Management of Multiple Myeloma: The Changing Paradigm · Management of Multiple Myeloma: The Changing Paradigm Relapsed/Refractory Disease. Patient Case • A 64-yr-old woman comes

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Management of Multiple Myeloma: The Changing Paradigm

Relapsed/Refractory Disease

Patient Case• A 64-yr-old woman comes with relapsed

myeloma. Her history is as follows:

– Initial studies 3 years ago showed 55% plasma cells in the bone marrow, hyperdiploidy, IgGκ 3.5 g/dL, and multiple lytic lesions

– Initially treated with RVD, followed by high-dose melphalan and peripheral blood stem cell transplantation

– She achieved a CR and was on observation

– 3 yrs later, M-protein reappears to 1.5 g/dL

• What is the right choice of therapy for her?

– Carfilzomib/lenalidomide/dex

– Ixazomib/lenalidomdie/dex

– Elotuzumab/lenalidomide/dex

– Evaluation for clinical trial

What Is Relapsed/Refractory Disease?

• Relapsed: recurrence after a response to therapy

• Refractory: progression despite ongoing therapy

• Relapsed and refractory: progression among patients who achieve minor response or better, or who progress within 60 days of their last therapy

• Primary refractory: Patients who never achieve at least a MR to initial induction therapy and progress while on therapy

Treatment options for relapsed and refractory

myelomaConsider

clinical

trial

Prior

SCT

Transplant eligible; has good PS

• Primary refractory- SCT

• Relapsed/refractory- SCT

Transplant ineligible

-If patient has previously responded to

the therapy, tolerated and relapsed at

least 6 months after prior drug

exposure

• repeat prior therapy

- Otherwise, consider

• *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

Subseque

nt relapse

*NCCN category 1 recommendations; RVD: lenalidomide, bortezomib and dexamethasone; VTD: bortezomib, thalidomide and dexamethasone, CFZ: carfilzomib; CRD: carfilzomib,

lenalidomide and dexamethasone; CPD: carfilzomib, pomalidomide and dexamethasone VCD: bortezomib, cyclophosphamide and dexamethasone; RCD: lenalidomide,

cyclophosphamide and dexamethasone; DCEP±V: dexamethasone, cyclophosphamide, etoposide, and cisplatin ± bortezomib; DT-PACE±V: dexamethasone, thalidomide,

cisplatin, doxorubicin, cyclophosphamide, and etoposide ± bortezomib; Pd: pomolidomide and dexamethasone; Td: thalidomide and dexamethasone; PLD: liposomal doxorubicin,

PS: performance ststus; SCT: autologous stem cell transplant; PFS: progression free survival; SCT2: second SCT

SCT2

Relapse

within 36

months

Relapse

beyond 36

months

Relapse

beyond

18-24

months

Relapse

within

18-24

months

Subsequent

relapse

Subsequent

relapse

Subseque

nt 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

Options for Relapsed/Refractory Disease Continue to Increase

When did you relapse from your initial therapy?

≤6 months

Different therapy

Stem cell transplant

>6 months

Stem cell transplant

Different therapy

Repeat initial therapy

Clinical trial

Factors to Consider in Treatment Selection

DISEASE-RELATED

• DOR to initial therapy• FISH/cytogenetics/genomics profile

PRIOR TREATMENT–RELATED

• Prior drug exposure• Toxicity of regimen• Mode of administration• Previous SCT

PATIENT-RELATED

• Pre-existing toxicity• Presence of other conditions• Age• General health• Personal lifestyle and preferences

DOR, duration of response; FISH, fluorescence in situ hybridization; SCT, stem cell transplantLonial S. Hematology Am Soc Hematol Educ Program. 2010;303.

Options at First Relapse

Proteasome Inhibitor:Kyprolis (carfilzomib)

*Overall response rate = complete response (CR) + very good partial response (VGPR) + partial response (PR) + minimal response (MR)

• Used alone (after two or more therapies):

− 23% overall response rate (CR + VGPR + PR + MR)

− On average, responses last 7.8 months

• In patients who have never received Velcade:

− 42% overall response rate

− On average, responses last 13 months

How effective is it?

• In combination with dex or with Revlimid + dex for the treatment of patients with relapsed or refractory MM who have received one to three lines of therapy

• As a single agent for the treatment of patients with relapsed or refractory MM who have received one or more lines of therapy

FDA-approved indication

• Standard: Kyprolis used alone or in combination with dex or in combination with Revlimid and dex

• Under investigation: combinations with Farydak, IMiDs such as Revlimid and Pomalyst, experimental therapies (for example, SAR650984, filanesib)

What combinations are used?

• High-risk features (for example, t(4;14) or 17p13 del or elevated β2-microglobulin)

• History of previous neuropathy

• Safe for patients with reduced kidney function

Who should take it?

Kyprolis (carfilzomib)

• Carfilzomib FDA approved in 2012 for treatment of

MM after ≥ 2 previous therapies, including bortezomib

and an IMiD, and with progression on or within 60 days

of treatment

1. Siegel DS, et al. Blood. 2012;120:2817-2825.

2. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.1.2014.

PFS

0 2.5 5.0 7.5 10.0 12.5 15.0 17.5

100

75

50

25

0

Median PFS: 3.7 mos (95% Cl: 2.8-4.6)

Mos From Start of Treatment

Pts

Alive a

nd

Wit

ho

ut

Pro

gre

ssio

n (

%)

Censored observations

Confidence band

• Approval based on single-arm

phase II PX-171-003 study (N =

266): ORR of 23.7% and median

DOR of

7.8 mos[1]

• Intravenously given on two

consecutive days each week for

three weeks (that is, days 1, 2, 8,

9, 15, and 16) followed by a 12-day

rest period (days 17–28)

Integrated Safety Profile of Single-Agent Carfilzomib (N=526)

4 phase II studies (PX-171-003-A0, PX-171-003-A1, PX-171-004, and PX-171-005)

Tolerable safety profile allows for administration of full-dose carfilzomib with low discontinuation rates

Siegel D, et al. Hematologica. 2013;98:1753-1761.

Select AEs, % All Grades Related Grade 3/4 Serious AE

Fatigue 55.5 41.4 7.6 0

Anemia 46.8 26.8 22.4 1.3

Nausea 44.9 35.2 1.3 0

Any cardiac event

Cardiac failure

22.1

7.2

NR 9.5

5.7

7.8

4.9

Any respiratory event

Dyspnea

69.0

42.2

NR 10.3

4.9

6.5

2.1

Any renal impairment

Serum creatinine

Acute renal failure

33.1

24.1

5.3

NR 7.2

2.7

4.4

6.1

1.3

4.2

Peripheral neuropathy 13.9 NR 1.3 NR

Berenson J, ASH 2015 Abst 373

CarfilzomibDays 1, 8, and 15

Duration of infusion: 30 minutes

and

Dexamethasone IV or PODays 1, 8, 15, and 22 (day 22 omitted for cycles 9+)

Both drugs given until PD or unacceptable toxicity

IV, intravenous; MTD, maximum tolerated dose; PD, progressive disease: PO, per oral.

Treatment Schedule (Phase 1 and 2)

Carfilzomib (mg/m2)a Dexamethasone (mg)

Phase 1 (3+3 dose-escalation schema)

Dose level 1 45 40

Dose level 2 56 40

Dose level 3 70 40

Dose level 4 88 40

Phase 2 MTD from phase 1 40aCarfilzomib 20 mg/m2 was administered to all patients on only cycle 1 day 1.

Dosing

28 day cycles:

CHAMPION-1 Study Design

• Median follow-up: 13.2 months

Median PFS (95% CI): 14.3 months (9.9–21.0)

1.00

0.75

0.50

0.25

0.00

Pro

po

rtio

n P

rog

ressio

n-F

ree

0 6 12 18 24

Time (months)

30

PFS ORR

Phase 1–2

70 mg/m2

(N=104)

Best overall response, n (%)

sCR 5 (5)

CR 13 (13)

VGPR 31 (30)

PR 31 (30)

MR 7 (7)

SD 12 (12)

PD 2 (2)

NE 3 (3)

ORR, % (95% CI) 77 (68–85)

CBR, % (95% CI) 84 (75–90)

≥VGPR=47%

DOR (≥PR), median months (95% CI) 16.3 (12.7–NA)

TTR (≥PR), median months (range) 1.6 (0.7–7.2)

ORR and CBR in Btz refr: 63% & 76% respect.

Berenson J, ASH 2015 Abst 373

Efficacy

ENDEAVOR Study Design

Vd

Bortezomib 1.3 mg/m2 (3–5 second IV bolus or subcutaneous injection)

Days 1, 4, 8, 11

Dexamethasone 20 mg

Days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycles until PD or unacceptable toxicity

Kd

Carfilzomib 56 mg/m2 IV

Days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only)

Infusion duration: 30 minutes for all doses

Dexamethasone 20 mg

Days 1, 2, 8, 9, 15, 16, 22, 23

28-day cycles until PD or unacceptable toxicity

Randomization 1:1

N=929

Stratification:

• Prior proteasome

inhibitor therapy

• Prior lines of

treatment

• ISS stage

• Route of V

administration

Dimopoulos M, J Clin Oncol 33, 2015 (suppl; abstr 8509)

Primary End Point: Progression-Free SurvivalIntent-to-Treat Population (N=929)

1.0

0.8

0.6

0.4

0.2

0

Pro

port

ion S

urv

ivin

g

Without P

rogre

ssio

n

0

Months Since Randomization

Kd

Vd

Kd

(n=464)

171 (37)

18.7

Vd

(n=465)

243 (52)

9.40.53 (0.44–0.65); 1-sided P<0.0001

Disease progression or death – n (%)

Median PFS – months

HR for Kd vs Vd (95% CI)

• Median follow-up: 11.2 months

6 12 18 24 30

Dimopoulos M, J Clin Oncol 33, 2015 (suppl; abstr 8509)

ASPIRE Study Design

Rd

Lenalidomide 25 mg Days 1–21

Dexamethasone 40 mg Days 1, 8, 15, 22

KRd

Carfilzomib 27 mg/m2 IV (10 min)

Days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only)

Lenalidomide 25 mg Days 1–21

Dexamethasone 40 mg Days 1, 8, 15, 22

Randomization

N=792

Stratification:

• β2-microglobulin

• Prior bortezomib

• Prior lenalidomide

After cycle 12, carfilzomib given on days 1, 2, 15, 16

After cycle 18, carfilzomib discontinued

28-day cycles

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

Primary Endpoint: Progression-Free SurvivalITT Population (N=792)

1.0

0.8

0.6

0.4

0.2

0.0

Pro

port

ion S

urv

ivin

g

Without

Pro

gre

ssio

n

KRd

Rd

0 6 12 18 24 30 36 42 48

Months Since Randomization

KRd Rd

(n=396) (n=396)

Median PFS, mo 26.3 17.6

HR (KRd/Rd) (95% CI) 0.69 (0.57–0.83)

P value (one-sided) <0.0001

No. at Risk:

KRd

Rd

396 332 279 222 179 112 24 1

396 287 206 151 117 72 18 1

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

Proteasome Inhibitor:Ninlaro (ixazomib)

• 78% overall response rate (PR or better)How effective is it?

• In combination with Revlimid and dex for the treatment of patients with MM who have received at least one prior therapy


• Standard: With Revlimid and dex

• Under investigation: with Treanda or Pomalyst in RR patients or with Revlimid in newly diagnosed patients


• Relapsed or relapsed/refractory following at least one prior therapy Who should take it?

TOURMALINE-MM1:

Ra

nd

om

iza

tio

n

Ixazomib + Lenalidomide + Dexamethasone

Ixazomib: 4 mg on days 1, 8, and 15

Lenalidomide: 25 mg* on days 1-21

Dexamethasone: 40 mg on days 1, 8, 15, 22

N=722

1:1

Placebo + Lenalidomide + Dexamethasone

Placebo: on days 1, 8, and 15

Lenalidomide: 25 mg* on days 1-21

Dexamethasone: 40 mg on days 1, 8, 15, 22

Repeat every 28 days until progression, or

unacceptable toxicity

Stratification:

• Prior therapy: 1 vs 2 or 3

• ISS: I or II vs III

• PI exposure: yes vs no

Global, double-blind, randomized, placebo-controlled study design

*10 mg for patients with creatinine clearance ≤60 or ≤50 mL/min, depending on local label/practice

1. Rajkumar S, et al. Blood 2011;117:4691–5.

Response and progression (IMWG 2011

criteria1) assessed by an independent

review committee (IRC) blinded to both

treatment and investigator assessment

Primary endpoint:

• PFS

Key secondary endpoints:

• OS

• OS in patients with del(17p)

Moreau P, NEJM Apr 28 2016

Phase 3 study of weekly oral ixazomibplus lenalidomide-dexamethasone

TOURMALINE-MM1:

A significant, 35% improvement in PFS with IRd vs placebo-Rd

Number of patients at risk:

IRd

Placebo-Rd

360 345 332 315 298 283 270 248 233 224 206 182 145 119 111 95 72 58 44 34 26 14 9 1 0

362 340 325 308 288 274 254 237 218 208 188 157 130 101 85 71 58 46 31 22 15 5 3 0 0

1.0

0.8

0.6

0.4

0.2

0.0

0 1 2 3 4 5 6 7 8 9 1

0

1

1

1

2

1

3

1

4

1

5

1

6

1

7

1

8

1

9

2

0

2

1

2

2

2

3

2

4

Pro

bab

ilit

y o

f p

rog

ressio

n-f

ree s

urv

ival

Time from randomization (months)

Log-rank test p=0.012

Hazard ratio (95% CI): 0.742 (0.587, 0.939)

Number of events: IRd 129; placebo-Rd 157

Median PFS:

IRd: 20.6 months

Placebo-Rd: 14.7 months

Median follow-up: ~15 months

Interim OS analysis @ 23 months of FU: 81 and 90 deaths in ixazomib and placebo, respectively


Final PFS analysis

TOURMALINE-MM1:

Response rates IRd (N=360) Placebo-Rd (N=362) p-value

Confirmed ORR (≥PR), % 78.3 71.5 p=0.035

CR+VGPR, % 48.1 39.0 p=0.014

Response categories

CR, % 11.7 6.6 p=0.019

PR, % 66.7 64.9 –

VGPR, % 36.4 32.3 –

Median time to response, mos 1.1 1.9 –

Median duration of response, mos 20.5 15.0 –

Median TTP, mos 21.4 15.7 HR 0.712

P=0.007


Improved response rates, durable responses, and improved time to progression (TTP) with IRd

Proteasome Inhibitor:Ninlaro (ixazomib)

• Common side effects include:

− Diarrhea

− Constipation

− Thrombocytopenia

− Peripheral neuropathy

− Nausea

− Peripheral edema

− Vomiting

− Back pain

What are the possible side effects?

• Oral

• Days 1, 8, and 15 of a 28-day cycle

How is Ninlaro administered?

Antibody-dependent

Cellular cytotoxicity

(ADCC)

ADCC

Effector cells:

MM

FcR

Complement-dependent

Cytotoxicity (CDC)

CDC

MM

C1q

C1q

Apoptosis/growth arrest

via targeting

signaling pathways

MM

• Lucatumumab or Dacetuzumab (CD40)

• Elotuzumab (CS1)

• Daratumumab (CD38)

• XmAb5592 (HM1.24)

• huN901-DM1 (CD56)

• nBT062-maytansinoid

(CD138)

• 1339 (IL-6)

• BHQ880 (DKK1)

• RAP-011 (activin A)



MAb-Based Therapeutic Targeting of Myeloma

Tai & Anderson Bone Marrow Research 2011

Monoclonal Antibody:Empliciti (elotuzumab)

• 78.5% overall response rate (PR or better)How effective is it?

• In combination with Revlimid and dex for the treatment of patients with MM who have received one to three prior therapies


• Standard: with Revlimid and dex

• Under investigation: with Revlimid and Velcade in newly diagnosed patients; with Pomalyst and nivolumab or Pomalyst and Velcade in RR patients


• Relapsed or relapsed/refractory following at least one to three prior therapies

Who should take it?

ELOQUENT-2 Study Design

• Open-label, international, randomized, multicenter, phase 3 trial (168 global sites)

• Endpoints:

– Co-primary: PFS and ORR

– Other: overall survival (data not yet mature); duration of response, quality of life, safety

• All patients received premedication to mitigate infusion reactions prior to Elo administration

Key inclusion criteria

• RRMM

• 1–3 prior lines of therapy

• Prior Len exposure permitted in 10% of study population (patients not refractory to Len)

Elo plus Len/Dex (E-Rd) schedule (n=321)

Elo (10 mg/kg IV): Cycle 1 and 2: weekly;

Cycles 3+: every other week

Len (25 mg PO): days 1–21

Dex: weekly equivalent, 40 mg

Len/Dex (Rd) schedule (n=325)

Len (25 mg PO): days 1–21;

Dex: 40 mg PO days 1, 8, 15, 22

Repeat every 28 days

Assessment

• Tumor response:

every 4 wks until

progressive

disease

• Survival: every

12 wks after

disease

progression

Lonial S, et al. N Engl J Med June 2nd 2015

Co-Primary Endpoint: Progression-Free Survival

PFS analysis used the primary definition of PFS

E-Rd-treated patients had a 30% reduction in the risk of disease progression or

death; treatment difference at 1 and 2 years was 11% and 14%, respectively

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

380 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

No. of patients at risk:

E-Ld

Ld321

325

303

295

279

249

259

216

232

192

215

173

195

158

178

141

157

123

143

106

128

89

117

72

85

48

59

36

42

21

32

13

12

7

7

2

57%

68%

27%

41%

1-year PFS 2-year PFS

PFS (months)

Pro

bab

ilit

y p

rog

ressio

n f

ree

E-Rd

Rd

0

0

1

0

E-Rd Rd

Hazard ratio = 0.70 (95% CI: 0.57, 0.85)

P=0.0004

Median

PFS

(95% CI)

19.4 mo

(16.6, 22.2)

14.9 mo

(12.1, 17.2)

Lonial S, et al. N Engl J Med June 2nd 2015

E-Ld Ld

HR 0.73 (95% CI 0.60, 0.89); p=0.0014

Median PFS

(95% CI)

19.4 mos

(16.6, 22.2)

14.9 mos

(12.1, 17.2)

PFS benefit with E-Ld was maintained over time (vs Ld):

• Overall 27% reduction in the risk of disease progression or death

• Relative improvement in PFS of 44% at 3 years

0.0

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

480 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

No. of patients at risk:

E-Ld

Ld

321

325

293

266

259

215

227

181

171

130

144

106

125

80

107

67

94

60

85

51

59

36

34

15

19

7

8

3

PFS (months)

Pro

bab

ilit

y p

rog

res

sio

n f

ree

3

0

195

157

E-LdLd0.1

1-year PFS 2-year PFS 3-year PFS

0

0

68%

41%

26%

57%

27%

18%

ELOQUENT-2

Dimopoulos M, ASH 2015 Abst 28

Extended Progression-Free Survival

Monoclonal Antibody:Empliciti (elotuzumab)


− Fatigue

− Diarrhea

− Pyrexia

− Constipation

− Cough


− Nasopharyngitis

− Upper respiratory tract infection

− Decreased appetite

− Pneumonia


• IV

• Every week for the first 2 cycles and every 2 weeks thereafter

How is Empliciti administered?

Options at Second Relapse and Beyond

IMiD: Pomalyst (pomalidomide)

*Overall response rate = complete response (CR) + very good partial response (VGPR) + partial response (PR) + minimal response (MR)

• Patients who received two or more prior therapies, including Velcade and an IMiD

− 29% overall response rate*

− On average, responses lasted 7.4 months

How effective is it?

• For MM patients who have received at least two prior therapies including Revlimid and Velcade and have demonstrated disease progression on or within 60 days of completion of the last therapy


• Standard: Pomalyst + dex

• Under investigation: combinations with Vel-dex, Kyprolis-dex; experimental drugs (for example, SAR650984, Filanesib, Ixazomib)


• Received two or more prior therapies, including Velcade and Revlimid

• High-risk myeloma with DNA alterations, including t(4;14); preliminary data indicates effectiveness in 17p13del

• Safe for patients with reduced kidney function

• Patients of all ages

Who should take it?

Pomalidomide + Low-Dose Dex in RRMM

• Pomalidomide + low-dose dexamethasone FDA approved in 2013 for treatment after ≥ 2 previous therapies (including lenalidomide and bortezomib) and progression during or within 60 days of treatment

– Approval based on phase II MM-002 study (N = 221) [1]: ORR of 33% with Pom + LoDexvs 18% with Pom[2]

– DoR of 8.3 mos with Pom + LoDex; 10.7 mos with Pom[2]

– Low rates of discontinuations due to AEs[2]

PFS[2]

Median PFS, Mos

4.2

2.7

Jagannath S, et al. ASH 2012. Abstract 450.

Richardson PG, et al. Blood. 2014;123:1826-1832.

Pom + LoDex

Pom

100

80

60

40

20

0

Pati

en

ts (

%)

0 2010 30

PFS (Mos)

HR: 0.68

P = .003

0.2

0.4

0.6

0.8

1.0

0.00.0

0.2

0.4

0.6

0.8

1.0

Phase 3 MM-003: POM + LoDEX vs HiDEXPFS and OS – ITT population

HiDEX, high-dose dexamethasone; LoDEX, low-dose dexamethasone;

POM, pomalidomide.

PFS (months)

Median PFS

POM + LoDEX (n = 302) 4.0 mos

HiDEX (n = 153) 1.9 mos

HR = 0.50

p < 0.001

4 8 12 16 20 240

Pro

po

rtio

n o

f p

ati

en

ts

OS (months)

Pro

po

rtio

n o

f p

ati

en

tsHR = 0.72

p = 0.009

4 8 12 16 20 24 280

Median OS

POM + LoDEX (n = 302) 13.1 mos

HiDEX (n = 153) 8.1 mos

Median follow-up 15.4 months• Median number of prior therapies 5

• >90% Len refractory, 75% Len + Bort refractory

1. San Miguel J, et al. Lancet Oncol. 2013;14:1055-1066.

2. Dimopoulos MA, et al. ASH 2013. Abstract 408.

Pomalidomide, bortezomib and dexamethasone: phase 1/2

Time (months)

100

80

40

20

0

60

Success (

%)

0 12 24 306 18

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%

4220

824

33

40

25

32

10

17

9

0

20

40

60

80

sCR/CRVGPRPR

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)

ORR and DOR2

Phase 1/2, pomalidomide, cyclophosphamide and dexamethasone: PFS

Median PFS: 9.5 vs 4.4 months (p = 0.1078)

Median OSa: not reached vs 16.8 months (p = 0.1308)

• Median number of prior therapies 4

• Must have been refractory to lenalidomide

• Refractory to bortezomib 71%

Pro

po

rtio

n

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. Blood. 2016.

IMiD: Pomalyst (pomalidomide)

*Reduced risk when taken with blood thinners


− Fatigue and weakness

− Low white blood cell counts

− Anemia

− Gastrointestinal effects (constipation, nausea, or diarrhea)

− Shortness of breath

− Upper respiratory infection

− Back pain

− Fever

− Blood clots*


• Capsule taken once daily for 21 days out of a 28-day cycle (3 weeks on, 1 week off)

• Blood thinners (for example, aspirin or low-molecule-weight heparin) are given along with Pomalyst to reduce the risk of blood clots

How is Pomalyst administered?

Histone Deacetylase Inhibitor:Farydak (panobinostat)

• 61% overall response rate (PR or better)How effective is it?

• In combination with Velcade and dex, treatment of MM patients who have received at least two prior regimens including Velcade and an IMiD (for example, Thalomid, Revlimid)


• Standard: with Velcade and dex

• Under investigation: with Kyprolis and experimental drugs (for example, ixazomib)


• Relapsed or relapsed/refractory following at least two prior regimens including Velcade and an IMiD

Who should take it?

Follow-up

Treatment Phase 1 Treatment Phase 2

Eight 21-Day cycles (24 wks) Four 42-Day cycles (24 wks)

Panobinostat +

bortezomib +

dexamethasone

Placebo + bortezomib + dexamethasone

Panobinostat + bortezomib + dexamethasone

Placebo + bortezomib + dexamethasone

Pts with clinical benefita in Treatment

Phase I, can proceed to Treatment Phase

II

• Primary endpoint: PFS (per modified EBMT criteria per investigator)1,2

• Key secondary endpoint: OS

• Other secondary endpoints: ORR, nCR/CR rate, DOR, TTR, TTP, QoL, and safety

Study conducted at 215 centers across 34 countries3

Pts(N = 768)

• Rel or Rel/Ref MM (BTZ-ref excluded)

• 1-3 prior lines of therapy

• Stratification factors

–Prior lines of therapy

–Prior BTZ

1. Blade J, et al. Br J Haematol. 1998;102:1115-11232. Richardson PG, et al. N Engl J Med. 2003; 348:2609-26173. San-Miguel JF, et al. Lancet Oncol. 2014;15:1195-1206

PANORAMA 1 Study Design Randomized, Double-Blind, Phase 3 Study in

Relapsed or Relapsed and Refractory MM

PANORAMA Trial: Pan-Bor-Dex in Relapsed MM

Panobinostat 20 mg orally d 1,3,5,8,12 in 21-day cycles

Bortezomib 1.3mg/m2

Dexamethasone 20 mg

PFS OS

Median OS

Pan-Bor-Dex 33.64 mos

Pbo-Bor-Dex 30.39 mos

PAN-Bor-Dex

Pbo-Bor-Dex

HR 0.87

P =0.259

Months

San-Miguel JF, et al. Blood. 2014;124: Abstract 4742.

PAN-Bor-Dex

Pbo-Bor-Dex

80

60

40

20

0

0 4 8 12 16 20 2

4

28 32 36

HR 0.63

P

<0.0001

Months

Median PFS

Pan-Bor-Dex 12.0 mos

Pbo-Bor-Dex 8.1 mos

100

Histone Deacetylase Inhibitor:Farydak (panobinostat)


− Diarrhea


− Asthenia/fatigue

− Nausea

− Peripheral edema

− Decreased appetite

− Vomiting


• Oral

• Taken once every other day for three doses per week of weeks 1 and 2 of a 4-week cycle (that is, on days 1, 3, 5, 8, and 12)

How is Farydak administered?

Monoclonal Antibody:Darzalex (daratumumab)

• 29% to 36% overall response rate (PR or better)How effective is it?

• Treatment of patients with MM who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent


• Standard: as monotherapy

• Under investigation: with Revlimid or Velcade in newly diagnosed patients


• Relapsed or relapsed/refractory following at least three prior lines of therapy including a PI and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent

Who should take it?

Daratumumab in monotherapy: Two studies: GEN501 & SIRIUS

• ≥18 years of age, ECOG status ≤21,2

• GEN5011

– Open-label, multicenter, phase 1/2, dose-escalation and dose-expansion study

– Relapsed from or refractory to ≥2 prior lines of therapy including PIs and IMiDs

• SIRIUS2

– Open-label, multicenter, phase 2 study

– Patients had received ≥3 prior lines of therapy, including a PI and an IMiD, or were double refractory to a PI and an IMID

• DARA was approved by the FDA on November 16, 2015, based on these studies

16 mg/kg(n = 16)

8 mg/kg(n = 18)

16 mg/kg(n = 106)

Response evaluated

Randomization

Additional 90 patientsenrolled at DARA 16 mg/kg

SIRIUS

Safety and response evaluated

Dose-escalation

Doses from 0.005-24 mg/kg

(n = 32)

Dose-expansion

GEN501

16 mg/kg(n = 42)

8 mg/kg(n = 30)

1. Usmani S, ASH 2015 Abst 29

2. Lokhorst HM, et al. N Engl J Med. 2015;373(13):1207-1219.

3. Lonial S, et al. Lancet. 2015. In press.

16 mg/kgN = 148

18%

10%

1%2%

0

5

10

15

20

25

30

35

16 mg/kgO

RR

, %

PR VGPR CR sCR

ORR = 31%

16 mg/kg (N = 148)

n (%) 95% CI

Overall response rate (sCR+CR+VGPR+PR)

46 (31) 23.7-39.2

Best responsesCRCRVGPRPRMRSDPDNE

3 (2)2 (1)

14 (10)27 (18)

9 (6)68 (46)18 (12)

7 (5)

0.4-5.80.2-4.8

5.3-15.412.4-25.42.8-11.2

37.7-54.37.4-18.51.9-9.5

VGPR or better (sCR+CR+VGPR) 19 (13) 7.9-19.3

CR or better (sCR+CR) 5 (3) 1.1-7.7

• ORR = 31%

• ORR was consistent in subgroups including age, number of prior lines of therapy, refractory status, or renal function

3%CR or better

13%VGPR or better

N = 148

Daratumumab in monotherapy: Two studies: GEN501 & SIRIUS – Efficacy in the combined analysis

Usmani S, ASH 2015 Abst 29

• For the combined analysis, median OS = 19.9 (95% CI, 15.1-NE) months

• 1-year overall survival rate = 69% (95% CI, 60.4-75.6)

Daratumumab in monotherapy: Two studies: GEN501 & SIRIUS – PFS and OS analysis

PD/NE: 3.7 (1.7-7.6) months

Responders: NE (7.4, NE)

MR/SD: 3.2 (2.8-3.7) months

PD/NE: 0.9 (0.9-1.0) months

0

Pat

ien

ts p

rogr

ess

ion

-fre

e an

d a

live

, %

2 6 8 12 14 18 20

Time from first dose, monthsPatients at risk

RespondersMR/SDPD/NE

0

25

50

75

100

4 10 16


467725

46450

35130

2730

1310

500

300

000

41210

1420

300

0

Pat

ien

ts a

live

, %

2 6 8 12 14 18 22

Time from first dose, monthsPatients at risk


0

25

50

75

100

4 10 16

MR/SD

467725

467416

456311

44577

42475

29374

310

000

466712

43537

15101

20

1351

Responders: NE (19.9, NE)

MR/SD: 17.5 (15.1-NE) months

PD/NE: 3.7 (1.7-7.6) months

Responders

PD/NE

Progression-free survival Overall Survival

Usmani S, ASH 2015 Abst 29

Monoclonal Antibody:Darzalex (daratumumab)


− Infusion reactions

− Fatigue

− Nausea

− Back pain

− Pyrexia

− Cough

− Upper respiratory tract infection


• IV

• Weekly for weeks 1 to 8 then every 2 weeks for weeks 9 to 24 and then every four weeks for weeks 25 onwards

How is Darzalex administered?

MMY-1001 (Dara + Pom-Dex arm)

• 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%

43%

VGPR or

better

9%

CR or

better

28%

33%

4%

5%

0

10

20

30

40

50

60

70

80

16 mg/kg

OR

R, %

PR VGPR CR sCR

N = 75

Chari A, ASH 2015 Abst 508

ORR to Dara + Pom-Dex

Keynote-023

N (%)Total

N = 17

Len

Refractory*

N = 9

Overall Response Rate 13 (76) 5 (56)

Very Good Partial Response 4 (24) 2 (22)

Partial Response 9 (53) 3 (33)

Disease Control Rate† 15 (88) 7 (78)

Stable Disease 3 (18) 3 (33)

Progressive Disease 1 (6) 1 (11)

*3 patients double refractory and 1 triple refractory (Len/Bor +Pom)†Disease Control Rate = CR +VGPR + PR + SD >12 weeks.

Data cutoff date: September 22, 2015

• Median (range) follow-up: 296 days (132-560)

• Median DOR: 9.7 month

• Median (range) time to achieve first objective response

– 1.2 month (1.0 - 6.5)

• 11% of patients upgraded the quality of response

VGPR

PR

PD

Len refractory

Treatment ongoing

Months

ORR TTP

San Miguel JF, ASH 2015 Abst 505

Pembrolizumab + LD Antitumor Activity

Phase 3 Clinical Studies for Relapsed/Refractory Patients

*Experimental therapy not yet FDA approved

Ask your doctor if you are a candidate for clinical trials.

Many phase 1 and 2 trials of new drugs and new combinations

• Revlimid + Dex±Empliciti

• Velcade + Dex±Darzalex

• Revlimid + Dex±Darzalex

• Pomalyst + Dex ±Pembrolizumab*

• Empliciti + PomalystNivolumab* + Dex

Monoclonal Antibodies

• Revlimid* + Dex ±Ninlaro*

• Kyprolis* + Dex vs Velcade* + Dex

• Pomalyst* + Velcade* + low-dose Dex

• Kyprolis* (once-vs twice-weekly) + Dex

CurrentlyAvailable Agents

• Revlimid* + Dex + Empliciti*

• Darzalex*

• Farydak* + Velcade* + Dex

ExpandedAccess

Conclusion: Example Patient Case

• A 64-yr-old woman comes with relapsed myeloma. Her history is as follows:

– Initial studies 3 years ago showed 55% plasma cells in the bone marrow, hyperdiploidy, IgGκ 3.5 g/dL, and multiple lytic lesions

– Initially treated with RVD, followed by high-dose melphalan and peripheral blood stem cell transplantation

– She achieved a CR and was on observation

– 3 yrs later, M-protein reappears to 1.5 g/dL

• All choices are optimal. Though she had multiple combination options available, she chose to go on combination daratumumab, lenalidomide and dexamethasone clinical trial and she remains in CR 20 months later. Other than IRR with 1st infusion, she tolerated regimen well currently has a great QOL.

NCCN guidelines 2016

NCCN guidelines V2.2016 and V3.2016

Summary: Relapsed/Refractory Myeloma

Relapsed/refractory multiple myeloma is treatable

Patients typically receive multiple lines of therapy

Treatment may sometimes be continued for an extended period of time

Six new drugs (Kyprolis, Pomalyst, Farydak, Darzalex, Empliciti, Ninlaro) introduced in last 4 years

With the introduction of each new drug, potential for additional combinations

Many promising new drugs/new combinations in clinical development—consider a clinical trial

Documents

Management of Multiple Myeloma: The Changing Paradigm · Management of Multiple Myeloma: The Changing Paradigm Relapsed/Refractory Disease. Patient Case • A 64-yr-old woman comes