Should we use different induction regimens for transplant eligible and transplant ineligible patients?

Jonathan L. Kaufman, MDAssociate ProfessorWinship Cancer Institute of Emory UniversityMarch 8th 2018

Should we use different regimens?

Yes

And No

CRAB criteria

Patient with plasma cell dyscrasia

CRAB criteria

Yes No

Myeloma defining events? Bone marrow plasma cells ≥ 60% or FLC ratio ≥ 100 or MRI >1 focal lesion

Assess Frailty Yes

Diagnostic work up: SPEP, SIFX, UPEP, UIFX, FLC, bone marrow biopsy with FISH and CTG, skeletal survey, MRI spine (as indicated for symptomatic dzor to evaluate occult lesions)

CRAB criteria:• C: Hypercalcemia• R: Renal failure• A: Anemia• B: Bone lesions

Frail Fit

Stdrisk

High risk

VMP; RVD liteRd vs Vd RVD lite

Low risk

High orintermediate

risk

ObservationClinical trials/observation

No

Smoldering myeloma

Stdrisk

High risk

RVD inductionautologous transplant

RVD maintenance

RVD inductionautologous transplant

Lenalidomide maintenance

Diagnostic work up: MRI of the spine and pelvis to evaluate for occult bone lesions

SPEP: serum protein electrophoresis, SIFX: serum immunofixation, UPEP: Urineprotein electrophoresis, UIFX: Urine immunofixation, FLC: free light chains, FISH: fluorescent in situ hybridization, CTG: cytogenetics, MRI: magnetic resonance imaging, Std: standard, Rd: lenalidomide and dexamethasone, Vd: bortezomib and dexamethasone, RVD: lenalidomide, bortezomib and dexamethasone

Consider clinical trial

Newly diagnosed myeloma

Yes No

High riskStandard risk

Transplant eligible?

Lenalidomidemaintenance

Early or delayed transplant

RVD induction therapy

Lonial S. Blood. 2015

T (4;14)

Earlytransplant

All other high-risk

Bortezomibmaintenance

RVD maintenance

VD: bortezomib/dexamethasone, Rd: lenalidomide/dexamethasone RVD: bortezomib/lenalidomide/dexamethasone, RVD-lite: modified RVDVMP: bortezomib/melphalan/prednisone

Standard risk High risk

RVD-liteVMP

T (4;14)

RVD lite, VMP, VD, Rd

All other high-risk

Bortezomibmaintenance

RVD maintenance

All other high-risk: del 17p, t (14;16), t (14;20) and plasma cell leukemia

CPD maintenance

SWOG S0777 (N = 525): RVd Versus Rd1

• Initial therapy: RVd for eight 21-day cycles vs Rd for six 28-day cycles in

patients not intending to proceed to transplant, followed by Rd in both arms

1. Durie B et al. Lancet. 2017;389:519-527.

IFM2009: RVd Alone Vs RVd + ASCT1

RVd 1Lenalidomide

12 mo

RVd 2-3 → PBSC collection → RVd 4-8

RVd 2-3 → PBSC collection → ASCT → RVd 4-5

1. Attal M et al. N Engl J Med. 2017;376:1311-1320.

IFM2009: Response1

OutcomeRVd-Alone

Group (n = 350)

Transplantation Group

(n = 350)

AdjustedPa

Best response during study, n (%)

CR

VGPR

PR

SD

169 (48)

101 (29)

70 (20)

10 (3)

205 (59)

102 (29)

37 (11)

6 (2)

.02

CR, n (%) 169 (48) 205 (59) .003

CR or VGPR, n (%) 270 (77) 307 (88) .001

Minimal disease not detected during study, n/total n with CR or VGPR (%)b 171/265 (65) 220/278 (79) < .001

a P values were adjusted for multiplicity with the use of the Holm procedure to control the family-wise error rate at 0.05. b MRD was detected by means of flow cytometry. As a result of decisions made by the patient or the investigator, 5 patients

in the RVd-alone group and 29 patients in the transplantation group were not tested.

1. Attal M et al. N Engl J Med. 2017;376:1311-1320.

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

Lenalidomide Maintenance: Meta-Analysis1

Median OS(95% CI), mo

HR (95% CI)P

Len maintenance

NR(NR-NR) 0.74 (0.62-0.89)

.001Placebo/observation

86.0(79.8-96.0)

a Log-rank test and Cox model stratified by study to assess impact of Len maintenance on OS. Median for len

treatment arm was extrapolated to be 115 mo based on median of control arm and HR (median, 86 mo; HR = 0.74).

1. Attal M et al. 2016 American Society of Clinical Oncology Annual Meeting (ASCO 2016). Abstract 8001.

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

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

No. at Risk

0.2

1.0

0.8

0.6

0.4

0

OS

Pro

bab

ilit

y

0 10 20 30 40 50 60 70 80 90 100 110 120

Months

7-y OS

62%

50%

Lenalidomide, bortezomib, and dexamethasone (RVD) as induction therapy in newly diagnosed multiple myeloma

Nisha Joseph ASH 2017

• In addition to RVd (SWOG0777), VMP is an option to consider in older patients/nontransplant candidates

What About Elderly Patients? Standard Options Include Triplet …

1. San Miguel JF et al. J Clin Oncol. 2013;31:448-455.

VMP vs MP1

… As Well as Doublets (FIRST Trial)

Continuous Rd Effective

in High-Risk Subgroup2Rd vs MPT1

1. Benboubker L et al. N Engl J Med. 2014;371:906-917. 2. Avet-Loiseau H et al. 57th American Society of

Hematology Annual Meeting and Exhibition (ASH 2015). Abstract 730.

ORR

77 ORR

67

ORR

68

35-Day CycleLenalidomide •15 mg/d on days 1-21

Bortezomib•1.3 mg/m2 once weekly subQ on days 1, 8, 15, and 22

Dexamethasone •20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 for patients aged ≤75 y, and days 1, 8, 15, and 22 for patients aged >75 y

How to Modify Upfront Therapy: RVd-Lite1

Response After 4 Cycles (N = 30) n (%)

ORR (≥PR) 27 (90.0)

CR 5 (16.7)

VGPR 11 (36.7)

PR 11 (36.7)

SD 3 (10.0)

≥VGPR 16 (53.3)

1. O'Donnell EK et al. ASH 2014. Abstract 4217.

1. Demo SD, et al. Cancer Res. 2007; 67:6383-6391. 2. Kirk CJ, et al, Blood.

2008;112:abstract 2765. 3. Siegel DS, et al. Blood 2012:120:2817-2825.

Next-Generation Proteasome Inhibitors1-4

Oral and next-generation PIs

Carfilzomib

Highly selective and irreversible; IV

Oprozomib

Oral; selective and irreversible

Izaxomib

Oral; selective

Rapid integration

into front-line

regimens

1. Demo SD et al. Cancer Res. 2007;67:6383-6391. 2. Siegel DS et al. Blood. 2012;120:2817-2825.

3. Chauhan D et al. Clin Cancer Res. 2011;17:5311-521. 4. Parameswaran N et al. ASH 2014. Abstract 3453.

Extended Therapy With KRd in Newly Diagnosed Myeloma1

Newly diagnosed MM, ASCT

eligible

KRd

(4 cycles)

ASCT

No ASCT

KRd

(4 cycles)

KRd

(10 cycles)

MRD MRD MRD

• KRd plus ASCT shows high rates of deep responses in newly diagnosed MM, with

higher rates of sCR compared with KRd without ASCT

• High rates of MRD-negative disease, up to 97% by MFC and 71% by NGS, which

appear higher than with KRd without ASCT

• Deep responses with KRd plus ASCT are associated with high rates of PFS and OS

• KRd regimen is generally well tolerated, and ASCT does not appear to add significant

toxicity

• Randomized studies needed to confirm results

Induction Consolidation Maintenance

1. Zimmerman T et al. ASH 2016. Abstract 675.

• Compared with standard intensive program with RVd regimen, time to response is rapid, with 78% of patients in VGPR or better at time of transplant (vs 50%)

• At the completion of consolidation, 70% of patients achieved MRD negativity by flow that is similar to RVd regimen

• Safety: Although no PN, 4 patients did not receive transplant because of toxicities; mechanisms of cardiovascular events need to be evaluated

Phase 2 IFM: KRd in Newly Diagnosed Myeloma1

Endpoint

(N = 46), n

After

Induction

After

ASCT

End of

Consolidation

Best Response,

n (%)

sCR 9 15 26 32 (70)

sCR + CR 11 19 28 35 (76)

VGPR 25 18 11 7 (15)

≥VGPR 36 37 39 42 (91)

PR 6 3 2 –

ORR 42 40 41 46 (100)

PD 1 1 1 –

KRd Followed by ASCT, KRd Consolidation, and Lenalidomide Maintenance

1. Roussel M et al. ASH 2016. Abstract 1142.

Cardiovascular Events: Summary

• Phase 2 IFM study:

30 of 45 patients

experienced serious

AEs, including

cardiac and vascular

issues in 8 patients1

• FORTE trial: Higher

ORR rate, including

more CRs, with KRd

vs KCd; KRd more

toxic but manageable

and reversible with

dose reductions2

Cardiac toxicity

1. Monitor patients for clinical signs or symptoms of cardiac failure or cardiac

ischemia

2. Withhold for Grade 3/4 cardiac AEs until recovery

Consider whether to restart at 1 dose level reduction based on a

benefit/risk assessment

Evaluate promptly if cardiac

toxicity is suspected

Suggestions for Managing Cardiovascular Events

With Carfilzomiba

Hydration required, though monitor for signs of volume overload;

adjust total fluid intake as clinically appropriate in patients with

baseline cardiac failure or who are at risk for cardiac failure

a In patients aged ≥75 y, the risk of cardiac failure is increased compared to patients aged ˂75 y.

1. Roussel M et al. ASH 2016. Abstract 1142. 2. Gay F et al. ASCO 2017. Abstract 8003.

IRd in Newly Diagnosed Myeloma1

CR plus

stringent

response

VGPR

PR

100

80

60

40

20

0Cycle 3

(85%)

90

70

50

30

10

Patients

, %

Cycle 6

(90%)

Cycle 9

(90%)

Cycle 12

(90%)

Time of Response Assessment

4842

3228

35

27

33

25

25

23

33

4

1. Kumar SK et al. Lancet Oncol. 2014;15:1503-1512.

IRd Before/After ASCT → Ixazomib Maintenance1

• IRd, 3 cycles of 28 days

– Ixazomib 4 mg on days 1, 8, and 15

– Lenalidomide 25 mg on days 1 to 21

– Dexamethasone 40 mg on days 1, 8, 15, and 22

Induction

• Mobilization: Cyclophosphamide 3 g/m2 and G-CSF 5 mcg/kg

PBSC harvest

• Melphalan 200 mg/m2Peripheral SCT

• IRd, 2 cycles of 28 daysEarly consolidation

• IR (without dexamethasone), 6 cycles of 28 daysLate consolidation

• Ixazomib 4 mg on days 1, 8, and 15 of each 28-day cycle

Maintenance therapy for 1 year

1. Moreau P et al. ASH 2016. Abstract 674.

IRd Induction/Consolidation → IxazomibMaintenance

Response, %Post-Induction

(n = 42)

Post-ASCT

(n = 37)

Post–Early

Consolidation

(n = 37)

Post–Late

Consolidation

(n = 34)

sCR 2.4 9.5 23.8 38.2

CR 9.5 7.1 4.8 5.9

VGPR 23.8 45.2 38.1 32.4

PR 42.9 21.4 19 17.6

SD 14.3 4.8 0 0

PD 4.8 0 2.4 5.9

NE 2.4 11.9 11.9 0

>PR 81 83.3 85.7 94.1

>VGPR 38.1 61.9 66.7 76.5

>CR 11.9 16.7 28.6 44.1

1. Moreau P et al. ASH 2016. Abstract 674.

IRd Safety Summary and Example for AE Management1,2

Hematologic Events

• Thrombocytopenia

• Neutropenia

Nonhematologic Events Also Noted

•Skin and subcutaneous tissue disorders

•Peripheral neuropathy

•Cardiac issues—atrial fibrillation

•Thrombosis

Example: Managing Hematologic Events (Thrombocytopenia) in Pts on IRd

✓ Withhold ixazomib and lenalidomide until platelet count is ≥30,000/mm3

✓ Post-recovery: Resume lenalidomide at next lower dose; resume ixazomib at

most recent dose

✓ If platelet count falls to <30,000/mm3 again, withhold regimen until platelet

count ≥30,000/mm3

✓ Post-recovery: Resume ixazomib at next lower dose, resume lenalidomide at

most recent dosea

a For additional occurrences, alternate dose modification of lenalidomide and ixazomib.

1. Kumar SK et al. Lancet Oncol. 2014;15:1503-1512. 2. Moreau P et al. ASH 2016. Abstract 674.

Ixazomib in Patients Not Proceeding to Transplant1

Patients with newly

diagnosed MM

N = 65; cohort of 42

that did not proceed to

SCT

Weekly ixazomib (4 mg) plus Rd

Patients continuing

on to receive

single-agent

ixazomib

(n = 25)

After Induction

• ORR: 80%• CR + VGPR: 63%• CR: 32%• Median OS: NR• 4-y OS: 82%

After Maintenance

• Increased depth of response noted with ixazomib maintenance

• 32% of patients improved their response during maintenance

NR: not reached

1. Kumar SJ et al. The 22nd European Hematology Association Congress (EHA 2017). Abstract S408.

Efficacy of Antibody Therapy in Newly Diagnosed Myeloma: Daratumumab Regimens in MMY10011,2

0

1

2

3

4

5

6

VD +DARA(n = 6)

VMP +DARA (n

= 6)

VTD +DARA (n

= 6)

POM-D +DARA (n

= 6)

Pati

en

ts,

n

PD

MR

PR

VGPR

sCR

Daratumumab-KRd in

Newly Diagnosed MM

12-mo PFS 94%

1. Mateos MV et al. ASH 2014. Abstract 176. 2. Jakubowiak A et al. ASCO 2017. Abstract 8000.

Best Response

Vd + Dara

(n = 6)

VMP + Dara

(n = 6)

VTd +Dara

(n = 6)

Pom/Dex+ Dara (n = 6)

ORR was 100% in newly diagnosed group, 50% in the relapsed group

• Triplets preferred: RVd, VCd, VMP; IRd, all oral regimen

• Doublets only in frail patients: Rd or Vd at reduced doses

Transplant Candidates

Transplant Ineligible

• Triplets preferred: RVd or VCd; KRd if neuropathy

• Doublets: Rarely used (ie, Vd to improve renal dysfunction, then

add lenalidomide)

• Maintenance: Lenalidomide in standard-risk patients; bortezomib

or RV in high-risk patients

Summary of Initial Therapy for Newly Diagnosed Myeloma

Efficacy of Antibody Therapy in Newly Diagnosed Myeloma: Daratumumab Regimens in MMY10011,2

0

1

2

3

4

5

6

VD +DARA(n = 6)

VMP +DARA (n

= 6)

VTD +DARA (n

= 6)

POM-D +DARA (n

= 6)

Pati

en

ts,

n

PD

MR

PR

VGPR

sCR

Daratumumab-KRd in

Newly Diagnosed MM

12-mo PFS 94%

1. Mateos MV et al. ASH 2014. Abstract 176. 2. Jakubowiak A et al. ASCO 2017. Abstract 8000.

Best Response

Vd + Dara

(n = 6)

VMP + Dara

(n = 6)

VTd +Dara

(n = 6)

Pom/Dex+ Dara (n = 6)

ORR was 100% in newly diagnosed group, 50% in the relapsed group

25

ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; EU, European Union; SC, subcutaneously; PO, oral ly;D, daratumumab; 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

Key eligibility

criteria:

• Transplant-

ineligible

NDMM

• ECOG 0-2

• Creatinine

clearance

≥40 mL/min

• No peripheral

neuropathy

grade ≥2

Stratification factors

• ISS (I vs II vs III)

• Region (EU vs other)

• Age (<75 vs ≥75 years)

1:1

Ran

dom

iza

tion (

N =

70

6)

D-VMP × 9 cycles (n = 350)

Daratumumab: 16 mg/kg IV

Cycle 1: once weekly

Cycles 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 weekly

Cycles 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

Every

4 weeks:

until PD

Statistical analyses

• 360 PFS events: 85% power for

8-month PFS improvementa

• Interim analysis: ~216 PFS events

• Cycles 1-9: 6-week cycles

• Cycles 10+: 4-week cycles

26

Efficacy: ORRa

PR, partial response; sCR, stringent complete response.aITT population. bP <0.0001; P value was calculated with the use of the Cochran–Mantel–Haenszel chi-square test. cResponders in response-evaluable population.

• Median duration of response: 21.3 months in VMP versus not reached in D-VMP

Significantly higher ORR, ≥VGPR rate, and ≥CR rate with D-VMP;

>2-fold increase in rate of sCR with D-VMP

VMP(n =

263)c

D-VMP(n =

318)c

Median (range)

time to first

response,

months

0.82

(0.7-

12.6)

0.79

(0.4-

15.5)

Median (range)

time to best

response,

months

4.11

(0.7-

20.5)

4.93

(0.5-

21.0)

2420

2529

1725

7

18

0

10

20

30

40

50

60

70

80

90

100

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

OR

R, %

PR VGPR CR sCR

P <0.0001

ORR = 74%

ORR = 91%

≥CR:

24%b

≥VGPR:

50%b

≥CR:

43%

≥VGPR:

71%

Efficacy: PFS

50% 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: 16.5 (0.1-28.1) months

27

VMP

Median: 18.1 months

D-VMP

Median: not reached

% s

urv

ivin

g w

ith

ou

t p

rogre

ssio

n

0

20

40

60

80

0 3 6 9 12 15 18 27

Months

356

350

303

322

276

312

261

298

231

285

127

179

61

93

0

0

2

10

No. at risk

VMP

D-VMP

21 24

18

35

100

12-month PFSa 18-month PFSa

HR, 0.50

(95% CI, 0.38-0.65; P <0.0001)

87%

72%

76%

50%

Efficacy: OS

VMP (n = 356)

D-VMP(n = 350)

Events, n (%) 48 (13.5) 45 (12.9)

• Median OS was not reached in either treatment arm

28

Data are immature after median follow-up of 16.5 months

Safety: Most Common TEAEsa

TEAE, treatment-emergent adverse event.aAny grade TEAEs in ≥20% of patients and grade 3 or 4 TEAEs in ≥10% of patients in either treatment group.

VMP (n = 354) D-VMP (n = 346)

Any

Grade

Grade 3

or 4

Any

Grade

Grade 3

or 4

Hematologic, n (%)

Neutropenia 186 (53) 137 (39) 172 (50) 138 (40)

Thrombocytopenia 190 (54) 133 (38) 169 (49) 119 (34)

Anemia 133 (38) 70 (20) 97 (28) 55 (16)

Nonhematologic, n (%)

Peripheral sensory

neuropathy121 (34) 14 (4) 98 (28) 5 (1)

Upper respiratory tract

infection49 (14) 5 (1) 91 (26) 7 (2)

Diarrhea 87 (25) 11 (3) 82 (24) 9 (3)

Pyrexia 74 (21) 2 (1) 80 (23) 2 (1)

Nausea 76 (22) 4 (1) 72 (21) 3 (1)

Pneumonia 17 (5) 14 (4) 53 (15) 39 (11)

• 1 patient in each

arm discontinued

treatment due to

pneumonia

• 1.4% and 0.9% of

patients receiving

VMP and D-VMP,

respectively,

discontinued

treatment due to

infection

29

VMP (n = 354) D-VMP (n = 346)

Deaths due to TEAEs, n

(%)19 (5) 19 (6)

Safety: IRRs

IRR, infusion-related reaction.

• Most IRRs occurred during the first infusion

• 5 (1.4%) patients discontinued daratumumab due to IRRs

• Montelukast was allowed as additional premedication and was used

in <5% of patients

D-VMP (n = 346)

All Grades Grade 3 Grade 4 Grade 5

Patients with IRRs,

n (%)96 (28) 15 (4) 2 (1) 0

30

Should we use different regimens?

Yes

Use best available agents upfront

Treat to progression

And No

Doses need modification

Not all patients can tolerate triplet regimens

Will Monoclonal antibodies change treatment for newly diagnosed patients?