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EOKMultiple Myeloma after ASH 2016

Financial Disclosure

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10% per year

1% per year

3% per year

1% per year


Diagnosis of MyelomaRevised Definition of Multiple Myeloma

Classical Definition HyperCalcemia

Renal insufficiency

Anemia

Bone disease

Expanded Definition: Myeloma defining events

Clonal BMPC ≥ 60%

> 1 focal lesion on MRI

Involved/uninvolved serum FLC ratio > 100

Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-548.

Predicts ≥ 80% probability of progression from smoldering to active disease within 2 yrs

Multiple Myeloma by the numbers

• 2nd most common hematologic malignancy

• More than 30,000 new cases in US every year

• Approximately 12,000 deaths in US every year

• African Americans 2X

• Male: Female: 1.4:1

• Age <40: 2%

• Median age at diagnosis 69 years; at death 75 years

• 5 year relative survival approximately 50% (2006‐2012)

1. American Cancer Society. Cancer facts & figures. 2014. 2. SEER stat fact sheet: myeloma. 2016.

Revised ISS Staging System

Palumbo A, et al. J Clin Oncol. 2015;33:2863-2869.

Definition

I

ISS stage I AND Normal LDH No t(4;14), t(14;16), or del(17p)

II Not stage I or III

III

ISS stage IIIAND Serum LDH > ULNOR With t(4;14), t(14;16), or del(17p)

1.0

0.8

0.6

0.4

0.2

00 12 24 36 48 60 72

R-ISS I NRR-ISS II 83R-ISS III 43

Median OS, Mos

Mos

Pro

bab

ilit

y o

f O

S

Definition

I Serum albumin ≥ 3.5 g/dL AND β2-M < 3.5 mg/L

II Not stage I or III

III β2-M ≥ 5.5 mg/dL

ISS Stage

R-ISS Stage


R-ISS stage: OS based on Therapy

Regardless of therapy

A. Non-autologous stem cell transplant

B. Autologous stem cell transplant

C. IMiD based therapy

D. PI based therapy

R-ISS stage differentiated patient outcomes

Revised ISS Stage Limitations

Pooled data from 3000+ patients on RCT!

- not real world patients who are not healthy enough to be on trials, frail patients

- 65% were less than 65 years old

- Majority of real world patients >70 years old

Excluded chromosome 1 abnormalities from analysis, evolving data supporting this is high risk

No host related factors: Age, performance status, comorbidities

No validation of this in an independent data set

Early deaths in high risk patientsNo plateau

Myeloma Treatment Paradigm

Induction

Induction followed by continuous therapy

Consolidation Maintenance

SC

T

Elig

ible

SC

T

Inel

igib

le

Dia

gn

osi

s an

d

Ris

k S

trat

ific

atio

n

Tumor Burden


Myeloma Rx heading into 2017Melphalan Prednisone versus Conventional chemotherapy

Attal M, et al. N Engl J Med. 1996;335:91-97.

Transplantation vs Conventional Chemotherapy

15 30 45 60

25

50

75

100

OS

(%

)

00

High dose

Conventional dose

Mos

63%

69%

35%

61%

12%

52%

Autologous Stem Cell TransplantMaintenance


What is the role of upfront transplant in the era of novel agents?IFM/DFCI 2009: Phase III Study Design

Primary objective: PFS

Secondary objectives: ORR, MRD, TTP, OS, safety

Attal M, et al. ASH 2015. Abstract 391.

Pts 65 yrs of age or younger with symptomatic

measurable NDMM; ECOG PS < 2

(N = 700)

Lenalidomidemaintenance

12 mos

*RVD: bortezomib 1.3 mg/m2 IV on Days 1, 4, 8, 11 + lenalidomide 25 mg on Days 1-14 + dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11, 12.†Included PBSC collection with cyclophosphamide 3 g/m2 + G-CSF after cycle 3.

RVd*†

8 cycles

RVd*3 cycles

RVd*2 cycles

consolidation

MEL200ASCT†

IFM 2009: Responses

At second interim analysis in June 2015 with median follow-up of 39 mos, the data and safety monitoring board for this trial recommended that the trial be stopped

Response, %RVD

(n = 350)Transplantation

(n = 350)P Value

CR 49 59

.02VGPR 29 29

PR 20 11

< PR 2 1

≥ VGPR 78 88 .001

Negative MRD by FCM 65 80 .001



IFM 2009: PFS

Pts

(%

)

Follow-up (Mos)

ASCTNo ASCT

100

80

60

40

20

00 12 24 36 48

P < .001

Pts at Risk, n

ASCTNo ASCT

350350

309296

261228

153128

2724

ParameterRVD

(n = 350)Transplantation

(n = 350)P Value

Median follow-up, mos 41 41

Progression or death, n 204 158

Median PFS, mos 34 43

4-yr PFS, % 35 47

HR (95% CI) 1 0.69 (0.56-0.84) < .001

Lenalidomide Maintenance


SPM risk

Is more treatment better?Role of tandem transplant or triple consolidationSTaMINA: Phase III Study Design

Primary endpoint: PFS at 38 mos

Secondary endpoints: OS, ORR, CR conversion rate, safety, infections, tx-related mortality, QoL

ASCT-eligible pts ≤ 70 yrswith symptomatic MM and ≥ 2 cycles systemic tx

initiated in past 12 mos;no prior progression;

adequate organ function(N = 758)

Single ASCTLenalidomide Maintenance until PD*

10 mg/day for 3 cycles, then 15 mg/day*(n = 257)

Bortezomib 1.3 mg/m² IV Days 1, 4, 8, 11Lenalidomide 15 mg Days 1-15

Dexamethasone 40 mg IV Days 1, 8, 15Four 28-day cycles

(n = 254)

Stadtmauer EA, et al. ASH 2016. Abstract LBA-1

Lenalidomide Maintenance until PD

10 mg/day for 3 cycles, then 15 mg/day*

Tandem ASCTMelphalan 200 mg/m² IV

Second ASCT(n = 247)

*Originally given for 3 yrs only but amended to until PD in 2014.

Stratified by risk group (high vs standard)

Melphalan 200 mg/m² IV

ASCT

STaMINA: PFS and OS for Overall Population

PFS (Primary Endpoint) OS

Stadtmauer EA, et al. ASH 2016. Abstract LBA-1. Reproduced with permission.

100

80

60

40

20

0

PF

S (

%)

0 12 24 38

38-Mo Estimate, % (95% CI)

Tandem ASCT: 56.5 (49.4-62.9)RVD consolidation: 56.7 (50.0-62.8)Single ASCT: 52.2 (45.4-58.6)

Pts at Risk, nTandem ASCT

RVD consolidation Single ASCT

247254257

200215213

153172158

879980

Mos From Randomization

100

80

60

40

20

0

OS

(%

)

0 12 24 38

38-Mo Estimate, % (95% CI)

Tandem ASCT: 82.0 (76.3-86.5)RVD consolidation: 85.7 (80.5-89.5)Single ASCT: 83.4 (77.9-87.7)

Pts at Risk, nTandem ASCT

RVD consolidation Single ASCT

247254257

231246247

204229227

147166148

Mos From Randomization

In high-risk patients, PFS was between 40% and 48% at 38 months, with no difference in OS


STaMINA: Secondary Primary Malignancies

Secondary Malignancy in First 38 Mos Single ASCT(n = 257)

RVD Consolidation

(n = 254)

Tandem ASCT

(n = 247)

No. of second malignancies 10 15 14

Cumulative incidence,* % (95% CI) 4.0 (1.9-7.2) 6.0 (3.4-9.6) 5.9 (3.3-9.6)

Most common malignancy, n Solid tumors, NR Leukemia, 9 Leukemia, 3

Stadtmauer EA, et al. ASH 2016. Abstract LBA-1.

*First secondary malignancy.

Non‐Transplant OptionsNovel agents

Combining agents with different mechanisms may have a synergistic effect

Integration of novel agents into myeloma management

• Target MM in the BM microenvironment to overcome conventional drug resistance in vitro, and in vivo

• Effective in relapse/refractory, relapsed, induction, consolidation, and maintenance therapy

• Median survival prolonged from 2‐4 years to approximately 6‐7 years, with additional prolongation from maintenance

• New approaches needed to create and ultimately prevent relapse


Therapeutic Agents in Myeloma: Old vs New

“Older” novel agents

– Bortezomib

– Lenalidomide

– Carfilzomib

– Pomalidomide

“Newer” novel agents

– Daratumumab

– Ixazomib

– Elotuzumab

– Panobinostat

Earlier lines or induction therapy, partner for

newer agents

Monoclonal antibody

Novel Myeloma Therapy DevelopmentNovel Therapies Novel Therapies

and Immunotherapy

Lenalidomide

Thalidomide

BortezomibLiposomal

Doxorubicin

Pomalidomide

Panobinostat

CAR T Investigational

VaccinesInvestigational

NivolumabInvestigational

AtezolizumabInvestigational

IsatuximabInvestigational

Elotuzumab

2003 2006 2007 2012 2013 2015 2016+

IMID

Proteasome inhibitor HDAC inhibitor

Chemotherapy

Adoptive T cell therapy

Vaccines

Checkpoint inhibitors

Carfilzomib

Ixazomib

Daratumumab

Backbone

FIRST: Lenalidomide/Dexamethasone vs MPT in NDMM SCT-Ineligible Pts

Ran

dom

ized

1:1

:1

Arm BRd18

Arm CMPT

Len + LoDex 18 cycles (72 wks) Lenalidomide 25 mg on Days 1-21/28LoDex 40 mg on Days 1, 8, 15, 22/28

Mel + Pred + Thal 12 cycles (72 wks)Melphalan 0.25 mg/kg on Days 1-4/42Prednisone 2 mg/kg on Days 1-4/42Thalidomide 200 mg on Days 1-42/42

PD

, OS

, and

subsequent anti-MM

Tx

PD

or unacceptable toxicity

Active treatment + PFS follow-up phase

Pts > 75 yrs: LoDex 20 mg on Days 1, 8, 15, 22/28; Thal 100 mg on Days 1-42/42; Mel 0.2 mg/kg on Days 1-4. Stratification: age, country, and ISS stage.

Len + LoDex ContinuouslyLenalidomide 25 mg on Days 1-21/28LoDex 40 mg on Days 1, 8, 15, 22/28

Arm AContinuous Rd

Hulin C, et al. ASH 2014. Abstract 81. Facon T, et al. Lancet. 2007;370:1209-1218. Hulin C, et al. J Clin Oncol. 2009;27:3664-3670. Benboubker L, et al. N Engl J Med. 2014;371:906-917

Phase III(N = 1623)

FIRST Trial: Rd (Continuous or Every 18 Mos) vs MPT

Pts

(%

)

100

80

60

40

20

0

HR:Continuous Rd vs MPT: 0.72; P < .001Continuous Rd vs Rd18: 0.70; P < .001

Continuous Rd (n = 535) Rd18 (n = 541)MPT (n = 547)

Median PFS, Mos

25.520.721.2

0 6 12 18 24 30 36 42 48 54 60

PFS OS

Benboubker L, et al. N Engl J Med. 2014;371:906-917.

Pts

(%

)

100

80

60

40

20

0

Continuous Rd (n = 535) Rd18 (n = 541)MPT (n = 547)

4-Yr OS, %595651

0 6 12 18 24 30 36 42 48 54 60

Mos Mos


Combinations in the upfront treatmentDoublet Vs Triplet UpfrontSWOG S0777: Study Design

Randomized phase III trial of VRd vs Rd

Lenalidomide 25 mg/day PO Days 1-21 +Dexamethasone 40 mg/day PO Days 1, 8, 15, 22

for six 28-day cycles(eligible n = 230)

Bortezomib 1.3 mg/m2 IV Days 1, 4, 8, 11 +Lenalidomide 25 mg/day PO Days 1-14 +

Dexamethasone 20 mg/day PO Days 1, 2, 4, 5, 8, 9, 11,12 for eight 21-day cycles

(eligible n = 243)

Rd maintenance

until PD, unacceptable

AE, or withdrawal of

consent

Stratified by ISS stage I/II/III and intent to transplant at progression

Durie B, et al. ASH 2015. Abstract 25.

Previously untreated active MM

(CRAB criteria) with measurable

disease (including FLC) and

CrCl > 30 cc/min(N = 525)

All pts received aspirin 325 mg/day; pts in bortezomib arm received HSV prophylaxis

Primary endpoint: PFS

Secondary endpoints: ORR, OS, safety


SWOG S0777: PFS

Pts

Wit

ho

ut

Pro

gre

ssio

n

Mos Since Registration

Median PFS, Mos

VRd (n = 242) 43Rd (n = 229) 30

HR: 0.71; P = .0018

100

80

60

40

20

00 24 48 72 96



SWOG S0777: OS

Pts

Rem

ain

ing

Ali

ve

Mos Since Registration

Median OS, Mos

VRd (n = 242) 75Rd (n = 229) 64

HR: 0.71; P = .025

100

80

60

40

20

00 24 48 72 96

S0777: VRd vs Rd

Grade ≥3 AE VRD Rd P value

Neuro 33 11 <.0001

Pain 12 4 .0002

Sensory 23 3 .004

GI 22 8 NA

20 patients experienced secondary primary malignancies, 10 (4%) on VRd and 10 (4%) on Rd

Initial Myeloma Rx: Summary

Combination of IMiD and PI should be considered standard

- RVd head-to-head winner vs Rd

Early single autologous transplant adds benefit and should be considered standard

- ORR, VGPR, PFS, MRD all better with ASCT

What’s coming?

- Rd+Carfilzomib; Rd+Dara; VRd+Elo

Relapsed/Refractory Multiple MyelomaWhen to consider retreatment

• Differences between biochemical relapse and asymptomatic relapse needs to be considered

• Does this patient really need to be treated now? Patients with asymptomatic rising M protein can be observed to determine the rate of rise and nature of the relapse

Caveat: patient with known aggressive or high risk disease should be considered for salvage even in the setting of biochemical relapse

• CRAB criteria are still listed as the indication to treat in the relapse setting. However, in patients with progression, treatment can avoid CRAB


Basic principles of selecting a treatment

Use new agent: Use drugs the patient has not received before; class switching

Using same drug in a different combination

Using another drug in the same class: patients progressing on thalidomide may respond to lenalidomide; those progressing on lenalidomide may respond to pomalidomide; those progressing on bortezomib may respond to carfilzomib

Increase dose: Patients progressing on lenalidomide at 10 mg may respond when dose is increased to 25 mg plus dexamethasone or addition of cyclophosphamide

Adding clarithromycin to lenalidomide, thalidomide or pomalidomide can be used to achieve a temporary response

Richardson PG, et al. Blood. 2014;123:1461-1469 Berenson et. al. Leukemia (2014) 28, 1529–1536.

Nijhof IS, et al. ASH 2013. Abstract 287. Richardson P, et al. Blood. 2009;114-772-778.

Factors to consider while selecting treatment

•Diabetes

•CHF, MI

•Renal failure

•Oral, IV, subcutaneous

•How active is the patient?

•Can the patient travel to receive treatment?

•Aggressiveness of disease

•Cytogenetics

•Quality and duration of previous response?

•Pre‐existing toxicities?

Prior Treatments

Disease characteristics

Comorbid conditions

Convenience

What is new?

New drugs/combinations recently approved by the FDA for R/R myeloma

Panobinostat (Oral): Feb 28, 2015: pan-deacetylase inhibitor, in combination with bortezomib and dex

Daratumumab (IV): Nov 16, 2015: Human anti-CD138 IgG1, single agent

Ixazomib (Oral): Nov 20, 2015: PI, in combination with lenalidomide and dex

Elotuzumab (IV): Nov 30, 2015: human IgG1 immunostimulatory monoclonal Ab targeting SLAMF-7 and activates NK cell, in combination with lenalidomide and dex

3 new combinations approved

Carfilzomib/Rev/dexDara/len/dexDara/bort/dex

2 vs 3 drugs in R/R myelomaDrug Class Study arm Control arm

Carfilzomib (27 mg/m2)

Proteasome Inhibitor Carfilzomib/lenalidomide/dex Lenalidomide/dex

Ixazomib Proteasome Inhibitor Ixazomib/lenalidomide/dex Lenalidomide/dex

Elotuzumab Monoclonal Antibody Elotuzumab/lenalidomide/dex Lenalidomide/dex

Panobinostat HDAC inhibitor Panobinostat/bortezomib/dex Bortezomib/dex

Daratumumab Monoclonal Antibody Daratumumab/lenalidomide/dex Lenalidomide/dex

Daratumumab Monoclonal Antibody Daratumumab/lenalidomide/dex Bortezomib/dex

Caveat: The randomized trials with KRd, ERd, and IRd included only those patients not refractory to lenalidomide, and we do not know how active these combinations are in lenalidomide‐refractory MM


Doublet Vs Triplet (ORR, ≥ VGPR, PFS)

Pubmed, Cochrane database, ASH, ASCO conference proceedings from 1/200 through 01/2016 to identify phase 3 RCTs that have randomized early relapsed myeloma patients (≤ 3 prior lines) to receive a triplet vs a doublet salvage regimen

Nooka et. al. ASCO 2016 oral abstract

Slide 7

Meta‐analysis of 5 RCT (PANORAMA‐1, MMVAR, ASPIRE, ELOQUENT‐2, TOURMALINE‐MM1)


Randomized phase II trial evaluating VDC, VDR, and VDCR in previously untreated MM

Four drug combination had similar efficacy, but with increased toxicity

EVOLUTION: 3 vs 4 Agents in Combination

Kumar S, et al. Blood. 2012;119:4375-4382.

Patients categorized as VGPR include those who have no measurable M-protein but have not yet had bone marrow assessments to confirm CR/nCR status.Response determined according to automated computer algorithm.

Response, n (%) VDCR (n = 48)

VDR (n = 42)

VDC (n = 33)

VDC-Mod (n = 17)

CR 10 (25) 10 (24) 7 (22) 8 (47)

≥ VGPR 23 (58) 21 (51) 13 (41) 9 (53)

ORR (≥ PR) 35 (88) 35 (85) 24 (75) 17 (100)

Should we aspire to use 3 drugs in R/R myeloma?ASPIRE: Addition of Carfilzomib to Rd in Relapsed/Progressive Myeloma

Randomized, open-label phase III trial

Pts with relapsed or progressive MM,

1-3 prior treatments with ≥ PR in

≥ 1 prior regimen, ECOG PS 0-2, and CrCl ≥ 50 mL/min

(N = 792)

Until PD or unacceptable

toxicity

KRdCarfilzomib Days 1, 2, 8, 9, 15, 16 for cycles 1-12,

Days 1, 2, 15, 16 for cycles 13-18,and discontinued after cycle 18 +

Lenalidomide Days 1-21 +Dexamethasone Days 1, 8, 15, 22

28-day cycle(n = 396)

RdLenalidomide Days 1-21 +

Dexamethasone Days 1, 8, 15, 2228-day cycle

(n = 396)

Stratified by β2-microglobulin, prior bortezomib, and prior lenalidomide

Carfilzomib: 20 mg/m2 Days 1, 2 of cycle 1; 27 mg/m2 thereafter. Lenalidomide: 25 mg. Dexamethasone: 40 mg.

Stewart AK, et al. N Engl J Med. 2015;372:142-152.


ASPIRE: PFS Significant improvement in PFS in KRd arm vs Rd arm

Stewart AK, et al. N Engl J Med. 2015;372:142-152.

KRd Rd(n = 396) (n = 396)

Median PFS, mos 26.3 17.6HR (95% CI) 0.69 (0.57-0.83)

P < .0001

100

80

60

40

20

0

PF

S (

%)

KRdRd

0 6 12 18 24 30 36 42 48Mos Since Randomization

Pts at Risk, nKRd

Rd396 332 279 222 179 112 24 1396 287 206 151 117 72 18 1

KRd in Pts With MM and Early Progression: Efficacy

ORR and median PFS better in KRd vs Rd arms in both subgroups

Ludwig H, et al. ASCO 2016. Abstract 8045.

Outcome Early Relapse Posttransplant Early Relapse

KRd(n = 87)

Rd(n = 72)

KRd(n = 48)

Rd(n = 49)

ORR, % (95% CI) 79.3 (69.3-87.3)

61.1 (48.9-72.4)

83.3 (69.8-92.5)

61.2 (46.2-74.8)

Best overall response, n (%) CR or better VGPR PR

19 (21.8)32 (36.8) 18 (20.7)

3 (4.2)24 (33.3) 17 (23.6)

6 (12.5)25 (52.1) 9 (18.8)

2 (4.1)13 (26.5) 15 (30.6)

Median DoR, mos (95% CI) 24.9 (17.5-30.4)

17.0 (9.7-NE)

18.5 (14.3-23.1)

19.6 (8.3-27.3)

Median PFS, mos 24.1 12.5 17.3 11.1

HR (95% CI) 0.750 (0.500-1.125) 0.870 (0.536-1.411)

Slide credit: clinicaloptions.com

Side effects

Stewart AK, et al. N Engl J Med. 2015;372:142-152

AE % Carfilzomib/len/dex Len/dexAll grades Grade >3 All grades Grade >3

Any grade 3/4 AE 83.7 80.7

Nonhematologic AE

Diarrhea 42.3 3.8 33.7 4.1

Fatigue 32.9 7.7 30.6 6.4

Cough 28.8 0.3 17.2 0

Pyrexia 28.6 1.8 20.8 0.5

Upper respiratory tract infection

28.6 1.8 19.3 1.0

Hypokalemia 27.6 9.4 13.4 4.9

Muscle spasms 26.5 1.0 21.1 0.8

Other AEs of interest

Peripheral neuropathy

17.1 NR 17.0NR

Dyspnea 19.4 2.8 14.9 1.8

Hypertension 14.3 4.3 6.9 1.8

Acute renal failure 8.4 3.3 7.23.1

Cardiac failure 6.4 3.8 4.1 1.8

Ischemic heart disease

5.9 3.3 4.62.1

Response and Safety

>PR Complete Response

Duration of Response(months)

Len/dex 67 9 21.2

Carfilzomib/Len/dex 87 32 28.6

Stewart AK, et al. N Engl J Med. 2015;372:142-152

Twice a week IntravenousRelatively safe in renal failureMonitor for dyspnea, HTN, cytopeniasNew onset or worsening of heart failure can occur, especially in >75 yrs oldDose 27mg/m2 in triplet (10 min); 56mg/m2 in doublet or monotherapy (30 min)Carfilzomib in combination with dex or with lenalidomide/dex approved in patients who have received 1‐3 prior lines of therapyMultiple ongoing trials in the upfront and relapsed setting


Which Proteasome Inhibitor is superior?ENDEAVOR: Kd vs Vd in Relapsed MM

Randomized, open-label, multicenter phase III trial

Primary endpoint: PFS

Secondary endpoints: OS, ORR, DoR, grade ≥ 2 peripheral neuropathy, safety

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

Relapsed MM with 1-3 prior lines of therapy; prior V or K if

response occurred with no discontinuation due to toxicity

(N = 929)

Kd* (n = 464)

Vd†

(n = 465)

Until PD or unacceptable

toxicity

Stratified by prior PI therapy, prior lines of treatment, ISS stage, and route of V administration (IV vs SC)

*Carfilzomib: cycle 1 only, 20 mg/m2 IV on Days 1, 2 followed by 56 mg/m2 on Days 8, 9, 15, 16, then 56 mg/m2 on Days 1, 2, 8, 9, 15, 16 of a 28-day cycles; dexamethasone: 20 mg on Days 1, 2, 8, 9, 15, 16, 22, 23 of a 28-day cycle. On days when carfilzomib is administered, dexamethasone given 30 mins to 4 hrs prior to carfilzomib. †Bortezomib: 1.3 mg/m2 IV bolus or SC on Days 1, 4, 8, 11 of a 21-day cycle; dexamethasone: 20 mg on Days 1, 2, 4, 5, 8, 9, 11, 12 of a 21-day cycle.

100

80

60

40

20

0

PF

S (

%)

0

Mos Since Randomization

KdVd

Kd(n = 464)

171 (37)18.7

Vd(n = 465)

243 (52)9.4

0.53 (0.44–0.65)1-sided P < .0001

Disease progression or death, n (%)Median PFS, mosHR for Kd vs Vd (95% CI)

Median follow-up: 11.2 mos

6 12 18 24 30

ENDEAVOR: PFS


Kd (n = 214)

Vd (n = 213)

1-SidedP Value

Kd (n=250)

Vd (n=252)

1-SidedP Value

Median PFS, mos NE 11.2 Median PFS, mos 15.6 8.1ORR, % (95% CI) 84 (78–88) 65 (59–72) < .0001 ORR, % (95% CI) 71 (65–77) 60 (54–66) .005

No Prior Bortezomib Prior Bortezomib100

80

60

40

20

0

PF

S (

%)

0 6 12 18 24 30


KdVd

100

80

60

40

20

0

PF

S (

%)


KdVd

0 6 12 18 24 30

ENDEAVOR: PFS by Prior Bortezomib


Survival and Response ratesCarfilzomib/dex Bortezomib/dex

>CR 13% 6%

>VGPR 54% 29%

>PR(Overallresponse)

77% 63%

Duration ofResponse

21.3 months 10.4 months

PFS 18.7 months 9.4 months

Serious side effects

48% 36%

Anemia 14 10

High BP 9 3

Low platelets 8 9

Peripheral neuropathy

2 8

Pneumonia 7 8

Longer follow up needed to ascertain if this translates in superior survivalCarfilzomib with dexamethasone could be considered in cases in which bortezomib with dexamethasone is a potential treatment option

Dimopoulos et. Al. Lancet Oncol 2016; 17: 27–38 Moreau P, et al. ASH 2015. Abstract 729.


First oral proteasome inhibitor: IxazomibTOURMALINE-MM1: Study Design

Randomized, double-blind, placebo-controlled phase III trial[1]

Primary endpoint: PFS by IRC per IMWG criteria[2]

Secondary endpoints (data not yet mature): OS, OS in del(17p) pts

1. Moreau P, et al. ASH 2015. Abstract 727. 2. Rajkumar SV, et al. Blood. 2011;117:4691-4695.

Ixazomib 4 mg PO D1,8,15 +Lenalidomide 25 mg* D1-21 +

Dexamethasone 40 mg D1,8,15,22(n = 360)

R/R MM pts with measurable disease; 1-3 prior treatments; CrCl ≥ 30 mL/min;

not refractory to PIs or lenalidomide

(N = 722)

Placebo D1,8,15 +Lenalidomide 25 mg* D1-21 +

Dexamethasone 40 mg D1,8,15,22(n = 362)

28-day cyclesuntil PD or

unacceptable toxicity

Stratified by prior therapy (1 vs 2-3), ISS stage (I-II vs III), and prior PI

exposure (yes vs no)

*10 mg for pts with CrCl ≤ 60 or ≤ 50 mL/min.

Slide credit: clinicaloptions.com

TOURMALINE-MM1: PFS

Moreau P, et al. ASH 2015. Abstract 727. Slide credit: clinicaloptions.com

Addition of ixazomib to Rd resulted in 35% improvement in PFS vs Rd alone

PFS benefit with ixazomib seen in all prespecified subgroups, including cytogenetic high risk, PI and IMiD exposed

100

80

60

40

20

0

Log-rank P = .012HR (95% CI): 0.742 (0.587-0.939)Number of events: IRD 129; placebo-Rd 157

Median PFS:IRd: 20.6 mosPlacebo-Rd: 14.7 mos

0 2 4 6 8 10 12 14 16 18 20 22 24Time from randomization (mos)

Pro

ba

bili

ty o

f P

FS

(%

)

Response and Safety

Ixazomib + Rd(n = 360)

Placebo + Rd(n = 362)

ORR, % CR VGPR PR

78.311.736.466.7

71.56.632.364.9

Median time to response, mos

1.1 1.9

Median DoR, mos 20.5 15.0

Median TTP, mos 21.4 15.7

Moreau P, et al. ASH 2015. Abstract 727.Moreau P, et. al. N Engl J Med 2016;374:1621‐34

Convenient, oral, once a week combination of Ixazomib with lenalidomide and dexRelatively safe in renal failure; reduce dose in severe renal failure or dialysisSide effects: diarrhea, low blood counts, peripheral neuropathy (mainly low grade), rashIxazomib is approved for use in combination with lenalidomide and dexamethasone for patients who have received one prior line of therapyMultiple ongoing trials in the upfront, relapsed and maintenance setting

AE, %Ixazomib + Rd

(n = 361)Placebo + Rd

(n = 359)

Any grade ≥ 3 AE 74 69

Grade ¾ low platelets

13% 5%

Grade ¾ neutropenia 19% 16%

Grade 3 diarrhea 6 2

Grade 3 Rash 5 2

Grade 3 neuropathy 2% 2%

All grade neuropathy 28% 21%

Targets for Monoclonal Antibodies in MM

CD229

CD200

CD28

CD19

BCMA

CD317

CD70

β2M

CD

74

PD

-1

CD

138

ICA

M-1

CD

38

CD

40

CD

56

CX

CR

4

SL

AM

F7

IL-6

BAFF

APRIL

In clinical development

Preclinical activity

Potential targets

Siltuximab

Tabalumab

Mila

tuzu

mab

Pem

brol

izum

abN

ivol

umab

Pid

ilizu

mab

Inda

tuxi

mab

Rav

tans

ine

BI-

50

5

Dar

atum

umab

Isat

uxim

abM

OR

202

Elo

tuzu

mab

Luca

tum

umab

Dac

etuz

umab

Lorv

otuz

umab

Ulo

cupl

umab

Lonial S. ASCO 2016. New Drugs in Oncology: Ixazomib, Elotuzumab, and Daratumumab in Myeloma

Approved agents

MM Cell


Daratumumab: Mechanism of Action

Anti-CD38 IgGκ monoclonal antibody

Direct and indirect antimyeloma activity[1-5]

Depletes CD38+ immunosuppressive regulatory cells[5]

Promotes T-cell expansion and activation[5]

1. Lammerts van Bueren J, et al. ASH 2014. Abstract 3474.2. Jansen JMH, et al. Blood. ASH 2012. Abstract 2974.3. de Weers M, et al. J Immunol. 2011;186:1840-1848.4. Overdijk MB, et al. MAbs. 2015;7:311-321.5. Krejcik J, et al. Blood. 2016;[Epub ahead of print].

Sanchez L, et al. J Hematol Oncol. 2016;30:51.

Daratumumab

106 patients heavily pretreated myeloma patientsMedian time since diagnosis was 4.8. yearsMedian number of prior therapies was 597% of the patient’s refractory to their last line of therapy and 95% were double refractoryORR 29%; >VGPR 12%; PFS 3.7 months

Lonial S, et al. Lancet. 2016;387:1551-1660.Lonial S, et al. ASCO 2015. Abstract LBA8512.

Side effects

>90% of Infusion reactions occurred during the first infusion. Most common included nasal congestion (12%); throat irritation (7%); cough, dyspnea, chills, and vomiting (6%)

Lonial et. al. Lancet 2016 Jan 6. pii: S0140‐6736(15)01120‐4

Other grade ¾ AE included anemia 24%; thrombocytopenia 19%; neutropenia 12%

Daratumumab (infusion)

Schedule Weeks

Weekly Weeks 1 to 8

Every 2 weeks Weeks 9 to 24

Every 4 weeks Week 25 onwards until progression

Almost a third of the patients benefited from getting the drug It was reasonably well tolerated and has impressive single agent activity Responses were rapid, durable, and deepened over time

Lonial et. al. Lancet 2016 Jan 6. pii: S0140‐6736(15)01120‐4


Daratumumab Combinations in Myeloma: ORR With Rd vs Pd

ORR in double-refractory patients: 67%

Clinical benefit rate (ORR + minimal response): 74%

Dara + Rd[1] Dara + Pd[2]

Clinical benefit rate (ORR + minimal response): 88%

1. Plesner T, et al. ASH 2015. Abstract 507.2. Chari A, et al. ASH 2015. Abstract 508.

100

80

60

40

20

0

OR

R (

%)

16 mg/kg

ORR: 81%

34%CR orbetter 63%

VGPR orbetter

sCR CR VGPR PR

19%

28%

9%

25%

100

80

60

40

20

0

OR

R (

%)

16 mg/kg

ORR: 71%

9%CR orbetter

43%VGPR or

better

sCR CR VGPR PR

28%

33%

4%5%

CASTOR: PFS With Addition of Daratumumab to Vd

Palumbo A, et al. ASCO 2016. Abstract LBA4. Reproduced with permission.

PF

S (

%)

0

20

40

60

80

100

0 3 6 9 12 15

Mos

1-yr PFS

60.7%

26.9%DVdVd

Median PFS, MosNR7.2HR: 0.39 (95% CI: 0.28-0.53; P < .0001)

POLLUX: PFS with Addition of Daratumumab to Rd

63% reduction in the risk of disease progression or death for DRd vs Rd

Dimopoulos M, et al. EHA 2016. Abstract LB238.

PF

S (

%)

0

20

40

60

80

100

0 3 6 9 12 15 18 21Mos

Rd

DRd

12-mo PFS*

83%

60%

18-mo PFS*

78%

52%

HR: 0.37 (95% CI: 0.27-0.52; P < .0001)

Median PFS: 18.4 mos

Daratumumab in R/R MM: MRD Negativity

Daratumumab + Rd or Vd significantly improved MRD negativity rate vs Rd or Vd alone

MRD-negative events accumulated rapidly and increased over time (within 3-18 mos)

Avet-Loiseau H, et al. ASH 2016. Abstract 246.

MRD Negative, %POLLUX (N = 286) CASTOR (N = 251)

Dara + Rd Rd P Value Dara + Vd Vd P Value

All pts 10-4

10-5

10-6

31.824.811.9

8.85.72.5

< .0001< .0001< .0001

18.310.44.4

3.62.40.8

< .0001< .005< .05

Patients with ≥ CR 10-4

10-5

10-6

655226

422713

< .005< .005< .05

603716

35229

< .05----

By cytogenetic risk High* Standard

1830

010

< .005< .0001

1412

02

< .005< .005

*Includes pts with t(4;14), t(14;16), or del(17p).


Lower risk of progression in pts who achieve MRD negativity, regardless of therapy

– DRd MRD-negative pts (n = 71); estimated 12-mo PFS > 90%

– DVd MRD-negative pts (26); estimated 12-mo PFS > 90%

– Rd MRD-negative pts (n = 16 in POLLUX and n = 6 in CASTOR); estimated 12-mo PFS > 90%

Daratumumab + Rd or Vd shows PFS benefit in MRD-positive pts over doublets alone

– POLLUX: estimated median PFS NR vs 17 months for DRd MRD-positive (n = 215) vs Rd MRD-positive pts (n = 267)

– CASTOR: estimated median PFS NR vs 7 months for DVd MRD-positive (n = 225) vs Vd MRD-positive pts (n = 241)

Daratumumab in R/R MM: PFS

Avet-Loiseau H, et al. ASH 2016. Abstract 246.

Daratumumab

Anti‐CD38 mAb, approved as combination in patients that have received 1 prior line of therapy and as monotherapy who have had at least 3 prior lines of therapy containing a PI and an IMiD (or who are double refractory)

Intravenous infusion

Pre‐meds required

Interferes with RBC compatibility testing • Dithiothreitol (DTT) prevents this • Talk to blood bank

Subcutaneous daratumumab studies ongoing (prelim efficacy similar and no new safety signals)

Multiple ongoing studies in combinations

Panobinostat/bortezomib/dex Vs Bortezomib/dex

• Randomized, multicenter, placebo‐controlled, double‐blind phase III trial

Pts with symptomatic

RRMM after 1-3 prior treatments

(bortezomib-refractory excluded)(N = 768)

Panobinostat20 mg Days 1, 3, 5 of Wks 1, 2

Bortezomib1.3 mg/m2 IV Days 1, 4 of Wks 1, 2

Dexamethasone 20 mg Days 1, 2, 4, 5 of Wks 1, 2

(n = 387)

Placebo Days 1, 3, 5 of Wks 1,2

Bortezomib 1.3 mg/m2 IV Days 1, 4 of Wks 1, 2

Dexamethasone 20 mg Days 1, 2, 4, 5 of Wks 1, 2

(n = 381)

San-Miguel JF, et al. Lancet Oncol. 2014;15:1195-1206.

Panobinostat 20 mg Days 1, 3, 5 of Wks 1, 2, 4, 5

Bortezomib 1.3 mg/m2 IV Day 1 of Wks 1, 2, 4, 5

Dexamethasone 20 mg Days 1, 2 of Wks 1, 2, 4, 5

Phase I: Eight 3-wk cycles Phase II: Four 6-wk cycles

Placebo Days 1,3,5 of Wks 1, 2, 4, 5

Bortezomib 1.3 mg/m2 IV Day 1 of Wks 1, 2, 4, 5

Dexamethasone 20 mg Day 1 of Wks 1, 2, 4, 5

≥ SD

≥ SD

Phase III PANORAMA-1 Trial: PFS, OS With Addition of Panobinostat to Vd

Primary endpoint reached: median PFS ↑ by 3.9 mos

Median OS ↑ by 4.5 mos: NS

1. San-Miguel JF, et al. Lancet Oncol. 2014;15:1195-1206.2. San-Miguel JF, et al. ASH 2015. Abstract 3026.

100

80

60

40

20

0Pro

bab

ility

of

PF

S (

%)

0 4 8 12 16 20 24 28 32 36

Mos

Pan + Vd

Placebo + Vd

12.0 (10.3-12.9)

8.1 (7.6-9.2)

0.63(0.52-0.76)

< .0001

P ValueHR

(95% CI)Median PFS, Mos (95% CI)Arm

Pan + VdPlacebo + Vd

PFS[1]

Pro

bab

ility

of

OS

(%

)

Mos

0.94(0.78-1.14) .5435

P ValueHR

(95% CI)Median OS,

Mos (95% CI)Arm

40.3 (35.0-44.8)

35.8 (29.0-40.6)

OS[2]

100

80

60

40

20

0

Pan + VdPlacebo + Vd

0 8 16 24 32 40 48 56 64

Pan + Vd

Placebo + Vd


Survival and Response ratesAE, %

Panobinostat

(n = 381)

Placebo

(n = 377)

Any grade 3/4 AE 96 82

Grade 3/4 nonhematologic AEs

Diarrhea 25 8

Asthenia or fatigue 24 12

Grade 3/4 hematologic AEs

Thrombocytopenia 68 31

Neutropenia 35 11

Serious AE 60 42

Discontinuation due to AE 24 12

Boxed Warning: increased risk of serious and potentially fatal diarrhea, cardiac ischemic events, and severe arrhythmiasApproved by the FDA for patients with MM who have received at least two prior therapies, including bortezomib and an immunomodulatory agent

San-Miguel JF, et al. Lancet Oncol. 2014;15:1195-1206.

New Novel Agents

Selinexor Mechanism of Action

XPO1 is the nuclear exporter for the majority of TSPs, the GR, and eIF4E-bound oncoprotein mRNAs

Selinexor is a first-in-class XPO1 inhibitor that induces nuclear retention and activation of TSPs and the GR in the presence of steroids and suppresses oncoprotein expression

CYTOSOL

NUCLEUS

Nuclear pore complex

Nuclear envelope Tumor

suppressors

SINE

XPO1

Tumor suppressors

p53Par-4PP2ApRB

p21IkBBRACA1p27

eIF4E

XPO1

Tumor suppressors

Vogl DT, et al. ASH 2016. Abstract 491. Reproduced with permission.

STORM (Selinexor Treatment of Refractory Myeloma): Study Design

Phase II clinical trial: selinexor plus low-dose dexamethasone for heavily pretreated patients with MM refractory to most recent treatment (N = 79; median age: 68 yrs)

– Quad: refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide

– Penta: quad refractory and also daratumumab or isatuximab (anti-CD38 antibodies)

Treatment: selinexor 80 mg plus dexamethasone 20 mg twice weekly; reductions or interruption as needed for toxicity

– Group 1: 6 doses/28-day cycle (3 wks on/1 wk off)

– Group 2: 8 doses/28-day cycle (4 wks continuously)

Primary endpoints: ORR and DoR (IRC assessed)

Secondary endpoints: PFS and OS

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


ORR: 21%CBR: 33%

515

13

35

12

21

417

8

44

8

19

713

20

20

17

23

614

10

41

8

22

419

19

22

19

19

STORM: Efficacy

Median time to response: 1 mo

Median DoR: 5 mos


100

80

60

40

20

0Overall(n = 78)

Quad(n = 48)

Penta(n = 30)

6 Doses per mo(n = 51)

8 Doses per mo(n = 27)

VGPRPRMRSDPDNE

Pts

(%

)

ORR: 21%CBR: 29%

ORR: 20%CBR: 40%

ORR: 20%CBR: 29%

ORR: 22%CBR: 41%

ORR: 38%CBR: 63%

STORM: Responses by Cytogenetic Risk


*1 pt with t(14;16) achieved PR; 1 pt with del(17p) and t(14;16) had PD (not included in graph).

514

23

50

9

6

29

18

35

12

13

25

25

25

13

50

50

33

67

100

80

60

40

20

0Standard

Risk(n = 22)

All High Risk*

(n = 17)

Del (17p)(n = 8)

t(4;14)(n = 4)

Del(17p) and

t(4;14) (n = 3)

VGPRPRMRSDPD

Pts

(%

)

ORR: 18%CBR: 41%

CBR: 33%

ORR: 35%CBR: 53%

ORR: 50%

STORM: OS and PFS

Median OS for all pts: 9.3 mos, ≥ MR: not reached

Median PFS for all pts: 2.3 mos, ≥ MR: 5.5 mos

OS and PFS: All Pts

OS (all)PFS (all)

N = 78Su

rviv

al (

%)

100

50

0200 5 10 15

Mos Following Initiation of Selinexor Treatment

OS and PFS: Pts with ≥ MR

OS ( ≥ MR)PFS ( ≥ MR)

N = 26Su

rviv

al (

%)

100

50

0200 5 10 15

Mos Following Initiation of Selinexor Treatment

Vogl DT, et al. ASH 2016. Abstract 491. Reproduced with permission.

Selinexor

Ongoing study with an expansion phase to include >100 penta-refractory patients

? Possibly the next agent to get approval


Venetoclax Monotherapy for Relapsed/Refractory MM: Phase I Study Design

Pts with previously treated MM with measurable disease;

ECOG PS 0/1 and adequate organ function (N = 66)

Venetoclax 50 mg*Venetoclax 300 mg*Venetoclax 100 mg*





Accelerating lead-inTest dose cycle 1+

21 days/cycle

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

(Safety cohort; n = 36)

*Pts who progressed on venetoclax could add dexamethasone and continue on study.

(n = 9)

(n = 6)

(n = 9)

(n = 6)

Primary objectives: safety, tolerability, MTD, recommended phase 2 dose, PK

Secondary objectives: ORR, TTP, DoR, pharmacodynamics, predictive biomarker analysis

Venetoclax Monotherapy for Relapsed/Refractory MM: TTP and DoR

Kumar S, et al. ASH 2016. Abstract 488. Reproduced with permission.

No. at riskNo. at riskNo. at risk

663036

332013

27198

20173

16133

972

321

11

11

11

11

11

TTP

No

t P

rog

ress

ed (

%)

100

80

60

40

20

00 2 4 6 8 10 12 14 16 18 20 22 24

Mos Since First Dose

All ptst(11;14)Non-t(11;14)

No. at riskNo. at risk

915

911

911

98

95

62

3 2 2 2 2 1

TTP

No

t P

rog

ress

ed (

%)

100

80

60

40

20

00 2 4 6 8 10 12 14 16 18 20 22 24

Mos Since First Dose

High BCL2:BCL2L1Low BCL2:BCL2L1

Gene expression ratioamong t(11;14) pts

Pembrolizumab/Pomalidomide/Dexamethasone for R/R MM: Background PD-1/PD-L1 pathway blockade being exploited in several cancers to

restore cytotoxic T-cell activity and anticancer immunity[1]

Pembrolizumab: humanized anti–PD-1 monoclonal antibody

Pomalidomide: immunomodulatory thalidomide analogue indicated in combination with dexamethasone for pts with MM and ≥ 2 previous treatments including lenalidomide and a PI with progression ≤ 60 days of last regimen

Current study evaluates the safety and efficacy of pembrolizumab combined with pomalidomide and dexamethasone in pts with R/R MM[2]

1. Boussiotis VA. N Engl J Med. 2016;375:1767-1778. 2. Badros AZ, et al. ASH 2016. Abstract 490.

Pembrolizumab/Pomalidomide/Dexamethasone for R/R MM: Study Design Exploratory trial

Primary endpoint: safety

Secondary endpoints: ORR, PFS, OS

Exploratory endpoints: correlation of BL levels of PD-1 and PD-L1 in BM with response

Badros AZ, et al. ASH 2016. Abstract 490.

Pts with R/R MM and 2 lines of previous tx including IMiD and

PI; ECOG PS < 2 and adequate organ function;

no active autoimmune disease requiring treatment or history of

severe autoimmune disease(N = 48)

Pembrolizumab* 200 mg IV Days 1, 14 +Pomalidomide 4 mg PO Days 1-21 +

Dexamethasone 40 mg† PO Days 1, 7, 14, 21Q28D

Mo 24

Pembrolizumab 200 mg IV/mo +Pomalidomide 4 mg PO +

Dexamethasone 40 mg† PO

*First 6 pts received pembrolizumab on Day 1 only.

Responders

†Pts > 70 yrs of age received 20 mg.


Pembrolizumab/Pomalidomide/Dexamethasone for R/R MM: Efficacy


Response, % Full Efficacy Population

(N = 45)

Refractory to 2 Classes(n = 32)

High-Risk Cytogenetics

(n = 27)

ORR 65 68 56

Clinical benefit 72 69 60

Best response sCR CR VGPR PR MR SD PD

72

20367

235

33

18443

224

744

414

317

sCR + CR + VGPR, % 29 24 15

Pembrolizumab/Pomalidomide/Dexamethasone for R/R MM: Duration of Response and Survival

PFS significantly longer in low-risk vs high-risk subgroups (P = .0366)


Outcome, Mos (95% CI) Full Efficacy Population(N = 45)

Median duration of response 16.3 (9.9-19.1)

Median PFS 17.4 (11.7-18.8)

Median OS Not reached (18.8-not reached)

The ‘Iceberg Hypothesis’ of multiple myeloma


Multiple Myeloma Clinical Trials at CTRC

Relapsed/Refractory Multiple Myeloma• An Open-Label, Randomized Phase 3 Trial of

Combinations of Nivolumab, Elotuzumab, Pomalidomide and Dexamethasone in Relapsed and Refractory Multiple Myeloma

• ACY-241: A selective oral HDAC6 inhibitor given with Pomalidomide and dexamethasone. All oral regimen.

Untreated Multiple Myeloma • Phase III trial Daratumumab in combination with

Revlimid/dexamethasone vs. Revlimid/ dexamethasone.

• E1A11 Endurance (VRd vs CRd) – A study comparing VRd vs. CRd followed by lenalidomidemaintenance for up to 24 cycles or until progressive disease or excessive toxicities in newly diagnosed MM of standard risk

Thank you for your attention!

ELOQUENT-2: Background

Elotuzumab: anti-SLAMF7 monoclonal antibody that acts via dual mechanism

– Directly activates natural killer cells

– Myeloma cell destruction by ADCC

In primary study analysis, elotuzumab + len/dex reduced risk of progression or death by 30% vs len/dex[1]

Elotuzumab approved November 30, 2015, for use with len/dex in pts with MM and 1-3 prior therapies[2]

Current analysis presents extended 3-yr safety and efficacy follow-up[3]

1. Lonial S, et al. N Engl J Med. 2015;373:621-631. 2. FDA.gov. Accessed December 5, 2015. 3. Dimopoulos MA, et al. ASH 2015. Abstract 28.

ELOQUENT-2: Background

Elotuzumab: anti-SLAMF7 monoclonal antibody that acts via dual mechanism

– Directly activates natural killer cells

– Myeloma cell destruction by ADCC

In primary study analysis, elotuzumab + len/dex reduced risk of progression or death by 30% vs len/dex[1]

Elotuzumab approved November 30, 2015, for use with len/dex in pts with MM and 1-3 prior therapies[2]

Current analysis presents extended 3-yr safety and efficacy follow-up[3]

1. Lonial S, et al. N Engl J Med. 2015;373:621-631. 2. FDA.gov. Accessed December 5, 2015. 3. Dimopoulos MA, et al. ASH 2015. Abstract 28.


Bahlis NJ Blood 2012;120(5);927-928

Myeloma evolution and alternating clonal dominanceClonal heterogeneity

Keats JJ et. Al. Blood 2012;120(5);1067-76

How close is a cure?

MRD

Attal M, et al. ASH 2015. Abstract 391. Slide credit: clinicaloptions.com

IFM 2009: OS

Pts (%)

Follow‐up (Mos)

ASCTNo ASCT

100

80

60

40

20

00 12 24 36 48

P = NS

350350

328338

309320

226244

5556

Pts at Risk, nASCT

No ASCT


Retreatment with Immunomodulatory drugs

Madan et. al. Blood 2011 Aug 18;118(7):1763-5

Len

LenN=48

Thal

LenN=58

Len

ThalN=11

Thal

ThalN=23

>Partial Response

54% 48% 20% 30%

Retrospective study in 140 patients treated with first line Len/dex (59; 42%) or Thal/dex (81; 58%)Retreatment with a regimen containing Lenalidomide (76%) and Thalidomide (24%)# of treatments before retreatment – median 2 (range 1‐6)Median time from diagnosis to repeat exposure was 28 months

Overall Survival has Improved in the Past Decade

<65 yrs >65 yrs

2006‐2010 73 56

2001‐2005 63 31

6 yr survival, %age

Meta‐analysis of 5 RCT (PANORAMA‐1, MMVAR, ASPIRE, ELOQUENT‐2, TOURMALINE‐MM1)



Aim of treatment is to prevent organ damage and it’s complications

Courtesy Rafael Fonseca MD

High Calcium, Renal (kidney) failure, Anemia, Bone lesions

‘CRAB’ criteria

IMWG ultra high‐risk that is now MM

GEM SMM trial ‘high‐

risk’

Low risk smoldering myeloma

(MGUS like)

Improved PFS and OS with Novel agents (thalidomide, lenalidomide, bortezomib) compared to conventional chemotherapy and improvement with maintenance

Old Regimen New regimen with novel agents

ORR 50‐60 80‐100

CR 16‐25 40‐60

VGPR 5‐10 20‐30

PFS 15 months 25‐30 mos (improved to >48 months with maintenance)

5 year OS 30‐35 50‐70

• Palumbo et al Lancet, 2006; Mateos Blood 2010; McCarthy NEJM 2012; Attal NEJM, 2012


Natural history of myeloma: the cycle of response, remission and relapse

Response

RemissionRelapse

Durie B; concise review of the disease and treatment options 2011/2012

What does relapsed, refractory mean?

• Relapsed and Refractory: progressing on therapy or within 60 days of last therapy

• Relapsed: progressing while off therapy

• How do we define disease progression?

‐ 25% increase from nadir in the monoclonal protein

‐ New bone abnormalities

‐ High calcium

‐ Kidney failure

‐Worsening blood counts (anemia)

Bahlis NJ Blood 2012;120(5);927-928

Patterns of Relapse


Treatment options

Steroids(Dex)

Chemotherapy

IMiDs

ProteasomeInhibitors

Monoclonal Antibodies

Lenalidomide

Bendamustine

Pomalidomide

Thalidomide

Cytoxan

ElotuzumabDaratumumab

Bortezomib Carfilzomib

Ixazomib

HDAC inhibitors

Panobinostat

Clarithromycin

Clinical trial enrollment a priority

Doxil

Changing the Treatment Landscape of MM (2000‐2016)Active Drugs and Combinations

1. Bortezomib

2. Thalidomide/dexamethasone (TD)

3. Lenalidomide/dexamethasone (Rd)

4. Bortezomib + liposomal doxorubicin

5. Bortezomib + melphalan/prednisone (VMP)

6. Revlimid + Melphalan/prednisone (MPR)

7. Bortezomib/dexamethasone (Vd)

8. Bortezomib/lenalidomide/dexamethasone (VRD)

9. Bortezomib/thalidomide/dexamethasone (VTD)

10. Cytoxan/bortezomib/dexamethasone (CyBorD)

11. Cytoxan/Revlimid/Dexamethasone (CyRevD)

12. Carfilzomib/Dex

13. Carfilzomib/Revlimid/dex (KRd)

14. Pomalidomide/dexamethasone

15. Carfilzomib/Pomalidomide/dex

16. Carfilzomib/Cytoxan/dex

17. Panobinostat/bortezomib/dexamethasone

18. Ixazomib/lenalidomide/dex

19. Elotuzumab/lenalidomide/dex

20. Daratumumab

Monoclonal AntibodiesDaratumumab

• CD38 is highly and ubiquitously expressed on myeloma cells1,2

• Daratumumab (DARA) is a human IgG1 monoclonal antibody (mAb) that binds to CD38‐ expressing malignant cells,

• Daratumumab depletes CD38+ immunosuppressive regulatory cells

• Promotoes T‐cell expansion and activation

• Induces cell death through multiple pathways including CDC,3 ADCC,3

ADCP4 and apoptosis5

1. Lin P, et al. Am J Clin Pathol. 2004;121:482‐88. 2. Laubach JP, et al. Expert Opin Investig Drugs. 2014;23:445‐52. 3. de Weers M, et al. J Immunol. 2011;186:1840‐48. 4. Overdijk MB, et al. MAbs. 2015;7:311‐21. 5. Jansen JH, et al. Blood.2012; 120. 2974

Adapted from Laubach JP, et al. Expert Opin Investig Drugs. 2014;23:445‐52


Dual mechanism of action of Elotuzumab

• Elotuzumab is a first‐in‐class humanized immunoglobulin G1 immunostimulatorymonoclonal antibody

• It targets signaling lymphocytic activation molecule F7 (SLAMF7, also called CS1, a glycoprotein expressed on myeloma and natural killer cells)

• It causes myeloma cell death via dual mechanism (NK cell activation and Tagging for Recognition)

Lonial et. al. N Engl J Med 2015; 373:621‐631

CASTOR: Study Design

Presented By Antonio Palumbo at 2016 ASCO Annual Meeting

Progression-free Survival


PFS: Subgroup Analysis



Where do we go from here?

Presented By Rafael Fonseca at 2016 ASCO Annual Meeting

Basic principles of selecting a treatment

Use new agent: Use drugs the patient has not received before

Using same drug in a different combination

Using another drug in the same class: patients progressing on thalidomide may respond to lenalidomide; those progressing on lenalidomide may respond to pomalidomide; those progressing on bortezomib may respond to carfilzomib

Increase dose: Patients progressing on lenalidomide at 10 mg may respond when dose is increased to 25 mg plus dexamethasone or addition of cyclophosphamide

Adding clarithromycin to lenalidomide, thalidomide or pomalidomide can be used to achieve a response

Richardson PG, et al. Blood. 2014;123:1461-1469 Berenson et. al. Leukemia (2014) 28, 1529–1536.

Nijhof IS, et al. ASH 2013. Abstract 287. Richardson P, et al. Blood. 2009;114-772-778.

• Calcium elevation (> 11.5 mg/L or ULN)

• Renal dysfunction, (serum creatinine >2 mg/dL)

• Anemia (Hb < 10 g/dL or 2g <normal)

• Bone disease (lytic lesions or osteoporosis)

Retreatment with Immunomodulatory drugs

Madan et. al. Blood 2011 Aug 18;118(7):1763-5

Len

LenN=48

Thal

LenN=58

Len

ThalN=11

Thal

ThalN=23

>Partial Response

54% 48% 20% 30%

Retrospective study in 140 patients treated with first line Len/dex (59; 42%) or Thal/dex (81; 58%)Retreatment with a regimen containing Lenalidomide (76%) and Thalidomide (24%)# of treatments before retreatment – median 2 (range 1‐6)Median time from diagnosis to repeat exposure was 28 months


What is new?

4 new drugs approved by the FDA in 2015 for relapsed myeloma

Panobinostat (Oral)

Ixazomib (Oral)

Daratumumab (IV)

Elotuzumab (IV)

Major drug categoriesImmunomodulatory drugs (IMiDs)

Proteasome Inhibitors (PI)

Steroids

Monoclonal Antibody (MoAb)

HDAC inhibitors

Conventional Chemotherapy

Treatment options in relapsed myeloma

Steroids(Dex)

Chemotherapy

IMiDs

ProteasomeInhibitors

Monoclonal Antibodies

Lenalidomide

Bendamustine

Pomalidomide

Thalidomide

Cytoxan

ElotuzumabDaratumumab

Bortezomib Carfilzomib

Ixazomib

HDAC inhibitors

Panobinostat

Clarithromycin

Clinical trial enrollment a priority

Doxil

3 vs 2 drugs in relapsed myeloma

Drug Class Study arm Control arm

Carfilzomib (27 mg/m2)

Proteasome Inhibitor Carfilzomib/lenalidomide/dex Lenalidomide/dex

Ixazomib Proteasome Inhibitor Ixazomib/lenalidomide/dex Lenalidomide/dex

Elotuzumab Monoclonal Antibody Elotuzumab/lenalidomide/dex Lenalidomide/dex

Panobinostat HDAC inhibitor Panobinostat/bortezomib/dex Bortezomib/dex


Natural history of myeloma: the cycle of response, remission and relapse

Response

RemissionRelapse

Durie B; concise review of the disease and treatment options 2011/2012

multiple myeloma after ash 2016 - office of continuing ...cme.uthscsa.edu/courses/panao/2017/online...

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