Consolidation and Maintenance Therapy; Emerging Role of Minimal Residual Disease (MRD)

Nikhil C. Munshi, MD

Professor of Medicine Harvard Medical School

Director, Basic and Correlative SciencesJerome Lipper Myeloma CenterDana-Farber Cancer InstituteBoston VA Healthcare System

Disclosures

Consulting AgreementsAbbVie Inc, Adaptive Biotechnologies, Amgen Inc, BeiGene, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, OncoPep, Takeda Oncology

Ownership Interest OncoPep

Case Presentation: Dr Brenner

51-year-old man

• Presents with severe back pain, fevers, night sweats, hepatomegaly

• Diagnosis: R-ISS Stage III IgG-lambda myeloma, with 14;16 translocation, hyperdiploid

Case Presentation: Dr Lamar77-year-old woman• Transferred from another hospital due to renal failure (Cr: 5)

• Diagnosis: IgM multiple myeloma

• CyBorD

82-year-old man• Presents with elevated creatinine

• Diagnosis: Multiple myeloma (M-spike: 3, 60% plasma cells)

• CyBorD, with excellent response but limited travel àixazomib/dexamethasone

Case Presentation: Dr Morganstein

Treatment Algorithm for Newly-Diagnosed Myeloma

Initial treatment Consolidation

RelapsedInduction +/- ASCT 1-2 Maintenance

VRD/KRDD-VMPDRDVTDVCDD-VTD/D-VRD

SCTClinical trial Lenalidomide

BortezomibIxazomib/IxaRElo/Len/Dara/Len

CombinationsPomalidomide, Carfilzomib, Daratumumab, Elotuzumab, Panobinostat, Selinexor, Venetoclax, Chemotherapy, Salvage ASCT,T/Immunotherpay

Consolidation

NoneVRDVTDKRD….

Maintenance

Role of Consolidation/Maintenance• Deepening of response• Prevent recurrence (maintain remission)

Meta-analysis: Lenalidomide Maintenance Delays Disease Progression and Improved OS in post-ASCT NDMM

1. McCarthy PL, et al. J Clin Oncol 2017;35:3279–3289; 2. Palumbo A, et al. N Engl J Med 2014;371:895–905; 3. McCarthy PL, et al. N Engl J Med 2012;366:1770–1781; 4. Attal M, et al. N Engl J Med 2012;366:1782–1791.

3 Phase III trials of R maintenance in NDMM patients after ASCT: GIMEMA RV-MM-PI-209, CALGB 100104, and IFM-2005-02

10 20 30 40 50 60 70 80 90 100 110 1200Time (months)

605 499 428 353 293 244 191 131 83 28 5 0603 419 275 179 125 90 71 52 30 9 0

Prob

abili

ty o

f PF

S

29 months

1.0

0.8

0.6

0.4

0.2

0

Median PFS52.8 vs. 23.5 monthsHR - 0.48 (0.41–0.55)

R maintenancePlacebo/obs

R maintenancePlacebo/obs

No. at risk:

Median OSNR vs. 86.0 Months

HR - 0.75 (0.63–0.90)R maintenancePlacebo/obs

605 577 555 508 473 431 385 282 200 95 20 1 0603 569 542 505 459 425 351 270 174 71 10 0

No. at risk:R maintenancePlacebo/obs

Time (months)

Prob

abili

ty o

f O

S

10 20 30 40 50 60 70 80 90 100 110 1200

1.0

0.8

0.6

0.4

0.2

0

PFS OS

HR

Important Considerations for Maintenance Therapy

In addition to demonstrated efficacy, extended therapy should preferably include:

Tolerability/

Manageable

Toxicity

No cumulative

toxicity

Convenient administration

Minimal impact on

QoL

No emergence of treatment-

resistant clones

Efficacy across

subgroups

McCarthy PL, et al. J Clin Oncol 2017;35:3279–3289.

Favours placebo/observation

Favours Rmaintenance

Female

I/II

III

CR

CR/VGPR

PR/SD

Male

≥60≤59

0.25 0.5 1 2 4

Age (years)

Sex

ISS stage

Responseafter ASCT

HR

Favours placebo/observation

Favours Rmaintenance

R maintenance (n)

Placebo/ observation

(n)HR (95% CI)

372 375 0.68 (0.54–0.86)233 228 0.85 (0.64–1.12)322 349 0.66 (0.52–0.83)283 254 0.92 (0.70–1.21)411 439 0.66 (0.52–0.82)113 90 1.06 (0.73–1.54)65 80 0.63 (0.34–1.15)

314 334 0.70 (0.54–0.90)227 215 0.88 (0.66–1.17)

≥50 mL/min

Yes

No

<50 mL/min

≥50 mL/min

<50 mL/min

>ULN

Normal

0.25 0.5 1 2 4

LDH

CrCl at diagnosis

Adverse cytogenetics

CrCl after ASCT

HR

R maintenance

(n)

Placebo/ observation

(n)HR (95% CI)

270 283 0.91 (0.70–1.18)45 45 1.17 (0.62–2.21)60 37 1.28 (0.71–2.31)

327 360 0.69 (0.54–0.89)56 36 1.17 (0.66–2.09)

232 243 0.79 (0.59–1.06)33 25 0.73 (0.33–1.60)

379 404 0.74 (0.59–0.92)

Meta-analysis: Limited OS Benefit with Lenalidomide Maintenance in High-risk SubgroupsHR for OS by patient subgroup

Consideration of Augmented Maintenance regimen

•High-risk Myeloma – t(4;14); del17p; t(14;16) and may be amp1q•High LDH disease•Patients with Renal failure• Inadequate response to Induction and/or post-ASCT

Lenalidomide Maintenance: Toxicity and Quality of Life

- Increased risk of SPM, that start to be significant after 2 years of maintenance

McCarthy et al. J Clin Oncol 2017

* In the IFM study, data from two cycles of lenalidomide consolidation are included.+ Data from the IFM and CALGB studies only.‡ System organ class presented with preferred terms nested below.§ Includes cysts and polyps.

Lenalidomide Maintenance and Risk of Second Primary MalignanciesMeta-analysis of seven Phase III trials of R maintenance in NDMM patients (N=3,218)

1. Palumbo A, et al. Lancet Oncol 2014;15:333–342.

Cumulative incidence (95% CI) 3 years 5 yearsLenalidomide 2.6% (1.8–3.3) 3.8% (2.7–4.9)No lenalidomide 2.9% (1.4–4.4) 3.4% (1.6–5.2)

Solid SPMs

0 1 2 3 4 5 6 70

5

10

LenalidomideNo lenalidomide

Cum

ulat

ive

inci

denc

e (%

)

3 years 5 years1.4% (0.8–2.0) 3.1% (1.9–4.3)0.4% (0.0–0.9) 1.4% (0.0–3.6)

Haematologic SPMs

0 1 2 3 4 5 6 70

5

10

LenalidomideNo lenalidomide

Time (years)

• Significant increased risk of hematologic SPMs with lenalidomide maintenance versus no maintenance

• Primarily driven by co-exposure to lenalidomide and oral melphalan

• Phase III, randomised, placebo-controlled, double-blind study:

Oral Ixazomib Maintenance After ASCT in NDMM TOURMALINE-MM3 Study:

NDMMN=656

SOC Induction (PI and/or IMiD)Mel200-ASCT

R3:2

Ixazomib maintenance (n=395)

Placebo (n=261)

3 mg PO: D1, 8, 15 in 28-day cycle for Cycles 1–43 or 4 mg PO: D1, 8, 15 in 28-day cycle for Cycles 5–26

PO: D1, 8, 15 in 28-day cycle for Cycles 1–26

Primary endpoint:

• PFS

Key secondary:• OS• TTP• PFS2• HRQoL

Dimopoulous MA et al Lancet. 2019;393:253-264

Stratification - Prior induction treatment (PI and/or IMiD); Type of response to ASCT; ECOG PS 0–2

INCLUSION CRITERIA• Received SOC induction - a PI and/or IMiD• Received single Mel200 ASCT within 12 months of diagnosis• Documented response to ASCT (CR, VGPR, PR)

EXCLUSION CRITERIA• Relapse from/or unresponsive to primary therapy• Double (tandem) ASCT• Post-ASCT consolidation therapy

“The randomized, Phase 3 TOURMALINE-MM4 study met its primary endpoint of progression-free survival (PFS). The trial evaluated the effect of single-agent oral ixazomib as a first line maintenance therapy versus placebo in adult patients diagnosed with multiple myeloma not treated with stem cell transplantation. TOURMALINE-MM4 is the first industry sponsored Phase 3 trial to explore the concept of “switch” maintenance, the use of medicines not included in initial induction therapy, in this setting. Ixazomib is currently not approved for this specific use.

The safety profile of Ixazomib in the maintenance setting was consistent with previously reported results of single-agent ixazomib use, and there were no new safety signals identified in TOURMALINE-MM4.”

Phase III TOURMALINE-MM4 Trial of Ixazomib as First-Line Maintenance Therapy Met Its Primary EndpointPress Release - November 7, 2019

https://www.businesswire.com/news/home/20191107005221/en/Phase-3-Trial-NINLAROTM-ixazomib-Line-Maintenance

Significant Improvement in PFS with Oral Ixazomib Maintenance After ASCT in NDMM: TOURMALINE-MM3 Study Results:

• 39% improvement in PFS • Median OS not reached in either arm

Prob

abili

ty o

f Pro

gres

sion

-Fre

e Su

rviv

al

00

Months from Randomization3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

0.2

0.4

0.6

0.8

1.0

IxazomibPlacebo

• Median PFS 26.5 vs. 21.3 months • HR: 0.72; (0.582–0.890); p=0.002

Dimopoulous MA et al Lancet. 2019;393:253-264

• 41% had improvement in response • 139/302 (46%) on the ixazomib vs 60/187 (32%) on the placebo arm

PFS benefit observed broadly across patient subgroups

*IMiD use reported by investigator

Variable

All subjects

Induction regimen

Age

Pre-induction ISS stage

Response at study entry

Cytogenetic risk

Renal function based onbaseline creatinine clearance

Subgroup

All (n = 656)

PI with IMiD (n = 196)PI without IMiD (n = 389)PI exposed (n = 585)

No PI; with IMiD (n = 71)

<60 years (n = 356)≥60 years and <75 years (n = 300)

I (n = 245)II (n = 221)III (n = 190)

CR (n = 225)VGPR (n = 294)PR (n = 137)

High-risk (n = 115)Standard-risk (n = 404)

30–<60 ml/min (n = 58)≥60 ml/min (n = 595)

Placebo

100

305989

11

4951

363529

364420

2158

892

HR

0.720

0.9660.6670.750

0.497

0.8350.662

0.6780.8760.661

0.8810.6860.693

0.6250.648

0.7080.738

95% CI

(0.582, 0.890)

(0.647, 1.442)(0.510, 0.874)(0.600, 0.938)

(0.254, 0.973)

(0.620, 1.125)(0.480, 0.914)

(0.471, 0.975)(0.611, 1.256)(0.438, 0.998)

(0.593, 1.307)(0.498, 0.945)(0.440, 1.093)

(0.383, 1.019)(0.490, 0.857)

(0.240, 2.090)(0.592, 0.920)

% of patientsIxazomib

100

305989

11

5842

383329

334521

1564

1090

0 0.25 0.5 0.75 1.0 3.0

Favors ixazomib Favors placebo

PI + thalidomide* (n = 177) 0.993 (0.643, 1.532)PI + lenalidomide* (n = 24) 0.594 (0.132, 2.683)

Dimopoulos MA et al. Lancet 2019;393(10168):253-64.

0

5

10

15

20

25

30

35

40

45

Throm

bocy

topen

ia

Anemia

Neutro

penia

Nause

a

Diarrhe

aRas

hURTI

Vomitin

g

Viral U

RTI

Cough

Arthral

gia

Pyrexia

Fatig

ue

Back p

ain PN

Influe

nza

Heada

che

Pneum

onia

% o

f pat

ient

sIxazomib Maintenance Associated with Low Toxicity

PN, peripheral neuropathy; URTI, upper respiratory tract infection

Hematologic NonhematologicCommon AEs of any cause •No difference in the

rate of new primary malignancy (3% versus 3%)

13

3

74

9 8

39

11

15

35

24

28

22

26

21

27

12

2427

2221 22 21

15

2017

2019 1915

1112 119 10

8

Ixazomib Placebo

All grade rates

Grade 1-2 Grade 1-2

Grade 3 Grade 3

Grade 4 Grade 4

XX

•AEs leading to study treatment discontinuation occurred in 7% (ixazomib) and 5% (placebo) of patients

Dimopoulos MA et al. Lancet 2019;393(10168):253-64.

MRD Negativity, Measured by Either NGF or NGS Improves Both PFS and OS

Munshi N et al., JAMA Oncol, 2017

Sensitivity Matters:

Superior PFS with Deeper Response

PFS OS

IFM/DFCI 2009 StudySuperior Survival with Minimal Residual

Disease negative StatusSuperior Overall Survival With MRD negativity

Perrot A et al Blood, 2018

MRD- patients have improvedoutcome irrespective of therapyused

MRD- Patients have improvedoutcome irrespective of riskcategory

Maintenance Therapy Achieves MRD Negativity

Perrot A et al Blood, 2018

Deepening of response withMaintenance - IFM-DFCI 2009 Study A PFS benefit observed in the

ixazomib group irrespective of MRD status at study entry

MRD positive patients pre-maintenance achieve MRD negativity after >1 year of

Lenalidomide maintenance EMN-02

MRD positiveMRD negative

% o

f pat

ient

s

52%

44%

LEN maintenance

100

80

60

40

20

0

6-12 months

Clinical Application of MRD

• Judge prognosis pre-maintenance and during maintenance• Inform the need for transplant as well as consolidation• Contribute to determining the type and length of

maintenance • Identify early relapse for close follow up and may consider

intervention – especially in high-risk patients• Role in management of relapsed disease• Measure real depth of the disease – in all patients who have

achieved VGPR or better