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Monoclonal antibodies for the treatment of multiple myeloma

Jorge J. Castillo, MD Assistant Professor of Medicine Harvard Medical School Jorgej_castillo@dfci.harvard.edu

Disclosures Consulting • Otsuka Pharmaceuticals • Biogen IDEC • Alexion Pharmaceuticals

Research Funding • Millennium Pharmaceuticals • Gilead Sciences • Pharmacyclics Inc. • Abbvie Inc.

Multiple myeloma • MM is a plasma cell neoplasm characterized by the accumulation of malignant plasma cells in the bone marrow producing a monoclonal paraprotein.

• MM accounts for 10% of all hematologic malignancies with an incidence that has remained stable for the last 5 decades • The median age at diagnosis is 66 years with a slight male predominance.

• The risk of MM is higher in blacks than in whites, and lower in Asians and Hispanics.

Myeloma subtypes

Castillo. CPPOP 2016

Diagnosis of myeloma • Clonal bone marrow plasma cells greater than or equal to 10% OR • Biopsy-proven bone or soft tissue plasmacytoma,

Rajkumar et al. Lancet Oncol 2014

• Hypercalcemia: serum calcium >11 mg/dL • Renal insufficiency: creatinine clearance <40 mL/min or serum creatinine >2 mg/dL • Anemia: hemoglobin <10 g/dL • Bone lesions: osteolytic lesions on radiographs, CT, or PET/CT

Diagnostic update • The following represent an 80% risk of developing active MM within 2 years and should be considered active MM: – Clonal bone marrow plasma cell involvement greater than or equal to 60% – Serum FLC ratio greater than or equal to 100; kappa:lambda in kappa-restricted myeloma or lambda:kappa in lambda-restricted myeloma – Greater than 1 focal lesion on MRI

Rajkumar et al. Lancet Oncol 2014

Revised International Staging System

Palumbo et al. J Clin Oncol 2015

Treatment for myeloma - frontline

Treatment for myeloma - relapsed

Improved survival in patients with myeloma

Kumar et al. Blood 2008

Kumar et al. Leukemia 2014

It is a new era in multiple myeloma

ASCT 1986 Orange peel + rhubarb + bloodletting 1844

Melphalan + steroids 1970 Melphalan 1960 Steroids 1950

Monoclonal Antibodies 2016 IMIDs 2006 Proteasome Inhibitors 2003

How are monoclonal antibodies produced?

Mechanism of action of monoclonal antibodies

Van de Donk et al. Blood 2016

DARATUMUMAB Approved as a single agent in November 2015 by the FDA and in May 2016 by the EMA for the treatment of relapsed multiple myeloma,

The target: CD38 • CD38 is a transmembrane receptor associated with calcium transport • Expressed in malignant plasma cells and B-cells • Expressed in normal B-cells, T-cells and NK cells • Also in brain, smooth muscle and osteoclasts • CD38 knock out associated with deficiency in antibody response to T-cell antigens

Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated myeloma GEN501 Open-label, multicenter, phase 1/2 Relapsed or refractory to â&#x2030;Ľ2 prior lines of therapy including PIs and IMiDs

SIRIUS Open-label, multicenter, phase 2 study Patients had received â&#x2030;Ľ3 prior lines of therapy, including a PI and an IMiD

DARA is approved by the FDA and EMA, based on these studies Lokhorst et al. N Engl J Med 2015 Lonial et al. Lancet 2016

GEN501 and SIRIUS combined analysis: efficacy

Usmani et al. Blood 2016

GEN501 and SIRIUS combined analysis Progression-free survival

Usmani et al. Blood 2016

Overall survival

Phase 1/2 study of Daratumumab, Lenalidomide, and Dexamethasone for Relapsed MM

N=32 patients, median 2 lines (1-3) Prior IMiD: 23 (72%) Prior Len : 11 (34%) Prior PI : 29 (91%) Prior PI + IMiD: 21 (66%) Bortezomib + lenalidomide: 9 (28%) ASCT : 25 (78%)

Response • ORR:81% • sCR: 8 (25%) • CR: 3 9%) • VGPR: 9 (28%) • PR: 6 (19%)

Plesner et al Blood 2016

Phase 1/2 study of Daratumumab, Lenalidomide, and Dexamethasone for Relapsed MM

18-month PFS 72%

18-month OS 90%

Grade 3/4 toxicity: Neutropenia (78%), thrombocytopenia (13%), anemia (13%), infusion reactions (6%)

Plesner et al Blood 2016

Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma Key eligibility criteria • RRMM • ≥1 prior line of therapy • Prior bortezomib exposure, but not refractory

R A N D O M 1:1 I Z E

DVd (n = 251)

Primary Endpoint • PFS

Daratumumab (16 mg/kg IV) Every week - cycles 1-3 Every 3 weeks - cycles 4-8 Every 4 weeks - cycles 9+

Vel: 1.3 mg/m2 SC, days 1,4,8,11 - cycles 1-8 Dex: 20 mg PO-IV, days 1,2,4,5,8,9,11,12 - cycles 1-8

Vd (n = 247) Vel: 1.3 mg/m2 SC, days 1,4,8,11 - cycles 1-8 Dex: 20 mg PO-IV, days 1,2,4,5,8,9,11,12 - cycles 1-8

Secondary Endpoints • TTP • OS • ORR, VGPR, CR • MRD • Time to response • Duration of response

• Cycles 1-8: repeat every 21 days • Cycles 9+: repeat every 28 days

Palumbo et al. N Engl J Med 2016

Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma P <0.0001 100 90 Response rate, %

80 70

83

P <0.0001

63

59

60 50

P = 0.001

40

29

30 20

19

9

10 0

ORR

â&#x2030;ĽVGPR

Median time to response DVd: 0.9 months Vd: 1.6 months

â&#x2030;ĽCR

Palumbo et al. N Engl J Med 2016

Daratumumab, Bortezomib, Dexamethasone for Multiple Myeloma Adverse events (G3/4) Thrombocytopenia (45%) Anemia (14%) Neutropenia (13%) Lymphopenia (10%) Pneumonia (8%) Hypertension (7%) Palumbo et al. N Engl J Med 2016

AFT-29 / MMY2004. A randomized, phase II study of lenalidomide, bortezomib and dexamethasone with or without daratumumab

Randomization

Induction 4, 21-day cycles Len: 25 mg PO D1-14 Bort: 1.3 mg/m2 SC D1, 4, 8, 11 Dex: 20 mg PO D1,2,4,5,8,9,11, 12

Transplant Stem cell mobilization: G-CSF ± Plerixafor

MEL 200 mg/m2

Consolidation 2, 21-day cycles Len: 25 mg PO D1-14 Bort: 1.3 mg/m2 SC D1, 4, 8, 11 Dex: 20 mg PO D1,2,4,5,8,9,11, 12

Maintenance 56-day cycles Len: 10 mg daily

Stratification Factors: ISS stage, CrCl 4, 21-day cycles Len: 25 mg PO D1-14 Bort: 1.3 mg/m2 SC D1, 4, 8, 11 Dex: 20 mg PO D1,2,8,9,15,16 Dara: 16 mg/kg IV D1, 8, 15

Stem cell mobilization: G-CSF ± Plerixafor

MEL 200 mg/m2

2, 21-day cycles Len: 25 mg PO D1-14 Bort: 1.3 mg/m2 SC D1, 4, 8, 11 Dex: 20 mg PO D1,2,8,9,15,16 Dara: D1

56-day cycles Len: 10 mg daily Dara: 16 mg/kg IV D1

R

Induction 4 cycles

Consolidation 2 cycles

VTD +

VTD +

Dara

Dara

HDM ASCT

VTD Endpoints: • sCR • PFS, OS

VTD

Stratify by: dara treatment, response, MRD status

Daratumumab trial in transplant eligible newly diagnosed MM – Hovon/IFM

Maintenance Dara

R Observation

The bad side Toxicity • Infusion related reactions – Premedications are essential

• Manage with dose delays and not dose reductions • COPD patients were excluded – PFT: FEV>50%

Resistance • CD38 expression (ATRA) • Soluble CD38 • Levels of complementinhibitory proteins • Fc-gamma receptor polymorphisms • KIR and HLA genotypes

Laboratory interference • Daratumumab is an IgG-kappa monoclonal antibody • Interference with SPEP and IFX – Daratumumab interference reflex assay (DIRA)

• Interference with flow cytometry – Develop novel antibodies for flow cytometry – Alternative plasma cell markers

• Interference with blood typing – Dithiothreitol (DTT) – RBC typing prior to daratumumab

ELOTUZUMAB Approved in November 2015 by the FDA and in May 2016 by the EMA for the treatment of relapsed multiple myeloma, in combination with lenalidomide and dexamethasone.

The target: SLAMF7 (CS1) • SLAMF7 is a cell surface glycoprotein receptor highly expressed on normal and malignant plasma cells.

• It mediates adhesion of plasma cells to bone marrow stromal cells.

• It is selectively expressed on plasma and natural killer cells and lacks expression on other tissues.

Elotuzumab clinical overview Elotuzumab in phase I/II studies in patients with relapsed/refractory MM

Trial Phase Treatment

Efficacy, & Median PFS

1701 I

Elotuzumab monotherapy

SD = 26.5

---

1702 I

Elotuzumab + bortezomib

ORR = 48

9.5 months

1703 I

Elotuzumab + ORR = 82 lenalidomide/dexamethasone

NR (median follow-up 16 months)

1703 II

Elotuzumab + ORR = 84 lenalidomide/dexamethasone

10 mg/kg: 33 months 20 mg/kg: 19 months

â&#x20AC;˘â&#x20AC;Ż Elotuzumab was generally well tolerated; incidence and severity of infusion reactions were mitigated by premedication

ELOQUENT-2 Study Design Open-label, international, randomized, multicenter, phase 3 trial Key inclusion criteria • RRMM • 1–3 prior lines of therapy • Prior Len exposure permitted in 10% of study population (patients not refractory to Len)

Elo plus Len/Dex (E-Ld) schedule (n=321) Elo (10 mg/kg IV): Cycle 1 and 2: weekly; Cycles 3+: every other week Len (25 mg PO): days 1–21 Dex: weekly equivalent, 40 mg

Len/Dex (Ld) schedule (n=325) Len (25 mg PO): days 1–21; Dex: 40 mg PO days 1, 8, 15, 22

Assessment • Tumor response: every 4 wks until progressive disease • Survival: every 12 wks after disease progression

Repeat every 28 days Endpoints Co-primary: PFS and ORR Other: overall survival (data not yet mature); duration of response, quality of life, safety

Dimopoulos et al. ASH 2015 (Abstract 28)

ELOQUENT-2: Progression-Free Survival

§ PFS benefit with E-Ld was maintained over time (vs Ld) § Overall 27% reduction in the risk of disease progression or death § Relative improvement in PFS of 44% at 3 years Dimopoulos et al. ASH 2015 (Abstract 28) Dimopoulos, MA et al. Presented at ASH 2015 (Abstract 28), oral presentation.

Interim Overall Survival 1-year OS

1.0

2-year OS

3-year OS

E-Ld

HR 0.77 (95% CI 0.61, 0.97; 98.6% CI 0.58, 1.03); p=0.0257

0.9 0.8

Probability alive

Ld

Median OS (95% CI)

0.7

43.7 mos (40.3, NE)

39.6 mos (33.3, NE)

0.6

E-Ld

0.5 0.4

Ld

0.3 0.2 0.1 0.0 0

3

6

No. of patients at risk: E-Ld 321 314 303 325 305 287 Ld

9

12

15

18

21

24

27

30

33

36

39

42

45

48

51

190 152 171 134

95 88

48 41

15 17

5 3

0 0

OS (months) 291 269

283 255

266 241

250 228

239 218

224 208

217 200

196 184

Dimopoulos et al. ASH 2015 (Abstract 28)

The bad side Toxicity • Infusion related reactions – Premedications are essential

• Manage with dose delays and not dose reductions Laboratory interference • SPEP/IFX

Resistance • Soluble SLAMF7 • Anti-idiotype antibodies (15%) • Levels of complementinhibitory proteins • Fc-gamma receptor polymorphisms

OTHER MONOCLONAL ANTIBODIES

Phase 1/2 study of MOR202 monotherapy

Raab et al. ASH 2015 (Abstract 3035)

Phase 2 study (TED10893) of isatuximab

Martin, T et al. ASH 2015 (Abstract 509)

Targeting Programmed Cell Death Protein 1 (PD-1) and its Ligand PD-L1 in MM

Plasma cells

PD-L1 expression on plasma cells – Immune evasion – Proliferative advantage – Resistance

Blockade of PD1-PD-L1 signaling may activate MM specific cytotoxic T cells that can be further enhanced by IMiDs Postow et al. J Clin Oncol 2015 Ray et al. Leukemia 2015

KEYNOTE-023: Pembrolizumab + Lenalidomide/Dex Design • Pembro 200 mg Q2W, Len 25 mg Dex 40 mg • N= 50 patients • Median prior lines: 4 – Lenalidomide: 96% • Len-Refractory : 76%

Response • ORR 76% • VGPR 24% • PR 53$ • SD 18% • PD 6%

– Bortezomib: 96% • Bort-Refractory: 64%

– Pomalidomide: 26% – Carfilzomib: 26%

San Miguel et al. ASH 2015

Monoclonal antibodies in clinical development

Conclusions • Monoclonal antibodies are here to stay.

• Monoclonal antibodies are safe and effective, and have been transformative.

• Likely to improve response and survival outcomes in combination with other agents.

• Infusion related reactions are the most common side effect and needs pre-medications.

• Aware of laboratory interference.

Monoclonal antibodies for the treatment of multiple myeloma

Jorge J. Castillo, MD Assistant Professor of Medicine Harvard Medical School jorgej_castillo@dfci.harvard.edu