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9/27/2017

1

The Problem of Relapse in Myeloma

PARAMESWARAN HARI

Medical College of Wisconsin

Relapse is the hallmark of multiple myeloma

•Definitions

•Relapse from CR / Biochemical

Progression / Clinical Relapse

•Biological Correlates

•Choosing when to treat

•Risk Stratification of Relapse

Definitions- Relapse

•From CR

•Mainly used for clinical trials

•Reappearance of serum or urine M-protein by immunofixation or electrophoresis or

abnormal FLC ratio

•Development of ≥5% plasma cells in BM

•Any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or

hypercalcemia)

•Clinical relapse

•New CRAB findings

•New plasmacytomas or bone lesions (fractures do not necessarily count)

•Increasing size of existing plasmacytomas (>50%)

•Hyperviscosity related to paraprotein

Kumar et al, Lancet Oncol, 2017

9/27/2017

2

Definitions- Progression

•Increase of 25% from lowest confirmed response value in one or more of:

–Serum M-protein (absolute increase must be ≥0.5 g/dL)

–Serum M-protein increase ≥1 g/dL, if the lowest M component was ≥5 g/dL

–Urine M-protein (absolute increase must be ≥200 mg/24 h)

–Light chain disease: the difference between involved and uninvolved FLC levels

(absolute increase must be >10 mg/dL)

•Non-secretory: 25% increase in bone marrow plasma-cell percentage irrespective of

baseline status (absolute increase must be ≥10%)

•Appearance of a new lesion(s), ≥50% increase from nadir

•≥50% increase in circulating plasma cells (minimum of 200 cells per μL) if this is the only

measure of disease

Kumar et al, Lancet Oncol, 2017

Multiclonal disease with spatial and temporal

heterogeneity

•Acquired genomic events with progression

Rasche L et al Nature Communications 8, Article number: 268(2017)

Case presentation

•62 YO M with standard risk MM dx’d in 1/2013

–Received RVD x 3nCR

–Auto-HCT with melphalan 200 in 6/2013sCR

–Maintenance lenalidomide started in 9/2013

•On routine bloodwork 4/2017 SPEP shows reappearance of M protein at

0.1 g/dL

Now what??

9/27/2017

3

Importance of full re-staging at suspected

relapse/progression

•History- determine co-morbidities

•Physical- determine PS

•Labs –including PB flow for PCs

•Bone marrow, including FISH, cytogenetics, +/- GEP

–Determine new clones

–Risk stratification

–Possibly help with clinical decision making (BCMA, 11:14)

•Imaging- beware of EMD

–PET/CT

–PET/MRI

Dingli et al, Mayo Clin Proc, 2017

Loss of CR or Never CR or Sustained CR

Hoering A et al Blood. 2009 Aug 13; 114(7): 1299–1305.

CR achieved and Lost

Never CR

•Re-appearance of

M protein/BJ

•Reappearance of

5% PCs in BM

•New CRAB event

•New plasmacytoma

•New hyperviscosity

•25% increase in M

protein/BJ/ FLD difference

•10% increase in BM

•50% increase in

plasmacytoma

•50% increase in circulating

PCs

Measured Measured

Clinically relevant

9/27/2017

4

Making your decision

•Immediate treatment for relapse

•Closer follow-up

•Regular follow-up

Indications for treatment

•Clinical relapse (CRAB or plasmacytomas)

•Significant biochemical progression without clinical relapse

•Doubling of the M-component in two consecutive measurements separated by 2

months with the reference value of 5 g/L, (=0.5 g/dL) or

•In two consecutive measurements any of the following increases:

–the absolute levels of serum M protein by ≥10 g/L (=1.0g/dL), or

–an increase of urine M protein by ≥500 mg per 24 hours, or

–an increase of involved FLC level by ≥20 mg/dL (= 200 mg/L) (plus an abnormal FLC

ratio) or 25% increase (whichever is greater)

Ludwig et al, The Oncologist, 2014

•Re-appearance of

M protein/BJ

•Reappearance of

5% PCs in BM

•New CRAB event

•New plasmacytoma

•New hyperviscosity

•50% increase in

plasmacytoma

•25% increase in M

protein/BJ/ FLD difference

•10% increase in BM

•50% increase in

plasmacytoma

•50% increase in circulating

PCs

•Doubling of M protein or

increase by >1 g/dL

•Increase in > 500 mg/24 H BJ

•Increase in LC > 200 mg/L

•Circulating plasma cells

Treatment Indicated

9/27/2017

5

Dingli et al, Mayo Clin Proc, 2017

When to treat if only biochemical

relapse/progression

•Aggressive clinical disease at diagnosis

•Short treatment-free interval/ suboptimal response to previous

treatment line

•Imminent risk for organ dysfunction (pts with previous light chain-

induced renal impairment)

•Unfavorable cytogenetics (t(4;14) or del17p)

Ludwig et al, Oncologist, 2014

Natural History of early relapse after transplant

Kumar S et al Tandem BMT meetings 2017

15

No relapse by 2 years:

5-year OS 80%

Relapse by 2 years:

5-year OS 32%

9/27/2017

6

How many pts relapse early?

P<0.001

0

10

20

30

40

50

60

70

80

90

100

Patients (%)

172 166 151 86 17MRD neg 65 57 43 30 4MRD pos

N at risk

012 24 36 48

Months of follow-up

MRD pos

MRD neg

IFM 2009

30% of MRD Pos

10% of MRD Neg

Attal M et al NEJM 2017

Back to the case…

•62 YO M with standard risk MM dx’d in 1/2013

–Received RVD x 3nCR

–Auto-HCT with melphalan 200 in 6/2013sCR

–Maintenance lenalidomide started in 9/2013

•On routine bloodwork 4/2017 SPEP shows reappearance of M protein at 0.1

g/dL

•BM: 5% involvement by plasma cells, normal cytogenetics/FISH

•PET/CT negative

•Followed q3 months with labs

•10/2013 M protein = 0.7

•11/2013 M protein = 1.1

Gray areas

•On maintenance with an M protein rise 0.20.6

–Should we treat earlier if the patient is already on maintenance?

•High-risk patients with increasing light chains, but not quite at

progression

•Persistently PET avid plasmacytomas

•True biochemical progression but questionable performance status

9/27/2017

7

Next Talks

•Choosing a regimen at relapse

–Early Relapse

–Refractory Relapse

•Options for the multirelapsed and refractory

patient

–Immunotherapy

–Clinical Trials of Newer Novel Agents

10/1/2017

1

Early Relapse: Choosing Among Different

Second Line Regimens

Ajay K. Nooka, MD, MPH, FACP

Associate Professor

Department of Hematology and Medical Oncology

Winship Cancer Institute of Emory University

Atlanta, Georgia

Disclosures

➢Advisory board: Celgene, Amgen, Novartis, Spectrum,

Pharmaceuticals and Adaptive technologies

2

Clinical Vignette

72-year-old female with diagnosis of standard risk myeloma

(hyperdiploidy on FISH studies) received induction therapy with RVd

regimen. She underwent upfront transplant and achieved stringent

CR. She opted not to go for maintenance therapy, and was monitored

closely. Four years from her transplant, she started showing

evidence of biochemical progression, and now she is anemic.

You suggest that the following second line regimen delivers the best

depth of response (≥VGPR) based on the data from available

lenalidomide based phase III studies:

1. Elotuzumab with lenalidomide and dexamethasone

2. Daratumumab with lenalidomide and dexamethasone

3. Ixazomib with lenalidomide and dexamethasone

4. Carfilzomib with lenalidomide and dexamethasone

10/1/2017

2

Why is it important to choose the best second

line regimen?

1. Kumar SK, et al. Mayo Clin Proc. 2004;79:867-874.

2. Kumar SK, et al. Leukemia. 2012;26:149-157.

3. Nooka A, et al. institutional data, unpublished.

Pts (%)

1

0

0

8

0

6

0

4

0

0

2

0

012 24 36 48 60

Mos

OS

EFS

Events, n/N

170/286

217/286

Median, Mos

(Range)

9 (7-11)

5 (4-6)

1

2

1

0

8

6

0

2

Firs

tSecond Third Fourth Fifth Sixth

Treatment Regimen

Median Response Duration (Mos)

4

Response Duration With

Increasing Treatment[1]

Survival Outcomes[2]

Response duration in refractory myeloma

Survival Outcomes at Emory[3]

Mos

Relapsed myeloma: previously treated myeloma that progresses in the absence

of any therapy and requires the initiation of salvage therapy.

*

Consider

clinical

trial

Prior

SCT

Transplant eligible; has good PS

•Primary refractory- SCT

•Relapsed/refractory- SCT

Transplant ineligible

-If patient has previous ly responded to

the therapy, tolerated and relapsed at

leas t 6 months after prior drug

exposure

•repeat prior therapy

- Otherwise, cons ider

•*Bortezomib ±Dexamethasone

•*Bortezomib + PLD

•*Lenalidomide + Dexamethasone

•RVD, VTD, CFZ, CRD, VCD, RCD,

DCEP, DT-PACE±V, Cytoxan, Pd,

T

Relapse within first 12

months

-Newer combination

strategies CRD, CPD,

RVD or clinical trial

-Allogeneic transplant

clinical protocol

Symptomatic relapse

Yes No

Relapse with

maintenance therapy

after SCT

Relapse without

maintenance therapy

after SCT

Factors to consider

•Treatment related factors

•Disease related factors

•Patient related factors

Subsequent

relapse

SCT2

Relapse

withi n 36

months

Relapse

beyond 36

months

Relapse

beyond

18-24

months

Relapse

withi n

18-24

months

Subsequent

relapse

Subsequent

relapse

Subsequent

relapse

Relapse beyond the first 12 months

*Bortezomib ±Dexamethasone

*Lenalidomide + Dexamethasone

*Bortezomib ±PLD

RVD, VTD, CFZ, CRD, VCD, RCD, DCEP±V, DT-

PACE±V, Cytoxan, Pd, Td

Nooka, et al. Blood. 2015;125(20):3085-99.

Treatment Options for Relapsed and Refractory

Myeloma (RRMM)

5

Factors to Consider to for Treatment Selection a

Relapse: Disease related Factors

➢Nature of relapse

➢indolent vs aggressive

➢Risk stratification

➢Genetics of initial and relapsed marrow

➢Disease burden

➢High vs low

➢R-ISS staging

➢1 vs 2-3

1. Nooka AK, et al. Blood. 2015;125:3085-3099.

2. Palumbo A, et al. N Engl J Med. 2011;364:1046-1060.

3. Palumbo A, et al. Blood. 2011;118:4519-4529.

4. Orlowski RZ, Lonial S. Clin Cancer Res. 2016;22:5443.

10/1/2017

3

Factors to Consider to for Treatment Selection a

Relapse: Treatment related Factors

➢Previous therapy

➢Pts with PD receiving IMiDs, PIs, or cytotoxic doublet/triplet therapies can

benefit from next-generation regimens

➢Avoid agents of previous regimen-related toxicity

➢Maintenance therapy

➢Regimen-related toxicity

➢Toxicity profile should be considered in light of pt comorbidities

➢Neuropathy: consider neuropathy sparing durgs (avoid bortezomib,

thalidomide)

➢Cardiac issues (uncontrolled HTN, CHF): careful consideration of

carfilzomib

➢COPD: monoclonal antibodies with caution (daratumumab)

➢DVT/PE: use anticoagulation with IMiDs

➢Depth and duration of previous response, tumor burden at relapse

➢Retreatment with previous therapies an option if pt had previous response to

the treatment, acceptable tolerance, and relapse occurred at least 6 mos

after previous exposure

1. Nooka AK, et al. Blood. 2015;125:3085-3099.

2. Palumbo A, et al. N Engl J Med. 2011;364:1046-1060.

3. Palumbo A, et al. Blood. 2011;118:4519-4529.

Factors to Consider to for Treatment Selection a

Relapse: Patient related Factors

➢Renal insufficiency: disease related or due to comorbidities

(hypertension, vascular disease, diabetes, nephrotoxicity)[1]

➢Hepatic impairment common in pts with RRMM[1]

➢Comorbidities and fraility[1]

➢Treatment decisions complicated in elderly

➢↑ toxicity due to ↓ organ function, physiologic reserve

➢European Myeloma Network vulnerability assessment algorithm

anticipates regimen-related toxicities and assists individualizing

therapy with least potential for interruption[2,3]

➢Patient preferences

➢Convenience, ease of travel, insurance and other social factors

1. Nooka AK, et al. Blood. 2015;125:3085-3099.

2. Palumbo A, et al. N Engl J Med. 2011;364:1046-1060.

3. Palumbo A, et al. Blood. 2011;118:4519-4529.

Lenalidomide and Bortezomib-Based Early

Relapse Regimens: PFS and OS

Trial Regimen

PFS (mon)

ORR (%)

VGPR (%) PFS (HR, 95% CI)

OS (HR, 95%

CI

)

ASPIRE

1

N=792

Rd + Carfilzomib 26.3 87.1 69.9 .69 (.57-.83)

P=.0001 .79 (.63-.99)

P=.04

Rd 17.6 66.7 40.4

TOURMALINE

-MM-1

2

N=722

Rd + Ixazomib 20.6 78.3 48.1 .74 (.59-.74)

P=.01 NR

Rd 14.7 71.5 39

ELOQUENT

-23

N=646

Rd + Elotuzumab 19.4 79 33 .70 (.57-.85)

P<.01 .78 (.63-.96)

Rd 14.9 66 28

POLLUX

4

N=569

Rd + Daratumumab

NR 93 75.8 .37 (.28-.50)

P<.0001 .63 (.42-.95)

Rd 18.4 76 44.2

PANORAMA

5

N=768

Vd + Panobinostat 11.99 60.7 28 .63 (.52-.76)

P<.0001 .87 (.69-1.10)

P=.26

Vd 8.08 54.6 16

CASTOR

6

N=498

Vd + Daratumumab

NR 83 59 .39 (.28-.53)

P<.0001 .63 (.42-.96)

Vd 7.2 63 29

ENDEAVOR

7

N=929

Carfilzomib + Dex 18.7 76.7 54 .53 (.44-.65)

P<.0001 .79 (.58-1.08)

P=.06

Vd 9.4 62.3 29

1. Stewart K, et al. N Engl J Med 2015;372:142-52. 2. Moreau P, et al. N Engl J Med 2016; 374:1621-1634.

3. Lonial S, et al. N Engl J Med 2015; 373:621-631. 4. Dimopoulus M, et al. N Engl J Med 2016; 375:1319-1331.

5. San Miguel J, Lancet Oncol 2014; 15: 1195–206. 6. Palumbo A, et al. N Engl J Med 2016; 375:754-766.

7. Dimopoulos M, et al. Lancet Oncol. 2016;17:27-38.

9

10/1/2017

4

FDA Approvals of Novel Agents for Patients with

RRMM

Novel Agent or Regimen

FDA Approval Date

Patient Population

Panobinostat +

bortezomib/dexamethasone

February 23, 2015

•

Patients with ≥2 prior standard therapies,

including bortezomib and an IMiD agent

Carfilzomib +

lenalidomide/dexamethasone

July 27, 2015

•

Patients with relapsed disease who had

received 1-3 prior lines of therapy

Daratumumab

November 16, 2015

•

Patients with at least 3 prior treatments

Ixazomib

+

lenalidomide/dexamethasone

November 20, 2015

•

Patients who had received at least 1 prior

therapy

Elotuzumab

+

lenalidomide/dexamethasone

November 30, 2015

•

Patients with 1-3 prior therapies

Carfilzomib + dexamethasone

January 21, 2016

•

Patients with relapsed disease and 1-3 prior

therapies

Daratumumab +

bortezomib/dexamethasone

November 21,2016

•

Patients who had received at least 1 prior

therapy

Daratumumab +

lenalidomide/dexamethasone

November 21,2016

•

Patients who had received at least 1 prior

therapy

Daratumumab +

pomali

domide/dexamethasone June 16, 2017

•

Patients who had received ≥2 prior standard

therapies, including bortezomib and an IMiD

agent

Orlowski RZ, Lonial S. Clin Cancer Res. 2016;22:5443.

10

Available Regimens in Early Relapse

NCCN Guidelines

Preferred Regimens

Other Regimens

Level 1 Regimens

Doublets

•

Bortezomib/dexamethasone

•

Carfilzomib/dexamethasone

•

Lenalidomide/dexamethasone

Triplets

•

Elotuzumab/lenalidomide/dexamethasone

•

Daratumumab/lenalidomide/dexamethasone

•

Ixazomib/lenalidomide/dexamethasone

•

Carfilzomib/lenalidomide/dexamethasone

•

Daratumumab/bortezomib/dexamethasone

Other

Regimens

•

Repeat primary induction therapy (if relapse at

>6 months)

•

Bortezomib/cyclophosphamide/dexamethasone

•

Bortezomib/lenalidomide/dexamethasone

Level 1 Regimens

•

Bortezomib/liposomal doxorubicin

•

Panobinostat/bortezomib/dexamethasone

Other

PI

-Based

•

Ixazomib/dexamethasone

•

Elotuzumab/bortezomib/dexamethasone

Alkylator

-Based

•

Bendamustine/bortezomib/dexamethasone

•

Bendamustine/lenalidomide/dexamethasone

•

Cyclophosphamide/lenalidomide/dexamethasone

•DCEP (dex/cyclophosphamide/etoposide/cisplatin)

•

DT-PACE (dex/thalidomide/cisplatin/doxorubicin/

cyclophosphamide/etoposide) ± bortezomib (VTD-

PACE)

•

High-dose cyclophosphamide

NCCN Guidelines, Version 3.2017. Accessed August, 2017.

Note: NCCN Guidelines do not break out regimens into separate categories of

early and late relapse

11

Depth of response

➢MRD negative rate POLLUX MRD negative rates CASTOR

Moreau P, et al. N Engl J Med 2016; 374:1621-1634

Palumbo A, et al. N Engl J Med. 2016;375(17):754-766.

10/1/2017

5

Benefit of antibodies as earlier lines of therapy:

MRD negativity and PFS from CASTOR

MRD –ve rate with DVd as 1st line vs ITT PFS with DVd as 1st line vs 2-3

Mateos MV, et al. Blood. 2016;128: Abstract 1150.

Relative Benefit of PFS: Possibility of delivering

therapy over long term

Betts K, et al. haematologica. 2017;102: Abstract E1300.

Salvage ASCT in the Relapsed Setting

➢Data from Mayo Clinic Transplant Center suggests that ASCT2 appears safe and effective

treatment for relapsed MM (N = 98)

➢ORR: 86%; median PFS: 10.3 mos; median OS: 33 mos

➢Rate of TRM: 4%, suggesting a favorable benefit-to-risk ratio

➢Shorter TTP after ASCT1 predicts shorter OS post–ASCT2

Gonsalves WI, et al. Bone Marrow Transplant. 2013;48:568-573.

TTP After ASCT1 Median From ASCT2, Mos (Range)

PFS OS

< 12 mos 5.6 (3-8) 12.6 (4-23)

< 18 mos

7.1 (6-8) 19.4 (10-42)

< 24 mos

7.3 (6-10) 22.7 (13-62)

< 36 mos

7.6 (7-12) 30.5 (19-62)

10/1/2017

6

Early relapse (1-3 prior lines of therapy)

-Len maintenance

+Len maintenance

- IRd

- ERd -DRd

-KRd

- ERd

- DPd

- KPd

*increase dose of lenalidomide to 25 mg

-DRd

- DVd

- KPd

Clinical trials

Emory Approach to Early Relapse

-Len maintenance

+Len maintenance

Indolent relapse Aggressive relapse/high risk

Car/Pan as second salvage if IMID used

Clinical Vignette

72-year-old female with diagnosis of standard risk myeloma

(hyperdiploidy on FISH studies) received induction therapy with RVd

regimen. She underwent upfront transplant and achieved stringent

CR. She opted not to go for maintenance therapy, and was monitored

closely. Four years from her transplant, she started showing

evidence of biochemical progression, and now she is anemic.

You suggest that the following second line regimen delivers the best

depth of response (≥VGPR) based on the data from available

lenalidomide based phase III studies:

1. Elotuzumab with lenalidomide and dexamethasone

2. Daratumumab with lenalidomide and dexamethasone

3. Ixazomib with lenalidomide and dexamethasone

4. Carfilzomib with lenalidomide and dexamethasone

Conclusions

➢Novel agents in combination can achieve prolonged

responses even in relapsed disease

➢Depth of response is key even in relapsed disease

➢There are many right ways to treat patients with multiple

myeloma in relapse

➢There are also wrong ways to do it, know your options

➢Regimen with good tolerability, and efficacy (monoclonal antibodies)

➢Despite major advances and newer options, a few

challenges that we face today are

‒how to sequence the available regimens?

‒how to personalize therapy to derive the maximize benefit (eg:

biomarkers)?

‒how to tailor therapy to minimize toxicity yet retain efficacy

10/1/2017

7

Questions??

anooka@emory.edu

10/1/2017

1

Approach to the Patient with Refractory and

Multiply Relapsed Multiple Myeloma

Peter Voorhees, M.D.

Member, Plasma Cell Disorders Program

Relapsed/Refractory Disease : Outcomes

•Despite the introduction of IMiDs and PIs,

most patients relapse and outcomes are poor

in relapsed or refractory patients1

•Median OS of 9 months in patients

refractory to bortezomib and ≥1 IMiD1

•Median OS of 8 months in patients with

relapsed or refractory MM who were

double refractory or had relapsed after

≥3 prior lines of therapy, including

pomalidomide and carfilzomib2

1.Kumar SK, et al. Leukemia. 2012;26(1):149-157.

2.Usmani S, et al. Oncologist. 2016. doi:10.1634/theoncologist.2016-0104.

Patients alive, %

Time, months

Kumar SK, et al. 2012.

0

20

40

60

100

80

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60

Usmani S, et al. 2016.

MM, multiple myeloma; IMiD, immunomodulatory drug; PI, proteasome

inhibitor; OS, overall survival.

Outline

•Available Therapeutic Regimens for later relapse

•General Principles to Guide Therapy Decisions

•Treatment of Later Relapse / Progression (≥2 prior lines of therapy

and/or lenalidomide/bortezomib refractory)

•Emerging therapeutics

•Conclusions

10/1/2017

2

Available Regimens in Late Relapse: NCCN Guidelines

Preferred Regimens

Other Regimens

Late Relapse (≥2 prior lines or

len/bort

refractory)

Level 1 Regimens

Doublets

•

Pomalidomide/dexamethasone

Other Regimens

•

Pomalidomide/bortezomib/dexamethasone

•

Pomalidomide/carfilzomib/dexamethasone

•Pomalidomide/daratumumab/dexamethasone

•

Daratumumab

Late

Relapse (≥2 prior lines or len/bort refractory)

•

Panobinostat/bortezomib/dexamethasone

•

Panobinostat/carfilzomib

•

Pomalidomide/cyclophosphamide/dexamethasone

•

DCEP (dex/cyclophosphamide/etoposide/cisplatin)

•

DT-PACE (dex/thalidomide/cisplatin/doxorubicin/

cyclophosphamide/etoposide) ± bortezomib (VTD-PACE)

•

High-dose cyclophosphamide

NCCN Guidelines, Version 3.2017, accessed August, 2017.

Note: NCCN Guidelines do not break out regimens into separate categories of early and late relapse

PANORAMA-2: A Phase 2 Study of Bortezomib,

Dexamethasone and Panobinostat

Response Category

%

ORR (≥PR)

34.5

CBR (≥MR)

52.7

CR 0.0

nCR 1.8

PR 32.7

MR 18.2

SD 36.4

PD 5.5

Progression-free Survival

Overall Survival

Time (months)

Time (months)

Median PFS: 5.4 mos

Median OS: Not reached

(Median F/U: 8.3 mos)

•55 pts with relapsed and bortezomib-refractory

multiple myeloma (54 prior lenalidomide tx)

•Median prior regimens: 4 (2 –11)

•Median time since diagnosis: 54.8 mos (7.5 –

263.6)

•21-day cycle. Bort 1.3 mg/m2IV D1, 4, 8, 11 (D1,

8 for cycle 9+); Dex 20 mg day of and after bort;

Pano/Placebo 3x/week for the first 2 weeks of

the cycle.

Richardson PG et al. Blood 2013;122:2331-7.

Pomalidomide-Dex vs Dex for

Relapsed/Refractory Multiple Myeloma

•Randomized, phase III study of Pom-Dex vs Dex in relapsed/refractory myeloma

•Baseline characteristics: 1) Median number of prior therapies = 5; 2) Len and bort refractory 75%

•ORR: 31% vs. 10%

•Median PFS 4.0 vs. 1.9 mos

•Median OS: 12.7 vs. 8.1 mos

Pom-Dex

Dex

Miguel JS, et al. Lancet Oncol. 2013;14:1055-1066.

10/1/2017

3

Carfilzomib, Pomalidomide and Dexamethasone for

Relapsed/Refractory Multiple Myeloma

•MTD in phase I: 4-week cycle.

CFZ 27 mg/m2D1, 2, 8, 9, 15, 16;

Pom 4 mg D1-21;

Dex 40 mg D1, 8, 15, 22

•Median lines of therapy: 6 (2–12)

•Len-refractory: 100%

•Bortezomib-refractory: 93.5%

Best Overall Response N=32

VGPR 16%

PR 34%

MR 16%

SD 25%

PD 9%

Median PFS 7.2 months, Median

OS 20.6 months

Shah JJ, et al. Blood. 2015;261:2284-2290.

Phase 1/2 Trial: Pomalidomide, Bortezomib and

Dexamethasone

Time (months)

100

80

40

20

0

60

Success (%)

012 24 30

618

OS

PFS

OS and PFS1

1. Lacy MQ, et al. Blood. 2014;124 (suppl, abstr 304). 2. Richardson PG, et al. Blood. 2015;124 (suppl, abstr 3036).

Median follow-up: 12 months N = 47

Response rate, n (%) 40 (85)

Median OS

Event free at 6 months (%)

Event free at 12 months (%)

NA

100

95

Median PFS, months 10.7 (95% CI 9.4–18.5)

Median DoR, months 13.7 (95% CI 8.5–16.8)

Median 2 prior lines

Prior lenalidomide 100%, prior bortezomib 57%

Refractory to immediate prior line 28%

Median follow-up: 12 months N = 34

Response rate, n (%) 22 (65)

Median DoR, months 7.4 (95% CI 4.4–9.6)

Median 2 prior lines

Prior lenalidomide 100%, prior bortezomib 97%

42 20 824

33

40

25

32

10

17

9

0

20

40

60

80

sCR/CR

VGPR

PR

Escalation

(n = 12)

MTD With

IV BORT

(n = 10)

Total

(N = 34)

MTD With

SC BORT

(n = 12)

Median TTR,

mos (95% CI)

Median DOR,

mos (95% CI)

1.1

(0.7-5.1)a

5.8

(1.2-10.1)

1.4

(0.9-3.2)a

7.4

(4.1-NE)

0.8

(0.7-1.0)a

NE

(3.2-NE)

1.0

(0.7-5.1)

7.4

(4.4-9.6)

OR R and DOR2

8

Phase 1/2 Trial: Pomalidomide, Cyclophosphamide and

Dexamethasone

Median PFS: 9.5 vs 4.4 months (P= .1078)

Median OSa: not reached vs 16.8 months (P= .1308)

•Median number of prior therapies 4

•Must have been refractory to lenalidomide

•Refractory to bortezomib 71%

Proportion

Progression-free survival (months)

1.0

0.8

0.6

0.4

0.2

0.0

Arm N Event Censored Median (95% CI)

POM-LoDEX 36 30 (83%) 6 (17%) 4.4 (2.3, 6.0)

POM-LoDEX + cyclo 34 26 (76%) 8 (24%) 9.5 (4.6, 13.6)

0 3 6 9 12 15 18 21 24 27

POM-LoDEX

POM-LoDEX + cyclo

Log-rank p = 0.1078

Baz R, et al. B lood. 2016;127(21):2561-8. 9

10/1/2017

4

18%

10%

1%

2%

0

5

10

15

20

25

30

35

16 mg/kg

ORR, %

PR VGPR CR sCR

•Median OS: 19.9 months

3%

CR or

better 13%

VGPR or

better

N = 148

Daratumumab as Monotherapy for

Relapsed/Refractory Multiple Myeloma

Progression-Free Survival

Usmani S, et al. Blood. 2016;128:37-44.

Pomalidomide, Dexamethasone and

Daratumumab for Relapsed/Refractory MM

Median OS = 17.5 months (85% CI 13.3 –NE)

Chari, A, et al. Blood 2017;130:974-81.

Median number of prior lines of therapy: 4 (range 1 –13), 71% PI and IMiD refractory, 25% with high risk CGs

Of 17 pts in ≥CR, 35%, 29% and 6% were MRD- at

thresholds of 10-4, 10-5 and 10-6, respectively Median PFS in high risk CG disease

(N=22): 3.9 months (95% CI 2.3 –NE)

Analysis of Daratumumab, Pomalidomide and

Dexamethasone in Relapsed/Refractory Multiple Myeloma

Best Response

Dara and Pom

Naive

(n = 19)

Dara and/or Pom

Refractory

(n = 22)

Dara and Pom

Refractory

(n = 12)

ORR, n % 17 (89.0) 9 (40.9) 4 (33.3)

sCR, n % 7 (36.8) 0 0

CR, n % 1 (5.3) 0 0

VGPR, n % 3 (15.8) 1 (4.5) 1 (8.3)

PR, n % 8 (42.1) 8 (36.4) 3 (25.0)

MR/SD, n % 1 (5.3) 9 (40.9) 6 (50.0)

PD, n % 1 (5.3) 4 (18.2) 2 (16.7)

Median cycles of tx,

n (range) 15 (1-23) 3 (1-8) 3 (1-8)

Nooka AK, et al. Blood. 2016;128:492. 12

10/1/2017

5

Efficacy, Mos All Cohorts

(N = 41)

Dara and Pom Naive

(n = 19)

Dara and Pom

Refractory (n = 12)

Median PFS 7 NR 3

Median follow-up 16 17 8

PFS Dara/Pom/Dex: All Cohorts

Cumulative Survival

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24

Mos

PFS Dara/Pom/Dex: SD or

Better vs No Response

Cumulative Survival

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24

Mos

No response

≥ SD

PFS Dara/Pom/Dex: Cohort 3 SD

or Better vs No Response

Cumulative Survival

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24

Mos

No response

≥ SD

Nooka AK, et al. Blood. 2016;128:492.

Analysis of Daratumumab, Pomalidomide and

Dexamethasone in Relapsed/Refractory Multiple Myeloma

General Treatment Principles

•Overlap between early and late relapse treatment choices

•An early or late relapse regimen may be appropriate as 2nd –4th line therapy

(1 –3 prior lines) depending on the circumstances

•The role of doublets and monotherapy is limited

•Several novel triplets now available with good toxicity profiles

•Consider in the more frail, heavily pretreated patients

•Prior treatment toxicity, disease resistance patterns and co-

morbidities figure particularly prominently into the decision making

process for these patients

•Assess for the presence of t(11;14)

•Always think about a clinical trial

PABST: The Blue Ribbon Approach to Therapy

Decisions for Previously Treated Multiple Myeloma

•Past medical history

•What co-morbidities will impact tolerability

of therapy?

•Adverse events

•What toxicities were experienced with prior

therapy?

•Biochemical vs clinical

relapse/progression

•Standard vs high-risk disease biology

•Treatment history

•Is the disease resistant to specific drug

classes?

10/1/2017

6

Biochemical vs Clinical Progression

•Biochemical progression:

•Progression of disease based on M

protein parameter increase only

•Timing of therapy institution /

escalation dependent on numerous

factors

•Pace of progression

•Original clinical presentation

•Standard vs high-risk disease biology

•Patient / physician comfort level

•Clinical relapse:

•“Direct indicators of increasing

disease and/or end organ dysfunction

(CRAB features) related to the

underlying clonal plasma-cell

proliferative disorder”

•Mandates immediate institution /

escalation of therapy

IMWG Consensus Criteria for Response in MM

Biochemical Progression Clinical Relapse

↑ of ≥25%

from nadir response value in

one or more of the following:

1)

Serum M protein (absolute increase

≥0.5 g/dL, ≥1 g/dL if nadir ≥5 g/dL)

2)

Urine M protein (absolute increase

≥200 mg/24 hours)

3)

Measurable by serum FLC testing

only: difference between involved

and uninvolved FLCs (absolute

increase ≥10 mg/dL)

4)

Non-secretory: bone marrow PC %

(absolute increase ≥10%)

1)

Development of new soft tissue

plasmacytomas or bone lesions

(osteoporotic fractures do not

constitute progression)

2)

Definite increase in the size of

existing plasmacytomas or bone

lesions. A definite increase is defined

as a 50% (and >=1 cm) increase as

measured serially by the SPD§§

of the

measurable les ion

3)

Hypercalcaemia (>11 mg/dL);

4)

Decrease in haemoglobin of >=2 g/dL

not related to therapy or other non-

myeloma-related conditions

5)

Rise in serum creatinine by 2 mg/dL

or more from the start of the therapy

and attributable to myeloma

6)

Hyperviscosity related to serum

paraprotein

≥50% increase

in circulating plasma cells

(minimum 200 cells /

uL) if this is the only

disease measure available

Kumar S et al. Lancet Oncol 2016;17:328-46

Standard vs High-Risk Disease Biology: IMWG

Consensus on Risk Stratification

High-Risk Standard-Risk Low-Risk

Parameters

ISS II/III and t(4;14) or

del(17p13)

Others ISS I/II and absence of

t(4;14), del(17p13) and

+1q21 and age <55

% of Patients

20% 60% 20%

Median OS

2 years 7 years >10 years

•Other factors: Gene expression profile, LDH. circulating plasma cells, response to prior therapy

Chng WJ et al. Leukemia 2014;28:269-77

Revised International Staging System

R-ISS stage 1: normal LDH, no high risk

cytogenetic abnormality (CA)*, ISS stage 1

disease

R-ISS stage 2: not stage 1 or 3

R-ISS stage 3: ISS stage 3 disease PLUS

high LDH OR high risk CA

Palumbo et al. JCO 2015;33:2863-2869

*High risk CA = del(17p)

and/or t(4;14) and/or t(14;16)

Transplant-Based Tx

Non Transplant-Based Tx

IMiD-Based Tx Bortezomib-Based Tx

10/1/2017

7

Treatment History

•What regimen(s) has the patient had in earlier lines of therapy?

•Is the disease refractory to a specific treatment?

•Refractory per the IMWG guidelines: disease progression on or within 60 days of the last dose of

therapy

•Lack of response (stable disease) with prior therapy has been included in the definition of refractory in some studies

•Carfilzomib has activity in bortezomib-refractory disease but the reverse has not been well studied

•Pomalidomide has activity in lenalidomide-refractory disease but the reverse has not been well studied

•If refractory, did the patient have disease progression on standard dosing, reduced dosing

due to prior toxicity or maintenance dosing?

•If dose reduced for toxicity, what were the toxicities, and how could they be better managed?

•For patients on maintenance, it is common practice to optimize therapy prior to changing to a non-

cross resistant regimen.

•Increase the dose of lenalidomide and reincorporate dexamethasone for a patient with progression on lenalidomide

maintenance. A 3rd agent is often included in such a scenario (e.g. elotuzumab) but patients with lenalidomide-

refractory disease were not allowed to participate in the ELOQUENT-1 study and the additional impact of this

maneuver has not been well studied

Treatment Choice Algorithm

•First Step

•Review resistance pattern with prior therapy

•Determine biochemical vs clinical relapse

•Assess standard vs high risk disease

•High risk FISH: del(1p), gain 1q, t(4;14), t(14;16), t(14;20), del(17p)

•High LDH, circulating plasma cells, plasma cell leukemia, extramedullary disease

•Second Step

•Refine choice based on co-morbidities and tolerability of previously used drug

classes

Disease Progression (≥2 prior lines of

therapy)

Disease Progression on

Maintenance

Disease Progression on

Standard Dose Therapy

Len/Bort Refractory

Escalate to standard

dose, add back dex

Clinical RelapseBiochemical Progression

or Early Clinical Relapse

with Minimal Morbidity

Biochemical Progression

or Clinical Relapse

+ Pom Ref + CFZ Ref Quad Ref

Len/Bort Ref only

Standard Risk

- KPd

- DPd

-Kd

-Pd

- CyPD

- Dara

High Risk / Clin

Relapse

- KPd

- DPd

Standard or

High Risk

-Kd

- KCyD

- Dara

- DPd

- Vtx-based**

Standard or

High Risk

- DPd

- CyPd

-Pd

- Dara

- Vtx-based**

Standard or

High Risk

- Dara

- DPd*

- Pano-based tx

- Alkylator-

based therapy

if not resistant

- Vtx-based**

Vtx = venetoclax

*Only if disease resistant to prior pom-dex and dara in separate lines of therapy. **If + for t(11;14) (off label use)

10/1/2017

8

Venetoclax Monotherapy (N=66)

Design: Phase I, open label, study of venetoclax monotherapy

Study Population: RRMM

•Median age: 63 yrs

•ISS stage II/III: 62%

•Median prior therapies: 5 (1-5)

•Prior BTZ: 94% (70% ref)

•Prior REV: 94% (77% ref)

Dosing & Schedule:

VEN: initial 2 week lead in period with weekly dose-escalation

•Final doses: daily at 300 mg, 600 mg, 900 mg, or 1200 mg

•Patients who progressed could receive VEN + dex and remain on study

Safety, n (%)

Venetoclax

Gr 3/4 (≥10%)

Thrombocytopenia (26%), neutropenia (20%),

lymphopenia (15%), anemia (14%), and

decreased white blood cells (12%)

SAEs

≥2 pts

Pneumonia (n=5), sepsis (3), pain, pyrexia,

cough, and hypotension (2 each)

Deaths

8 (all considered unrelated to VEN)

•Median time on VEN: 2.5 mo (0.2-23); 26% received VEN +

dex for a median of 1.4 mo (0.1-11)

Kumar S, et al. ASH 2016. Abstract 488.

Venetoclax + Vd (N=66)

Design: Phase Ib, open label, dose escalation study of

venetoclax + Vd

Study Population: RRMM

•Median age: 64 yrs

•ISS stage II/III: 59%

•Median prior therapies: 3 (1-13)

•Prior BTZ: 32% ref

•Prior REV: 56% ref

Dosing & Schedule:

VEN: daily, 50 mg –1200 mg dose escalation

•RP2D: 800 mg qd

Vd: Dose and schedule not reported

Moreau P, et al. ASH 2016. Abstract 975.

Safety, n (%)

Venetoclax

Gr 3/4 (≥10%)

Thrombocytopenia (29%), anemia (15%)

and neutropenia (14%)

SAEs

≥2 pts

Febrile neutropenia, thrombocytopenia,

cardiac failure, pyrexia, influenza, lower

respiratory tract infection, pneumonia,

sepsis, acute kidney injury, respiratory

failure, embolism, and hypotension

1 DLT: lower abdominal pain (1200 mg Ven)

Deaths

5 (4=PD, 1=RSV infection)

•Discontinuations: 43 (65%), PD

(33), AE (5), withdrawn consent

(2), not specified (3)

Efficacy

All 1-3 Priors

DOR

8.8 mo V non-ref: 10.6 mo

V naïve: 15.8 mo

TTP

8.6 mo V non-ref: 11.3 mo

V naïve: 17.1 mo

Efficacy

With

t(11;14)

Without

t(11;14)

ORR

78% 66%

STORM: Selinexor + Dex (N=79)

Design: Phase II study of Sd

Study Population: RRMM

•48 pts refractory to REV, POM, V, K (Quad)

•33 pts refractory to above + anti-CD38 mAbs

(Penta)

Dosing & Schedule:

S: 80 mg BIW for 6 or 8 doses of a 28 d cycle

D: 20 mg BIW

Median age: 68 yrs

Efficacy

All Quad Penta

ORR

CBR

21%

32%

21%

29%

20%

37%

Vogl DT, et al. ASH 2016. Abstract 491.

Safety, n (%)

Gr 3/4 (≥10%)

All patients

Thrombocytopenia

Neutropenia

Anemia

Fatigue

Hyponatremia

58

21

25

14

20

•Most quad patients (83%) received 6 doses/cycle; penta patients (65%) received 8

dose s/cycle

Efficacy

All Responders Non-

responders

mOS

PFS

DOR

9.3 mo

2.1 mo

NR (>11 mo)

5 mo

5.7 mo

Efficacy

ORR, n (%)

Standard Risk

High

Risk

(17p13)

t(14;16)

t(4;14)

4 (17)

6 (33)

3 (38)

1 (100)

2 (50)

10/1/2017

9

PAVO: SC Daratumumab (N=41)

Design: Ph Ib, open label, multicenter, dose-escalation study

of SC Dara with rHuPH20 (Dara-PH20)

Study Population: N=41

• ≥2 prior lines of therapy

•Prior therapy included an IMiD and a PI

Dose & Schedule:

D (cohort 1): 1200 mg in 60 mL over 20 min (n=8)

D (cohort 2): 1800 mg in 90 mL over 30 min (n=33)

Dara-PH20 was infused via a syringe pump in rotating areas

on the abdomen in 4-week treatment cycles: QW for 8 weeks,

Q2W for 16 weeks, and Q4W thereafter

Efficacy

1200 mg 1800 mg

ORR

25% 41%

Usmani S, et al. ASH 2016. Abstract 1149.

•Part 2 of the study will examine the RP2D of Dara-PH20 vs IV Dara monotherapy

•1800 mg was selected as the RP2D

Safety

Gr 3/4

Fatigue (2 pts), influenza, hypertension,

dyspnea, and tumor lysis syndrome

ONLY SEEN IN 1200 MG DOSE

IRR

(most Gr 1/2)

Chills, fever, rigors, vomiting, itching, edema of

the tongue, non-cardiac chest pain, and

wheezing; all occurred at 1st

infusion and were

controlled with treatment

NO GRADE 3 IRR SEEN IN 1800 MG DOSE

First in Human Study with GSK2857916,

An Antibody Drug Conjugated to Microtubule-disrupting

Agent Directed Against B-cell Maturation Antigen (n=30)

–BCMA expression is restricted to B cells at later stages

of differentiation and is requisite for the survival of long

lived plasma cells

–BCMA is broadly expressed at variable levels on

malignant plasma cells

Cohen A, et al. ASH 2016.

–GSK2857916 was well tolerated with no DLTs up to 4.6

mg/kg q3w; MTD was not reached

–AEs were manageable with ocular toxicity emerging as

the most frequent reason for dose modifications

–Hematologic toxicities such as thrombocytopenia and

anemia are expected in the disease under study

–66.7% ORR including a stringent CR observed at

higher doses of GSK2857916 in this refractory

population

–3.4 mg/kg was selected as the dose to investigate

in the expansion phase of the study based on the

totality of the data from Part 1

–Pharmacodynamic and correlative analyses are

ongoing

B-cell Maturation Antigen (BCMA)-specific chimeric antigen receptor T

cells (CART-BCMA) for MM

Anti-BCMA CAR Bb2121 LCAR-B38M CART-BCMA

Group/Company NCI Bluebird/Celgene/NCI Nanjing Legend Biotech Novartis/UPenn

Binder/co-stimulatory

signaling

Murine/CD3 & CD28 Murine/CD3 & 41-BB Murine/CD3 & 41-BB Fullay human/CD3 & 41-BB

Transfection Gamma-retroviral Lentiviral Lentiviral Lentiviral

Trial ID NCT02215967 NCT02658929 NCT03090659 NCT02546167

BCMA expression

required?

Yes Yes Yes No

Median prior lines of

therapy

7 7 3 9

Latest efficacy 1 CR (relapsed), 7 PRs

in 16 patients

4 CRs, 12 PRs in 18

patients

15 CRs and 13 PRs in 35

patients

1 CR, 3 PRs in 9 patients

Safety summary Substantial but

reversible

1 death,

cardiopulmonary

arrest (unrelated)

Transient CRS 1 death –progressive

disease/candidaemia

10/1/2017

10

Conclusions

•There are many right ways to treat patients with multiple myeloma in relapse

•There are also wrong ways to do it

•As long as you have a PABST (review PMHx, adverse events, biochemical vs

clinical relapse, standard vs high-risk disease, treatment history), you will come to

a good answer for your patient

•Use your local/regional Myeloma Specialists as a resource when questions arise

about risk status, when to change treatment in biochemical relapse, optimal

therapy when the preferred regimens may not be good options

•Always consider a clinical trial, especially in increasingly refractory and / or high

risk disease. We have gotten better at treating this disease but have a long ways

to go!

9/28/2017

1

2017 Trends in MM Rx:

Restoring Immune Function

•Immunomodulatory drugs, other small molecules

(eg, HDACi’s)

•Monoclonal antibodies

•Checkpoint inhibitors

•Vaccines

•Cellular therapies

Monoclonal Antibodies Kill MM

Through Multiple Mechanisms

Rd (n = 325)

LEN: 25 mg, d1–21

DEX: 40 mg, d1, 8, 15, 22

28-day cycles until progression

N=646

RRMM

1–3 prior lines

Not LEN-refractory

ERd (n = 321)

ELO: 10 mg/kg, d1, 8, 15, 22

(cycles 1–2); d1, 15 (cycles ≥ 3);

LEN: 25 mg, d1–21

DEX: weekly equivalent, 40 mg

28-day cycles until progression

•Primary end points: PFS, ORR

•Secondary end points: OS, DoR, QoL, safety

ELOQUENT 2:

Elotuzumab-Rd (ERd) vs Rd

Lonial S et al. N Engl J Med. 2015;373:621.

9/28/2017

2

ELOQUENT-2: ERd vs Rd

Progression-Free Survival

Dimopoulos MA et al. Blood. 2015;126: Abstract 28.

ERd

(n=321) Rd

(n=325)

Median

PFS, mos

(95% CI)

19.4

(16.6−22.2) 14.9

(12.1−17.2)

HR=0.73

(95% CI 0.60−0.89;

P

=0.0014)

3

-yr PFS,

%

26 18

CR

VGPR

PR

ELOQUENT-2: ERd vs Rd

Efficacy

*Values may not sum due to rounding.

46 38

28

21

4

7

0

20

40

60

80

100

ERd Rd

Patients (%)

ORR 79%a

ORR 66%*

n=321 n=325

P<0.001 ERd

(n=321) Rd

(n=325) HR;

Pvalue

Median

PFS,

months219.4 14.9 0.73;

0.0014

Median

TTNT,

months233 21

0.62

(95%

CI

0.50–

0.77)

Median OS,

months243.7 39.6 0.77;

0.0257

Median

DoR,

months120.7 16.7 NR

Responses1

1. Lonial S et al. N Engl J Med. 2015;373:621-31.

2. Dimopoulos MA et al. Blood. 2015;126: Abstract 28.

Daratumumab: Mechanism of Action

9/28/2017

3

Phase 3 Randomized Controlled Study of DVd vs Vd

in Pts With Relapsed or Refractory MM: CASTOR

Phase 3 Randomized Controlled Study of DVd vs Vd

in Pts With Relapsed or Refractory MM: CASTOR

Overall Response Ratea

aResponse-evaluable population.

P <0.0001

83

63 59

29

19

9

0

10

20

30

40

50

60

70

80

90

100

Response rate, %

ORR ≥VGPR

P <0.0001

P = 0.0012 DVd

Vd

14

3

0

2

4

6

8

10

12

14

16

18

20

%

MRD-neg (10-4)≥CR

11

9/28/2017

4

Phase 3 Randomized Controlled Study of DRd vs Rd

in Pts With Relapsed or Refractory MM: POLLUX

Phase 3 Randomized Controlled Study of DRd vs Rd

in Pts With Relapsed or Refractory MM: POLLUX

12

MRD-negative Rate

DRd

Rd

0

5

10

15

20

25

30

35

40

45

50

MRD-negative rate (%)

MRD-neg (10-4) MRD-neg (10-5)MRD-neg (10-6)

30%

8%

P <0.0001

23%

5%

P <0.0001

10%

2%

P <0.0001

Response-evaluable set. Assessed by next g eneratio n sequenci ng in bone marrow.

Significantly higher MRD-negative rates for DRd vs Rd

9/28/2017

5

Daratumumab in High-Risk Patients

Rationale for DARA + POM-D

14

•In a randomized, Phase 3 study, pomalidomide plus low-dose

dexamethasone (POM-D) in patients relapsed from or refractory to

previous treatment with bortezomib or lenalidomide1 resulted in the

following:

–ORR = 31%

–Median PFS of 4.0 months

–Median OS of 12.7 months

•Pomalidomide increases CD38 expression in a time and dose-

dependent fashion in multiple myeloma cells2

1. San Mi guel J, et al. Lancet Oncol. 2013;1 4(11)1055-1066.

2. Boxha mmer R, et al. Presented at 51st American Socie ty of Clinical Oncolog y (ASCO)

Annu al Meeti ng; May 29 -June 2, 2015; Chicago, IL. Abstract 8588.

MMY1001: DARA + POM-D Arm

Treat 6 patients with DARA + POM-D

If ≤1 patient has DLTs

Enroll 6 additional patients

Expand up to 88 patients

Eligibility criteria

•Refractory to last line of therapy

• ≥2 prior lines of therapy,

including 2 consecutive cycles

of lenalidomide and bortezomib

•Pomalidomide naïve

•ECOG score ≤2

•Absolute neutrophil count

≥1.0×109/L, and platelet count

≥75×109/L for patients with

<50% plasma cells (>50×109/L,

otherwise)

•Calculated creatinine clearance

≥45 mL/min/1.73 m2

15

DARA* IV 16 mg/kg +

Pomalidomide 4 mg (Days 1-21) +

Dexamethasone 40 mg QW

Open-label, multicenter, six-arm, Phase 1b

study

(28-day cycles)

*QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W beyond.

9/28/2017

6

Overall Response Rate:

DARA + POM-D

•ORR = 71%

•ORR in double-refractory patients = 67%

•Clinical benefit rate (ORR + minimal response) = 73%

DARA + POM-D

(N = 75)

n (%) 95% CI

Overall response rate

(

sCR+CR+VGPR+PR) 53 (71) 59.0-80.6

Best response

sCR

CR

VGPR

PR

MR

SD

PD

4 (5)

3 (4)

25 (33)

21 (28)

2 (3)

17 (23)

3 (4)

1.5-13.1

0.8-11.2

22.9-45.2

18.2-39.6

0.3-9.3

13.8-33.8

0.8-11.2

VGPR

or better (sCR+CR+VGPR

)

32 (43) 31.3-54.6

CR

or better (sCR+CR) 7 (9) 3.8-18.3

ORR = 71%

16

43%

VGPR or

better

9%

CR or

better

28%

33%

4%

5%

0

10

20

30

40

50

60

70

80

16 mg/kg

ORR, %

PR VGPR CR sCR

N = 75

Progression-free Survival at 6 Months:

DARA + POM-D

17

0

Patients progression-free and alive, %

2 6

Time from first dose, months

0

20

60

80

100

4

40

Patients at risk 98 67 39 19

6-month PFS rate = 66% (95% CI, 52.3-75.9)

•Median follow-up of 4.2 months

Coming Soon?;Recombinant

Human Hyaluronidase

▪ENHANZE™ platform of recombinant

human hyaluronidase (rHuPH20)

temporarily breaks down the hyaluronan

barrier, allowing rapid absorption of

injected drugs1

▪Herceptin SC®and MabThera SC®are

approved in Europe as co-formulate

products with rHuPH202,3

–Dosing time is 5 to 8 minutes with SC

versus 0.5 to 6 hours with IV4-6

18

1. Halozyme Therapeutics. Mechanism of action for Hylenex recombinant

(hyaluronidase human injection). www.hylenex.com/mechanism-of-action.

Accessed 11/8/2016.

2. European Medicines Agency. Herceptin: EPAR –product information. 2016

3. European Medicines Agency. MabThera: EPAR –product information. 2016.

4. Ismael G, et al. Lancet Oncology. 2012;13(9):869-878.

5. Shpilberg O, et al. Br J Cancer. 2013;109(6):1556-1561.

6. De Cock E, et al. Plos One. 2016;11(6):e0157957.

Schematic of rHuPH201

Aim: To determine the safety, pharmacokinetics, and efficacy of

DARA as SC administration

9/28/2017

7

Key eligibility criteria

•RRMM with measurable disease

• ≥2 prior lines of treatment

•Not received anti-CD38 therapy

PAVO: Study Design

Phase 1b, open-label, multicenter, dose-finding, proof of concept study

19

RRMM, relapsed or refractory multiple myeloma; QW, weekly; Q2W, every 2 weeks; Q4W, every 4 weeks; Ctrough, trough concentration; ORR, overall response rate; CR, complete response;

PK, pharmacokinetic.

aGroup 2 comprises 4 distinct cohorts, each treated with DARA 1,800 mg and rHuPH20 45,000 U. Ctrough on Cycle 3/Day 1 in Group 1 supported dose selection for Group 2. The study

evaluation team reviewed safety after Cycle 1 and PK after Cycle 3/Day 1 for each group.

bAdminis tered 1 hour prior to infusion.

Group 1 (n = 8)

DARA: 1,200 mg

rHuPH20: 30,000 U

Group 2a(n = 45)

DARA: 1,800 mg

rHuPH20: 45,000 U

Dosing schedule

▪Approved schedule for IV

▪1 Cycle = 28 days

Infusion time

▪1,200 mg: 20-min infusion (60 mL)

▪1,800 mg: 30-min infusion (90 mL)

Pre-b/post-infusion medication

▪Acetaminophen,

diphenhydramine, montelukast,

and methylprednisolone

Primary endpoints

•Ctrough of DARA at

Cycle 3/Day 1

•Safety

Secondary endpoints

•ORR

•CR

•Duration of response

•Time to response

IRRs

20

1,200 mg

n = 8

1,800 mg

n = 45

IRR, % (n)

13 (1) 24 (11)

Chills 13 (1) 9(4)

Pyrexia 0(0) 9(4)

Pruritus 0(0) 4(2)

Dyspnea 13 (1) 0(0)

Flushing 0(0) 2(1)

Hypertension 0(0) 2(1)

Hypotension 0(0) 2(1)

Nausea 0(0) 2(1)

Non-cardiac chest

pain

13 (1) 0(0)

Oropharyngeal pain 0(0) 2(1)

Paresthesia 0(0) 2(1)

Rash 0(0) 2(1)

Sinus headache 0(0) 2(1)

Tongue edema 0(0) 2(1)

Vomiting 0(0) 2(1)

Wheezing 0(0) 2(1)

▪All IRRs in the 1,800-mg

group were grade 1 or 2

▪One grade 3 IRR of dyspnea

in the 1,200-mg group

▪No grade 4 IRRs were

observed

▪All IRRs occurred during or

within 4 hours of the first

infusion

▪No IRRs occurred during

subsequent infusions in

either group

▪Abdominal wall SC injections

were well tolerated

Low IRR incidence and severity with DARA SC

Immune Checkpoint Inhibitors in MM

9/28/2017

8

Immune Checkpoint Inhibitors for

Relapsed/Refractory Multiple Myeloma

Pneumonitis

Type Trial Patient Types Study

Phase Site(s)

CAR T

CART-19 for multiple myeloma

Relapsed/ refractory

1University of

Pennsylvania

Safety study of CAR-

modified T cells

targeting NKG2D-ligands

Relapsed/ refractory

1Dana-Farber

Cancer Institute

Study of T cells targeting B-cell

maturation antigen (BCMA) for

previously treated multiple myeloma

Relapsed/ refractory

1

National Cancer

Institute

University of

Pennsylvania

MILs

Tadalafil and lenalidomide

maintenance with or without activated

marrow infiltrating lymphocytes (MILs)

in high-risk myeloma

Newly diagnosed;

relapsed (without

prior ASCT) 2Sidney Kimmel

Comprehensive

Cancer Center

Adoptive immunotherapy with

activated marrow-infiltrating

lymphocytes and cyclophosphamide

graft-versus-

host disease prophylaxis

in patients with relapse of hematologic

malignancies after allogeneic

hematopoietic cell transplantation

Relapsed/ refractory

1Sidney Kimmel

Comprehensive

Cancer Center

Affinity-

enhanced

T cells

Engineered autologous T cells

expressing an affinity-

enhanced TCR

specific for NY-ESO-1 and LAGE-1

Relapsed/

refractory 1/2 City of Hope

University of

Maryland

DLI CD3/CD28 activated Id-KLH primed

autologous lymphocytes Post-transplant 2 University of

Pennsylvania

9/28/2017

9

Myeloma CAR Therapy

•Which Target:

–CD19, CD138, CD38, CD56, kappa, Lewis Y, CD44v6, CS1 (SLAMF7),

BCMA

•Many questions remain about CAR design:

–Optimal costimulatory domains

–Optimal vector

–Optimal dose and schedule

–Need for chemotherapy

–Perhaps “cocktails” of multiple CARs or CARs + chemotherapy will be

required for best outcomes

Which Target: BCMA

Multiple myeloma cells

expressing BCMA

(brown color = BCMA protein)

B cell maturation antigen (BCMA)

▪A member of the TNF receptor

superfamily

▪Expression is largely restricted to

plasma cells and mature B cells

▪Not detectable in any other normal

tissues

▪Expressed nearly universally on multiple

myeloma cells

▪Anti-MM efficacy validated in initial

studies11. Ali et al., Blood 2016 128: 1688. Cohen et al.,

ASH 2016, abstract 1147

CRB-401 Study Design

9/28/2017

10

▪No DLTs to date

▪Cytopenias related

to fludarabine/

cyclophosphamide

lymphodepletion,

as expected

▪No ≥ Grade 3

cytokine release

syndrome or

neurotoxicity

Adverse Events Generally Mild, No ≥ Grade 3

CRS* or Neurotoxicity

*CRS uniformly graded according

to Lee et al., Blood 2014;124:188-

195

Best Response and Time Since bb2121 Infusion

Cytokine Release Syndrome Summary

9/28/2017

11

UPENN; BCMA CAR TRIAL

•Primary objective

–Safety

•Secondary

–Feasibility

–Efficacy (response rates, PFS, OS, MRD)

•Exploratory:

–CART-BCMA expansion, persistence, phenotype

–Impact on normal B cell and PC compartments

–BCMA expression pre- and post-treatment

–Cytokine/chemokine levels

–Soluble BCMA, BAFF, APRIL levels

–Assess for anti-CAR immune responses

–Impact on tumor microenvironment

Cohort 1

1 - 5 x 108

CAR+ T cells

(n=3-6)

Cohort 2

Cytox 1.5 g/m2

+

1 - 5 x 107

CAR+ T cells

(n=3-6)

Cohort 3

Cytox 1.5 g/m2

+

1 - 5 x 108

CAR+ T cells

(n=3-6)

Up to n=9 Up to n=9 Up to n=9

4 week

delay

between

subjects

CD8

BCMA-CAR

Pre Day 7

2) qPCR

1) Flow

Patient characteristics –Cohort 1 (n=9)

Characteristic Median (range) or %

Age 57 (44 –70)

Gender 67% male; 33% female

Isotype IgG (33%), IgA (44%), LC (22%)

Prior lines of therapy 9 (4-11)

Lenalidomide

100% (refractory: 78%)

Bortezomib

100% (refr: 89%)

Pomalidomide

100% (refr: 89%)

Carfilzomib

100% (refr: 89%)

Autologous SCT

78%

Cyclophosphamide

100% (refr: 67%)

Daratumumab

44% (refr: 44%)

Anti-

PD1

33% (refr: 33%)

High-risk genetics

-17p or TP53

mutation

100%

67%

Extramedullary dz 33%

% BM plasma cells 80 (15 –95)

Day 0 absolute CD3 258/µL (117 –1354)

Bi-Specific Antibody (bsAb) Constructs

9/28/2017

12

Conclusions

•Immunotherapy is an active strategy for myeloma

therapy

•Optimal targets for immunotherapy remain under

study