New Strategies for Targeting CD38 in Multiple Myeloma Take Root

During the past 5 years, therapies targeting CD38, a protein highly expressed on the surface of plasma cells, have helped fuel the rapidly growing treatment options for patients with multiple myeloma (MM). Investigators are seeking to build on that success by expanding uses for existing drugs and exploring novel strategies aimed at CD38 activity in MM.

In November 2015, daratumumab (Darzalex) became the first monoclonal antibody (mAb) directed at CD38 to gain FDA approval for patients with MM. The initial indication was for those who have received at least 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) or are double refractory to those drugs.¹ The uses of daratumumab have since been expanded into various combination regimes in relapsed/ refractory and frontline settings.²

Daratumumab has now been joined by isatuximab-irfc (Sarclisa), an anti-CD38 mAb with a novel mechanism of action.3 In March 2020, the FDA approved isatuximab in combination with dexamethasone and the IMiD pomalidomide (Pomalyst) for patients with relapsed/refractory MM who had previously received at least 2 therapies, including a PI and lenalidomide (Revlimid), an IMiD.⁴

Several novel strategies directed at CD38 in MM are in earlier stages of development, including ones utilizing bispecific antibodies and chimeric antigen receptor (CAR) T cells. Notably, BM38, a dual-targeted CAR, recently demonstrated promise in a phase 1 study in relapsed/refractory disease.⁵

Multiple Functions of CD38

Cluster of differentiation 38 is a glycoprotein found on the surface of mature immune cells, with the highest expression levels on the antibody-producing plasma cells. It is also expressed on other lymphoid and myeloid cells, as well as some nonhematopoietic cells.^6-8

Originally discovered in the early 1980s as a marker of T-cell differentiation,^9-11 CD38 has been revealed over the past 4 decades to be a protein with numerous functions. As a receptor for the ligand CD31, CD38 influences cellular processes such as proliferation and adhesion and plays a role in T-cell activation.^10-13

CD38 is also now known to have important enzymatic functions, acting as a nicotinamide adenine dinucleotide (NAD)degrading enzyme (NADase) in several tissues. Specifically, it breaks down NAD into nicotinamide and adenosine diphosphate ribose (ADPR) or, to a lesser extent, cyclic ADPR (cADPR). In this manner, CD38 regulates the homeostasis of NAD, a crucial cofactor in cell signaling and metabolism, while controlling the availability of its metabolites. ADPR acts as a second messenger in calcium signaling and can be further metabolized into the nucleoside adenosine.^7,8,10-13

In the large majority of cases, CD38 is oriented in the membrane with its catalytic domain outside the cell (type II orientation); thus, it acts as an ectoenzyme, exerting its effects extracellularly. A smaller proportion of CD38 is found on intracellular membranes or on the plasma membrane in a type III orientation, with its catalytic domain facing inside the cell.⁷

Given its primary enzymatic role in the catabolism of extracellular NAD, the fact that the majority of NAD is intracellular seems paradoxical. However, CD38 has also been shown to break down NAD precursors before they are taken up into the cell and fed into the NAD biosynthetic pathway.⁸

Through both its receptor and enzymatic functions, CD38 has pleiotropic roles in cell signaling, metabolism, immunity, and beyond.^6,12,13 It is also implicated in numerous diseases, including cancer.

MM is a plasma cell malignancy, and CD38 has been found to be uniformly highly expressed on MM cells, making it an ideal therapeutic target.^10,13 Much as in normal cells, studies suggest that CD38 has varied functions in cancer cells, promoting growth, survival, and adhesion. Overall, these mechanisms are conducive to targeting with CD38-directed mAbs (Figure).¹³

Figure. MCD38-Directed Monoclonal Antibodies in Action Against MM Cells¹³

CD38 expression also is thought to contribute to the immunosuppressive microenvironment. It is expressed on many immunosuppressive cell types, including regulatory T and B cells and myeloid-derived suppressor cells. Increased CD38 expression results in increased production of adenosine, which also is immunosuppressive.^6,11,13-15

Daratumumab Sets the Pace

Although development of CD38-targeted mAbs in MM began in the 1990s,^3,14 it was not until 2008 that an agent first entered clinical trials.¹⁶ In 2015, that drug, daratumumab, made history by becoming the first mAb approved for the treatment of MM.¹⁷

Based on results from the phase 1/2 GEN501 (NCT00574288) and phase 2 SIRIUS (NCT01985126) trials, daratumumab was approved as monotherapy for the treatment of patients with relapsed or refractory MM who had received 3 or more prior lines of therapy, including a PI and an IMiD.^18,19

Because the majority of patients treated with daratumumab ultimately progress¹², the focus shifted to combinations in an attempt to improve efficacy and response durability.

A pair of phase 3 trials, POLLUX (NCT02076009) and CASTOR (NCT02136134), led to the 2016 approval of daratumumab in combination with dexamethasone and either the IMiD lenalidomide or the PI bortezomib (Velcade) in patients with relapsed/refractory MM after at least 1 prior line of therapy.^20-23 Then, in 2017, results of the EQUULEUS trial (NCT01998971) led the FDA to approve the combination of daratumumab and dexamethasone with a different IMiD, pomalidomide, for the treatment of patients with relapsed/ refractory disease after at least 2 prior therapies, including lenalidomide and a PI.²⁴

More recently, daratumumab has begun to be evaluated in the frontline setting. The quadruplet regimen of daratumumab, bortezomib, melphalan, and prednisone was evaluated in patients ineligible for autologous stem cell transplant (ASCT) in the phase 3 ALCYONE trial (NCT02195479), leading to FDA approval in 2018. Among 706 patients, the overall response rate (ORR) was 90.9% with the quadruplet regimen and 73.9% without daratumumab. The rates of complete response (CR) and minimal residual disease (MRD) negativity were also significantly higher in the daratumumab arm. The most common grade 3/4 adverse events (AEs) were neutropenia, thrombocytopenia, and anemia. Infusion-related reactions (IRRs) are the most prevalent CD38 mAb-related toxicity,¹⁴ and daratumumab-associated IRRs occurred in 27.7% of patients.²⁵

In a recent update, after a median follow-up of 40.1 months, daratumumab was associated with significant improvements in both progression-free survival (PFS; median, 36.4 vs 19.3 months) and overall survival (OS; median not reached; HR for death, 0.60), marking the first report of an OS benefit with daratumumab in patients with MM.²⁶

In the MAIA trial (NCT02252172), 737 ASCT-ineligible patients with newly diagnosed MM were randomized to receive daratumumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone. Over a median follow-up of 28 months, the ORR was 92.9% versus 81.3% (P <.001), and the median PFS was not reached compared with 31.9 months, respectively. The most common grade 3/4 AEs were neutropenia, lymphopenia, pneumonia, anemia, and leukopenia. IRRs related to daratumumab occurred in 40.9% of patients. On the basis of these results, this combination received approval in 2019.²⁷

Also in 2019, daratumumab received its first approval in the frontline setting for patients eligible for ASCT. In the pivotal CASSIOPEIA trial (NCT02541383), 1085 patients received 4 pretransplant induction and 2 posttransplant consolidation cycles of bortezomib, thalidomide, and dexamethasone, with or without daratumumab.

The addition of daratumumab boosted response rates after ASCT; the stringent CR (sCR) rate after consolidation was 29% versus 20% (P = .001), and the percentages of patients achieving CR or better, very good partial response (VGPR) or better, and MRD negativity were also significantly higher. Median PFS was not reached in either group (HR for progression or death, 0.47). The most common grade 3/4 AEs were neutropenia, lymphopenia, and stomatitis.²⁸

The ongoing phase 2 GRIFFIN trial (NCT02874742) is evaluating a quadruplet with a different IMiD in this setting (daratumumab plus lenalidomide, bortezomib, and dexamethasone). Data presented at the 2019 American Society for Hematology (ASH) Annual Meeting showed that the sCR rate after consolidation was higher in the daratumumab arm (42.4% vs 32.0%), as were the rates of ORR, CR or better, and VGPR or better. PFS and OS data were immature.²⁹

A subcutaneous (SC) formulation of daratumumab has also been developed and was compared with the intravenous (IV) formulation in the phase 3 COLUMBA trial (NCT03277105). Among 552 previously treated patients, the SC formulation demonstrated noninferiority in both primary end points (ORR and pharmacokinetics) and a significantly reduced incidence of IRRs (12.7% vs 34.5%; P <.0001).³⁰ As a result, the FDA approved the SC formulation of daratumumab in May 2020.

Isatuximab Enters the Picture

Isatuximab, the second CD38-targeted mAb approved for the treatment of relapsed/refractory MM, has several distinguishing features. It is a humanized mAb that binds to a different CD38 epitope than daratumumab and has a shorter infusion time compared with daratumumab.^3,31,32 Both antibodies have been shown to induce complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity and phagocytosis as part of their antitumor mechanism of action in MM.11,12 Isatuximab can also directly induce apoptosis of MM cells without needing to cross-link with Fc-γ receptors.^31,33

Approval was based on the ICARIA-MM trial (NCT02990338), in which the combination of isatuximab, pomalidomide, and dexamethasone significantly improved PFS compared with pomalidomide and dexamethasone alone (11.5 vs 6.5 months; HR, 0.596; P = .001). The most common AEs in the triplet regimen were IRRs, upper respiratory tract infection, diarrhea, bronchitis, and pneumonia. Serious AEs were observed in 62% and 54% of patients, respectively.³⁴

Novel Strategies

Beyond daratumumab and isatuximab, several novel CD38-targeting strategies are in development, mostly for MM but also for other hematologic malignancies and for solid tumors, according to a search of the ClinicalTrials.gov website (Table).

Table. Clinical Development of CD38-Targeting Drugs in Select Studies

These include other mAbs such as TJ202 and TAK-079. TJ202, formerly MOR202, was originally developed by MorphoSys in collaboration with Celgene. The companies ended their partnership in 2015, and MorphoSys discontinued development of MOR202 in MM in 2018. However, MorphoSys signed a deal with a Chinese pharmaceutical company, I-Mab Biopharma, which is continuing clinical trials in China and Taiwan (NCT03952091 and NCT03860038).^35,36

TAK-079 is a fully human IgG1 mAb that was more effective when administered SC compared with IV infusion in a f irst-in-human trial in healthy subjects (NCT02219256).³⁷ Results from a phase 1 multicenter study (NCT03499280) in patients with relapsed/refractory MM were presented at ASH 2019. Thirty-one patients had been enrolled across 4 dose cohorts (45, 135, 300, and 600 mg SC). Among 28 patients evaluable for safety, fewer than 1% grade 1 injection- site reactions were reported across more than 500 injections administered. There were no dose-limiting toxicities (DLTs), and the maximum tolerated dose was not reached. Treatment-related AEs (TRAEs) of any grade included fatigue and anemia, and there were 2 grade 3 TRAEs (decreased neutrophil count and anemia). Among 14 patients receiving at least 4 cycles of therapy, the ORR was 43%.³⁸

Takeda is developing 2 other CD38targeted drugs. TAK-573 is a CD38 mAb fused to attenuated interferon (IFN)-α, which has potent anti-MM activity. TAK-573 acts like an antibody-drug conjugate, targeting delivery of IFN-α to CD38-expressing MM cells to avoid off-target effects. TAK-169 is an engineered toxin body, described as a deimmunized form of the ribosome-inactivating Shiga-like toxin A subunit genetically fused to an antibody fragment that binds to CD38. TAK-169 is designed to internalize into CD38-expressing MM cells and inactivate ribosomes, directly causing cell death by inhibiting protein synthesis.^39-41

Also in development are several bispecific antibodies that bind to both CD38 and the CD3 protein on the surface of T cells, bringing cytotoxic T cells in close proximity to CD38-positive MM cells to facilitate an anti-MM immune response. Glenmark Pharmaceuticals received an orphan drug designation for its GBR 1342 in 2019, and Amgen is developing AMG 424.^42,43

CAR T cells are a form of adoptive cell therapy that employs genetically engineered T cells designed to target tumor-specific antigens. CD19-targeted CAR T cells have proved effective in the treatment of several hematologic malignancies and are approved by the FDA. There is considerable interest in generating CAR T-cell therapies targeting alternative antigens, including CD38 and BCMA, as key targets in MM.

CAR T cells are a form of adoptive cell therapy that employs genetically engineered T cells designed to target tumor-specific antigens. CD19-targeted CAR T cells have proved effective in the treatment of several hematologic malignancies and are approved by the FDA. There is considerable interest in generating CAR T-cell therapies targeting alternative antigens, including CD38 and BCMA, as key targets in MM.

Median follow-up was 36 weeks, and there were no DLTs. The most concerning toxicities associated with CAR T-cell therapies are cytokine release syndrome (CRS) and neurotoxicity. No grade 3 or higher neurotoxicity occurred, and only 4 patients had grade 3 or higher CRS, which resolved with treatment. ORR was 87.5%, including 8 sCRs, 2 VGPRs, and 4 partial responses. The longest duration of response was more than 51 weeks.⁵

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