1

MyelomaCloser to a Cure than Ever

Before

Jeffrey Wolf, MDMyeloma Program

University of California, San Francisco

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Prop

ortio

n Su

rviv

ing

0 2 4 6 8 10 12 14 16 18 20Follow up from diagnosis (years)

Kumar S. Blood 2008;111: 2516 – 2520; Kumar S. Leukemia (2014) 28, 1122–1128.

Survival in Myeloma

2011-14

1961-70

2001-10

1991-2000

2

Changes in Diagnosis

Free Light Chain Ratio

Percentage Plasma Cells on Diagnostic Marrow

Use of Modern Imaging

Kyle R et al. N Engl J Med 2007;356:2582-2590

Characteristics of Active Multiple Myeloma and Its Precursors

3

Myeloman MM is characterized by:

n Excessive numbers of abnormal plasma cells in the bone marrow

u Overproduction of intact monoclonal immunoglobulins (IgG, IgA, IgD) or free antibody light chains

u concomitant drop in other immunoglobulins

u CRAB CriteriauHyperCalcemiauRenaluAnemiauBone Lesions Kufe. Cancer Medicine. 6th ed. 2003:2219.

Reproduced with permission from the Multiple Myeloma Research Foundation Web site. Available at: http://www.multiplemyeloma.org/about_myeloma/index.html

100

80

60

40

20

0

51% will convert in first 5 yrs~ 10% per yr

0 5 10 15 20 25

Prob

abili

ty o

f Pro

gres

sion

(%)

51

6673 78

4 1016

21

MGUSSmoldering MM

Smoldering Multiple Myeloma

Kyle RA, et al. N Engl J Med. 2007;356:2582-2590. Greipp PR, et al. J Clin Oncol. 2005;23:3412-3420.Yrs Since Diagnosis

27% more will convert in remaining 15 yrs~ 2% per yr

Mimics MGUS

4

HR: 13.7; P < .001

Biomarkers to Predict Risk of Progression

n FLC ratio ≥ 100 predicts risk (P < .0001)

n Clonal plasma cells in BM predicts risk (P < .001)

Larsen JT, et al. Leukemia. 2013;27:941-946. Kastritis E, et al. Leukemia. 2013;27:947-953.

FLC ratio ≥ 100FLC ratio < 100Median TTP:

15 mos Median TTP:55 mos

1.0

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0.6

0.4

0.2

00 20 40 60 80 100 120

Mos to Progression

BM plasma cells < 60%

BM plasma cells ≥ 60%

% Pr

ogre

ssio

n to

Sy

mpt

omat

ic M

yelo

ma

% Pr

ogre

ssio

n to

MM

Mos to Progression720 6 12 18 24 30 36 42 48 54 60 66

1.0

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0

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% to 60%

§ No myeloma defining events

Multiple Myeloma

§ Underlying plasma cell proliferative disorder

§ AND 1 or more myeloma defining events

§ ≥ 1 CRAB* feature§ Clonal plasma cells in

BM ≥ 60%§ Serum free light

chain ratio ≥ 100§ > 1 MRI focal lesion

5

Why are we Failing to Achieve Long Term Survival In 25% of

Patients?

Clonal Competition with Alternating Dominance

in Multiple Myeloma

6

Clonal Competition with Alternating Dominance in Multiple MyelomaBased on iFISH and Array Comparative Genomic Hybridization (aCGH) at 7 time points

Keats, et.al.Blood, 2012

Pt with t(4;14)

New Staging

Revised International Staging SystemR-ISS

7

R-ISSn Stage I

uB2M < 3.5 mg/LuAlbumin > 3.5 gm/dL

n Stage IIuNot Stages I or II

n Stage IIIuB2M > 5.5 mg/LuLDH > ULNuAbnormal iFISH (del (17p), t(4;14), t(14;16))

(A) Overall survival (OS) in patients with multiple myeloma stratified by revised International Staging System (R-ISS) algorithm.

Antonio Palumbo et al. JCO, 2015

Revised ISS

8

Evidence that Depth of Response Matters

CR and MRD

The Iceberg

9

CR vs nCR / VGPR / PR vs Less

Martinez-Lopez J, et al. Blood. 2011;118:529-534.

PFSP = 0.00001

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0.50.4

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0.00 05 510 1015 1520 years 20 years

CR (n=63) nCR (n = 66) + VGPR (n = 54) + PR (n = 114) SD (n = 12) + PD (n = 14)

Prognostic effect of CR patients vs those in nCR or VGPR or PR vs patients with SD or PD after HDT/ASCT

OSP = 0.00001

1.0

Minimal Residual Disease (MRD)

Standard Flow – 10-4

EuroFlow (8 color) – 10-5

Next Generation Sequencing – 10-6

10

Spanish Retrospective Look at MRD and Survival

Time to progression for patients achieving conventional complete remission (CR), according to minimal residual disease

(MRD) status as determined by deep sequencing (NGS).

Martinez-Lopez J et al. Blood 2014;123:3073-3079

11

Further Evidence that MRD Matters

IFM/DFCI 2009

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Frontline Therapy for Patients Eligible (or Ineligible) for

Transplant

Discovery of Active Drugs in Multiple Myeloma

§ Melphalan§ Cytoxan§ Prednisone§ Dexamethasone§ Doxorubicin

§ Oprozomib§ Marizomib

§ Isatuximab

§ Venetoclax

§ Selinexor

§ CAR-T§ BiTES§ ADCs

§ Carfilzomib§ Pomalidomide§ Panobinostat

§ Daratumumab§ Ixazomib§ Elotuzumab

Old Drugs(1960s)

Recently ApprovedDrugs (2013-2015)

Future Drugs

§ Bortezomib§ Thalidomide§ Lenalidomide§ Liposomal

doxorubicin

Approved Drugs(2003-2007)

13

Improving Response Rates with Combination Therapies for Induction

Role of Autologous Transplant

IFM/DFCI 2009

14

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IFM/DFCI Study Schema

12 months lenalidomide maintenance

5 cycles RVD

N=700(289assessedbyNGS

duetosampleavailability)

Melphalan + ASCT + 2

cycles RVD

BMMRD BMMRD

3 Cycles RVD

BMID

*comparisons to flow at all MRD time points

Ran

dom

izat

ion

IFM/DFCI2009

P<0.001

0

10

20

30

40

50

60

70

80

90

100

Patie

nts (

%)

350 296 228 128 24no HDT350 309 261 153 27HDT

N at risk

0 12 24 36 48

Months of follow-up

HDTno HDT

Transplant improved PFS

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Impact of Treatment Arm on MRD and PFS

IFM/DFCI 2009MRD Impact on OS

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Further Evidence for Role of Auto ASCT

KRd (? Improvement over RVd?)Jakubowiak, 2015

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KRd + ASCTZimmerman, 2016

Role of Maintenance (Continuation) Therapy

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Myeloma XI – Role of Lenalidomide Maintenance

Maintenance Meta-Analysis

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Treatment of Relapse

PFS in Recent Relapsed Phase 3 trials

17.5

HR, hazard ratio; NR, not reached; PFS, progression-free survival.1. Stewart AK, et al. N Engl J Med 2015;372:142–52; 2. Moreau P, et al. N Engl J Med 2016;374:1621–34; 3. Lonial S, et al. N Engl J Med 2015;373:621–31; 4. Bahlis NJ, et

al. ASCO 2017, abstract #8025; 5. Dimopoulos ME, et al. Lancet Oncol 2016;17:27–38; 6. Lentzsch S, et al. J Clin Oncol 2017;35:Suppl (abstr 8036).

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19.4

14.7

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ASPIRE1

TOURMALINE-MM12ELOQUENT-23 POLLUX4

KRd(n=396)

Rd(n=396)

Rd+I(n=360)

Rd(n=362)

Rd(n=325)

Rd+E(n=321)

Rd(n=283)

Rd+D(n=286)

PFS

(mon

ths)

HR=0.69;p=0.0001

HR=0.70; p<0.001

HR=0.74; p=0.01

HR=0.37; p<0.001

NR 9.418.7

ENDEAVOR5

Kd(n=464)

Vd(n=465)

HR=0.53; p<0.0001

7.1

CASTOR6

Vd(n=247)

DVd(n=251)

HR=0.39; p<0.001

NR

20

Castor: Vd vs Dara Vd

Pollux: Rd vs Dara Rd

21

New and Variations on Old Therapies

Venetoclax90 Minute Daratumumab (Sub Q Coming)

Once Weekly Carfilzomib

Efficacy of Venetoclax as Targeted Therapy for Relapsed/Refractory

t(11;14) Multiple Myeloma

Shaji Kumar, Jonathan L. Kaufman, Cristina Gasparetto, Joseph Mikhael, Ravi Vij, Brigitte Pegourie, Lofti Benboubker, Thierry Facon, Martine Amiot, Philippe Moreau, Elizabeth A. Punnoose, Stefanie Alzate, Martin Dunbar, Tu Xu, Suresh K. Agarwal, Sari Heitner Enschede, Joel D. Leverson, Jeremy A. Ross, Paulo C. Maciag, Maria Verdugo and Cyrille Touzeau

Blood 2017 :blood-2017-06-788786; doi: https://doi.org/10.1182/blood-2017-06-788786

22

Venetoclax in t(11;14) Mutated iFISH

Venetoclax (ABT-1999 / GDC-0199) Combined with Rituximab Induces Deep Responses in Relapsed / Refractory CLL 43

Venetoclax Combined With Bortezomib and Dexamethasone for Patients With

Relapsed/Refractory Multiple Myeloma

Philippe Moreau,1 Asher Chanan-Khan,2 Andrew W. Roberts,3 Amit B. Agarwal,4 Thierry Facon,5 Shaji Kumar,6 Cyrille Touzeau,1 Jaclyn Cordero,7 Jeremy Ross,7 Wijith Munasinghe,7 Jia Jia,7 Ahmed H. Salem,7 Joel Leverson,7 Paulo Maciag,7 Maria Verdugo,7 Simon J. Harrison8

American Society of Hematology – 58th Annual Meeting ● San Diego, California, USA ● December 4, 2016

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0

2 0

4 0

6 0

8 0

1 0 0

Pe

rce

nta

ge

of

Pa

tie

nts

sCR CR VGPR PR

A l lP a t ie n t s

N = 6 6

P r io r T h e r a p ie s 1 - 3 > 3

n = 3 7 n = 2 9

O R R 6 7 %

24%

23%

15%

5 %

O R R 8 9 %

24%

32%

24%

9%

O R R 3 8 %

24%

10%

B o r t e z o m i bN o n - r e f r a c to r y R e f r a c t o r y S e n s i t i v e N a iv e n = 3 9 n = 2 6 n = 2 7 n = 1 2

O R R 9 0 %

26%

36%

20%

8%

O R R 3 1 %

23%

4 %

O R R 8 9 %

33%

30%

19%

7%

O R R 9 2 %

8%

50%

25%

9%

4 %4 %

ORR=PR or better; numbers are based on evaluable patients per subgroups.

Objective Responses

0

2 0

4 0

6 0

8 0

1 0 0

Pe

rce

nta

ge

of

Pa

tie

nts

sCR CR VGPR PR

A l lP a t ie n t s

N = 6 6

P r io r T h e r a p ie s 1 - 3 > 3

n = 3 7 n = 2 9

O R R 6 7 %

24%

23%

15%

5 %

O R R 8 9 %

24%

32%

24%

9%

O R R 3 8 %

24%

10%

B o r t e z o m i bN o n - r e f r a c to r y R e f r a c t o r y S e n s i t i v e N a iv e n = 3 9 n = 2 6 n = 2 7 n = 1 2

O R R 9 0 %

26%

36%

20%

8%

O R R 3 1 %

23%

4 %

O R R 8 9 %

33%

30%

19%

7%

O R R 9 2 %

8%

50%

25%

9%

4 %4 %

B o r te z o m ibN o n -R e f r a c to r y

a n d 1 - 3 P r io rT h e r a p ie s

n = 3 0

O R R 9 7 %

41%

23%

10%

23%

45Data cutoff of 19Aug2016

Dara Carfilzomib Dexamethasone

D-Kd

24

Study Design: D-Kd Arm of MMY1001

Ajai Chari, MD

• Open-label, non-randomized, multicenter, phase 1b study in RRMM patients• Per protocol, DARA was administered as a single first dose (n = 10) or as a split

first dose (n = 75)

D-Kd, daratumumab/carfilzomib/dexamethasone; IMiD, immunomodulatory drug; ECOG, Eastern Cooperative Oncology Group; LVEF, left ventricular ejection fraction; ANC, absolute neutrophil count; IV, intravenous; QW, every week; Q2W, every 2 weeks; Q4W, every 4 weeks; PD, progressive disease; PO, oral; OS, overall survival; NGS, next-generation sequencing; IFE, immunofixation; CR, complete response; VGPR, very good partial response.

Eligibility/treatment

• Relapsed MM– 1-3 prior lines of

therapy, including bortezomib and an IMiD

– Len-refractory patients allowed

• Carfilzomib-naïve• ECOG status ≤2

• LVEF ≥40%

• ANC ≥1 × 109/L• Platelet count ≥75 ×

109/L

Dosing schedule (28-day cycles)

DARA: • Split first dosea: 8 mg/kg Days 1-2 of Cycle 1• Single first dose: 16 mg/kg on C1D1• 16 mg/kg IV QW on Cycles 1-2, Q2W on Cycles

3-6, and Q4W thereafter until PDCarfilzomibb: • 20 mg/m2 IV Cycle 1 Day 1• Escalated to 70 mg/m2 Cycle 1 Day 8+; weekly

(Days 1, 8, 15) until PDDexamethasone: • 40 mg/week (Days 1, 8, 15, 22) IV or PO until

PD

EndpointsPrimary• Safety, tolerabilitySecondary• ORR

• OSExploratory• PFS• MRD (NGS)c

• PK

aIn 500-mL dilution volume.bBoth 20 mg/m2 and 70 mg/m2 were administered as 30-minute IV infusions.cAmong patients evaluated for MRD, MRD was assessed using NGS at time of suspected CR and at 12 and 18 months after initial dose. In cases where DARA is suspected of interfering with IFE and preventing clinical CR response calls, subjects with VGPR may also be evaluated for MRD.

47

Most Common TEAEs (All Treated)

Ajai Chari, MD

Hematologic (>20%)

Percentage of patients

22

21

21

31

25

29

47

67

0 50 100

Lymphopenia

Neutropenia

Anemia

Thrombocytopenia

All

Grade 3/4

• Low neutropenia rates with D-Kd in RRMM• Similar safety profile observed for len-refractory patients

Percentage of patients

TEAE, treatment-emergent adverse event; URTI, upper respiratory tract infection.

Non-hematologic (>20%)

0

1

0

14

2

4

1

2

1

12

1

1

22

22

25

25

31

31

33

34

37

38

39

40

0 10 20 30 40 50

Back pain

Headache

Cough

Hypertens…

Diarrhea

Insomnia

Pyrexia

Dyspnea

Vomiting

Asthenia

URTI

Nausea

All

48

25

13% 10% 17%

44% 50% 37%

16% 10% 20%

11%8%

17%

0

10

20

30

40

50

60

70

80

90

100

All-treated n = 82

Len-refractory n = 48

Len-exposedbut not refractory

n = 30

OR

R, %

PR VGPR

Overall Responsea and Confirmed MRD-negative Rates

Ajai Chari, MD

• Median follow-up: 12.0 months• Optional MRD testing in 11 patients with CR/sCR; 4 were MRD negative at 10-5

Responses are anticipated to deepen over longer follow-up

≥CR27%

≥VGPR71%

ORR = 84%

4/11 pts

1/5 pts

2/4 pts

0

10

20

30

40

50

60

MR

D-n

egat

ive

rate

, %

36%

20%

50%

Len-refractory n = 5

MRD-negative rates (10-5) among

MRD-tested CR/sCR patients

All-treatedn = 11

PR, partial response; sCR, stringent complete response.aIn response-evaluable patients (received at least 1 administration of any component of study treatment and have at least 1 post baseline disease assessment) who were treated more than 2 cycles or discontinued study treatment.

Len-exposed but not

refractoryn = 4

ORR = 90%

≥CR37%

≥VGPR73%

49

≥CR19%

≥VGPR69%

ORR = 79%

Progression-free Survival Across Subgroups

Ajai Chari, MD

Encouraging PFS observed in lenalidomide- and PI/IMiD-refractory patients

• Median follow-up: 12.0 months

00 3 6 9 2412

60

40

20

80

100

% s

urvi

ving

with

out p

rogr

essi

on

Months1815

85513025

72412721

66352719

60322517

13672

2612136

11561

0000

No. at riskAll-treated

Len-refractoryLen-exposed

PI/IMiD-refractory

21

8351

NE, not estimable.50

14.1(95% CI, 12.0-NE)

Len-refractory

Len-exposed but not refractory

NE(95% CI, 9.4-NE)PI/IMiD-refractory

Median PFS, mo

NE

62%

87%

51%

12-month PFS, %

All-treated NE 71%

26

n Ninety-Minute Daratumumab Infusion Is Safe in Multiple Myeloma

n Hallie Barr, et. al. n Blood 2017 130:1889;

BCMA CAR-T Cell Therapy

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Summary of Ongoing BCMA CAR-T Trials for MM

Name Anti-BCMA CAR Bb2121 LCAR-B38M CART-BCMA

Group NCI Bluebird/ Celgene Nanjng/Legend Biotech Novartis/Penn

Binder/co-stimulatory signal

Murine/CD3ζ, CD28

Murine/CD3ζ, 4-1BB

Murine/CD3ζ, 4-1BB

Fully human/CD3ζ,

4-1BB

Transfection γ-retroviral Lentiviral Lentiviral Lentiviral

BCMA expression required? Yes Yes Yes No

• All responding patients evaluated for MRD were MRD negative at 1 or more time points

• 2 nonresponders evaluated for MRD were MRD positive at month 1

BB 2121 PHASE I: TUMOR RESPONSE BY MRD

Response 50 × 106 150 × 106 450 × 106 800 × 106 TotalMRD-evaluableresponders

0 4 11 1 16

MRD-nega 0 4 (100) 11 (100) 1 (100) 16 (100)

Data cutoff: March 29, 2018. a

Of 16 MRD-negative responses: 4 at 10-6, 11 at 10-5, 1 at 10-4 sensitivity by Adaptive next-generation sequencing assay.

28

BB 2121 PHASE I: PROGRESSION-FREE SURVIVAL

PFS at Inactive (50 × 106) and Active (150–800 ×106) Dose Levelsa PFS in MRD-Negative Patientsa

Data cutoff: March 29, 2018. Median and 95% CI from Kaplan-Meier estimate. NE, not estimable. aPFS in dose escalation cohort.

50 × 106

(n=3)150–800 ×106 (n=18)

Events 3 10mPFS (95% CI), mo

2.7 (1.0–2.9)

11.8 (8.8–NE)

150–800 ×106 (n=16)

mPFS (95% CI), mo

17.7 (5.8–NE)

• mPFS of 11.8 months at active doses (≥150 × 106 CAR+ T cells) in 18 subjects in dose escalation phase

• mPFS of 17.7 months in 16 responding subjects who are MRD-negative

mPFS = 11.8 mo

mPFS = 2.7 mo

mPFS = 17.7 mo

BB 2121 Phase I

29

30

Thank You