New treatment options and international research Jens Hillengass MD Section Multiple Myelom Department of Hematology and Oncology University of Heidelberg and Department E010 Radiology German Cancer Research Center
Indication for treatment
Jens Hillengass MD University of Heidelberg, S.D.G
Stages of monoclonal plasma cell disease Monoclonal Gammopathy Monoclonal Gammopathy of of undetermined undetermined Significance Significance (MGUS) (MGUS)
clonal plasma cells in bone marrow monoclonal protein End organ damage Jens Hillengass MD University of Heidelberg, S.D.G
smoldering Early myeloma Myeloma
Multiple Myeloma
10%
>10%
30g/l
>30g/l
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)
Jens Hillengass MD University of Heidelberg, S.D.G
Rajkumar 2014 Lancet oncol
IMWG Criteria (2003) MGUS
M-Protein < 30 g/l; clonal plasma cells < 10%; no „ROTI“*
smoldering MM
M-Protein ≥ 30 g/l and/ or clonal plasma cell ≥ 10%; no „ROTI“*
symptomatic MM M-protein in serume and/ or urine; clonal plasma cells or plasmacytoma and ROTI* including bone lesions ROTI
*ROTI = myeloma Related Organ or Tissue Impairment Calcium level > 2.75 mmol/l Renal 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) Others: symptomatic hyperviscosity; amyloidosis; recurrent bacterial infections (> 2 episodes in 12 months
Jens Hillengass MD University of Heidelberg, S.D.G
IMWG 2003 Br. J. Haematol.
Smoldering Multiple Myeloma
Jens Hillengass MD University of Heidelberg, S.D.G
Treatment of smoldering Multiple Myeloma
Jens Hillengass MD University of Heidelberg, S.D.G
Dispenzieri 2013 Blood
The
n e w e ng l a n d j o u r na l
Smoldering Multiple Myeloma 100
&$ " (+$ &$ & '' $#
Smoldering Multiple Myeloma
80 73
78
66
60 51 40
MGUS
20 10
4 0
0
16
5
10
15
21
20
25
&'' # #$' '
Figure 2. Probability of Progression to Active Multiple Myeloma or Primary
Jens Hillengass MD University of Heidelberg, S.D.G
of
m
of persons w who would b the risk of a 50 (Table 1 stage II dise tiple myelom stage III ha eloma (med and 15.1 mo sion of smo progression death owing vascular an plasma-cell 10 years, 30% overall rate
Kyle 2007 NEJM
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 N = 65 FL > 1 high risk N = 9 (14%)
Jens Hillengass MD University of Heidelberg, S.D.G
N = 149 FL > 1 high risk N = 23 (15%)
Kastritis 2014 Leukemia, Hillengass 2010 JCO
New definition of multiple Myeloma N = 273 sFLC ratio abnormal high risk = n.d.
Jens Hillengass MD University of Heidelberg, S.D.G
N = 586 FLC ≧ 100 high risk = 90 (15%)
Dispenzieri 2008 Blood, Larsen 2013 Leukemia
New definition of multiple Myeloma N = 126 BMPC ≧ 60% high risk N = 21 (17%)
N = 121 BMPC ≧ 60 high risk N = 6 (5%)
high risk intermediate risk low risk
Jens Hillengass MD University of Heidelberg, S.D.G
Rajkumar 2011 NEJM, Waxman 2014 ASCO
New Definition of Multiple Myeloma • 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 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 1 focal lesions on magnetic resonance imaging studies Jens Hillengass MD University of Heidelberg, S.D.G
SLIM-CRAB
Rajkumar 2014 Lancet oncol
Treatment of smoldering Multiple Myeloma
Jens Hillengass MD University of Heidelberg, S.D.G
Mateos 2013 NEJM
History of myeloma treatment 2004 Lenalidomide 1980s High dose melphalan + KMT
1962 Melphalan
1970
1980
1968 Melphalan + Prednisone
1990s Single ASCT
1990
1984 VAD
1984 Supportive therapy
2000s Tandem ASCT
2000
2014 Pomalidomide
2010
1999 Thalidomide
2002 Bortezomib
Jens Hillengass MD University of Heidelberg, S.D.G
2015 Panobinostat
2014 Carfilzomib
Ixazomib Elotuzumab Daratumumab SAR650984 ...
How to treat in the future
Jens Hillengass MD University of Heidelberg, S.D.G
initial treatment paths
Jens Hillengass MD University of Heidelberg, S.D.G
Treatment paths
Patients with Multiple Myeloma
transplantation-eligible • up to 70 years (?) • normal organ function • stem cells collected • patient choice
Jens Hillengass MD University of Heidelberg, S.D.G
not transplant-eligible • >70 years • comorbidities • no stem cells • patient choice
Treatment paths Transplantation 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
Jens Hillengass MD University of Heidelberg, S.D.G
maintenance therapy
What to do first?
Jens Hillengass MD University of Heidelberg, S.D.G
„Classical“ chemotherapy (Vincristin) Vinca-Alkaloid Spindelgift Mikrotubulusdestabilisation
Antibioticum Interkalator: DNA-Strangbrüche Topoisomerase-II-Inhibitor Alkylans DNA-Strangbrüche
Doxorubicin
Jens Hillengass MD University of Heidelberg, S.D.G
Cyclophosphamid Melphalan Bendamustin
Benefit of novel agents
Jens Hillengass MD University of Heidelberg, S.D.G
Kumar Blood 2008, Kumar Leukemia 2014
Immunomodulatory drugs Thalidomide/ Lenalidomide/ Pomalidomide
Jens Hillengass MD University of Heidelberg, S.D.G
Proteasome inhibitors Bortezomib/ Carfilzomib/ Ixazomib
Jens Hillengass MD University of Heidelberg, S.D.G
Improvement of induction therapy GMMG-MM5 3 x PAd (A1 + B1)
3 x VCD (A2 + B2)
CAD + stem cell collection 1-2 high dose melphalan + ASCT 2x Lenalidomide consolidation
A1
B1 Len for 2 years
Jens Hillengass MD University of Heidelberg, S.D.G
A2 Len if no CR
B2 Len for 2 years
Len if no CR
Improvement of induction therapy GMMG-MM5 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%
/=65
Patienten
154
153
152
338
344
PFS (median)
13
14
31
16,6
24
3-‐year OS (%)
66
62
70
13
13
16,3 71
71
71
FIRST
San Miguel 2013 JCO
>/=65
Rd 18
Rd kont
MPT
MP
MPT
Mel100
13
13
18
kont
18
18
18
5
71
37 71
211
68
73
51,5 73
73
>/=40 176 68
34,4
46
56,4
43,1
>/=65
541
535
547
196
125
126
20,7
25,5
21,2
17,8
27,5
19,4
66
70
62 33,2
51,6
38,3
35
76
65
0
6 (any)
0
9 (any)
13 (any)
49 (any)
OS (median)
NR
NR
45,2
NR
NR
ORR
50
68
77
35
71
73
75
62
Grad 4 Neutropenie
8
32
35
15
10
26 (3+4)
28 (3+4)
45 (3+4)
Grad 4 febrile Neutropenie Grad 3 PNP
0
1
2 0
13
0
1
1 (3+4)
1 (3+4)
9 (3+4)
Grad 4 PNP Grad 3 Infektionen
7
13
9
Grad 4 Infektionen
0
2
1
Jens Hillengass MD University of Heidelberg, S.D.G
4 5 Pneumoni Pneumoni 1 2 e e Pneumoni Pneumoni
Facon 2007 Lancet
VMP
>/=65
5-‐year OS (%)
Benboubker 2014 NEJM
MP 60 ,1
71
IFM99-‐06
Comparison Firstline VISTA
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
Grad 3 Infektionen
5 Pneumonie
Jens Hillengass MD University of Heidelberg, S.D.G
1 (3+4)
Outcome in terms of PFS and OS on ITT analysis (n=233) Median follow-up: 30 m (9-43)
PFS
1,0
OS
1,0
Alternating: 71% at 3 yrs 0,8
Alternating: 34 m
0,6
0,8
Sequential : 73% at 3 yrs
0,6
Sequential: 32m 0,4
0,4
0,2
0,2
p=NS
0,0 0
5
10
15
20
25
30
35
VISTA: 21m FIRST: 25m (cont Rd); 21m (Rd18)
40
45
p=NS
0,0 0
5
10
15
20
25
30
35
40
45
VISTA: 68% at 3 yrs FIRST: 59% at 4yrs (cont Rd); 56% at 4yrs (Rd18) Mateos et al. ASH 2014 (Abstract 178); oral presentation
Jens Hillengass MD University of Heidelberg, S.D.G
Comparison Firstline VISTA
FIRST
San Miguel 2008 NEJM
Benboubker 2014 NEJM
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
4 (3+4)
3 (3+4)
Grad 3 Infektionen
5 Pneumonie
6 (3+4)
6 (3+4)
Jens Hillengass MD University of Heidelberg, S.D.G
1 (3+4)
Alternating Mateos 2014 ASH
ASCT in elderly patients
Jens Hillengass MD University of Heidelberg, S.D.G
Merz 2013 Ann Oncol
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 1,2 - effectivity of VMP proven in VISTA trial 3 - effectivity of Rd proven in FIRST trial • Bortezomib/ Thalidomid / Prednison (VTP) equivalent to VMP for elderly patients with
4 myelosuppression
- toxicity mainly cardio-tox (Thalidomid)
Jens Hillengass MD University of Heidelberg, S.D.G
1 San Miguel 2008 N Engl J Med 2 Mateos 2010 J Clin Oncol 3 Benboubker 2014 NEJM 4 Mateos 2010 Lancet Oncol
What to do when the disease comes back?
PD Dr. Jens Hillengass Universitätsklinik Heidelberg, S.D.G
re-exposition NCCN Re-exposition if relapse > 6 months after completion of initial therapy IMWG Re-exposition after „sustained“ remission change after „short“ remission EMN Re-exposition if relapse > 12 months after completion of initial therapy Change after „short“ remission
Jens Hillengass MD University of Heidelberg, S.D.G
NCCN Clinical Practice Guidelines in Oncology Myeloma V. 2012, Palumbo 2009 Leukemia, Ludwig 2012 The Oncologist, Rajkumar 2011 Blood
Novel Agents at relapse
Jens Hillengass MD University of Heidelberg, S.D.G
adapted from Lonial 2011 CCR
Novel Agents at relapse
Jens Hillengass MD University of Heidelberg, S.D.G
adapted from Lonial 2011 CCR
Auto-SCT at relapse Retrospective analysis of 200 patients => Overall survival depending on remission after first auto-SCT
Jens Hillengass MD University of Heidelberg, S.D.G
Sellner Cancer 2013
ReLApsE-trial of the GMMG
Jens Hillengass MD University of Heidelberg, S.D.G
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)
Jens Hillengass MD University of Heidelberg, S.D.G
NCCN Clinical Practice Guidelines in Oncology Myeloma V. 2012, Mothy 2012 Leukemia, Petrucci 2010 Haematologica, Hrusovsky 2010 Oncology
future options
Jens Hillengass MD University of Heidelberg, S.D.G
Targets for treatment
Jens Hillengass MD University of Heidelberg, S.D.G
Ocio Leukemia 2014
Proteasome inhibitors Bortezomib/ Carfilzomib/ Ixazomib Ixazomib+Rd - Ixazomib maintenance
Jens Hillengass MD University of Heidelberg, S.D.G
Carfilzomib+Rd versus Rd
Kumar Lancet oncol 2014 Stewart NEJM 2014
Antibodies Elotuzumab/ Daratumumab/ SAR650984
Jens Hillengass MD University of Heidelberg, S.D.G
Jagannath Myeloma.org
Antibodies Elotuzumab/ Daratumumab Daratumumab dose escalation
Jens Hillengass MD University of Heidelberg, S.D.G
Elotuzumab+Rd
Lokhorst NEJM 2015 Lonial NEJM 2015
Histone deacetylase inhibitors Panobinostat Panobinostat + Vel/Dex
Jens Hillengass MD University of Heidelberg, S.D.G
San Miguel Lancet oncol 2015
Current research focus
Jens Hillengass MD University of Heidelberg, S.D.G
Assessment of minimal residual disease ASO-PCR
Flowcytometry
Next-Generation Sequencing
Applicability
60-70%
nearly 100%
90 %
Requirements for the sample
1 Million < 1 Million cells 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
Jens Hillengass MD University of Heidelberg, S.D.G
adapted from Kumar
Thank you very much for your attention
Jens Hillengass MD University of Heidelberg, S.D.G
