Pharmacotherapy 5

The emerging role of monoclonal antibodies in the treatment of

K. Fostier, MD1, R. Schots, MD, PhD1

Monoclonal antibodies have a profound impact on the prognosis and survival of patients with haemato- logical malignancies. In the treatment of multiple myeloma, until recently, results of monoclonal antibodies have been disappointing. The introduction of two novel classes of monoclonal antibodies holds great promise to change this. (and related antibodies) is a directed to CD38, an intriguing multifunctional surface protein abundantly expressed on malignant plasma cells and their precursors. Daratumumab displays impressive single agent activity in heavily pretreated multiple myeloma patients and due to its favourable safety profile, this molecule seems to be an excellent accessory companion to known anti-multiple myeloma regimens and also in monotherapy as a maintenance agent. , to the contrary, is an anti-CS1 monoclonal antibody, which does not show any clinically relevant single agent activity, but when combined with other anti-multiple myeloma drugs appears to greatly enhance their efficacy and can even revert the refractory state to the agents. When these promising results are confirmed in phase III trials, immunotherapy can finally be incorporated in the treatment schedule of newly diagnosed and relapsed/refractory multiple myeloma patients. (Belg J Hematol 2015;6(5):209-15)

Introduction enter the clinical field. (an anti-CD20 mAb) has significantly im- The new anti-CD38 and anti-CS1 mAbs show great proved survival in several B-cell malignancies including promise in the treatment of MM. This review briefly non-Hodgkin’s lymphoma, chronic lymphocytic leu- summarises the physiological role of these two surface kaemia and Waldenström’s macroglobulinemia. The molecules, their modes of action and the exciting data disappointing results of anti-CD20 immunotherapy in available from early phase clinical trials on daratu- multiple myeloma (MM) are believed to be related to the mumab (DARA) and elotuzumab (ELO). paucity (~20%) and heterogeneity of CD20 expression on malignant plasma cells.1,2 Also, rituximab was never CD38 tested in combination with the more recent anti-MM CD38 (also known as cyclic ADP ribose hydrolase) is drugs such as bortezomib (BORT) or lenalidomide (LEN). a type II single chain transmembrane molecule. The Several other monoclonal antibodies (mAbs) have been functional molecule exists as a dimer or multimer and tested in MM: (anti-IL6 mAb), is expressed on the cytoplasmic part of the membrane. (anti-vascular endothelial growth factor), CD38 has at least a dual function: it displays an ecto- (anti-CD40), lurvatuzumab (anti-CD56), milatuzumab enzymatic activity in the metabolism of nicotinamide (anti-CD74) and anti-CD138.3,4 However, results have adenine dinucleotide (NAD+) and it acts as a receptor been disappointing and most of these agents will not involved in adhesion and signalling in leukocytes.5 The

1Department of Clinical Haematology, UZ Brussel, Brussels, Belgium. Please send all correspondence to: K. Fostier, MD, UZ Brussel, Department of Clinical Haematology, Laarbeeklaan 101, 1090 Brussels, Belgium, tel: +32 2 477 62 11, fax: +32 2 477 62 10, email: [email protected]. Conflict of interest: The authors have nothing to disclose and indicate no potential conflict of interest. Keywords: CD38, CS1, daratumumab, elotuzumab, monoclonal antibodies, multiple myeloma.

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(4) and it can modulate the CD38 ecto-enzymatic func- tion (Figure 2). Other mAbs to CD38 (SAR650894, MOR03087 and Ab79) are also in preclinical/clinical development. They are distinct in several biochemical aspects which may translate into a differential clinical efficacy Table( 1).

Daratumumab in phase I-II trials The first in-human dose-escalation trial of DARA recruited pretreated MM patients (≥2 prior regimens and transplant ineligible) in a phase I-II trial design.13 In the first part, a 3+3 dose-escalation design was applied and DARA monotherapy was administered over a 9-week period as two pre- and seven full-doses at doses ranging from 0.005 mg/kg to 24 mg/kg. At lower concentrations (≤2 mg/kg) a rapid clearance of the Figure 1. Functionality of CD38. mAb was observed, indicating a dose-related target- mediated clearance. At doses ≥4 mg/kg, the observed pharmacokinetic values approximated model-predicted non-substrate-ligand for CD38 is CD31 (also known as values. platelet endothelial cell adhesion molecule-1 (PECAM-1)) In the phase II part, a dose of 8 mg/kg was chosen and and binding can recapitulate the downstream effect patients received DARA weekly for eight weeks fol- of agonistic mAbs.6 The signalling through metabolism lowed by dosing every 2nd week for sixteen weeks and of NAD+ and ligand-receptor interaction converges to every 4th week further on.14 In the patient group (n=12) intracellular Ca2+ fluxes and triggers the phosphorylation who received ≥ 4 mg/kg (patients for the phase I dose of a cascade of intracellular substrates. This leads to finding study were also included), five partial responses activation of the NF-κB complex and other signalling (PR) and three minimal responses (MR) were observed. cascades (Figure 1). CD38 signalling is also involved in The most common adverse effect (AE) was infusion the cross-talk of antigen-receptor complexes on T and related reactions which occurred mostly during first full B cells.7 infusion. Six related SAEs (one anaemia, one thrombo- CD38 expression is high on cell populations of the cytopenia, two bronchospasm, one cytokine release, immune system when cell-to-cell interactions are a and one AST increase) were reported. crucial developmental step.8 CD38 is highly expressed An expansion of 30 patients in the 8 mg/kg cohort on plasma cells and plasma cell precursors alike, sug- (median five prior anti-MM lines) and fifteen additional gesting that this target may also be expressed on the patients (median four prior anti-MM lines) in a 16 mg/ MM stem cell.9-11 kg cohort was recently published.15 Most common AEs reported (in ≥20% of all patients) were pyrexia, allergic Daratumumab and other anti-CD38 rhinitis, fatigue, upper respiratory tract infection, diar- monoclonals rhoea, dyspnoea, and cough. Two SAEs occurred: throm- DARA is a high-affinity human IgG1 mAb against a bocytopenia and lymphocytopenia. The ORR was mar- CD38 epitope. It was developed by immunising trans- kedly better in the 16 mg/kg cohort compared to the genic mice bearing the human Ig locus with CD38 8 mg/kg (46% versus 8%). Even though these results expressing cells.12 It induces killing of tumour cells are impressive, the limited number of patients (thirteen through a number of different mechanisms: included in the 16 mg/kg cohort) should raise cautious- (1) complement-dependent cytotoxicity (CDC), ness as to the interpretation of these results. As no (2) antibody-dependent cell-mediated cytotoxicity dose-related increase of AEs was observed, 16 mg/kg (ADCC), was chosen as the optimal dosing schedule and will be (3) antibody-dependent cellular phagocytosis (ADCP) used in the phase III trials. by macrophages. In addition, DARA induces apop- DARA is also being tested in combination with other tosis upon secondary cross-linking anti-myeloma backbones (e.g. BORT-dexamethasone,

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Figure 2. Mechanisms of action of DARA. (1) Complement-dependent cytotoxicity (CDC), (2) modulation of ecto-enzymatic function of CD38, (3) Antibody-dependent cellular phagocytosis by macrophages (ADCP), (4) Antibody-dependent cell-medicated cytotoxicity (ADCC) and (5) induction of apoptosis through antibody crosslinking.

BORT-thalidomide-dexamethasone, BORT-melphalan- phase III study (IFM2015-01 – HO131) comparing four prednisone, and pomalidomide-dexamethasone) in new- cycles of VTD induction, high dose chemotherapy, two ly diagnosed, relapsed/refractory, transplant eligible and cycles of VTD consolidation (comparator arm) to four non-eligible patients. Preliminary results (in a limited cycles of DARA-VTD induction, high dose chemotherapy number of patients) show that adding DARA to these and two cycles of DARA-VTD consolidation (experi- backbone regimens is (except for infusion related reac- mental arm) will soon be initiated in France, Belgium tions) generally well tolerated and does not create and The Netherlands for newly diagnosed transplant- additional toxicity.16 eligible patients. In the second part of the study, patients who obtain at least a PR can further proceed with either Ongoing and planned phase III studies DARA maintenance therapy (q8w for maximum of two DARA is currently extensively investigated as an ad- years) or observation only. junct to many known anti-myeloma combinations in newly diagnosed and relapsed/refractory MM patients. Elotuzumab Furthermore, the favourable safety profile also makes it ELO (HuLuc63/BMS-901608) is a fully humanised a valuable drug in the maintenance setting and many monoclonal IgG1 antibody directed to the extracellular protocols allow for a prolonged DARA maintenance. part of CS1 (also known as signalling lymphocytic An overview of the currently registered phase III studies activation molecule family 7 (SLAMF7)). CS1 belongs to (www.clinicaltrials.gov) can be found in Table 2. SLAM family, a subset of CD2 superfamily of immuno- Most interestingly, a very large (1.080 to be included) globulin domain containing molecules. Their function

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Table 1. CD38 monoclonal antibodies in pre- and clinical development comparing their modes of action.

Daratumumab SAR650894 MOR03087 Ab79

Janssen Sanofi-Aventis MorphoSys AG Millennium/Takeda

Affinity to CD38 ~0.1 ~0.1 ~0.3 ~0.1

(EC50) (µg/ml)

CDC YES NONE MODESTLY MODESTLY

Apoptosis through Ab YES YES YES YES crosslinking

ADCP YES Not tested MODESTLY YES

Modulation of CD38 MODESTLY YES NONE MODESTLY enzyme function

Current development Phase 1,2,3 Phase 1,2 in relapsed Phase 1,2 in relapsed/ Preclinical status in multiple myeloma CD38 expressing haemato- refractory multiple myeloma logical malignancies

EC50: half maximal effective concentration; CDC: Complement-dependent cytotoxicity; ADCC: antibody-dependent cell-medicated cytotox- icity and ADCP: Antibody-dependent cellular phagocytosis by macrophages.

remains somewhat elusive but they are considered vity of T and NK cells and as these cells play a critical important immunomodulatory receptors.17 CS1 is nor- role in the mode of action of ELO, the combination mally expressed on natural killer (NK), NK-like T cells, LEN+ELO seems very rational. In vitro, the tumouri- mature dendritic cells and CD8+ T cells, with no cidal effect on MM cell lines of LEN-pretreated PBMC binding detected on hematopoietic CD34+ stem cells. effector cells was greatly enhanced through combina- It is also highly expressed on malignant plasma cells, tion with ELO. The activities of BORT, dexamethasone, either cell lines or in CD138+ purified plasma cells perifosine and U2106 (a MEK inhibitor) also seem to from patients with MGUS, smoldering and symptomatic be enhanced in combination with ELO.20,21 As CS1 is MM.18 The gene of CS1 is located on human chromo- also expressed on NK cells, ELO decreases the number some 1q23 and, most interestingly, amplification of 1q of circulating NK cells by 20%. This may explain the is associated with a dismal prognosis in MM.19 decreased effect of ELO when used in higher concen- trations.18 Mechanism of action ELO itself does not show significant in vitro activity on Elotuzumab in phase I trials MM cells lines, except in the presence of peripheral Monotherapy blood mononuclear cells (PBMCs) or purified NK cells. Escalating doses of single agent ELO (0.5 – 20 mg/kg The proposed mechanism of action of ELO is mainly q2w) showed limited efficacy in 35 patients with RR a NK-mediated antibody dependent cell mediated MM (at least two, median 4.5 prior lines of treatment cytotoxicity (ADCC) (Figure 3). The ELO tagged mye- therapies). The best response was stable disease observed loma cell is recognised by the FC receptors (CD16) on in nine patients (27%). No dose limiting toxicity was NK cells, activating the granzyme-perforin pathway. observed and saturation of CS1 occurred on MM cells ELO may also interfere with the microenvironment/ at concentrations of 10-20 mg/kg. However, infusion- myeloma-cell interaction, however, these data are not related reactions occurred, which prompted the use of very solid.20 antihistamines, corticosteroids and paracetamol (aceta- ELO seems to enhance the effect of many of the known minophen).22 Except for the infusion-related reactions, anti-MM drugs. Lenalidomide (LEN) enhances the acti- no serious grade 3-4 adverse events occurred.

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Table 2. Ongoing and planned phase III studies of DARA in newly diagnosed and relapsed/refractory MM patients. (Accessed www.clinicaltrials.gov on 01/03/2015).

Primary Setting Experimental arm Comparator arm Start n endpoint

Relapsed / refractory MM Lenalidomide 25 mg (qd) Lenalidomide 25 mg qd PFS 05/2014 560 > 1 prior treatment line (D1-21 / 28 days cycle) (D1-21 / 28 days cycle) at least PR to 1 treatment line Dexamethasone 40 mg qw Dexamethasone 40 mg qw Not refractory to lenalidomide (or 20 mg qw age > 75 year or a body (or 20 mg qw if age > 75 year Not intolerant to lenalidomide mass index < 8.5) or a body mass index < 8.5) Daratumumab 16 mg/kg (1 qw - cycle 1 and 2; 1 q2w - cycle 3-6; 1 q4w onwards)

Newly diagnosed MM Lenalidomide 25 mg (qd) Lenalidomide 25 mg (qd) PFS Not yet 730 Non transplant eligible (D1-21 / 28) (maximum 2 years) (D1-21 /28) recruiting Dexamethasone 40 mg qw Dexamethasone 40 mg qw (maximum 5 years) (maximum 5 years)

Lenalidomide backboneLenalidomide Daratumumab 16 mg/kg (1 qw - cycle 1 and 2; 1 q2w - cycle 3-6; 1 q4w onwards) (maximum 5 years)

Relapsed / refractory MM Bortezomib 1,3 mg /m² SC Bortezomib 1,3 mg /m² SC PFS 08/2014 480 > 1 prior treatment line (D1,4,8,11 / 21 days cycle) (D1,4,8,11 / 21 days cycle) at least PR to 1 treatment line (maximum 8 cycles) (maximum 8 cycles) Not refractory to bortezomib Dexamethasone 20 mg PO Dexamethasone 20 mg PO Not intolerant to bortezomib (D1,2,4,5,8,9,11,12 / 21 days cycle) (D1,2,4,5,8,9,11,12 / 21 days (maximum 8 cycles) cycle )(maximum 8 cycles) Daratumumab 16 mg/kg IV (1 qw - cycle 1-3; 1 q3w - cycle 4-9; 1 q4w onwards)

Newly diagnosed MM Bortezomib 1,3 mg /m² SC Bortezomib 1,3 mg /m² SC PFS 12/2014 700 Non transplant eligible (D1,4,8,11,22,25,29,32) / 42 days cycle) (D1,4,8,11,22,25,29,32) / 42 days (cycle 1) then 1,3 mg /m² SC cycle) (cycle 1) then 1,3 mg /m² (D1,8,22,29) / 42 days cycle) (cycle 2-9) SC (D1,8,22,29) / 42 days cycle) (maximum 9 cycles) (cycle 2-9) (maximum 9 cycles) Melphalan 9 mg/m² PO Melphalan 9 mg/m² PO

Bortezomib backbone (D1-4 / 42 days cycles) (D1-4 / 42 days cycles) (maximum 9 cycles) (maximum 9 cycles) Prednisone 60 mg/m² PO Prednisone 60 mg/m² PO (D1-4/ 42 days cycles) (D1-4/ 42 days cycles) (maximum 9 cycles) (maximum 9 cycles) Daratumumab 16 mg/kg IV (1 qw - cycle 1; 1 q3w - cycle 2-9; 1 q4w onwards)

Combination regimens In combination with BORT (1.3 mg/m² on day 1, 4, 8, Also, in combination with LEN and low dose dexame- and 11 of a 21-day cycle), ELO (dose escalating from thasone (40 mg weekly), dose escalating ELO (5-20 mg/ 2.5 – 20 mg/kg on day 1 and 11) resulted in an ORR kg on day 1, 8, 15, and 22 (two first cycles and once of 48% in 28 RR MM patients (1-3 prior lines – BORT biweekly onwards) demonstrated an ORR of 82% in pre-treatment allowed). Interestingly, two partial re- 29 RR MM patients (>1 line, median three, prior LEN sponses were seen in patients who were considered exposure permitted). Again, in two of the six patients BORT refractory.23 Severe treatment-emergent adverse with prior LEN exposure an objective response was events (grade >3) were lymphocytopenia (25%), fatigue noted.24 Severe treatment-emergent adverse events (grade (14%), thrombocytopenia (11%), hyperglycaemia (11%), >3) were neutropenia (36%), thrombocytopenia (21%), peripheral neuropathy (11%), and pneumonia (11%). diarrhoea (11%), and fatigue (11%).

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with the landmark studies for both BORT (APEX) and LEN (MM 009/010). Based on these promising findings, the Food and Drug Administration (FDA) granted a breakthrough therapy designation to ELO combined with LEN/dexamethasone in relapsed myeloma patients.

Ongoing phase III studies Two phase III trials have been started: ELOQUENT 1 (n: 750 – closed for recruitment in 09/2013) studies the effect of LEN and dexamethasone with or without ELO in newly diagnosed previously untreated MM patients and ELOQUENT 2 (n: 640 – still open for recruitment in the United States) will study the same drug combination in relapsed/refractory MM patients. The treatment schedule in both studies is the same: LEN PO 25 mg (D1-21), oral dexamethasone (28 mg PO + 8 mg IV on ELO dosing days, or 40 mg PO once Figure 3. Modes of action of ELO, a mAb directed against CS1. weekly on non-ELO dosing days) and ELO 10 mg/kg, weekly, on days 1, 8, 15, and 22 (cycles one and two); days 1 and 15 (cycles three and beyond). Primary end- Efficacy data (phase II data) on point in both studies is PFS. elotuzumab Eligible patients in ELOQUENT 2 must have had 1-3 The final results of the 1703 phase Ib/II study of ELO prior lines of therapy and prior LEN was permitted as in combination with LEN and dexamethasone were long as best response (under LEN) was ≥PR, no more presented at ASH 2014.25 In the phase II part, 73 relap- than nine cycles were given and no grade 3 AE or larger sed/refractory MM patients with 1-3 prior therapies occurred. Finally no more than nine months should were enrolled, randomised to either an ELO 10 mg/kg have elapsed between last dose of LEN and progression. or 20 mg/kg arm. Cycles lasted 28 days and patients received ELO on day 1, 8, 15 and 22 for two cycles, Conclusion and ELO on day one and fifteen thereafter. Oral LEN The new monoclonal antibodies DARA (anti-CD38) was given daily at 25 mg (D1-21) in combination with and ELO (anti-CS1) show impressive activity in early- oral dexamethasone (28 mg PO + 8 mg IV on ELO phase clinical trials in relapsed/refractory MM patients dosing days, or 40 mg PO once weekly on non-ELO when combined with known anti-MM drug combina- dosing days). ORR was 84% (92% in 10 mg/kg cohort tions. DARA even has impressive single agent activity. and 76% in 20 mg/kg cohort). High quality responses Except for infusion-related reactions, these drugs have (VGPR or better) were seen in 57% of patients. Median favourable toxicity profiles which render them ideal PFS was 29 months with a slight advantage in the 10 candidates for prolonged use or single agent maintenance mg/kg compared to the 20 mg/kg arm (32 versus 25 therapy. months respectively). Most frequent treatment emergent AEs were diarrhoea (66%), muscle spasms (62%), fatigue References (56%), constipation (51%), nausea (48%), and upper 1. Zojer N, Kirchbacher K, Vesely M, et al. Rituximab treatment provides no clinical respiratory tract infections (47%). SAEs occurred in benefit in patients with pretreated advanced multiple myeloma. Leuk lymphoma. 58% of patients and pneumonia was most frequently 20 0 6;47(6):1103-9. cited (12%). Infusion related reactions could be mitigated 2. Mateo G, Castellanos M, Rasillo A, et al. Genetic abnormalities and patterns by prior paracetamol and dexamethasone administra- of antigenic expression in multiple myeloma. Clin Cancer Res. 2005;11(10):3661-7. tion and occurred at low frequency at infusion rates up 3. Tai YT, Li X, Tong X, et al. Human anti-CD40 antagonist antibody triggers to 5 ml/min. significant antitumor activity against human multiple myeloma. Cancer Res. In both these phase I-II combination studies, the main 2005;65(13):5898-906. toxicity could be attributed to BORT and LEN, respec- 4. Kaufman JL, Niesvizky R, Stadtmauer EA, et al. Phase I, multicentre, dose-esca- tively. The ORR observed seems to compare favourably lation trial of monotherapy with milatuzumab (humanized anti-CD74 monoclonal

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Key messages for clinical practice

1. DARA is an anti-CD38 mAb which shows an impressive single agent activity in pretreated MM patients. Other anti-CD38 mAbs are currently in preclinical/clinical development.

2. ELO is a novel anti-CS1 mAb with little or no single agent anti-MM activity. However, when combined with other anti-MM agents (especially LEN) its efficacy is greatly enhanced.

3. The main toxicity of DARA and ELO is related to infusion (shivering, dyspnoea, anaphylaxis, etc.) and can be mitigated by prior corticosteroid, antihistamines and paracetamol administration.

4. Because of their favourable toxicity profiles, anti-CD38 and anti-CS1 immunotherapy lend themselves as valuable adjuncts to known anti-MM combinations and as maintenance agents.

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