably influenced OS in pts with both high-risk cytogenetics

and ultra high-risk cytogenetics

• Conclusion

• Higher CR rates and extended PFS with Vel-based regimens

• PFS benefit retained across pts with and without high-risk cytogenetics

• Vel-based ASCT significantly improved outcome of pts with high-risk

cytogenetics, but did not overcome the adverse prognosis imparted by

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



risk cytogenetics: Results from European trials

Vel-based

regimens

Non Vel-based

regimens

P


Overall


14.5%

18.6%

4%

0.6%

< 0.001

< 0.001

Median PFS

Overall





41.5 mos

32 mos

47 mos

36 mos

27 mos

33 mos

22 mos

38 mos

24 mos

19 mos

< 0.001

< 0.001

0.01

0.001

0.014

• Vel-based ASCT not associated with prolonged PFS in pts with both t(4;14) and

del(17p) (ultra high-risk): they had shortest PFS (median: 21 mos)

• Double ASCT favorably influenced OS in pts with both high-risk cytogenetics and

ultra high-risk cytogenetics


# 404 - 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 et al.

# 767 - Double Vs Single Autologous Stem Cell Transplantation After Bortezomib-

Based Induction Regimens For Multiple Myeloma: An Integrated Analysis Of Patient-

Level Data From Phase European III Studies Cavo et al.

# 3369 - GMMG MM5 Trial In Newly Diagnosed Multiple Myeloma To Evaluate PAd Vs

VCD Induction Prior To High Dose Treatment Followed By Lenalidomide Consolidation

and Maintenance – Final Analysis On Induction Therapy Goldschmidt et al.

HOVON-65/GMMG-HD4 Trial Conclusion

Bortezomib-based treatment improves PFS (median 27 months vs 36 months) and OS (median 84 months vs not reached, p=0.05)

Bortezomib significantly improves long-term outcome of pts with renal failure (P<0.001)

Double ASCT improves PFS and OS in pts with ISS1

Bortezomib improves outcome in pts with intermediate/poor risk disease

No increased risk of SPM

Sonneveld et al. ASH 2013 #404

CR plus nCR rate post-transplantation

Sonneveld et al, J Clin Oncol, 2013

Post-transplantation CR/nCR rate

by patients subgroup

Sonneveld et al., J Clin Oncol, 2013

Progression-free survival


PFS, for the individual studies


HOVONGMMGCox LR P =0.02

N140148

D5233

HOVONGMMG

At risk:140148

136139

127131

115120

106113

8588

4453

1817

HOVON

GMMG

0

25

50

75

100

months0 12 24 36 48 60 72 84

Cum

ula

tive p

erc

enta

ge


N9791

D5749

HOVONGMMG

At risk:9791

7674

5967

5155

4848

4035

2011

62

HOVON

GMMG

0

25

50

75

100

months0 12 24 36 48 60 72 84

Cum

ula

tive p

erc

enta

ge


N9791

D5749

HOVONGMMG

At risk:9791

7674

5967

5155

4848

4035

2011

62

HOVON

GMMG

0

25

50

75

100

months0 12 24 36 48 60 72 84

Cum

ula

tive p

erc

enta

ge

ISS 3

ISS 2 ISS 1

OS by ISS group:

single (HOVON) vs double (GMMG) transplant

P=0.02 NS

NS


F27139

26023

N36845

37636

VAD, BLC<2VAD, BLC>2PAD, BLC<2PAD, BLC>2

VAD, BLC<2

VAD, BLC>2

PAD, BLC<2

PAD, BLC>2

0

25

50

75

100

months0 12 24 36 48 60 72 84

Cum

ula

tive p

erc

enta

ge


by treatment arm


N36845

37636

D15935

14916

VAD, BLC<2

VAD, BLC>2

PAD, BLC<2

PAD, BLC>2

0

25

50

75

100

months0 12 24 36 48 60 72 84

Cum

ula

tive p

erc

enta

ge

PFS OS

HR=0.44, CI 0.26-0.75 P=.003 HR=0.38, CI 0.21-0.69, P<.001



by treatment arm


N36845

37636

D15935

14916

VAD, BLC<2

VAD, BLC>2

PAD, BLC<2

PAD, BLC>2

0

25

50

75

100

months0 12 24 36 48 60 72 84

Cum

ula

tive p

erc

enta

ge

OS

HR=0.38, CI 0.21-0.69, P<.001


A: VADB: PADLogrank P =0.16

N270230

F215170

A: VADB: PAD

At risk:270230

203188

148128

10589

6963

3639

1215

37

A: VADB: PAD

0

25

50

75

100

months0 12 24 36 48 60 72 84

Cum

ula

tive p

erc

enta

ge

A: VADB: PADLogrank P =0.05

N270230

D10874

A: VADB: PAD

At risk:270230

255220

226203

197190

172162

100106

4642

87

A: VAD

B: PAD

0

25

50

75

100

months0 12 24 36 48 60 72 84

Cum

ula

tive p

erc

enta

ge

Progression-free and overall survival

from start of maintenance

PFS OS

P= NS HR=0.71, CI 0.52-0.98, p=0.035

Conclusions (2)

• Double HDT and ASCT improves PFS

and OS in patients with ISS 1 NDMM in

the era of novel agents

• Bortezomib improves outcome in patients

with intermediate/poor risk based on

FISH/ISS

• No increased risk of SPMs was observed

Conclusions (1)

• Bortezomib-based treatment consistently

improves PFS (median 27 m vs 36 m)

and OS (median 84 m vs not reached,

p=0.05) in patients with newly diagnosed

MM who are transplant eligible

• Bortezomib significantly improves the

long-term outcome of patients presenting

with renal failure (p<0.001)

Progression-free survival with censoring

at allo-SCT: primary endpoint

A: VADB: PADCox LR Stratified

N373371

F225197

P =0.005

A: VADB: PAD

10 Nov 2010-15:13:13

At risk:373371

258295

176218

97

112

2636

A: VAD

B: PAD

0

25

50

75

100

months0 12 24 36 48

Cum

ulat

ive

perc

enta

ge

PFS with censoring at allo-SCT

HR = 0.75 (0.62-0.91), P=0.004

P. Sonneveld et al., JCO 2012

PFS (allo censored) OS

t HR p t HR p

Arm 0.74 .002 Arm 0.70 .013

WHO 1.22 .005 WHO 1.49 <.001

IgA 1.62 .002 IgA 1.82 .01

IgG 1.33 .041 IgG 1.71 .008

LDH 1.25 .10 LDH 1.59 .006

ISS 1.25 .001 ISS 1.47 <.001

13q- 1.43 .001 13q- 1.62 .002

SG 0.81 .039 SG 0.73 .031

Multivariate Cox regression analysis

P. Sonneveld et al., JCO 2012

PFS in IR and HR groups compared to

good risk per treatment arm

Arm Relative risk P value

VAD IR HR 2.26,

CI 1.42-3.58

<0.001

HR HR 5.02,

CI 2.89-8.73

< 0.001

PAD IR HR 1.26

CI 0.82-1.92

0.29

HR HR 2.04

CI 1.20-3.48

0.009


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

prognostic index for OS

• Validation of scoring system in large data set:

– GIMEMA (VTD vs TD) 474 pts

– PETHEMA/GEM (VTD vs TD vs VBMCP/VBAD/Vel) 386 pts

– HOVON/GMMG (PAD vs VAD) 827 pts

– IFM (VD vs VAD) 482 pts

– Total 2169 pts

– Data for risk factors available for 1601 pts

• 21% ISS 3, 20% t(4;14) and/or del17p, 60% LDH > normal

Score % of pts (n=1601) Outcome: 2-year OS

0 56% 93%

1 32% 85%

2 4% 67%

3 7% 55%

Moreau et al. ASH 2012 (Abstract 598), oral presentation



Score Definition % of overall

population Outcome

0

Absence of adverse factors (neither

high LDH, nor ISS 3, nor t(4;14) and

/or del(17p))

57% 3-year OS: 89%

1

Presence of only 1 adverse factor

(either high LDH or ISS 3 or t(4;14)

and/or del(17p))

32% 3-year OS: 73%

2

Presence of high LDH plus ISS 3 in

the absence of t(4;14) and /or

del(17p)

6% 3-year OS: 68%

3 Presence of t(4;14) and/or del(17p) in

addition to either ISS 3 or high LDH 5%

Median OS:

19 mos

3-year OS: 24%




• Study details: investigation of prognostic parameters of pts enrolled in

the IFM2005-01 trial

• Results

– Multivariate logistic regression analysis: risk of death from PD

within 2 years from start of therapy related to:

• high LDH > normal value (p = 0.0014)

• ISS 3 (p = 0.0097)

• cytogenetic abnormalities (= presence of either t(4;14) or 17p

deletion (p = 0.0002))

– Development of scoring system

– Identification of small group of pts with very high-risk disease

and a shortened survival despite use of intensive novel agent-

based therapy


Mateos M et al. NEJM 2013

Landgren et al. ASH abstract #1939, poster

8 Zyklen Carfilzomib 20/36 mg/m2 + Len/Dex, anschl. 24 Zyklen Len 10 mg/d

MM-003: OS by Cytogenetic Profile

Median OS

Standard Risk (n = 148) 14.0 mos

del(17p)/t(4;14) (n = 77) 9.9 mos

OS (mos)

Pro

po

rtio

n o

f P

ati

en

ts

0.2

0.4

0.6

0.8

1.0

0.0 4 8 12 16 20 24 0 28

del(17p)/t(4;14) vs. Standard Risk

P = .041

Dimopoulos et al. ASH 2013 # 408

IFM 94 IFM 90 Attal et al., N Engl J Med 2003 Attal et al., N Engl J Med 1996

Stellenwert von Hochdosistherapie und

Transplantationen beim Multiplen Myelom

Rev/dex vs Rev/DEX for newly diagnosed MM

Rajkumar et al.Lancet Oncol 2010; 11: 29–37

Sonneveld et al.,J Clin Oncol. 2013 Sep 10;31(26):3279-87

After follow up of 37 months 24% of patients died

Median OS had not been reached in either group

There was a significant improvement in OS in the bortezomib-based

induction group (HR, 0.81; 95% CI, 0.66 to 0.99; P .0402)

3-year OS rates were 79.7% and 74.7%, respectively

Bortezomib-Based Versus Non-Bortezomib-Based

Induction Treatment Before Autologous Stem-Cell Transplantation

Sonneveld et al.,J Clin Oncol. 2013 Sep 10;31(26):3279-87

Randomization

NDMM, age 18–65 y

CAD + GCSF

3 x VAD

CAD + GCSF

3 x PAD

MEL 200 + PBSCT

In GMMG 2nd

MEL 200 + PBSCT

MEL 200 + PBSCT

In GMMG 2nd

MEL 200 + PBSCT

Thalidomide

maintenance

50 mg/day for

2 years

Bortezomib

Maintenance

1.3 mg/m2 / 2 weeks

for 2 years

Trial design

Bortezomib 1.3 mg/m2

i.v.

Doxorubicin 9 mg/m2

Dexameth 40 mg


Symptomatic MM. CR necessary for OS?

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