Mayo Clinic College of MedicineMayo Clinic Comprehensive Cancer Center

Treatment of Multiple Myeloma in Transplant Ineligible Patients

S. Vincent RajkumarProfessor of Medicine

Mayo Clinic

Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida

Disclosures

No conflicts to disclose

The Last Decade

§ New Lab tests§ New Imaging

§ New Criteria(MDE)

Diagnosis

§ PET§ MRD

(NGF, NGS)

§ New Response Criteria (MRD)

Response

§ FISH§ GEP§ Molecular

methods

§ New Staging (RISS)

Prognosis

§ Carfilzomib§ Pomalidomide§ Panobinostat§ Ixazomib§ Elotuzumab§ Daratumumab

§ New Drugs§ (Abs)

Treatments

Rajkumar SV © 2019

Risk Stratification of Myeloma

§ t(4;14) (FGFR3,MMSET)

§ t(14;16) (C-MAF)§ t(14;20) (MAF-B)

§ Trisomies* § t(11;14) (CCND1)§ t(6;14) (CCND3)

*~10% have both trisomies and IgH translocationsKumar S, et al. Blood. 2012;119:2100-2105

Disease Aggressiveness

Rajkumar SV © 2018

del 17p, p53 mutations, gain 1q

Dise

ase

Aggr

essi

vene

ss

INITIAL THERAPY

FIRST Trial: MPT vs Rd18 vs Rd till progressionKaplan–Meier Estimates of Progression-free Survival and Overall Survival

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

SWOG VRd vs RdEight 21-day Cycles of VRd

Bortezomib 1.3/mg2 IVDays 1, 4, 8, and 11Lenalidomide 25 mg/day PODays 1-14Dexamethasone 20 mg/day PODays 1, 2, 4, 5, 8, 9, 11, 12

Six 28-day Cycles of Rd

Lenalidomide 25 mg/day PODays 1-21Dexamethasone 40 mg/day PODays 1, 8, 15, 22

RandomizationN = 525

Newly diagnosed MM

Stratification:• ISS (I, II, III)• Intent to

transplant @ progression (yes/no)

9

After induction; Both arms recevied Rd Maintenance Until PD, Toxicity or Withdrawal

Durie BGM, et al. ASH 2015

Durie et al. The Lancet 2017 389, 519-527DOI: (10.1016/S0140-6736(16)31594-X) Copyright © 2017 Elsevier Ltd Terms and Conditions

S0777 Trial: VRd vs Rd Progression-free Survival

Durie et al. The Lancet 2017 389, 519-527DOI: (10.1016/S0140-6736(16)31594-X) Copyright © 2017 Elsevier Ltd Terms and Conditions

S0777 Trial: VRd vs Rd Overall Survival

Age >75

• SWOG S0777 trial VRd vs Rd• PFS and OS Age <65, 65–75, >75 years • VRd was superior in Age >75 years

• Median PFS 39 vs 20 months • Median OS 63 vs 31 months (P<0.05)

Durie et al. The Lancet 2017 389, 519-527DOI: (10.1016/S0140-6736(16)31594-X)

FRAILTY

• Factors– 3-drug vs 2-drug induction– Duration of therapy

important, even in elderly

http://www.myelomafrailtyscorecalculator.net

Palumbo. Blood. 2015;125:2068.

Ran

dom

izat

ion

Inte

rmed

iate

Fit

(1:1

) Induction

*9x Rd

*Rd Continuous

Maintenance

RV-MM-PI-0752 Trial

Larocca, et al. Blood 2018 132:305

Initial Treatment of Myeloma

Not Transplant Candidate

VRd x 9 months;Len maintenanceuntil progression

Frail PatientsRd x 1 year;

Len maintenance until progression

Rajkumar SV © 2019

Key Questions

• Can we improve on the VRd triplet?• Carfilzomib based (eg., KRd)• Monoclonal Antibody based (eg., DRd)

• Should we use a quadruplet?• Cost• Toxicity

Rajkumar SV © 2019

T Facon et al. N Engl J Med 2019;380:2104-2115.

MAIA TRIAL: DRd vs VRd

M Mateos et al. N Engl J Med 2018;378:518-528.

Dara-VMP followed by Dara versus VMP (ALCYONE TRIAL)

CLARION: KMP vs VMP: Overall Survival

0Months

KMPVMP

KMP(n=478)

107 (22.4)NE

VMP(n=477)95 (19.9)

NE

1.08 (0.82–1.43)Nominal 1-sided P=0.71

Death – n (%)Median OS – monthsHR for KMP vs VMP (95% CI)

12 18 24 366 30

478477

410411

367363

270264

1110

433428

127114

42

0

1.0

0.8

0.6

0.4

0.2

0Prop

ortio

n Su

rviv

ing

Number at risk:KMPVMP

• At the data cutoff date for the primary analysis of PFS (Jul 15, 2016), the HR for OS was 1.21

• In an updated evaluation of OS (Nov 4, 2016), the HR for OS was 1.08

Median follow-up time: 27.1 months for KMP and 26.3 months for VMPFacon T. IMW 2017

eastern cooperative oncology group

VRd vs KRd

Accrual complete

E1A11: Phase III – Newly Diagnosed Myeloma*(PI: Shaji Kumar)KRd vs VRd

VRd x 12 cycles

KRd x 12 cycles

LenalidomideX 2 years

LenalidomideUntil prog

Continue therapytill prog. or toxicity

Continue therapytill prog. or toxicity

RANDOMIZATION

Newly Diagnosed MM: TOURMALINE MM2

Placebo-Rd x 18 cycles

Ixa-Rd x 18 cycles

Ixa-RUntil prog

Placebo-RUntil prog

Continue therapytill prog. or toxicity

Continue therapytill prog. or toxicity

RANDOMIZATION

Metrics

• Control Arm• VRd vs Rd• DRd vs Rd• ERd vs Rd• IRd vs Rd

• Adjudication• Number of

RCTs?• Hazard ratio?• Absolute length

of PFS?• Cost?• Convenience?• Endpoint?

Rajkumar SV © 2019

Myeloma: Frontline Treatment

Not Transplant Candidate

VRd x 8-12 cyclesLen maintenance

orDRd until progression

Frail PatientsRd x 1 year;

Len maintenance until progression

*Based on S0777, MAIA, CASSIOPEIA Rajkumar SV © 2019

Newly Diagnosed MyelomaTransplant Ineligible

High Risk MM in USA

?Quadruplet

Len not available

VTd

Acute renal failure

VCD

PCLEMD

?Quadruplet

OtherSituations

IRd

Rajkumar SV © 2019

Active Drugs in Multiple Myeloma

§ Alkylators§ Steroids§ Interferon§ Anthracyclines

Old Drugs

§ Carfilzomib§ Pomalidomide§ Panobinostat

§ Ixazomib§ Daratumumab§ Elotuzumab§ Selinexor

Recently ApprovedDrugs (2013-2015)

§ Bortezomib§ Thalidomide§ Lenalidomide§ Liposomal

doxorubicin

Older Drugs(2003-2007)

Rajkumar SV. 2019

§CAR-Ts§Belantamab mafodotin (GSK2857916)§AMG 420/ AMG701§Isatuximab§Iberdomide (CC-220)§Venetoclax§Filanesib§LGH 447§Dinaciclib§Oprozomib§Marizomib

Future Drugs

R

E

G

I

S

T

R

A

T

I

O

N

R

A

N

D

O

M

I

Z

A

T

I

O

N

Arm A:KRd Cycles 1-9 MRD Analysis1

Arm B:Dara + KRdCycles 1-9

Arm C: KRd Cycles 1-9

Arm D: Dara +

Lenalidomide Cycles 10-33

Arm E: Lenalidomide Cycles 10-33

Observation until disease progression

Observation until disease progression

Step 1: InductionStep 2: Consolidation and Maintenance

Stratification• R-ISS Stage at Diagnosis: 1 vs 2 vs 3• MRD Status: Positive vs Negative

1. All patients will be randomly assigned regardless of biomarker status.

Accrual Goal: 1450 patients

EQUATE TRIAL