Novel Therapeutics for Multiple Myeloma

Marc S. Raab, MDMax-Eder-Group

Experimental Therapies for Hematologic Malignancies

Department of Medicine V, Heidelberg University Medical Center

&German Cancer Research Center

(DKFZ)

Novel Therapeutics ‐ success

• 1,056 patients grouped into 2001–2005 and 2006–2010 cohorts• Survival improved over time, particularly in patients aged > 65

years (p = 0.001)

Kumar SK, et al. Blood. 2012;120:[abstract 3972]. Updated data presented at IMW2013.

Survival 2001–2005

2006–2010 p

Median OS, years 4.6 NR 0.0011-year survival, % 83 905-year estimated OS, %

Overall 48 66> 65 years 31 56 0.001< 65 years 63 73 NS

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Diagnosed 2006–2010

Diagnosed 2001–2005

Novel Therapeutics – unmet medical need

• Patients refractory to bortezomib and relapsed or refractory to or ineligible to immunomodulatory drugs

Median PFS: 5 months (range 4–6)Median OS: 9 months

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Kumar SK, et al. Leukemia. 2012;26:149-57.

Novel agents against myeloma

ImmunmodulatorsThalidomide

Lenalidomide

Pomalidomide

Proteasome-InhibitorsBortezomib

Carfilzomib

Monoclonal ABs

Elotuzumab

Tabalumab

Daratumumab

Siltuximab

BHQ880

MOR202

The second generation proteasome inhibitor: Carfilzomib

Tetrapeptide epoxyketone

Novel proteasome inhibitor

– Binds the β5 and β5i subunits irreversibly

Active against bortezomib-resistant MM cell lines and samples from pts with bortezomib resistance[1]

Well tolerated in phase II investigation[2]

Active alone and in a number of combinations[3] in relapsed/refractory MM, as well as in initial therapy

Recently FDA approved for rel/ref MM in US

1. Kuhn DJ, et al. Blood. 2007;110:3281-3290. 2. O’Connor OA, et al. Clin Cancer Res. 2009;15:7085-7091. 3. Vij R, et al. Blood. 2012;[Epub ahead of print].

Carfilzomib

O O O O

O O ON N

HNH

HN

HN

Carfilzomib: Phase II Studies ‐ efficacy

Direct comparisons across studies are not possible, given differences in study design and patient populations.

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Relapsed andrefractory MM

003-A1(73% BORT-refractory)

Single agent + dexpremed

(N = 257)

Relapsed and/orrefractory MM004 (BORT-naive)

Single agent(N = 67)

Median5 prior treatments

Median2 prior treatments

1–3 prior treatments

Relapsed MM006 (75% prior BORT)

CFZ + Rd(N = 51)

≥ VGPRPRMR

13

18

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12

24

28

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37

41

Siegel D, et al. Blood. 2012;120:2817-25. Vij R, et al. Blood. 2012;119:5661-70.Wang M, et al. J Clin Oncol. 2011; 29:[abstract 8025]. Updated data presented at ASCO 2011.

Carfilzomib: Phase II Studies ‐ safety

Other important toxicities included transient renal impairment and shortness of breath as well as hypertension and rare cases of significant cardiac dysfunction

Incidence and severity of treatment-emergent adverse events (≥ 25%) and carfilzomib-related adverse events (n = 266)

Adverse events All grades, n (%)

Grades 3 or 4, n (%)

All grades carfilzomib-related, n (%)

HaematologicalAnaemia 122 (46) 63 (24) 59 (22)Thrombocytopenia 103 (39) 77 (29) 77 (29)Lymphopenia 62 (23) 52 (20) 44 (17)Neutropenia 48 (18) 29 (11) 40 (15)Leukopenia 37 (14) 18 (6.8) 31 (12)

Non-haematologicalFatigue 130 (49) 20 (7.5) 98 (37)

Siegel D, et al. Blood. 2012;120:2817-25.; updated at IMW2013

Other Novel Proteasome Inhibitors

1. Chauhan D, et al. Cancer Cell. 2005;8:407-19. 2. Chauhan D, et al. Clin Cancer Res. 2011;17:5311-21;3. Richardson et al, Blood 2011. 4.Kumar et al., Blood. 2012;120:[abstract 332].

Marizomib and Ixazomib: 2nd generation proteasome inhibitors with promising activity in RRMM:

Marizomib (NPI‐0052):  induces apoptosis in cell lines resistant to conventional and bortezomib‐based 

therapies1

in animal models, NPI‐0052 was well tolerated and prolonged survival1

active in RRMM patients (ORR ~ 25% at MTD +/‐ dex)3

Ixazomib (MLN9708):  shows selective anti‐MM activity in cell lines and an animal model2

is currently being tested in clinical trials, with promising activity, esp. in combination, and has favourable tolerability4

Pomalidomide: Third Generation of IMiDs

Pomalidomide: novel immunomodulatory agent structurally similar to thalidomide and lenalidomide[1]

– Distinct safety and efficacy profile

– Improved potency

Clinical activity after use of bortezomib and lenalidomide shown in relapsed/refractory myeloma

– MTD: 2 mg once daily, 5 mg every other day, 4mg daily[1,2,4]

Phase II data showed efficacy in combination with low-dose dexamethasone in relapsed myeloma patients[3]

Recently approved for rel/ref MM in US

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1. Schey SA, et al. J Clin Oncol. 2004;22:3269-3276. 2. Streetly MJ, et al. Br J Haematol. 2008;141:41-51. 3. Lacy MQ, et al. J Clin Oncol. 2009;27:5008-5014. 4. Richardson PG, et al. ASH 2010

Pomalidomide: MM‐003 Trial

• Primary endpoint: PFS

• Key secondary endpoints: OS, ORR (≥ PR), DoR, safety

N = 455•Age ≥ 18 yrs•≥ 2 prior therapies•Refractory to last treatment•Refractory, intolerant or relapsed ≤ 6 mos (if ≥ PR) to BORT and LEN

POM + LoDEX (n = 302):POM: 4 mg, d1–21

LoDEX: 40 mg (≤ 75 y) or20 mg (> 75 y), d1, 8, 15, 22

28-day cycles

HiDEX (n = 153):HiDEX: 40 mg (≤ 75 y) or

20 mg (> 75 y)d1–4, 9–12, 17–20

28-day cycles

Companion trial MM‐003C POM 21/28 days

PD orintolerable AE

PD

Follow‐up for OS and SPM until 5 years post‐enrollment

Dimopoulos MA, et al. Blood. 2012;120:[abstract LBA-6]. Updated data presented at IMW2013.

Pomalidomide: MM‐003 Trial ‐ PFS

ITT: intent-to-treat.

Median PFSPOM + LoDEX (n = 221) 3.2 months

HiDEX (n = 108) 1.7 months

Median PFSPOM + LoDEX (n = 302) 3.6 months

HiDEX (n = 153) 1.8 months

PFS (months)

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ITT population LEN- and BORT-refractory

HR = 0.45p < 0.001

HR = 0.48p < 0.001

Dimopoulos MA, et al. Blood. 2012;120:[abstract LBA-6]. Updated data presented at IMW2013.

Pomalidomide: MM‐003 Trial – overall survival

Median OS (95% CI)POM + LoDEX (n = 221) NR (8.5–NE)

HiDEX (n = 108) 7.4 months (4.3–9.2)

Median OS (95% CI)POM + LoDEX (n = 302) NR (11.1–NE)

HiDEX (n = 153) 7.8 months (5.4–9.2)

OS (months)

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HR = 0.53p < 0.001

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ITT population* LEN- and BORT-refractory*

* 29% of pts received POM after progressing on HiDEX.ITT: intent-to-treat

Dimopoulos MA, et al. Blood. 2012;120:[abstract LBA-6]. Updated data presented at IMW2013.

Pomalidomide: MM‐003 Trial – safety

Discontinuation due to AEs: 7% POM + LoDEX; 6% HiDEX

VTE, all grades: 3% POM + LoDEX; 2% HiDEX

Peripheral neuropathy, all grades: 12% POM + LoDEX; 11% HiDEX

Grade 3 and 4 AEs, % POM + LoDEX(n = 300)

HiDEX(n = 149)

Neutropenia 42 15Febrile neutropenia 7 0

Anaemia 27 29Thrombocytopenia 21 24Infections 24 23

Pneumonia 9 7Haemorrhage 3 5Glucose intolerance 3 7Fatigue 5 5

Dimopoulos MA, et al. Blood. 2012;120:[abstract LBA-6]. Updated data presented at IMW2013.

Target Antibody Company Type

CS1 Elotuzumab Abbot/BMS Humanized

IL‐6 Siltuximab Orthobiotec Chimeric

CD138 BT062 Biotest Chimeric; conjugated to Maytansinoid

Anti‐KIR IPH2101 Innate Pharma Fully Human

CD40 SGN‐40, HCD122 Dacetuzumab, Lucatumumab

Seattle GeneticsNovartis

HumanizedFully Human

CD56 IMGN901, Lorvotuzumab Meransine

ImmunoGen Humanized; conjugated to Maytansinoid

CD38 MOR202 MorphoSys Fully Human

CD38 Daratumumab Genmab Fully Human

RANKL Denosumab Amgen Fully Human

DKK‐1 BHQ880 Novartis Fully Human

FGFR3 PRO‐001 Prochon Biotech Genetech

Humanized

BAFF Ly2127399 Lilly Fully Human

Daratumumab

Daratumumab: anti-CD38 antibody; kills MM cells via ADCC, CDC, and induction of apoptosis

Patients: relapsed/refractory MM (≥ 2 different therapies), not eligible for ASCT; 3 patients/dosing group

Efficacy based on serum and/or urine M-component analyses

Weekly x 8 w followed by /14d up to week 24w (MTD: 8 mg/kg)

In 15 of 32 (47%)….reduction in paraprotein (following 8 w of Dara in doses up to 24mg/kg)

4 PR (13%) + 6 MR (19%) + 5 SD

At doses > 4mg/kg, 8 of the 12 (66%) had at least a MR

Adverse events were manageablePlesner T, et al. ASCO 2012. Abstract 8019.

Phase I/II Study in Relapsed/Refractory MM

Daratumumab

Plesner T, et al. ASH 2012. Abstract 8019, updated at IMW2013

Phase I/II Study in Relapsed/Refractory MM9 2

51 20

19 10 12 3116 29 8 13

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2 mg/kg 4 mg/kg 8 mg/kg 16 mg/kg 24 mg/kg≤ 1 mg/kg

A Phase 2 Study of Elotuzumab in Combination With Lenalidomide and Low-Dose Dexamethasone in Patients With

Relapsed/Refractory Multiple Myeloma Sagar Lonial,1,2 Andrzej J. Jakubowiak,1,3 Sundar Jagannath,1,4 Marc S. Raab,5

Thierry Facon,6 Ravi Vij,1,7 Philippe Moreau,8 Donna E. Reece,9 Darrell White,10 Lotfi Benboubker,11 Jeffrey Zonder,12 Jean-Francois Rossi,13 Claire

Tsao,14 Teresa Parli,14 Glenn Kroog,15 Anil K. Singhal,14 Paul G. Richardson,1,16 on behalf of the 1703 Study Investigators

1Multiple Myeloma Research Consortium, Norwalk, CT, USA; 2Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA; 3University of Michigan, Ann Arbor, MI, USA; 4Mount Sinai Medical Center, New York, NY, USA;

5Universitaetsklinikum Heidelberg, Heidelberg, Germany; 6Hopital Claude Huriez, Service des Maladies du Sang, Lille, France; 7Washington University School of Medicine, St. Louis, MO, USA; 8Hematology Department, University Hospital, Nantes, France;

9Princess Margaret Hospital, Toronto, Ontario, Canada; 10Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia,Canada; 11CHU Tours-Hopital Bretonneau, Tours, France; 12Karmanos Cancer Institute, Detroit, MI, USA; 13CHU de Montpellier-Hopital Saint-Eloi, Montpellier, France; 14Abbott Biotherapeutics Corporation, Redwood City, CA, USA; 15Bristol-Myers Squibb,

Princeton, NJ, USA; 16Dana-Farber Cancer Institute, Boston, MA, USA

Elotuzumab 10 mg/kg

Elotuzumab20 mg/kg Total

Patients, n 36 37 73

ORR (≥PR), n (%) 33 (92) 28 (76) 61 (84)

CR/stringent CR, n (%) 5 (14) 4 (11) 9 (12)

VGPR, n (%) 17 (47) 14 (38) 31 (43)

PR, n (%) 11 (31) 10 (27) 21 (29)

<PR, n (%) 3 (8) 9 (24) 12 (16)

• Overall median time to response: 1 month (range, 0.7-19.2)

• Overall median time to best response: 2.5 months (range, 0.7-24.7)

• Median duration of objective response: 17.8 months (range, 1.0-30.4)

Richardson PG, et al. ASH 2012. Abstract 202.

Elotuzumab ‐ efficacy

Elotuzumab ‐ efficacy

Richardson, et al. 2012 ASH Abstract 8020. Updated data presented at IMW2013.

At a median follow-up of 20.8 months, median PFS has not been reached in the 10 mg/kg arm – Preliminary median PFS of 26.9 months was reported in the abstract; after 2.7 months of

additional follow-up, no new PD or death reported. These pts had an increased PFS duration, and in the updated analysis, median PFS was not yet reached

Median Time to Progression/Death:10 mg/kg (n=36): not yet reached20 mg/kg (n=37): 18.6 mos (95% CI 12.9-29.7)

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10 mg/kg

20 mg/kg

• Future of Myeloma Therapy

• Major advances: Bortezomib, Thalidomid, Lenalidomid

• “2nd Generation“: Carfilzomib, Pomalidomid – => major advances?– more bullets in the pocket, but head-to-head comparisons are

missing

• Antibodies: promising, but no phase III data yet

• Personalized therapy

Outlook

Cereblon – Predicts Sensitivity to Lenalidomid

MM1.S MM1.S res

CRBN

‐actin

Zhu YX, et al. Blood. 2011;118:4771-9.

Lenalidomide resistant myeloma cells lack cereblon

Cereblon – Predicts Sensitivity to Lenalidomid

Gene Expression Levels of Cereblon Predict PFS of Pomalidomide Treated Patients

3 months versus 17 months

Schuster SR, et al. Blood 2012;120:[abstract 194].

P=0.0001

3 months versus 17 months

Cereblon – Predicts Sensitivity to Thalidomid

Broyl A, et al. Blood. 2013;121:624-7.

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> median< median

42 31 13 430 19 4 0

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48 38 18 940 31 16 6

B

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60

A-B: thal-treated, C-D: bort-treated

Cereblon – Predictor for Sensitivity to IMiDs?

CRBN

-actin

MM1.S OPM2 KMS11 JJN3 OCIMY5 OPM1 SKMM2 KMS12PE MM1.S res

Zhu YX, et al. Blood. 2011;118:4771-9.

Signaling in Myleoma

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012

BRAF V600E, 2‐4% in myeloma

Cancer Discovery 2013.

27

Years after diagnosis of multiple myeloma

0 1 2 3 4

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vemurafenib

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mutated

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subclone

extramedullary disease

Figure 2

BRAF V600E, 2‐4% in myeloma

Cancer Discovery 2013.

Clinical Inhibition of BRAF V600E

Cancer Discovery 2013.

Clinical Inhibition of BRAF V600E

Cancer Discovery 2013.