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The Emerging Role of Monoclonal Antibodies in the Treatment of Multiple Myeloma

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The Emerging Role of Monoclonal Antibodies in the Treatment of Multiple Myeloma Pharmacotherapy 5 The emerging role of monoclonal antibodies in the treatment of multiple myeloma 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. Daratumumab (and related antibodies) is a monoclonal antibody 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. Elotuzumab, 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. Rituximab (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: siltuximab (anti-IL6 mAb), bevacizumab is expressed on the cytoplasmic part of the membrane. (anti-vascular endothelial growth factor), dacetuzumab 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. Belgian Journal of Hematology Volume 6, Issue 5, December 2015 209 Pharmacotherapy (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, Belgian Journal of Hematology Volume 6, Issue 5, December 2015 210 5 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
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