Anti-CD38 Monoclonal Antibodies in the Treatment of Multiple Myeloma

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Anti-CD38 monoclonal antibodies in the treatment of multiple myeloma

S. Vlayen, MSc1,2,3*, N. Kint, MD, PhD1,2*, M. Delforge, MD, PhD¹

SUMMARY As the surface antigen CD38 is highly expressed on malignant plasma cells, it provides an interesting therapeutic target for the treatment of multiple myeloma (MM). At present, three anti-CD38 monoclonal antibodies (mAb) have been studied in MM: daratumumab, isatuximab and MOR202. All three anti-CD38 mAb show complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody- dependent cellular phagocytosis (ADCP) activities. Moreover, immunomodulatory effects of daratumumab and isatuximab have been demonstrated. At present, daratumumab has been the most extensively studied anti-CD38 mAb in clinical trials. Following the excellent results of phase III clinical trials in relapsed/refractory MM (RRMM), daratumumab has recently also been studied in phase III clinical trials in newly diagnosed patients. The effects of isatuximab and MOR202 have been studied in phase III and phase I clinical trials, respectively, in patients with RRMM. (BELG J HEMATOL 2019;10(8):326-31)

INTRODUCTION brane glycoprotein found on the surface of many cell types. Over the last 20 years, immunotherapy has emerged as an CD38 is not only highly expressed on normal and malig- important treatment strategy in haematological malignan- nant plasma cells, but also on lymphocytes and red blood cies, including multiple myeloma (MM). MM is a malignant cells (RBCs). Additionally, CD38 is expressed on the cell plasma cell disorder characterised by severe complications, surface of non-haematopoietic cells, such as prostate epi- such as bone lesions and renal failure.1 Recently, mono- thelial cells, pancreatic islet cells and renal tubules.2,3 CD38 clonal antibodies (mAb) were introduced in the treatment is involved in the adhesion of lymphocytes to endothelial arsenal for patients with MM. This article provides a review cells as CD38 acts as a receptor for the trans-membrane on the role of anti-CD38 mAb in the treatment of MM. More molecule CD31, which is a member of the Ig superfamily.4 specifically, we will focus on both the molecular mecha- Binding of CD31 to CD38 regulates proliferation of and nisms of anti-CD38 mAb and on the different clinical trials cytokine release by lymphocytes.3 Second, CD38 is a multi- that have investigated these anti-CD38 mAb. functional ecto-enzyme that catalyses the catabolic reaction of nicotinamide adenine dinucleotide (NAD+) and nico- MOLECULAR MECHANISMS OF tinamide adenine dinucleotide phosphate (NADP) into ANTI-CD38 MONOCLONAL ANTIBODIES nicotinamide, adenosine diphosphate-ribose (ADPR) and CD38 cyclic ADPR, which is an endogenous regulator of calcium- CD38 or cyclic ADP ribose hydrolase is a type 2 transmem- dependent calcium release.2,4

¹Department of Internal Medicine, Haematology, University Hospitals Leuven, Leuven, Belgium, ²Stem Cell Institute Leuven, University Hospitals Leuven, Leuven, Belgium, ³Aspirant strategisch basisonderzoek FWO-Vlaanderen, 1S39720N. *both authors contributed equally to this manuscript. Please send all correspondence to: S. Vlayen, MSc, Department of Internal Medicine, Haematology, University Hospitals Leuven, Herestraat 49, bus 804, 3000 Leuven, Belgium, email: [email protected]. Conflict of interest: M. Delforge received consultancy fees from Janssen and Sanofi. The other authors have nothing to disclose and indicate no potential conflict of interest. Keywords: anti-CD38 monoclonal antibodies, CD38, daratumumab, isatuximab, MOR202, multiple myeloma.

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ANTI-CD38 MONOCLONAL ANTIBODIES MOR202 is used in combination with bortezomib and lena- Since CD38 is highly expressed on MM cells, it provides an lidomide. Furthermore, MOR202 in combination with bor- interesting therapeutic target for the treatment of MM.2 This tezomib and lenalidomide showed a complete abolishment section will discuss the mechanisms of action of the three of bone lysis in a xenograft mouse model.10 MOR202 is cur- anti-CD38 mAb that have been studied in the treatment of rently under investigation in a phase III clinical trial in com- MM: daratumumab, isatuximab and MOR202. bination with lenalidomide and dexamethasone for RRMM.11

Daratumumab Immunomodulatory effects of anti-CD38 monoclonal antibodies Daratumumab was the first anti-CD38 mAb to demonstrate Besides their direct anti-MM effects, anti-CD38 mAb also activity against MM in preclinical studies in both cell lines have immunomodulatory effects. In fact, as the cell surface and mouse models.3 In 2015, daratumumab also became antigen CD38 is expressed on different types of haemato- the first anti-CD38 mAb to be approved by the FDA for poietic cells, anti-CD38 mAb also have a profound effect on patients with relapsed MM who have received at least 3 the bone marrow micro-environment.9 CD38-expression is previous lines of therapy, including a proteasome inhibitor significantly increased on regulatory T (Treg) cells and MM (PI) and an immunomodulatory agent (IMiD), or for the cells in comparison with conventional T (Tcon) cells from treatment of patients whose disease is double-refractory to patients with RRMM who received daratumumab mono- proteasome inhibitors and IMiDs.5 Since then, the registration therapy. Treatment with daratumumab showed deletion of for daratumumab was increasingly broadened and recently, CD38+ Treg cells, regulatory B (Breg) cells and myeloid- the FDA also approved daratumumab in combination with derived suppressor cells, whereas CD8+ and CD4+ T cells lenalidomide and dexamethasone for newly diagnosed were expanded.3,9,12 Isatuximab inhibits Treg cells through patients with MM who are transplant ineligible.6 Daratu- reduction of Foxp3 and IL-10 and restores proliferation of mumab is a fully humanised IgG1-Kappa mAb that can kill Tcon cells. Furthermore, isatuximab upregulates CD107a CD38+ MM cells in different ways. A first mechanism of and IFNγ on CD38+ T cells and natural killer cells (NK action consists of complement-dependent cytotoxicity (CDC). cells), enhancing lysis of MM cells.13 At present, it is not Daratumumab also exhibits antibody-dependent cellular clear whether MOR202 has similar immunomodulatory cytotoxicity (ADCC) and antibody-dependent cellular pha- effects as daratumumab and isatuximab.14 gocytosis (ADCP) activities.2,5 Furthermore, daratumumab induces apoptosis through Fcγ-mediated cross-linking.3,5,7 CLINICAL EFFICACY OF ANTI-CD38 A preclinical study showed that ADCC activity of daratu- MONOCLONAL ANTIBODY TREATMENT mumab was significantly increased in peripheral blood OF MULTIPLE MYELOMA mononuclear cells (PBMCs) derived from patients with MM This section will detail the most important results of several who were treated with lenalidomide.8 key clinical trials on the use of anti-CD38 mAb in MM.

Isatuximab DARATUMUMAB-BASED REGIMENS IN THE Isatuximab is a chimeric IgG1-Kappa mAb and is currently TREATMENT OF MULTIPLE MYELOMA under review by the FDA as a potential treatment for patients Being the first-in-class anti-CD38 mAb, several studies have with relapsed/refractory MM (RRMM). Like daratumumab, already addressed the efficacy of the fully humanised mAb isatuximab exhibits CDC, ADCC and ADCP activities against daratumumab in different treatment regimens. The first MM cells as demonstrated in MM cell lines, primary MM phase I/II trials addressed the toxicity profile and efficacy of cells and in vivo xenograft models.2,9 Furthermore, isatuximab daratumumab in monotherapy in 148 heavily pre-treated has strong pro-apoptotic activity independent of Fcγ-mediated patients with MM, of which 86.5% were refractory to both cross-linking and immune effector cells, which distinguishes proteasome inhibitors and immunomodulatory drugs. Even isatuximab from other anti-CD38 mAb.3,9 Isatuximab also in this patient cohort with highly treatment-refractory disease, inhibits CD38 ecto-enzyme function.2 daramumab monotherapy at 16 mg/kg resulted in an overall response rate (ORR) of 31.1%, with a median progression- MOR202 free survival (PFS) of 4.0 months and a median overall Finally, MOR202 is a fully humanised IgG1-Gamma mAb, survival (OS) of 20.1 months in combination with a highly which kills MM cells via CDC, ADCC and ACDCP as shown favourable toxicity profile. Responding patients in this trial in both MM cell lines and primary MM cells.2,3 In vitro studies obtained a median PFS of 15 months, while the median OS in showed that the activity of MOR202 is enhanced when this subgroup was not reached at the time of publication.15,16

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In follow-up of these promising data, several phase III trials recent, data collection on long-term overall survival (OS) were designed to study the efficacy of daratumumab-based is mostly still ongoing. Nevertheless, daratumumab-based combinations in patients with relapsed MM. One trial pros- regimens have consistently shown to improve the minimal pectively evaluated the effect of daratumumab in combination residual disease (MRD)-negativity rates as compared to with bortezomib and dexamethasone (Vd) in 498 patients the control regimens. It has been established that MRD- with RRMM. In this study, the addition of daratumumab to negativity in MM correlates with improved PFS-rates and Vd led to a significant improvement in the ORR (82.9% and probably also OS,24 but mature OS data are necessary to see 63.2% for dara-Vd and Vd, respectively, p < 0.0001) and whether this is also the case in these studies. In general, the an almost 50% increase in the 12-month PFS rate (77.5% vs. consistent success of daratumumab-based regimens, both 29.4%, respectively, hazard ratio [HR]: 0.31, p < 0.001).17 in treatment of RRMM as well as frontline treatment have Another trial studied the efficacy of daratumumab in combi- led to further ongoing phase III trials in both frontline MM nation with lenalidomide and dexamethasone (Rd) in 569 treatment for transplant-eligible (PERSEUS trial) and trans- patients with RRMM. In this study, the addition of daratu- plant-ineligible (CEPHEUS trial) patients. mumab to Rd similarly resulted in a strongly improved ORR (92.9% vs. 76.4% for dara-Rd and Rd, respectively, p < 0.001), OTHER ANTI-CD38 MONOCLONAL ANTIBODIES while the 12-month PFS rate increased from 60.1% with Rd IN THE TREATMENT OF MULTIPLE MYELOMA to 83.2% with dara-Rd (HR: 0.37, p< 0.001).18 These excel- In addition to daratumumab, several other anti-CD38 mAb lent results have subsequently resulted in regulatory appro- have been developed. The chimeric anti-CD38 mAb isa- val of dara-Vd and dara-Rd for patients with RRMM. Along tuximab yielded promising results in several phase I trials. the same line, combinations of daratumumab with poma- For instance, the combination of isatuximab and lenalido- lidomide and carfilzomib yielded promising results in phase mide-dexamethasone demonstrated an ORR of 56% in 52 Ib studies and further studies are currently ongoing.19,20 patients with RRMM, with a median PFS of 8.5 months.25 Building further on the success of daratumumab in the Similarly, the combination of isatuximab with pomalido- treatment of RRMM, several phase III studies evaluated mide and dexamethasone was associated with an ORR daratumumab in the frontline setting. In MM patients who of 62% with a median PFS of 17.6 months in 45 patients are eligible for an autologous stem cell transplantation with RRMM.26 This combination regimen is currently being (ASCT), the addition of daratumumab to the bortezomib- further explored in the ongoing phase III ICARIA trial, thalidomide-dexamethasone (VTD) induction and post- including patients with RRMM who had received at least ASCT consolidation regimens resulted in a significantly two prior lines of therapy with lenalidomide and a PI.27 At a improved complete response (CR) rates in the daratumum- median follow-up of 11.6 months, the median PFS was ab-VTD arm compared to the VTD arm (39% vs. 26%, p = significantly longer in the isatuximab plus pomalidomide 0.001). Furthermore, the addition of daratumumab resulted arm compared to the pomalidomide arm (11.5 vs. 6.5 months; in a 53% reduction in the risk of disease progression or HR: 0.59; p= 0.001). Also the ORR was significantly in- death (HR: 0.47, p< 0.0001).21 creased when isatuximab was added (60.4% vs. 35.3%; p < Similarly, several phase III trials looked into the addition 0.0001) with a rate of very good partial response (VGPR) of daratumumab to standard-of-care frontline treatment or better of 31.8% vs. 8.5%.28 Additionally, preliminary data regimens in transplant-ineligible patients. The ALCYONE from a phase I study of isatuximab plus bortezomib, lena- trial evaluated the combination of daratumumab to the lidomide and dexamethasone (VRd) in newly diagnosed, bortezomib-melphalan-dexamethasone (VMP) regimen. In transplant-ineligible patients with MM showed a very high this study, dara-VMP was associated with a strongly ORR of 93%, with all responders except one demonstrating improved ORR (90.9% vs. 73.9% in the control group, res- a VGPR or better.28 pectively, p< 0.001), while also the 18-month PFS rate Finally, the fully humanised anti-CD38 mAb MOR202 increased by more than 20% (71.6% vs. 50.2%, HR: 0.50, has been studied in patients with RRMM in combination p< 0.001).22 Additionally, the MAIA trial addressed the with lenalidomide and dexamethasone (MOR-Rd), as well effects of adding daratumumab to the commonly used lena- as pomalidomide and dexamethasone (MOR-Pd). Both com- lidomide-dexamethasone (Rd) regimen. Daratumumab-Rd binations showed a promising ORR of 65% and 48%, res- significantly improved both ORR (92.9%vs . 81.3% in the pectively, as opposed to 28% in patients treated with MOR202 Rd-treated patients, p< 0.001) and the 30-month PFS rate and dexamethasone alone (MOR-dex). Additionally, median (70.6% vs. 55.6% in the Rd group, HR: 0.56, p< 0.001).23 PFS was not reached yet in patients treated with MOR-Rd As the phase III trials described above are still relatively and MOR-Pd, as opposed to a median PFS of 8.3 months in

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TABLE 1. Mode of action of the different anti-CD38 mAb.

Features Daratumumab Isatuximab MOR202

Isotype Fully humanised Chimeric IgG1-Kappa mAb Fully humanised IgG1-Kappa mAb IgG1-Gamma mAb

CDC ✔ ✔ ✔

ADCC ✔ ✔ ✔

ADCP ✔ ✔

Inhibition of ecto-enzyme No ✔ No function

Immunomodulatory effects ✔ ✔ Not yet known

patients treated with MOR-dex.11 However, it is still unclear nistration (IV). If there is a good initial tolerability, sub- whether MOR202 will be further developed. Additional sequent infusions with daratumumab can be safely adminis- trials are necessary to establish the precise roles of each tered over 90 minutes. The subcutaneous form of daratu- anti-CD38 mAb in the treatment of MM and even more mumab (1800 mg fixed dose) is currently being evaluated importantly to understand the efficacy of retreatment with in clinical trials and its administration is associated with an anti-CD38 antibody. similar efficacy compared to the IV formulation while it reduces the IRRs to less than 10%, with only a small mino- TOXICITY OF ANTI-CD38 MONOCLONAL rity of patients developing local skin reactions.29 ANTIBODY TREATMENT Overall, anti-CD38 mAb have a favourable toxicity profile. RESPONSE ASSESSMENT Mostly, side effects involve infusion-related reactions (IRR), As MM is characterised by the secretion of high quantities which are generally mild (grade 1/2) and consist of mild of monoclonal antibodies or M proteins, treatment response respiratory symptoms such as transient dyspnoea, cough in MM is generally assessed through the quantification of or wheezing. Almost all IRRs (95.6%) occur during the first these M proteins by M-spike quantification, free light chain infusion and later infusions are rarely associated with IRRs. measurement and immunofixation in serum or urine. Hence, Both daratumumab- and isatuximab-related IRRs occur treatment with mAb-based therapy might theoretically in approximately 50% of the patients, whereas IRRs were interfere with response assessment. This has especially only observed in approximately 10% of MOR202-treated proven to be a potential issue in case the MM-associated M patients. In all cases, anti-CD38 mAb-related IRRs are protein has the same isotype as the anti-CD38 mAb, which managed by a temporary interruption of the infusion, as is IgG-kappa for daratumumab. More specifically, in this well as administration of supportive medication such as particular situation, the bands generated during protein ntihistaminics or corticosteroids.11,15-28 However, in clinical electrophoresis by the anti-CD38 mAb and the M protein practice, patients already preventively receive antihistaminic will overlap, resulting in a potential underestimation of treatment, montelukast and/or bronchodilators prior to the treatment response, especially in patients with low M first infusion. spikes. Fortunately, this effect can be mitigated in the case of daratumumab through the use of the daratumumab- PRACTICAL CONSIDERATIONS specific immunofixation reflex assay (DIRA), which uses ASSOCIATED WITH ANTI-CD38 an anti-daratumumab antibody and subsequently alters its MONOCLONAL ANTIBODY TREATMENT migration pattern during electrophoresis.30 In practice, the MODE OF ADMINISTRATION use of this assay can be advised in patients with an IgG- Anti-CD38 mAb are currently given by intravenous admi- kappa-expressing MM, who have a low concentration of M

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protein (≤ 2 g/L).31 At present, a similar assay is not available port the synergistic effect of an anti-CD38 mAb and an yet for isatuximab and MOR202, though this will likely immunomodulatory drug. Several trials with different treat- become available in the future. ment combinations are still ongoing and will likely further expand the applicability of anti-CD38 mAb and might BLOOD TRANSFUSION further improve long-term disease control in an increasing As mentioned before, apart from its expression in plasma proportion of patients with MM. cells, CD38 is also expressed on other cell types.2 Especially CD38 expression on RBCs has high clinical relevance, REFERENCES as the presence of anti-CD38 mAb in the serum will result 1. Eslick R, Talaulikar D. Multiple myeloma: from diagnosis to treatment. Aust in positive indirect antiglobulin tests (IAT). 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Effect of MOR202, a human Hence, phenotyping/genotyping prior to treatment initiation CD38 antibody, in combination with lenalidomide and bortezomib, on bone still remains the preferred method in current clinical practice. lysis and tumor load in a physiologic model of myeloma. JCO. 2011;29:8078. 11. Raab MS, Chatterjee M, Goldschmidt H, et al. MOR202 with Low-Dose CONCLUSIONS Dexamethasone (Dex) or Pomalidomide/Dex or Lenalidomide/Dex in Relapsed The introduction of mAb in clinical practice has revolutio- or Refractory Multiple Myeloma (RRMM): Primary Analysis of a Phase I/IIa, nised the treatment of a large number of medical conditions, Multicenter, Dose-Escalation Study. Blood. 2018;132:153. with rituximab-based treatment regimens being the pioneer 12. Krejcik J, Casneuf T, Nijhof IS, et al. Daratumumab depletes CD38+ immune in the treatment of haematological malignancies. 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