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