Recent Updates in Multiple

Myeloma: Newly Diagnosed MM

Keith Stewart

Mayo Clinic

Goals of Initial Therapy

• High response rate; rapid response

• Depth of response

• Improve performance status and QOL

• PBSC mobilization (for younger patients)

Continuous Improvement in Response

Seen With Combinations of Newer

Agents

Stewart AK et al. Blood. 2009;114:5436-5443. Jakubowiak A et al. Blood. 2012;120:1801-1809.

100

90

80

70

60

50

40

30

20

10

0TDVAD VTDRD CVDPAD CVRDRVD

CR/nCR

Res

po

nse

(%

)

Induction Regimen

KRD

ORR VGPR

RVd has become the standard where available

Log-rank P value = 0.0018 (one sided)*

HR = 0.712 (0.560, 0.906)*Log-rank P value = 0.0250 (two sided)*

HR = 0.709 (0.516, 0.973)*

Durie at al, Lancet 2017

Triplet is better than a doublet

KRd in Newly Diagnosed MM: Responses

Pati

ents

(%

)

N = 53; Median 12 Cycles (Range 1-25)

Initial Response Best Response

Jakubowiak AJ et al. Blood 2012;120:1801-1809.

100

75

50

25

0

M-P

rote

in L

evel

(%

of

Bas

elin

e)

100

75

50

25

00 121110987654321Cycle

≥ nCR sCR M-protein

100

80

60

40

0

20

≥ PR

≥ nCR

≥ VGPR

sCR

42

62

81

98

CRd = carfilzomib/lenalidomide/dexamethasone

R

Eligibility

• Newly diagnosed, symptomatic standard-risk MM

• No prior history of Grade 2 or higher peripheral neuropathy

Carfilzomib + lenalidomide +

low-dose dexamethasone limited OR indefinite lenalidomide maintenance

Bortezomib + lenalidomide +

low-dose dexamethasone limited OR indefinitelenalidomide maintenance

Protocol ID: NCT01863550

Target Accrual: 756 (open)

www.clinicaltrials.gov; Accessed December 2014

ECOG-E1A11: A Phase III Study of Bortezomibor Carfilzomib with Lenalidomide and

Dexamethasone for Newly Diagnosed MM

Primary endpoint: Overall survival

Select secondary endpoints: Progression-free survival, overall response rate, duration of response, incidence of Grade ≥2 peripheral neuropathy and cardiac toxicity

IFM 2009: RVd beats Rd for PFS

but Transplant Still required

RVD armN=350

Transplant arm

N=350p-value

CR 49% 59%

VGPR 29% 29% 0.02

PR 20% 11%

<PR 2% 1%

At least VGPR 78% 88% 0.001

Neg MRD by FCM n (%)

228 (65%)

280 (80%) 0.001

Attal et al Abstract 391 ASH 2015

If 3 is good is 4 better?

ORR 81% 93% 96% 96%

96% ORRCR in 42% post SCT

Daratumumab + KRd in Newly Diagnosed MM: Response

Jakubowiak AJ, et al. ASCO 2017. Abstract 8000.

Median follow-up: 10.8 mos (range: 4.0-12.5)

OS: 100% at follow-up

Median number of treatment cycles: 11.5 (range: 1.0-13.0)

100

80

60

40

20

0Resp

on

se r

ate

(%

)

After 4 Cycles, n = 21

100

71

5 5

100

80

60

40

20

0Resp

on

se r

ate

(%

)

After 8 Cycles, n = 15*

10087

27 27

100

80

60

40

20

0Resp

on

se r

ate

(%

)

Best Response, n = 21

10091

4329

Depth of response improved with duration of treatment

*5 pts who proceeded to ASCT before cycle 8 and 1 pt who discontinued due to PD at cycle 7 were excluded.

14

• Median (range) follow-up: 16.8 (15.9-18.7) months

Responses continued to deepen over time

50

38

6

6

38

31

25

63

0

10

20

30

40

50

60

70

80

90

100

End ofinduction

End ofconsolidation

Duringmaintenance(4-13 cycles)

OR

R, %

PR VGPR CR sCR

≥VGPR

56%

≥CR

6%

≥VGPR

100%

≥CR

63% ≥CR

94%

≥VGPR

100%

ORR = 94%

ORR = 100% ORR = 100%

VRD-Dara

ORR, overall response rate; CR, complete response; VGPR, very good partial response; PR, partial response.

38

Maintenance ?

Overall Survival: LenalidomideMaintenance Meta analysis

0.00 10 20 30 40 50 60 70 80 90 100 110 120

0.2

0.4

0.6

0.8

1.0

There is a 26% reduction in risk of death, representing an estimated 2.5-year increase in median survivala

605 578 555 509 474 431 385 282 200 95 20 1 0

604 569 542 505 458 425 350 271 174 71 10 0

Overall Survival, mos

Su

rviv

al P

rob

ab

ilit

y

Patients

at risk

7-yr OS

62%

50%

N = 1209 LENALIDOMIDE CONTROL

Median OS(95% CI), mos

NE(NE-NE)

86.0(79.8-96.0)

HR (95% CI)P value

0.74 (0.62-0.89)

.001

a Median for lenalidomide treatment arm was extrapolated to be 116 months based on median of the control arm and HR (median, 86 months; HR = 0.74). HR, hazard ratio; NE, not estimable; OS, overall survival.

Attal et al ASCO 2016McCarthy et al EHA 2016

39% improvement in overall PFS with ixazomib vs. placebo

• There was a significant 39%

improvement in overall PFS from time of

randomization for patients receiving

ixazomib vs. placebo maintenance:

• HR: 0.72; 95% CI: 0.582–0.890

• p=0.002

• Median 26.5 months vs. 21.3 months

• With only 14% of deaths reported, at a

median follow-up of 31 months, median

OS has not been reached in either

treatment arm and follow up continues

CI, confidence interval; HR, hazard ratio; OS, overall survival.

Pro

bab

ility

of

Pro

gre

ssio

n-F

ree

Su

rviv

al

00

Months from Randomization

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

0.2

0.4

0.6

0.8

1.0

No. of patients at risk:Ixazomib 395 363 340 311 279 255 238 213 187 135 93 56 35 9 3 0Placebo 261 238 210 195 174 153 130 117 100 69 46 32 15 3 0 0

IxazomibPlacebo

Nontransplant Patient

100

80

60

40

20

0

100

80

60

40

20

0

FIRST Trial: Efficacy Analysis of Len/Dex vs MPT in SCT-Ineligible Pts

With MM

• Overall response (continuous Rd vs MPT): 75% vs 62% (P < .00001)

• Similar, tolerable safety profiles between treatment groups

• Incidence of second primary malignancies: 3% with continuous Rd vs 6% with Rd18 vs 5% with MPT

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

Mos

PFS

(%

)

0 6 12 18 24 30 36 42 48 54 60

72

wks

Median PFS, Mos

Rd (n = 535) 25.5

Rd18 (n = 541) 20.7

MPT (n = 547) 21.2

HR (P Value)

Rd vs MPT: 0.72 (.00006)

Rd vs Rd18: 0.70 (.00001)

Rd18 vs MPT: 1.03 (.70349)

4-Yr OS, %

Rd (n = 535) 59.4

Rd18 (n = 541) 55.7

MPT (n = 547) 51.4

HR (P Value)

Rd vs MPT: 0.78 (.0168)

Rd vs Rd18: 0.90 (.307)

Rd18 vs MPT: 0.88 (.184)

Mos

OS

(%)

0 6 12 18 24 30 36 42 48 54 60

SWOG S0777

Log-rank P value = 0.0018 (one sided)*

HR = 0.712 (0.560, 0.906)*Log-rank P value = 0.0250 (two sided)*

HR = 0.709 (0.516, 0.973)*

Durie at al, Lancet 2017

Triplet is better than a doublet

Overall survival

21Durie BGM, et al. ASH 2018 [abstract 1992].

• Based on current eligibility (N=460)

Deaths/N Median, mos

Rd 125/225 69 (59-88)

RVd 102/235 NR

P = .0114

RVd: 55% OS at 7 years

• Forest plot techniques showed other correlates of improved outcomes (PFS and OS) with RVdwere Sβ2M (< 4), BMPC (60%), hemoglobin (> 10 g/dL), serum creatinine (< 2 mg/dL) i.e. predominantly good risk (early disease) risk features

Impact of age on outcomes

22a For all analyses, both SWOG and IRC assessments have been conducted using the fully updated datasets with current datalock in May 2018.Durie BGM, et al. ASH 2018 [abstract 1992].

Age (yrs) RVd Rd

< 65 48 34

≥ 65 34 24

> 75 34 17

Overall Survival by AgeMedian PFS (mos)

Deaths/N Median, mos

Rd < 65 yrs 56/119 88 (67- )

Rd ≥ 65 yrs 67/106 56 (45-70)

RVd < 65 yrs 46/144 NR

RVd ≥ 65 yrs 50/91 65 (54- )

SWOG S0777: VRd vs. Rd

• Median age 63

• 43% of patients ≥ 65 years old

• ≥ 65 years old 34 month PFS

• 23% in VRd v. 10% in Rd discontinued

induction treatment because of adverse

events

• No treatment-related deaths in the Rd

group and two in the VRd group

23Durie BG, et al. Lancet. 2017;389(10068):519-27

RVD Lite: Results

Best overall response N=50 %

stringent complete response 6 12

complete response 16 32

very good partial response 11 22

partial response 10 20

minimal response 1 2

stable disease 3 6

not evaluable1 3 6

ORR 43 86

VGPR or better 33 661Received less than 4 cycles of therapy

IMWG Criteria; ORR, overall response rate; VGPR,

very good partial response

O’Donnell et al. BJH. 2018 Jul; 182(2): 222-230

Response (n = 64)

Overall response rate 92%

CR 27%

VGPR 31%

PR 34%

≥Grade 3 AEs (n = 65) 63%

Skin/subcutaneous tissue disorders 17%

Neutropenia 12%

Thrombocytopenia 8%

Peripheral neuropathy 6%

ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; EU, European Union; SC, subcutaneously; PO, oral ly;IV, intravenously; PD, progressive disease; PFS, progression-free survival; ORR, overall response rate; VGPR, very good partial response;

CR, complete response; MRD, minimal residual disease; NGS, next-generation sequencing; OS, overall survival. a8-month PFS improvement over 21-month median PFS of VMP.

ALCYONE Study Design: Updated Results

Key eligibility criteria:

• Transplant-ineligible NDMM

• ECOG 0-2• Creatinine

clearance ≥40 mL/min

• No grade ≥2 peripheral neuropathy or grade ≥2 neuropathic pain

Stratification factors

• ISS (I vs II vs III)

• Region (EU vs other)

• Age (<75 vs ≥75 years)

1:1

Ran

do

miz

atio

n (N

= 7

06

)

D-VMP × 9 cycles (n = 350)

Daratumumab: 16 mg/kg IVCycle 1: once weeklyCycles 2-9: every 3 weeks

+

Same VMP schedule

Follow-up

for PD

and

survival

Primary endpoint:

• PFS

Secondary endpoints:

• ORR

• ≥VGPR rate

• ≥CR rate

• MRD (NGS; 10–5)

• OS

• Safety

VMP × 9 cycles (n = 356)

Bortezomib: 1.3 mg/m2 SC Cycle 1: twice weeklyCycles 2-9: once weekly

Melphalan: 9 mg/m2 PO on Days 1-4 Prednisone: 60 mg/m2 PO on Days 1-4

DCycles 10+

16 mg/kg IV

Every4 weeks: until PD

Statistical analyses

• 360 PFS events: 85% power for

8-month PFS improvementa• Cycles 1-9: 6-week cycles• Cycles 10+: 4-week cycles

27

Efficacy: PFS

57% reduction in the risk of progression or death in patients receiving D-VMP

HR, hazard ratio; CI, confidence interval.aKaplan-Meier estimate.

• Median (range) follow-up: 27.8 (0-39.2) months

No. at riskVMP

D-VMP

VMP Median:19.1 mo

D-VMPMedian: not reached

% s

urv

ivin

g w

ith

ou

t p

rogr

essi

on

0

20

40

60

80

0 3 9 15 18 21 27 39Months

356350

304322

262298

245292

169243

127220

59138

00

30 33

2773

10024-moa

HR, 0.43(95% CI, 0.35-0.54; P <0.0001)

63%

36%

6 12 24 36

277312

206265

102203

531

09

60%

28%

30-moa

Daratumumab monotherapy phase (D-VMP only)

28

Sustained MRD Negativitya

Addition of daratumumab to VMP induced higher rate of sustained MRD negativity

36 (10%)

8 (2%)

0

4

8

12

D-VMP (n = 350) VMP (n = 356)

Su

sta

ine

d M

RD

-ne

ga

tive

ra

te, %

P <0.0001

• Defined as maintenance of MRD negativity for ≥1 year without loss of MRD negativity

aAssessed at time of confirmation of CR/sCR and, if confirmed, at 12, 18, 24, and 30 months after first dose.

MAIA Study Design

• Phase 3 study of D-Rd vs Rd in transplant-ineligible NDMM (N = 737)

Key eligibility criteria:

• Transplant-ineligible NDMM

• ECOG 0-2

• Creatinine clearance ≥30 mL/min

1:1

Ran

do

miz

atio

nPrimary endpoint:

• PFS

Key secondary endpointsc:

• ≥CR rate• ≥VGPR rate• MRD-negative rate (NGS;

10–5)• ORR• OS• Safety

Stratification factors• ISS (I vs II vs III)• Region (NA vs other)• Age (<75 vs ≥75 years)

Cycle: 28 days

Rd (n = 369)

R: 25 mg PO daily on Days 1-21 until PDd: 40 mgb PO or IV weekly until PD

D-Rd (n = 368)

Daratumumab (16 mg/kg IV)a

Cycles 1-2: QW Cycles 3-6: Q2W Cycles 7+: Q4W until PD

R: 25 mg PO daily on Days 1-21 until PD d: 40 mgb PO or IV weekly until PD

aOn days when daratumumab was administered, dexamethasone was administered to patients in the D-Rd arm and served as the treatment dose of steroid for that day, as well as the required pre-infusion medication.bFor patients older than 75 years of age or with BMI <18.5, dexamethasone was administered at a dose of 20 mg weekly. cEfficacy endpoints were sequentially tested in the order shown.

ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; NA, North America; IV, intravenously; QW, once weekly; Q2W, every 2 weeks; Q4W, every 4 weeks; PD, progressive disease; PO, orally; CR, complete response; VGPR, very good partial response; MRD, minimal residual disease; NGS, next-generation sequencing; ORR, overall response rate; OS, overall survival; BMI, body mass index.

Efficacy: ORR and MRD (NGS; 10–5 Sensitivity Threshold)

Significantly higher ORR, ≥CR rate, ≥VGPR rate, and MRD-negative rate with D-Rd

1428

32

28

17

12

30 12

0

10

20

30

40

50

60

70

80

90

100

D-Rd(n = 368)

Rd(n = 369)

OR

R, %

PR VGPR CR sCR

P <0.0001

ORR = 81%

ORR = 93%

≥CR:

48%c

≥VGPR:

79%c

≥CR:

25%

≥VGPR:

53%

24%

0

5

10

15

20

25

30

D-Rd(n = 368)

Rd(n = 369)

MR

D-n

ega

tive

rate

, %

P <0.0001

3.4X

30 moa

Efficacy: PFS

44% reduction in the risk of progression or death in patients receiving D-Rd

CI, confidence interval.aKaplan-Meier estimate.

Median follow-up: 28 months (range: 0.0-41.4)

% s

urv

ivin

g w

ith

ou

t p

rogr

essi

on

0

20

40

60

80

100

0 3 6 9 12 15 18 42

Months

27

369368

332347

307335

280320

254309

236300

219290

00

149203

No. at riskRd

D-Rd

21 24 30

94146

1835

200271

RdMedian: 31.9 mo

D-RdMedian: not reached

33 36

311

5086

39

21

HR, 0.56;95% CI, 0.43-0.73; P <0.0001

71%

56%

31

Efficacy: PFS by MRD Status

• >3-fold higher MRD negativity achieved with D-Rd

• Lower risk of progression or death with MRD negativity

No. at riskRd MRD negative

D-Rd MRD negativeRd MRD positive

D-Rd MRD positive

2789

342279

% s

urv

ivin

g w

ith

ou

t p

rogr

essi

on

0

20

40

60

80

100

0 3 6 9 12 15 18 42

Months

27

2789

305258

2788

280247

2788

253232

2786

227223

2786

209214

2786

192204

0000

2170

128133

21 24 30

12558291

1121723

2584

175187

Rd MRD negative

Rd MRD positive

D-Rd MRD negative

D-Rd MRD positive

33 36

0536

5334553

0120

39

32

3 Drug Induction now STANDARD

Should we add a 4th drug?

Will ASCT become unnecessary

Is MRD negativity the goal?

The Future: