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Multiple Myeloma: What are the Optimal Therapies in 2016?

12th Annual California Cancer Consortium Conference

Aaron Rosenberg MD, MSAssistant Professor of Medicine

University of California, Davis School of MedicineUniversity of California, Davis Comprehensive Cancer Center

[email protected]

17th Annual Advances in OncologySeptember 30-October 1, 2016

Sacramento, CA

Aaron Rosenberg, M.D.Multiple Myeloma: What are the Optimal

Therapies in 2016?

No relevant financial relationships in the past twelve months by presenter or spouse/partner.

The speaker will directly disclosure the use of products for which are not labeled (e.g., off label use) or if the product is still investigational.

UC Davis Comprehensive Cancer Center

Disclosures

• No Financial Disclosures• I will discuss some off-label therapies within

the context of recently reported data• Some slides have been provided by Celgene


Outline

• Current “Standard” Approaches• Review newly approved agents:

– Ixazomib– Daratumumab– Elotuzumab– Panobinostat

• New tactics?– PDL-1– CAR T-cells


Unabated Progress in Survival

http://seer.cancer.gov/faststats accessed 4/22/16Kyle RA, Rajkumar VS, Blood 2008; 111 (6): 2962

1969: Melphalan/Prednisone

1947: Urethane

1958: Melphalan

1983: 1st Autologous Stem Cell Transplants

1999: Thalidomide

2003: Bortezomib

1962: Single Agent Steroids

2006: Lenalidomide

2013: Pomalidomide

2012: Carfilzomib

2010: Zolendronic acid1996: OS Benefit From Autologous Stem Cell Transplant

2015: Panobinostat

2015: Ixazomib

2015: Elotuzumab

2015: Daratumumab

http://seer.cancer.gov/faststats


Front-Line Therapy: RD vs RVD

• SWOG S0777• Randomized phase III trial

– RVD (21 d): R: 25 mg, d1-14; D: 20 mg d 1,2, 4,5, 8,9, 11,12; V: 1.3mg/m2 1,4, 8, 11

– Rd (28 d): R: 25 mg d1-21; D: 40 mg, d 1, 8, 15, 22

• Patients treated until progression, toxicity– 525 patients

• Women and older patients less likely to get RVd

Durie et al, ASH 2015, Abstract #25


RVd Wins

RVd (n=242) Rd (n=232)Progression Free Survival

43 months 31 months

1-sided log-rank P= 0.007Overall Survival Not Reached 63 months2-sided log rank P = 0.01

Durie et al, ASH 2015, Abstract #25


ASH 2015: CyBorD now DOA? Author Abstract # Details

Jimenez-Zepeda 1845 • Retrospective cohort study comparing CyBorD vs Rd• Transplant ineligible• Baseline characteristics fairly well balanced• Response: 23% (CyBorD) vs 28% (Rd), CR 32% vs

38%• Median OS: CyBorD 40 months vs Rd 66 month

(p=0.12)

Cornell 396 • CIBMTR Study of post-autologous HSCT patients• CyBorD 12%, RVD 39%• No effect of primary treatment on outcome as a

whole, however PFS improved with RVd (HR 0.68, p=0.04)

Moreau 393 • Prospective, randomized comparison: VTD vs CyBorD

• Primary Endpoints: response rate• CR rates similar, VGPR and PR rates higher in VTD

arm


Relapsed Myeloma

• What are the options– Carfilzomib + Dex ORR ~ 20-25%– Polmalidomide + Dex ORR ~ 30-35%

• + Biaxin ~50%

– Carlifzomib + Polmalidomide +Dex ORR ~ 50%– Bortezomib + Panabinostat + Dex ORR ~ 30-35%– Carlifzomib + Lenalidomide + Dex ORR ~87%

• PFS 23mo + improved OS vs Rd

Siegal DS et al Blood 2012, Dimopoulus MA et al, ASH 2013, Ab# 408, Rossin A et al ASH 2012, Ab# 8036,

Shah JJ et al ASH 2013, Richardson PG et al Blood 2013, Stewart KA et al NEJM 2015


Carfilzomib/ Lenalidomide/ Dexamethasone:Effect of Prior Len Exposure

ASPIRE Trial: 20% prior lenalidomide exposure

Wang et al: 73% prior lenalidomide exposure

• ORR 77%, median PFS 15.4 months

• Among lenalidomideexposed:– ORR 70%– PFS 8 months

Stewart KA et al NEJM 2015, Wang et al Blood 2013


Ixazomib

• Oral proteasome inhibitor• FDA Indication: treatment of multiple

myeloma in combination with lenalidomideand dexamethasone in patients who have received 1 prior therapy


TOURMALINE-MM1: Design

Randomization1:1

- 28 Day Cycles- Ixazomib 4mg PO d1, 8, 15- Lenalidomide 25mg PO d1-21- Dexamethasone 40mg PO weekly

- 28 Day Cycles- Placebo PO d1, 8, 15- Lenalidomide 25mg PO d1-21- Dexamethasone 40mg PO weekly

Moreau et al, NEJM 2016


TOURMALINE-MM1: PFS

Moreau et al NEJM 2016


TOURMALINE-MM1: High Risk Cytogenetics

Moreau et al, NEJM 2016


Daratumumab

• Anti-CD38 antibody (IgG Kappa)• FDA indication: relapsed/refractory after at

least 3 prior lines of therapy including an imidand a proteosome inhibitor or are double refractory to imids/proteosome inhibitors


SIRIUS: Study Design/Flow

Lonial et al, Lancet 2016


SIRIUS: Response Rates



Sirius: SurvivalMedian PFS: 4 mo12 months OS: 65%Median OS:

Responders: Not reached

Non-Responders: 14 months


Progression Free Survival


CASTOR Trial

Patients Relapsing after ≥ 1 prior therapy

Bortezomib/ DexamethasoneX 8 cycles

Dartumumab/Bortezomib/ DexamethasoneX 8 cycles

R

Palumbo, NEJM 2016

Indefinite Dartumumab


Primary Endpoint: PFSOverall Response Rate- Bortez/Dex: 63%- Dara/Bortez/Dex: 82%

Palumbo, NEJM 2016

Phase 1b Trial of DARA, POM and DEX Trial in RRMM: Response

DARA + POM + DEX(N = 75)

n, % 95% CIORR (≥ PR), n (%) 53 (71) 59.0-80.6Best response

sCR 4 (5) 1.5-13.1CR 3 (4) 0.8-11.2VGPR 25 (33) 22.9-45.2PR 21 (28) 18.2-39.6MR 2 (3) 0.3-9.3SD 17 (23) 13.8-33.8PD 0.8-11.2

≥ VGPR 32 (43) 31.3-54.6≥ CR 7 (9) 3.8-18.3

CR, complete response;; DARA, daratumumab; DEX, dexamethasone; MR, minimal response; ORR, overall response rate; PD, progressive disease; POM, pomalidomide; PR, partial response; RRMM, relapsed/refractory multiple myeloma; sCR, stringent complete response, SD, stable disease; VGPR, very good partial response.Chari A, et al. Open-Label, Multicenter, Phase 1b Study of Daratumumab in Combination with Pomalidomide and Dexamethasone in Patients with at Least 2 Lines of Prior Therapy and Relapsed or Relapsed and Refractory Multiple Myeloma. ASH 2015, abstract #508.

• ORR was 71%• ORR in double refractory

pts was 67%• Clinical benefit rate (≥ MR)

was 73%• Median time to first

response was 1.2 months• At median time of 4.2

months– Median time to best

response was 2.8 months– Responses are deepening

over time– 47 of 53 of responders

(89%) had not progressed

ASH 2015 Update, Courtesy of Celgene


Elotuzumab

• Anti-SLAM F7 antibody (IgG)• FDA Indication: in combination with

lenalidomide/dexamethasone for patient relapsing after 1-3 prior therapies


ELOQUENT-2

Lonial et al, NEJM 2015

Randomization

Lenalidomide 25 mg d1-21Dexamethasone 40 mg weeklyElotuzumab 10mg/kg IV

- weekly for 8 weeks- Every other week

Lenalidomide 25 mg d1-21Dexamethasone 40 mg weekly


ELOQUENT-2: PFS

Lonial et al, NEJM 2015

ELOQUENT-2 Phase 3 Trial of ERd vs Rd in RRMM: OS

ERd, elotuzumab, lenalidomide, and dexamethasone; HR, hazard ratio; NE, not evaluable; OS, overall survival; Rd, lenalidomide and dexamethasone; RRMM, relapsed/refractory multiple myeloma.Dimopoulos MA, et al. Eloquent-2 Update: A Phase 3, Randomized, Open-Label Study of Elotuzumab in Combination with Lenalidomide/Dexamethasone in Patients with Relapsed/RefractoryMultiple Myeloma: 3-Year Safety and Efficacy Follow-up. ASH 2015, abstract #28.

• Prespecified interim analysis for overall survival indicates a strong trend (P = .0257) with early separation sustained over time for ERd vs Rd

ASH 2015 Update, Courtesy of Celgene

ELOQUENT-2 Trial: ERd vs Rd in RRMM Subsets Overall Survival in Subgroups

a ISS stage II or III, t(4;14)+, or del(17p)+. b ISS stage I or II; t(4;14)−, del(17p)−, or 1q21−; age < 55 yrs. c ≥ 1 cell del(17p)+. BORT, bortezomib; ERd, elotuzumab, lenalidomide, and dexamethasone; HR, hazard ratio; ISS, International Staging System; LEN, lenalidomide; NE, not estimable; OS, overall survival; Rd, lenalidomide and dexamethasone; RRMM, relapsed/refractory multiple myeloma.Lonial S, et al. ELOQUENT-2 Update: Phase 3 Study of Elotuzumab + Lenalidomide/Dexamethasone vs Lenalidomide/Dexamethasone in Relapsed/Refractory Multiple Myeloma—Identifying Responders by Subset Analysis. ASCO 2016, abstract #8037. ASCO 2016 Update, Courtesy of Celgene


Panobinostat

• Pan-histone deacetylase inhibitor• FDA Indication: relapsed/ refractory myeloma

after at least two prior therapies, including bortezomib


Re-Analysis of PANORAMA-1

Richardson et al, Blood 2016


Relapsed MM – Fit Patients

Carfilzomib/Rev/Dex(KRd)

Clinical Trials

Fit? Yes Personalize to Patient

and Situation

No


What do I Mean Personalize?!My take on existing/available treatments

Patient Factors Therapeutic Choice

All Patients CLINICAL TRIALTolerating therapy, wants an all-oral regimen

Biaxin/Pomalidomide/Dex

Needs a break from infusion center/ intolerant of imids

Daratumumab

Pom refractory Cytotoxic (Bendamustine, Doxil) based regimen

High risk cytogenetics:del(17p), t(4;14)

Wants an all oral regimen

Triplet therapyIxazomib based therapy

No prior/remote Lenalidomide exposure

Elo-Len-Dex

Physically fit, no prior cardiac disease, multiply refractory

Panobinostat/Bortezomib/Dex


Drug Specific Management Issues and Challenges

ixazomib • Nausea/vomiting and diarrhea, esp during first 3-4 cycles• Approved for use with lenalidomide

daratumumab • Long infusions during first treatments• Infusion reactions in ~50% of patients• Monoclonal Antibody (IgG Kappa) Interferes with

SPEP/Immunofixation

elotuzumab • No single agent activity – needs to be paired with imid• Pairing with bortezomib has not been approved• Infusion reactions uncommon (10%)• GI and liver toxicity seen• Monoclonal Antibody (IgG Kappa) Interferes with

SPEP/Immunofixation

panobinostat • 30% stopped treatment due to AE• Arrhythmia• diarrhea• Hepatotoxicity


NEW AGENTS COMING DOWN THE PIPELINE


New Drugs/ treatments in Development (curated list)

• PD1 inhibitors (in combtination)– Pembrolizumab– MPDL3280A

• Anti-CD 38 antibodies– Isatuximab

• Proteosome inhibitors– Oprozomib– Marizomib

• Anti-BCL2– Venetoclax

• CAR-T Cells


Pembrolizumab

• Keynote-23 presented at ASCO 2016– Pem 200 mg every other week– Lenalidomide 26mg– Dex 40 mg weekly– Toxicity included tumor lysis syndrome (despite 96%

prior lenalidomide exposure)– ORR: 50% overall, 38% in lenalidomide refractory

• Two Phase III Trials Ongoing:– Keynote 183 (relapse/refractory) – Keynote 185 (newly diagnosed)


Pembrolizumab + Pom/DexASH abstract 506

ASH Abstract 506, Badros et alSlide Courtesy of Dr. Badros

Day 1 Day 7 Day 14 Day 21

Pembrolizumab 200 mg IV 1st 6 patients treated on day 1 only

x x

Pomalidomide 4 mg orally

Dexamethasone 40 mg Orally20 mg for patients > 70 yr. old

x x x x

- Cycles are repeated every 28 days for responding/stable pts

- After 24 months; responding patients can continue pomalidomide and dexamethasone alone until progression.

Baseline Patients’ DemographicsCharacteristic N=33

Age – yrMedian (Range) 65 (42-81)

Sex – no. (%)MaleFemale

24 (73%)9 (27%)

Race – no (%)CaucasiansAfrican AmericansOthers (Hispanic, Asian)

17 (52%)13 (39%)3 (9%)

Isotype – no.(%)IgGIgALight chain

18 (55%)7 (21%)8 (24%)

LDH – Median (range) 415 (148- 4800)

Cytogenetics – no. (%)High risk [del 17p, t(4:14) and/or t(14:16)]del 13q1q+

14 (42%)16 (48%)23 (70%)

ASH Abstract 506, Badros et al, Slide Courtesy of Dr. Badros

Best Response to Treatment (IMWG Criteria)Evaluable Pts (n=27)

AllN=27

Double refractoryN=20

High risk cytogeneticsN=12

ORR (≥ PR), %sCRCRVGPRPR

104

11

0029

0015

Stable Disease 8 (30%) 6 (30%) 5 (42%)

Progressive disease 3 (10%) 3 (15%) 1 (8%)

60% 55% 50%

ASH Abstract 506, Badros et al, Slide Courtesy of Dr. Badros


CAR-T Cells: anti-CD19

Garfall et al NEJM 2015


CAR-T Cells: Anti BCMA

• Phase I Dose Escalation• At highest dose level, both patients

responded, including 1 stringent complete response

Ali et al, ASH 2015 abstract LBA-1

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