Initial Therapy
Sagar Lonial, MDChair and Professor
Department of Hematology and Medical OncologyChief Medical Officer, Winship Cancer Institute
Emory University School of Medicine
Topics
When to treat? Smoldering vs SymptomaticChoice of Induction regimenRole of HDTRole of consolidation/maintenance
Criteria for Diagnosis of Myeloma
MGUS < 3 g M spike < 10% plasma cells
AND
SMM 3 g M spike 10% plasma cells
Active MM 10% plasma cells M spike +
AND
No anemia, bone lesions,normal calcium, and
kidney function
MGUS = monoclonal gammopathy of unknown significance; SMM = smoldering multiple myeloma. Kyle et al, 2009.
Anemia, bone lesions,high calcium, or
abnormal kidney function
Kyle R et al. N Engl J Med 2007;356:2582-2590
Not all Smoldering patients are the same
27% will convert in 15 yearsRoughly 2% per year
Free Light is Useful for Risk Assessment in AMM
Dispenzeri et al Blood 2008
Updated IMWG Criteria for Diagnosis of Multiple Myeloma
C: Calcium elevation (> 11 mg/dL or > 1 mg/dL higher than ULN)R: Renal insufficiency (creatinine clearance < 40 mL/min or serum creatinine > 2 mg/dL)A: Anemia (Hb < 10 g/dL or 2 g/dL < normal)B: Bone disease ( 1 lytic lesions on skeletal radiography, CT, or PET-CT)
Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.
MGUS M-protein < 3 g/dL Clonal plasma cells in BM
< 10% No myeloma defining events
Smoldering Myeloma M-protein 3 g/dL (serum)
or 500 mg/24 hrs (urine) Clonal plasma cells in BM
10% - 60% No myeloma defining events
Multiple Myeloma Underlying plasma cell
proliferative disorder AND
1 or more myeloma defining events including either:
1 CRAB feature(s)OR
1 Biomarker Driven
Biomarker driven (1) Sixty-percent (60%) clonal PCs by BM; (2) serum free Light chain ratio involved:uninvolved 100; (3) >1 focal lesion detected by MRI
ECOG/SWOG: Phase III Asymptomatic Myeloma*(PI: SL)Lenalidomide vs. observation
Observation
Lenalidomide CR/PR/Stable
Prog.anytime
Continue therapytill prog. or toxicity
Off Rx
RANDOMIZATION
Control/standard arm
No Dex to isolate the effect of len
Ongoing Investigations
RD + Dara RD+ Pembro/nivo Vaccine + len + Durva KRD auto transplant KRD KRD + Dara auto KRD Len
PETHEMA Cure with old Drugs
Martinez-Lopez et al, Blood 2011
Functional cure?
Survival outcomes in newly diagnosed myeloma patients with RVD induction among all patients
(at a median follow up of 66 months)
Nooka et al, unpublished
Three Drugs Are Better Than Two
0
10
20
30
40
50
60
70
80
90
100
TD RD VD VTD VCD RVD
ORR
VGPR
Nooka et al. Cancer 2013. DOI: 10.1002/cncr.28325
Induction regimens in MM
Progression Free Survival Overall Survival
Impact of IMIDs on OS and PFS with translocations
Barwick et al
CR and VGPR rates in high risk subgroups of patients
P
Randomized Trial VTD vs VCD Shows superiority of IMID/PI
Moreau et al, Blood 2016
VCD is no longer a reasonable induction choice
RVD is better than VCD
Compass trial, IA9
SWOG S0777 Study Design (continued)
VRd
Rd
After induction
Rd Maintenance Until PD, Toxicity or Withdrawal
Lenalidomide 25 mg PO days 1-21
Dexamethasone 40 mg PO days 1, 8,15, 22
All patients received Aspirin 325 mg/day VRd patients received HSV prophylaxis
17
Durie et al, Lancet 2017
Confirmed Response*: VRd versus Rd
*Assessable patients
VRd RdCR 15.7% 8.4%
VGPR 27.8% 23.4%
PR 38% 39.7%
ORR (PR or better) 81.5% 71.5%
SD 15.7% 24.3%
SD or better 97.2% 95.8%
PD or Death 2.8% 4.2%
1818
Durie et al, Lancet 2016
Progression-Free Survival By Assigned Treatment Arm
Log-rank P value = 0.0018 (one sided)*
*Stratified
19
HR = 0.712 (0.560, 0.906)*
19Durie et al, ASH 2015*Assessable patients 1919D i t l ASH 2015
Durie et al, Lancet 2016
Overall Survival By Assigned Treatment Arm
Log-rank P value = 0.0250 (two sided)*
HR = 0.709 (0.516, 0.973)*
20
*Stratified*Assessable patients
2020
Durie et al, Lancet 2016
Where are we?
Risk stratify Smoldering IMID/PI combination is the standard of care Which PI?
KRD for newly diagnosed Myeloma
Frontline Therapy with Carfilzomib, Lenalidomide, and Dexamethasone(KRd) Induction Followed By Autologous Stem Cell Transplantation,
KRd Consolidation and Lenalidomide Maintenance in Newly Diagnosed Multiple Myeloma (NDMM) Patients:
Primary Results of the Intergroupe Francophonedu Mylome (IFM) KRd Phase II Study
NCT02405364
M. Roussel, V. Lauwers-Cances, N. Robillard, K. Belhadj, T. Facon, L. Garderet, M. Escoffre, B. Pegourie, L. Benboubker, D. Caillot, C. Fohrer, P. Moreau, X. Leleu,
H. Avet-Loiseau, and M. Attal for the IFM
STUDY DESIGNOpen-label, multicenter, phase II study in frontline MM pts < 65 yrs
Induction KRd 1-428-day cycles Carfilzomib/Len/Dex
PBSC harvest:Cyclophosphamide high dose
MaintenanceLenalidomide 10mg D1-21
13 cycles (1 year)
IntensificationHD Melphalan 200 mg/m2
Consolidation KRd 5-828-day cycles Carfilzomib/Len/Dex
KRd Induction
Carfilzomib 20-36mg/m2 D1, 2, 8, 9, 15, 16
Lenalidomide 25 mg D1-21Dexamethasone 20 mg1-2, 8-9, 15-16, 22-23
KRd Consolidation
Carfilzomib 36mg/m2 D1,2, 8, 9, 15, 16
Lenalidomide 25 mg D1-21Dexamethasone 20 mg D1, D8, D15, D22
Mandatory LMWH
MRD evaluation for VGPR pts (CMF/NGS)
RESPONSE RATES at the completion of Consolidation
MRD CMF 10-4/10-5MRD NGS clonoSEQ Adaptive 10-6
N=46 n %
sCR 26 57
4 patients were not evaluable due to toxicities
N=46 n %
sCR 26 57
MRD - CMF 32 70
MRD - NGS 23/34 68
N=46 n %
sCR 26 57
MRD - CMF 32 70
MRD - NGS 23/34
At least CR 28 61
At least VGPR 39 85
ORR 41 89
PD 1 2
RESPONSE RATES
Post Induction
Post ASCT Post
Consolidation Best Response
n n n n %
sCR 9 15 26 32 70
CR+sCR 11 19 28 35 76
VGPR 25 18 11 7 15
VGPR or better 36 37 39 42 91
PR 6 3 2
ORR 42 40 41 46 100
PD 1 1 1
CARDIO-VASCULAR + PULMONARY TOXICITIES all grades
25 CARDIAC AND VASCULAR EVENTS Total No of events No of patients (%)
Cardiac Failure 2 2 (4)Pulmonary Embolism 2 2 (4)Venous Thrombosis 2 2 (4)Intra Cardiac Thrombus 1 1 (2)Superfical Thrombosis 8 8 (17)Bradycardia 2 2 (4)Arrhythmia 1 1 (2)Atrial Fibrillation 1 1 (2)Tachycardia 1 1 (2)Hypertension 5 4 (9)
Cough 11 9 (20)Dyspnea 5 5 (11)
IRD Response Rates
Kumar SK, et al. Lancet Oncol. 2014;15(13):15031512
Ixazomib-Lenalidomide-Dexamethasone (IRd) combination before and after ASCT followed by
Ixazomib maintenance in patients with newly diagnosed multiple myeloma:
a phase 2 study from the Intergroupe Francophone du Mylome (IFM)
P Moreau, C Hulin, D Caillot, G Marit, A Perrot, L Garderet, T Facon,L Benboubker, L Karlin, M Tiab, B Arnulf, JP Fermand, X Leleu,
C Touzeau, M Roussel, L Planche, H Caillon, S Minvielle, MC Bn,H Avet-Loiseau, T Dejoie, M Attal
1- Induction: 3 cycles of Ixazomib RD, every 28 days- Ixazomib 4 mg/d; D1, 8, 15- Lenalidomide 25 mg/d ; D1 to 21- Dexamethasone 40 mg/d; D1, 8, 15, 22
2- PBSC harvestMobilization: Cyclophosphamide 3 g/m2 and G-CSF 5 g/kg
3- Peripheral stem cell transplantationMelphalan 200 mg/m2
4- Early consolidation : 2 cycles of Ixazomib/Len/Dex, every 28 days
5- Late consolidation: 6 cycles of Ixazomib/Len (without Dex), every 28 days
6 Maintenance therapy for 1 year (13 cycles) Ixazomib weekly 4 mg D1, 8, 15, every 28 days
Study design
Responses intent-to-treatPost-induction
N = 42Post-ASCT
N = 42
Post-earlyConsoN = 42
Post-lateConsoN = 42
sCR (%)CR (%)VGPR (%)PR (%)Stable (%)PD (%)NE (%)
> PR (%)> VGPR (%)> CR (%)
2.49.523.842.914.34.82.4
8138.111.9
10.88.1
51.424.35.400
94.670.318.9
275.4
43.221.6
02.70
97.375.732.4
314.8
26.214.3
04.819
76.261.935.7
During induction : 2 PD, 1 RashFeasibility ASCT: 37 / 42 (88%)
ASCT: no toxic death, no PDFeasibility: 37 / 42
Early consolidation : no SAE, 1 PDFeasibility: 37 / 42
Late consolidation: 1 SAE (rash), 1 PDFeasibility 34 / 42 (81%)
Maintenance ongoing : 1 thrombocytopenia precluding maintenance, 2 PD
Intent-to-treat / feasibility
AEs leading to exclusion- During induction : 1 rash- Late consolidation: 1 rash- Before maintenance: 1 thrombocytopenia
12 cases of non-hematologic grade 3-4 toxicities were reported:-infections (8 cases),-abdominal pain (2),-atrial fibrillation (1),-thrombosis (1)
No cardiac failure, no ischemic heart disease, no renal impairment
No grade 3-4 peripheral neuropathy
Safety (excluding ASCT, and maintenance)
ELO+ RVD phase II study
Newly Diagnosed
Multiple Myeloma
4 cycles Elo-RVD
ASCT NO
High Risk:Elotuzumab LenalidomideBortezomib Dexamethasone
Low Risk:ElotuzumabLenalidomideDexamethasone
Stem Cell Mobilization
ASCT YES
4 cycles Elo-RVD
Autologous Stem Cell Transplantation
Induction therapy and Transplant Maintenance28-day cycles
Screening
Follow Up Visits
every 3 months
Follow Up
Laubach et al, ASH 2016
Response After 4 Cycles
Laubach et al, ASH 2016
On-study death and treatment discontinuations due to AEs One patient died on study
Hospitalized due to respiratory failure and sepsis during cycle 2 and subsequently died as a result of these AEs
One patient died > 30 days after discontinuing study therapy Patient became acutely ill during cycle 1, hospitalized for febrile neutropenia and
hypotension related to sepsis, then developed renal failure. Participant was removed from study and died more than 30 days later.
Five additional patients discontinued from treatment due to the following AEs: Grade 3 peripheral neuropathy, discontinues treatment after cycle 3 Grade 3 mood disturbance, discontinues treatment after cycle 3 Grade 4 hyperglycemia, discontinues treatment after cycle 2 Grade 3 orthostatic hypotension and demyelinating polyneuropathy, d/cs treatment after
cycle 4 Grade 3 lung infection, discontinues treatment after cycle 2
Laubach et al, ASH 2016
Where are we?
Risk stratify Smoldering IMID/PI combination is the standard of care Which PI?
Bz has the most data, randomized trials in progress Role of HDT?
Registration
RVD 1 Lenalidomide + Bortezomib + Dexamethasone
25mg/d (d1 to 14) 1.3mg/m2 (d 1, 4, 8, 11) 20mg/d (d1,2,4,5,8,9,11,12)
)
Randomization (stratified on ISS and FISH)
Arm A Arm BRVD 2 and 3
PBSC Collection (cyclophosphamide 3g/m2 and G-CSF)
10mcg/kg/d)ASCT
HDM 200mg/m2 RVD 4 to 8
RVD 4 and 5
Lenalidomide Maintenance 12 months (10-15 mg/d)
RVD 2 and 3
PBSC Collection (cyclophosphamide 3g/m2 and G-CSF)
IFM 2009 : Study Design.
Lenalidomide Maintenance 12 months (10-15 mg/d)
IFM 2009: Best Response.
RVD armN=350
Transplant armN=350 p-value
CR 49% 59%
VGPR 29% 29% 0.02
PR 20% 11%
IFM 2009: PFS (9/2015)
P < 0 .0 01
0
10
20
30
40
50
60
70
80
90
10 0
Pa
tie
nts
(%
)
3 5 0 296 2 28 12 8 24no H D T35 0 309 2 61 15 3 27H D T
N a t risk
0 12 24 36 48
M o n th s o f f o l lo w -u p
H D T
no H D T
P N S
0
10
20
30
40
50
60
70
80
90
10 0
Pat
ient
s (%
)
3 5 0 33 8 3 20 24 4 56no H D T35 0 32 8 3 09 22 6 55H D T
N a t risk
0 12 24 36 48
M o n th s o f f o l lo w -u p
H D T
no H D T
IFM 2009: OS (9/2015)
KRD outcomes by Transplant Status
Jakubowiak et al, EHA 2016
Getting to Minimal Residual Disease (MRD): New Definitions for CR
S.S. Patient
11012
Stringent CR
Molecular/Flow CR?Cure?
Disease burden
Newly diagnosed
1108
1104
0.0
AntibodiesMaintenance
Therapy
CR
MRD
P-value (trend) : p
Where are we?
Risk stratify Smoldering IMID/PI combination is the standard of care Which PI
Bz has the most data, randomized trials in progress Role of HDT
Continues to offer benefit in achievement of MRD- Role of consolidation/Maintenance
Up-front single versus double autologous stem cell transplantation
for newly diagnosed multiple myeloma: an intergroup, multicenter, phase III study
of the European Myeloma Network (EMN02/HO95 MM Trial)
Michele Cavo*, Maria Teresa Petrucci, Francesco Di Raimondo, Elena Zamagni, Barbara Gamberi, Claudia Crippa, Giulia Marzocchi, Mariella Grasso, Stelvio
Ballanti, Donatella Iolanda Vincelli, Paola Tacchetti, Massimo Offidani, Giampietro Semenzato, Anna Marina Liberati, Anna Pascarella, Giulia Benevolo,
Rossella Troia, Angelo D. Palmas, Nicola Cantore, Rita Rizzi, Fortunato Morabito, Mario Boccadoro, and Pieter Sonneveld
On behalf of EMN02/HO95 MM Trial participants* Seragnoli Institute of Hematology, Bologna University School of Medicine, Italy
0.00
0.50
1.00
% P
roba
bilit
y
208 171 132 50 9 0HDM1207 185 145 69 19 1HDM2
Number at risk
0 12 24 36 48 60months
HDM2 HDM1
PFS by randomization 1 (HDM-1 vs HDM-2)
HDM-2 HDM-1PFS median, mos NR NRPFS at 3 yrs, % 73.6 62.2
HR (95% CI): 0.70 (0.49-1.01); p = 0.05
Median follow-up: 32 months (IQR 26-41)
PFS by high-risk cytogenetics
0.00
0.50
1.00
% P
roba
bilit
y
43 34 20 7 1 0HDM138 35 28 9 2 1HDM2
Number at risk
0 12 24 36 48 60months
HDM2 HDM1
HDM-2 HDM-1PFS median, mos 46.8 26.5PFS at 3 yrs, % 64.9 41.4
HR (95% CI): 0.49 (0.24-0.99); p = 0.046
EMN02 / HOVON 95 MMA randomized phase III study to compare Bortezomib,
Melphalan, Prednisone (VMP) with High Dose Melphalan followed by Bortezomib, Lenalidomide,
Dexamethasone (VRD) consolidation and Lenalidomide maintenance in patients with newly
diagnosed multiple myeloma
(NTR2528, Eudract 2009-017903-28)
The European Intergroup Trial of the European Myeloma Network EMN
Design of EMN02 trial
4 VCD +Stem cell apheresis
R1
4 VMP HDM 1/2
2 VRD None
Lenalidomide Lenalidomide
HDM/ASCT at 1st relapse
RegistrationInduction
Stem cell mobilization in all pts
Consolidation
Maintenanceuntil relapse
R2 MRD
Early or late ASCT, once or twice
https://clinicaltrials.gov/ct2/show/NCT01208766 [Accessed March 2015]
Sonneveld et al. ASH 2016
EMN02 / HO95 MM 51
no consolidationVRDCox LR P=0.045 (adjusted for 1st random.)
N435450
F137115
no consolidation
VRD
At risk:435450
336371
187196
4952
no consolidation
VRD
0
25
50
75
100
Cum
ulat
ive
perc
enta
ge
months0 12 24 36
Progression free survival
HR = 0.78 (0.61-1.00)
Progression-free survival
Sonneveld et al. ASH 2016
Stadtmauer et al. ASH 2016
Stadtmauer et al. ASH 2016
Stadtmauer et al. ASH 2016
Where are we? Risk stratify Smoldering IMID/PI combination is the standard of care Which PI
Bz has the most data, randomized trials in progress Role of HDT
Continues to offer benefit in achievement of MRD- Role of consolidation
Limited role, tandem transplant does not offer benefit Role of Maintenance
Overall Survival: Median Follow-Up of 80 Months
0.00 10 20 30 40 50 60 70 80 90 100 110 120
0.2
0.4
0.6
0.8
1.0
There is a 26% reduction in risk of death, representing an estimated 2.5-year increase in median survivala
605 578 555 509 474 431 385 282 200 95 20 1 0604 569 542 505 458 425 350 271 174 71 10 0
Overall Survival, mos
Surv
ival
Pro
babi
lity
Patients at risk
7-yr OS
62%
50%N = 1209 LENALIDOMIDE CONTROL
Median OS(95% CI), mos
NE(NE-NE)
86.0(79.8-96.0)
HR (95% CI)P value
0.74 (0.62-0.89).001
a Median for lenalidomide treatment arm was extrapolated to be 116 months based on median of the control arm and HR (median, 86 months; HR = 0.74). HR, hazard ratio; NE, not estimable; OS, overall survival.
0 . 2 5 0 . 5 1 2
5 0 m L / m i n
< 5 0 m L / m i n
N o
Y e s
N o n - L E N
L E N
P R / S D / P D
C R / V G P R
C R
I I I
I o r I I
F e m a l e
M a l e
6 0 y r s
< 6 0 y r s
H R
LENa CONTROLa HR (95% CI)
Age372 375 0.68 (0.54-0.86)233 229 0.83 (0.63-1.10)
Sex322 349 0.65 (0.52-0.83)283 255 0.91 (0.69-1.19)
ISS stage411 440 0.65 (0.52-0.81) 113 90 1.04 (0.72-1.51)
Response after ASCT66 80 0.63 (0.35-1.16)
320 339 0.70 (0.54-0.90)218 210 0.86 (0.65-1.15)
Prior induction therapy147 146 0.48 (0.31-0.75)458 458 0.82 (0.67-1.00)
Adverse-risk cytogeneticsb56 36 1.18 (0.66-2.10)
231 243 0.79 (0.59-1.06)
CrCl after ASCTc33 25 0.73 (0.33-1.60)
379 404 0.74 (0.59-0.92)
Overall Survival: Subgroup Analysis
Favors controlFavors LEN
Suggested Approach for Newly Diagnosed MM
Transplant Eligible
Yes No
RVD
High RIsk Std RIsk
Early Transplant Early vs Delayed Transplant
t(4:14)
Bz Maintenance
Del 17p Other high risk features
RVD Maintenance
Len Maintenance
Std RIsk High RIsk
RVD-liteMPV
t(4:14)
Bz Maintenance
Del 17p Other high risk features
RVD Maintenance
Rd, Vd,
Nooka et al, JOP 2016
Failure to achieve VGPR
Car/Pom/DexMaintenance
Emory OS by Genetics
Nooka et al, Leukemia 2013
N= 256 all patients received RVD
High risk all received 3 drug maintenance
Minimal exposure to alkylators
New directions
IMID/PI is the standard of Care for Newly diagnosed MM, question on optimal PI remains the subject of trials
Transplant continues to have an important role in quest to achieve MRD negativityTandem in US patients not standard
Maintenance is not one size fits all 4 drug induction is on the way
Thanks to:Jonathan KaufmanCharise Gleason Danni CassabourneMelanie Watson Donald HarveyRenee SmithColleen LewisAmelia Langston L.T. Heffner Ebeneezer David Claire TorreS-Y Sun Jing Chen Fadlo Khuri Leon BernalLarry Boise
IMSGolfers Against CancerT.J. Martell Foundation
And Many Others who are part of the B-cell Team
Initial TherapyTopicsCriteria for Diagnosis of MyelomaSlide Number 4Free Light is Useful for Risk Assessment in AMMUpdated IMWG Criteria for Diagnosis of Multiple MyelomaSlide Number 7Ongoing InvestigationsPETHEMA Cure with old DrugsSlide Number 10Three Drugs Are Better Than TwoSlide Number 12Impact of IMIDs on OS and PFS with translocationsSlide Number 14Randomized Trial VTD vs VCD Shows superiority of IMID/PI RVD is better than VCDSlide Number 17Slide Number 18Slide Number 19Slide Number 20Where are we?Slide Number 22Slide Number 23Slide Number 24Slide Number 25Slide Number 26Slide Number 27IRD Response RatesIxazomib-Lenalidomide-Dexamethasone (IRd) combination before and after ASCT followed by Ixazomib maintenance in patients with newly diagnosed multiple myeloma:a phase 2 study from the Intergroupe Francophone du Mylome (IFM)Study designSlide Number 31Intent-to-treat / feasibilitySafety (excluding ASCT, and maintenance)ELO+ RVD phase II studyResponse After 4 CyclesOn-study death and treatment discontinuations due to AEsWhere are we?Slide Number 38Slide Number 39Slide Number 40Slide Number 41Slide Number 42Getting to Minimal Residual Disease (MRD): New Definitions for CRSlide Number 44Where are we?Slide Number 46Slide Number 47Slide Number 48Slide Number 49Design of EMN02 trial Progression-free survivalSlide Number 52Slide Number 53Slide Number 54Where are we?Overall Survival: Median Follow-Up of 80 MonthsOverall Survival: Subgroup AnalysisSlide Number 58Slide Number 59New directionsSlide Number 61Top Related