Initial Therapy Sagar Lonial, MD Chair and Professor Department of - - PowerPoint PPT Presentation

Initial Therapy

Sagar Lonial, MD Chair and Professor Department of Hematology and Medical Oncology Chief Medical Officer, Winship Cancer Institute Emory University School of Medicine

Topics

• When to treat? Smoldering vs Symptomatic
• Choice of Induction regimen
• Role of HDT
• Role 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 years Roughly 2% per year

Free Light is Useful for Risk Assessment in AMM

Dispenzeri et al Blood 2008

Updated IMWG Criteria for Diagnosis

• f 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)
• r ≥ 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 therapy till prog. or toxicity Off Rx

R A N D O M IZ A TI O N

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

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< 0.001 P< 0.001 P= 0.155 P< 0.001

Responses to both VTD and VCD were reassessed centrally

Does it matter which 3 drugs are used?

Cavo et al, Leukemia 2016

Randomized Trial VTD vs VCD Shows superiority

• f 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 Rd CR

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%

18 18

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)*

19

Durie et al, ASH 2015

*Assessable patients

19 19

D 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

20 20

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 Francophone du Myélome (IFM) KRd Phase II Study

• 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 DE Y DESIGN

Open-label, multicenter, phase II study in frontline MM pts < 65 yrs Induction KRd 1-4

28-day cycles Carfilzomib/Len/Dex PBSC harvest: Cyclophosphamide high dose

Maintenance

Lenalidomide 10mg D1-21 13 cycles (1 year)

Intensification

HD Melphalan 200 mg/m2

Consolidation KRd 5-8

28-day cycles Carfilzomib/Len/Dex KRd Induction Carfilzomib 20-36mg/m2 D1, 2, 8, 9, 15, 16 Lenalidomide 25 mg D1-21 Dexamethasone 20 mg1-2, 8-9, 15-16, 22-23 KRd Consolidation Carfilzomib 36mg/m2 D1,2, 8, 9, 15, 16 Lenalidomide 25 mg D1-21 Dexamethasone 20 mg D1, D8, D15, D22 Mandatory LMWH MRD evaluation for ≥VGPR pts (CMF/NGS)

RESPONSE RATES at the completion of Consolidation

MRD CMF 10-4/10-5 MRD 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

CARDI DIO-VASCULAR + + PULMON ONARY Y TOXIC ICIT ITIE IES all

l 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):1503–1512

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 Myélome (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 Béné, 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 harvest Mobilization: Cyclophosphamide 3 g/m2 and G-CSF 5 µg/kg 3- Peripheral stem cell transplantation Melphalan 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-treat

Post-induction N = 42 Post-ASCT N = 42 Post-early Conso N = 42 Post-late Conso N = 42 sCR (%) CR (%) VGPR (%) PR (%) Stable (%) PD (%) NE (%) > PR (%) > VGPR (%) > CR (%) 2.4 9.5 23.8 42.9 14.3 4.8 2.4 81 38.1 11.9 10.8 8.1 51.4 24.3 5.4 94.6 70.3 18.9 27 5.4 43.2 21.6 2.7 97.3 75.7 32.4 31 4.8 26.2 14.3 4.8 19 76.2 61.9 35.7

During induction : 2 PD, 1 Rash Feasibility ASCT: 37 / 42 (88%) ASCT: no toxic death, no PD Feasibility: 37 / 42 Early consolidation : no SAE, 1 PD Feasibility: 37 / 42 Late consolidation: 1 SAE (rash), 1 PD Feasibility 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
• Lenalidomide
• Bortezomib
• Dexamethasone

Low Risk:

• Elotuzumab
• Lenalidomide
• Dexamethasone

Stem Cell Mobilization ASCT YES 4 cycles Elo-RVD Autologous Stem Cell Transplantation

Induction therapy and Transplant

Maintenance

28-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/c’s 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 B RVD 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 arm N=350 Transplant arm N=350 p-value CR 49% 59% VGPR 29% 29% 0.02 PR 20% 11% <PR 2% 1% At least VGPR 78% 88% 0.001 Neg MRD by FCM , n (%) 228 (65%) 280 (80%) 0.001

IFM 2009: PFS (9/2015)

P < 0 .0 01 10 20 30 40 50 60 70 80 90 10 0

P a tie nt s (% )

35 0 296 2 28 12 8 24 no H D T 35 0 309 2 61 15 3 27 H D T N at risk 12 24 36 48

M o n th s of f ollo w -u p

H D T no H D T

P N S 10 20 30 40 50 60 70 80 90 10 0

P a tie nts (% )

35 0 33 8 3 20 24 4 56 no H D T 35 0 32 8 3 09 22 6 55 H D T N a t risk 12 24 36 48

M o n th s of f ollo 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 1×1012 Stringent CR Molecular/Flow CR ?Cure?

Disease burden

Newly diagnosed 1×108 1×104 0.0

Antibodies Maintenance Therapy

CR MRD

P-value (trend) : p<0.0001

<10-6 [10-6;10-5[ [10-5;10-4[ >=10-4

0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Patients without progression (%)

40 40 (0) 40 (0) 40 (0) 33 (6) 23 (9) 15 (6) 4 (4) 2 (1) [10

• 4;10
• 3[

23 23 (0) 23 (0) 23 (0) 22 (1) 19 (3) 14 (2) 3 (5) 2 (0) [10

• 5;10
• 4[

29 29 (0) 29 (0) 29 (0) 28 (0) 22 (5) 16 (3) 4 (4) 1 (1) [10

• 6;10
• 5[

86 86 (0) 86 (0) 86 (0) 86 (0) 77 (5) 61 (3) 36 (5) 10 (0) <10

• 6

N at risk (events)

6 12 18 24 30 36 42 48

Months since randomization

MRD at post-maintenance

Outcomes for patients are the same if they achieved MRD negativity

2/3 of these patients were from HDT, 1/3 from delayed HDT

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

• f 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 % Probability 208 171 132 50 9 HDM1 207 185 145 69 19 1 HDM2 Number at risk 12 24 36 48 60 months HDM2 HDM1

PFS by randomization 1 (HDM-1 vs HDM-2)

HDM-2 HDM-1 PFS median, mos NR NR PFS 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 % Probability 43 34 20 7 1 HDM1 38 35 28 9 2 1 HDM2 Number at risk 12 24 36 48 60 months HDM2 HDM1

HDM-2 HDM-1 PFS median, mos 46.8 26.5 PFS at 3 yrs, % 64.9 41.4 HR (95% CI): 0.49 (0.24-0.99); p = 0.046

EMN02 / HOVON 95 MM

A 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 Registration Induction

Stem cell mobilization in all pts

Consolidation Maintenance until relapse

R2

MRD

Early or late ASCT,

• nce or twice

https://clinicaltrials.gov/ct2/show/NCT01208766 [Accessed March 2015]

Sonneveld et al. ASH 2016

EMN02 / HO95 MM 51

no consolidation VRD Cox LR P=0.045 (adjusted for 1st random.) N 435 450 F 137 115 no consolidation VRD At risk: 435 450 336 371 187 196 49 52

no consolidation VRD 25 50 75 100 Cumulative percentage

months

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

0.0 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 1 604 569 542 505 458 425 350 271 174 71 10 Overall Survival, mos Survival Probability 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) Age 372 375 0.68 (0.54-0.86) 233 229 0.83 (0.63-1.10) Sex 322 349 0.65 (0.52-0.83) 283 255 0.91 (0.69-1.19) ISS stage 411 440 0.65 (0.52-0.81) 113 90 1.04 (0.72-1.51) Response after ASCT 66 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 therapy 147 146 0.48 (0.31-0.75) 458 458 0.82 (0.67-1.00) Adverse-risk cytogeneticsb 56 36 1.18 (0.66-2.10) 231 243 0.79 (0.59-1.06) CrCl after ASCTc 33 25 0.73 (0.33-1.60) 379 404 0.74 (0.59-0.92)

Overall Survival: Subgroup Analysis

Favors control Favors 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-lite MPV 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/Dex Maintenance

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 negativity

• Tandem in US patients not standard
• Maintenance is not one size fits all
• 4 drug induction is on the way

Thanks to:

Jonathan Kaufman Charise Gleason Danni Cassabourne Melanie Watson Donald Harvey Renee Smith Colleen Lewis Amelia Langston L.T. Heffner Ebeneezer David Claire Torre S-Y Sun Jing Chen Fadlo Khuri Leon Bernal Larry Boise IMS

Golfers Against Cancer T.J. Martell Foundation

And Many Others who are part of the B-cell Team