New treatment options and international research€¦ · IMWG 2003 Br. J. Haematol. Smoldering Multiple Myeloma Jens Hillengass MD University of Heidelberg, S.D.G . Treatment of smoldering

New treatment options and international researchJens Hillengass MD

Section Multiple MyelomDepartment of Hematology and Oncology

University of Heidelbergand

Department E010 RadiologyGerman Cancer Research Center

Jens Hillengass MD University of Heidelberg, S.D.G

Indication for treatment


Stages of monoclonal plasma cell diseaseMonoclonal Gammopathy

of undetermined Significance

(MGUS)

smoldering myeloma

MultipleMyeloma

Monoclonal Gammopathy of undetermined Significance

(MGUS)

EarlyMyeloma

clonal plasma cells in bone marrow

<10% >10% >10%

monoclonal protein <30g/l >30g/l >30g/l

End organ damage NO NO YES

Smoldering Multiple Myeloma

Current definition according to IMWG: ≥ 10% Plasma Cells in Bone Marrow NO End Organ Damage (CRAB) or myeloma-defining event (MDE)

Rajkumar 2014 Lancet oncolJens Hillengass MD University of Heidelberg, S.D.G

IMWG Criteria (2003)


symptomatic MM M-protein in serume and/ or urine; clonal plasma cells or plasmacytoma and ROTI* including bone lesions

MGUS M-Protein < 30 g/l; clonal plasma cells < 10%; no „ROTI“*

ROTI *ROTI = myeloma Related Organ or Tissue ImpairmentCalcium level > 2.75 mmol/lRenal insufficiency (Kreatinin > 173 mmol/l oder 2.0 mg/dl)Anemia (hemoglobin < 10 g/dl)Bone lesions (lytic lesions or osteoporosis with fracture (X-ray, CT or MRI)

smoldering MM M-Protein ≥ 30 g/l and/ or clonal plasma cell ≥ 10%; no „ROTI“*

Others: symptomatic hyperviscosity; amyloidosis; recurrent bacterial infections (> 2 episodes in 12 months

IMWG 2003 Br. J. Haematol.



Treatment of smoldering Multiple Myeloma

Dispenzieri 2013 BloodJens Hillengass MD University of Heidelberg, S.D.G

Smoldering Multiple MyelomaT h e n e w e ng l a nd j o u r na l o f m e dic i n e

n engl j med 356;25 www.nejm.org june 21, 20072586

protein level of 0.1 g or less per 24 hours was found in 84%; only four patients (1.5%) had a level of more than 1.0 g per 24 hours.

The bone marrow aspirate and biopsy speci-mens were examined in all 276 patients (Fig. 1). In the plasma-cell category, the most common proportion was 15 to 19%. Of the 276 patients, 10% had less than 10% plasma cells in the mar-row, and 10% had 50% or more plasma cells. Cy-clin D1 was expressed by the plasma cells in 18% of the bone marrow specimens.

OutcomeDuring 2131 cumulative person-years of follow-up (range, 0 to 29; median, 6.1), 85% of the patients with smoldering multiple myeloma died (median follow-up of those still living, 11.6 years). During this period, active multiple myeloma developed in 158 patients (57%), who had a median survival af-ter the time of diagnosis of 3.4 years; amyloidosis developed in 5 (2%) (Table 1). The cumulative prob-ability of progression to active multiple myeloma or amyloidosis was 51% at 5 years, 66% at 10 years, and 73% at 15 years; the median time to progres-sion was 4.8 years (Fig. 2). The overall risk of pro-gression was 10% per year for the first 5 years, ap-proximately 3% per year for the next 5 years, and 1% per year for the last 10 years.

The number of patients with progression to ac-tive multiple myeloma was 522 times the number

of persons without smoldering multiple myeloma who would be expected to have active disease, and the risk of amyloidosis was increased by a factor of 50 (Table 1). Of 16 patients with Durie–Salmon stage II disease, 15 had progression to active mul-tiple myeloma; both patients with Durie–Salmon stage III had progression to active multiple my-eloma (median time to progression, 13.8 months and 15.1 months). Among patients with progres-sion of smoldering multiple myeloma, 97% had progression to active multiple myeloma. Rates of death owing to other diseases, including cardio-vascular and cerebrovascular disease and non–plasma-cell cancers, were 18% at 5 years, 26% at 10 years, 30% at 15 years, and 35% at 20 years. The overall rate of survival was 60% at 5 years, 34% at 10 years, and 20% at 15 years (median, 6.3). In the 128 patients who did not have progression to ac-tive disease after more than 10 years after diag-nosis, the disease was of the IgG subtype in 81%, the baseline median level of plasma cells in the bone marrow was 16%, the median spike in the serum monoclonal protein level was 2.8 g per deciliter, and uninvolved immunoglobulins were reduced in 78%.

Risk Factors for ProgressionWe evaluated baseline factors with respect to pro-gression of smoldering multiple myeloma to active disease or amyloidosis in 163 patients. These fac-tors included sex, hemoglobin level, a spike in the serum monoclonal protein level of 4 g per deciliter or more, the type of serum heavy chain, the serum albumin level, the presence and type of urinary light chain, a reduction in levels of uninvolved im-munoglobulins, the expression of cyclin D1, the proportion of plasma cells in the bone marrow, in-volvement of the interfatty marrow space, decreased proportion of normal hematopoietic elements (10% or more below the expected level for age), and as-signment to prognostic group 1, 2, or 3 (as defined in the Methods section). Significant baseline risk factors for progression of smoldering multiple myeloma to active disease or amyloidosis in the univariate analysis included the level of serum monoclonal protein (P<0.001), the presence of IgA monoclonal protein (P = 0.004), the presence of uri-nary light chain (P = 0.04), the extent of bone mar-row involvement (plasma cells, ≥20%; P<0.001), a reduction in levels of uninvolved immunoglob-ulins (P = 0.001), and the pattern of plasma-cell

100

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60

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00 5 10 15 20 25


MGUS

AUTHOR:

FIGURE:

JOB:

4-CH/T

RETAKEICM

CASE

EMail LineH/TCombo

Revised

REG F

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1st2nd3rd

Kyle

2 of 4

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ARTIST: ts

35625 ISSUE:

22p3

51

6673

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2116

104

Figure 2. Probability of Progression to Active Multiple Myeloma or Primary Amyloidosis in Patients with Smoldering Multiple Myeloma or Monoclonal Gammopathy of Undetermined Significance (MGUS).

I bars denote 95% confidence intervals.

The New England Journal of Medicine Downloaded from nejm.org on October 26, 2013. For personal use only. No other uses without permission.

Copyright © 2007 Massachusetts Medical Society. All rights reserved.

Kyle 2007 NEJMJens Hillengass MD University of Heidelberg, S.D.G

High Risk Smoldering Multiple Myeloma

Intended definition according to IMWG:=> progression of 80% within 2 years (IMW 2011 London) => 40% progression per year?!

Jens Hillengass MD University of Heidelberg, S.D.G Rajkumar 2014 Lancet oncol

New definition of multiple Myeloma

Kastritis 2014 Leukemia, Hillengass 2010 JCO

N = 65FL > 1high risk N = 9 (14%)

N = 149FL > 1high risk N = 23 (15%)


Dispenzieri 2008 Blood, Larsen 2013 Leukemia

N = 273sFLC ratio abnormalhigh risk = n.d.

N = 586FLC ≧ 100high risk = 90 (15%)



Rajkumar 2011 NEJM, Waxman 2014 ASCO

N = 126BMPC ≧ 60%high risk N = 21 (17%)

N = 121BMPC ≧ 60high risk N = 6 (5%)

high risk

intermediate risk

low risk



New Definition of Multiple Myeloma

Rajkumar 2014 Lancet oncol

• Clonal bone marrow plasma cells ≥10% or biopsy proven plasmacytoma (not M-protein) and

ANY ONE OR MORE OF THE FOLLOWING MYELOMA DEFINING EVENTS (MDE)

• Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically

• Hypercalcemia: Serum calcium >0.25 mmol/L above upper limit of normal or > 2.75 mmol/L (> 1mg/dL above upper limit of normal)

• Renal insufficiency: Creatinine Clearance <40 ml/min or Serum creatinine > 173 µmol/L (>2mg/dL)

• Anemia: Normochromic, normocytic with a hemoglobin value of >2 g/dL below the lower limit of normal or a hemoglobin value <10 g/dL

• Bone lesions: Lytic lesions, or osteoporosis with compression fractures detected by X-ray, CT or PET-CT

• Any one or more of the following biomarkers of malignancy • Clonal bone marrow plasma cell percentage ≥ 60% (IHC, Flow, Immunofluorescence) • Involved/uninvolved serum free light chain ratio ≥100 and involved FLC ≥100 mg/L • >1 focal lesions on magnetic resonance imaging studies

SLIM-CRABJens Hillengass MD University of Heidelberg, S.D.G

Treatment of smoldering Multiple Myeloma

Jens Hillengass MD University of Heidelberg, S.D.G Mateos 2013 NEJM

History of myeloma treatment


2015Panobinostat

2004Lenalidomide

2002Bortezomib

IxazomibElotuzumabDaratumumabSAR650984...

1970 1980 1990 2000 2010

1962Melphalan

1968Melphalan + Prednisone

1980sHigh dose melphalan + KMT

1984VAD

1990sSingleASCT

1984Supportivetherapy

2000sTandemASCT

1999Thalidomide

2014Carfilzomib

2014Pomalidomide


How to treat in the future


initialtreatment paths

Treatment paths

transplantation-eligible• up to 70 years (?)• normal organ function• stem cells collected• patient choice

not transplant-eligible• >70 years• comorbidities• no stem cells• patient choice


Patients with Multiple Myeloma


Treatment pathsTransplantation not possible Transplantation possible

age (65/ 70), performance status, comorbidities

Induction therapy Induction therapy(4-6 cycles)

maintenance therapy stem cell collection

stem cell transplantation

consolidation therapy

maintenance therapy


What to do first?


(Vincristin)

CyclophosphamidMelphalanBendamustin

Doxorubicin

Vinca-AlkaloidSpindelgift

Mikrotubulusdestabilisation

AntibioticumInterkalator: DNA-Strangbrüche

Topoisomerase-II-Inhibitor

AlkylansDNA-Strangbrüche

„Classical“ chemotherapy


Benefit of novel agents

Kumar Blood 2008,Kumar Leukemia 2014


Immunomodulatory drugsThalidomide/ Lenalidomide/ Pomalidomide


Proteasome inhibitorsBortezomib/ Carfilzomib/ Ixazomib


Improvement of induction therapyGMMG-MM5

3 x PAd (A1 + B1) 3 x VCD (A2 + B2)

CAD + stem cell collection

1-2 high dose melphalan + ASCT

2x Lenalidomide consolidation

Len for2 years

Len if no CR

Len for2 years

Len if no CR

A1 B1 A2 B2


Improvement of induction therapyGMMG-MM5

Mai 2015 Leukemia

N = 504 newly diagnosed transplantat-eligible MM-patients

VCD PAd P-value⩾VGPR 37.0% 34.3% 0,001

PD 0.4% 4.8% 0,003

Leukopenia ⩾ 3° 35.2% 11.3% <0,001

Neuropathy 8.4% 14.9% 0,03

SAE total 24.0% 32.7% 0,04


Induction therapy

Stewart Blood 2009; Jakubowiak Blood 2012

Stewart AK, et al. Blood. 2009;114:5436-5443. Jakubowiak AJ, et al. Blood. 2012;120:1801-1809.

100

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70

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30

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0 TD VAD VTD RD CVD PAD CVRD RVD

CR/nCR R

espo

nse

(%)

Induction Regimen CRD

ORR VGPR


Induction therapyKRD

Jakubowiak Blood 2012

All Pts (N = 66)

Phase II Pts (n = 35)

100 90 80 70 60 50 40 30 20 10 0

CR Near CR

VGPR PR

29

11

27

33

37

20

17

26


Induction therapyKRD

Jakubowiak Blood 2012

Pat

ient

s (%

)

N = 53; Median 12 Cycles (Range 1-25)

Initial Response Best Response 100

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0

M-P

rote

in L

evel

(% o

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elin

e)

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≥ nCR sCR M-protein

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98


Improvement of induction therapyGMMG-HD6

4 x VRD (A1 + A2) 4 x VRD + Elo (A2 + B2)

CAD + stem cell collection

1-2 high dose melphalan + ASCT

Len for2 years

Len+Elo for 2 years

Len for2 years

A1 A2 B1 B22xVRD 2xVRD

+Elo 2xVRD 2xVRD+Elo

Len+Elo for 2 years


Do we still need transplantation?

Palumbo 2014 NEJM

Novel agent versus auto-SCT


Conclusion

• auto-SCT leads to improved PFS and OS

• Lenalidomide maintenance improves PFS

Novel agent versus auto-SCT

Palumbo 2014 NEJMJens Hillengass MD University of Heidelberg, S.D.G

http://www.clinicaltrials.gov/ct2/show/NCT01208662?term=nct01208662&rank=1

Early versus late high dose chemotherapy

IFM/DFCI 2009 study Newly diagnosed MM patients (SCT candidates)

VRD x 3

VRD x 2

VRD x 5

Lenalidomide 12 mos

Melphalan 200mg/m2* +

ASCT

Induction

Consolidation

Maintenance

CY (3g/m2) MOBILIZATION Goal: 5 x106 cells/kg

VRD x 3

CY (3g/m2) MOBILIZATION Goal: 5 x106 cells/kg

Randomize, stratification ISS & FISH

Collection

Lenalidomide 12 mos SCT at relapse

MEL 200 mg/m2 if <65 yrs, ≥65 yrs 140mg/m2


How can autologous transplant be improved?

• Induction with novel agents

• improvement of conditioning regimen

• consolidation and maintenance


Harousseau 2007 ASH

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36

Placebo Revlimid

IFM 2005-02 : PFS from randomization

Placebo

Revlimid

Consolidation and maintenance


Neben 2011 Blood

Consolidation and maintenance


Summary: Young patient (< 65/70 years)

• Autologous stem cell transplantation: standard of care

• Survival advantage is depending on achievement of a CR (VGPR)

• TBI (12Gy) or busulfan should not be used anymore

• Consider Double ASCT for patients, if no CR or nearCR after first SCT

PD Dr. Jens Hillengass Universitätsklinik Heidelberg, S.D.G

The elderly patient (≥ 65/70 years)


Prospective study with 447 patients between 65 and 75 years=> Novel agent combination (MPT) better than MP and Mel100

Novel Agents versus ASCT

Facon 2007 LancetJens Hillengass MD University of Heidelberg, S.D.G

VISTA trial-update

San Miguel 2013 JCOJens Hillengass MD University of Heidelberg, S.D.G

VMP = Bortezomib (Velcade) + Melphalan + Prednison

FIRST trial

Benboubker 2014 NEJMJens Hillengass MD University of Heidelberg, S.D.G

Rd = Lenalidomid (Revlimid) + Dexamethason

Comparison FirstlineMM-‐015 VISTA VISTA FIRST IFM99-‐06

Palumbo 2012 NEJMPalumbo 2012 NEJMPalumbo 2012 NEJM San Miguel 2008 NEJM

San Miguel 2008 NEJM

San Miguel 2013 JCOSan Miguel 2013 JCO Benboubker 2014 NEJMBenboubker 2014 NEJMBenboubker 2014 NEJM Facon 2007 LancetFacon 2007 LancetFacon 2007 LancetSubstanzen MP MPR MPR-‐R MP VMP MP VMP Rd 18 Rd kont MPT MP MPT Mel100

Therapiedauer 9 9 kont 13 13 13 13 18 kont 18 18 18 5Follow-‐up 30 16,3 60 ,1 37 51,5

Medianes Alter 72 71 71 71 71 71 71 73 73 73Alter >/=65 >/=65 >/=65 >/=40 >/=65

Patienten 154 153 152 338 344 211 176 541 535 547 196 125 126PFS (median) 13 14 31 16,6 24 20,7 25,5 21,2 17,8 27,5 19,43-‐year OS (%) 66 62 70 68 68 66 70 625-‐year OS (%) 34,4 46OS (median) NR NR 45,2 NR NR 56,4 43,1 33,2 51,6 38,3

ORR 50 68 77 35 71 73 75 62 35 76 65Grad 4 Neutropenie 8 32 35 15 10 26 (3+4) 28 (3+4) 45 (3+4)Grad 4 febrile Neutropenie

0 1 2Grad 3 PNP 0 13Grad 4 PNP 0 1 1 (3+4) 1 (3+4) 9 (3+4) 0 6 (any) 0

Grad 3 Infektionen 7 13 9 4 Pneumoni

e

5 Pneumoni

e

9 (any) 13 (any) 49 (any)Grad 4 Infektionen 0 2 1 1

Pneumoni2

PneumoniJens Hillengass MD University of Heidelberg, S.D.G

Comparison FirstlineVISTA FIRST

San Miguel 2008 NEJM Benboubker 2014 NEJM

Substanzen VMP Rd kont

Therapiedauer 13 kont

PFS (median) 24 25,5

3-‐year OS (%) 68 70

OS (median) NR

ORR 71 75

Grad 4 Neutropenie 10 28 (3+4)

Grad 3 PNP 13

Grad 4 PNP 1 1 (3+4)

Grad 3 Infektionen 5 Pneumonie


Outcome in terms of PFS and OS on ITT analysis (n=233)

Median follow-up: 30 m (9-43)

OS

Sequential : 73% at 3 yrs

Alternating: 71% at 3 yrs

PFS

Sequential: 32m

Alternating: 34 m

p=NS

45 40 35 30 25 20 15 10 5 0

1,0

0,8

0,6

0,4

0,2

0,0

45 40 35 30 25 20 15 10 5 0

1,0

0,8

0,6

0,4

0,2

0,0

p=NS

VISTA: 21m FIRST: 25m (cont Rd); 21m (Rd18)

VISTA: 68% at 3 yrs FIRST: 59% at 4yrs (cont Rd); 56% at 4yrs (Rd18)

Mateos et al. ASH 2014 (Abstract 178); oral presentation


Comparison FirstlineVISTA FIRST Alternating

San Miguel 2008 NEJM Benboubker 2014 NEJM Mateos 2014 ASHMateos 2014 ASH

Substanzen VMP Rd kont Sequential Alternating

Therapiedauer 13 kont 18 18

PFS (median) 24 25,5 32 34

3-‐year OS (%) 68 70 73 71

OS (median) NR

ORR 71 75 77 80

Grad 4 Neutropenie 10 28 (3+4)

Grad 3 PNP 13

Grad 4 PNP 1 1 (3+4) 4 (3+4) 3 (3+4)

Grad 3 Infektionen 5 Pneumonie 6 (3+4) 6 (3+4)


ASCT in elderly patients

Merz 2013 Ann OncolJens Hillengass MD University of Heidelberg, S.D.G

The elderly patient (≥ 65/70 Jahre)


• Melphalan + prednisone + novel agent or lenalidomide + dexamethason for the majority of patients

- rarely MPT: improving PFS but not OS

- effectivity of VMP proven in VISTA trial1,2

- effectivity of Rd proven in FIRST trial3

• Bortezomib/ Thalidomid / Prednison (VTP) equivalent to VMP for elderly patients with myelosuppression4

- toxicity mainly cardio-tox (Thalidomid)1 San Miguel 2008 N Engl J Med

2 Mateos 2010 J Clin Oncol3 Benboubker 2014 NEJM

4 Mateos 2010 Lancet Oncol

What to do when the disease comes back?


re-exposition


NCCN

Re-exposition if relapse > 6 months after completion of initial therapy

IMWG

Re-exposition after „sustained“ remissionchange after „short“ remission

EMN

Re-exposition if relapse > 12 months after completion of initial therapyChange after „short“ remission

NCCN Clinical Practice Guidelines in Oncology Myeloma V. 2012,Palumbo 2009 Leukemia,

Ludwig 2012 The Oncologist,Rajkumar 2011 Blood

Jens Hillengass MD University of Heidelberg, S.D.Gadapted from Lonial 2011 CCR

Novel Agents at relapse

Jens Hillengass MD University of Heidelberg, S.D.Gadapted from Lonial 2011 CCR

Novel Agents at relapse

Sellner Cancer 2013

Retrospective analysis of 200 patients

=> Overall survival depending on remission after first auto-SCT

Auto-SCT at relapse


ReLApsE-trial of the GMMG


Summary


-NCCN: Re-exposition after at least 6 months

-European opinion: after at least 12 months

-Re-exposition with Bortezomib: effective (but retrospective and no prospective trials)

-Re-exposition with IMiDs: effective (but mainly studies with Len after Thal)

NCCN Clinical Practice Guidelines in Oncology Myeloma V. 2012, Mothy 2012 Leukemia, Petrucci 2010 Haematologica, Hrusovsky

2010 Oncology


future options

Targets for treatment

Jens Hillengass MD University of Heidelberg, S.D.G Ocio Leukemia 2014


Proteasome inhibitorsBortezomib/ Carfilzomib/ Ixazomib

Kumar Lancet oncol 2014Stewart NEJM 2014

Ixazomib+Rd - Ixazomib maintenance Carfilzomib+Rd versus Rd


AntibodiesElotuzumab/ Daratumumab/ SAR650984

Jagannath Myeloma.orgJagannath Myeloma.org


AntibodiesElotuzumab/ Daratumumab

Lokhorst NEJM 2015Lonial NEJM 2015

Elotuzumab+RdDaratumumab dose escalation


Histone deacetylase inhibitorsPanobinostat

San Miguel Lancet oncol 2015

Panobinostat + Vel/Dex


Current research focus


Assessment of minimal residual disease

ASO-PCR Flowcytometry Next-Generation Sequencing

Applicability 60-70% nearly 100% 90 %

Requirements for the sample

<1 Million cells Currently > 1 Million cells

< 1 Million cells

Processing of the sample

can be delayed within 48-72 hours can be delayed

Sensitivity ≧ 1 : 10-5 approx. 1 : 10-5 ≧ 1 : 10-6

adapted from Kumar


Thank you very much for your attention

Documents

New treatment options and international research€¦ · IMWG 2003 Br. J. Haematol. Smoldering Multiple Myeloma Jens Hillengass MD University of Heidelberg, S.D.G . Treatment of smoldering