New Strategies in Multiple Myeloma: Immunotherapy as a Novel Approach to Treat Patients with Multiple Myeloma

IMiDs.

IMiDs, such as thalidomide, lenalidomide, and pomalidomide, exert significant activity in the treatment of multiple myeloma (2, 21, 22). They are recognized to bind to cereblon and induce degradation of transcriptional factors Ikaros and Aiolos (23). They have multifaceted mechanisms of action by mediating tumor cell killing via Myc and IRF4 downregulation (24) and enhancing immune function. In an Aiolos-dependent mechanism, IMiDs stimulate IL2 production, which in turn triggers the expansion of T cells as well as the activation and proliferation of natural killer (NK) cells. T and NK cells release IFNγ, which can induce the activation of DCs (25–27). They are also known to reduce the function of Tregs (28). Of note, Sehgal and colleagues (29) demonstrated in vivo the ability of pomalidomide to induce polyfunctional T-cell activation, with increased proportion of coinhibitory receptor BTLA⁺ T cells and Tim-3⁺ NK cells. These immunomodulatoy effects are rapid, involve both adaptive and innate immunity, and correlate with clinical outcome, even in heavily pretreated multiple myeloma patients. These properties make IMiDs an attractive backbone in combination regimens with other immune-based therapies. The clinical effects of these combinations are discussed in more detail below.

Immune checkpoint inhibitors (PD-1/PD-L1 axis).

PD-1 is a type I transmembrane protein expressed on the surface of activated T cells that, interacting with its ligands, PD-L1 and PD-L2, acts as an immunologic checkpoint to suppress antitumor immunity (30). Several studies have shown that PD-1 is largely expressed on tumor-infiltrating T cells and PD-L1 is detected on many different tumor cells, including multiple myeloma (18). PD-L1 expression on multiple myeloma cells is significantly upregulated compared with cells from patients with MGUS or healthy volunteers, and it increases with disease progression (31), allowing tumor cells to escape from host immune response. The interaction of PD-1⁺ T cells with PD-L1–expressing cells inhibits T-cell responses, by suppressing the secretion of stimulatory cytokines by T cells and by inhibiting tumor-reactive CD8⁺ cytotoxic T lymphocytes (32, 33). Recent work by Gorgun and colleagues (34) also demonstrated that PD-1/PD-L1 blockade induces anti–multiple myeloma immune response and lenalidomide further enhances effector cell–mediated cytotoxicity, providing the framework for clinical evaluation of combination therapy. At present, there are multiple clinical trials exploring the use of checkpoint inhibitors in patients with relapsed/refractory multiple myeloma (RRMM). Preliminary results of several phase I studies (35, 36) exploring the use of checkpoint inhibitors as single agents were disappointing, with no objective responses in patients with multiple myeloma, confirming the need for combinatory studies to antagonize additional inhibitory signals (37). Pembrolizumab is a highly selective anti–PD-1 mAb that has been recently evaluated in patients with RRMM in combination with IMiDs, due to their ability to enhance multiple myeloma–specific cytotoxic T cells. Preliminary results of a phase I trial exploring the safety, tolerability, and efficacy of pembrolizumab in combination with lenalidomide (Len)/dexamethasone (Dex) showed promising efficacy in heavily pretreated RRMM. The objective response rate (ORR) was 76%, including very good partial response (VGPR) and partial response (PR) also in patients with IMiD-refractory and double refractory disease (38). The combination also has a tolerable safety profile. The most common adverse events were anemia, pneumonia, neutropenia, thrombocytopenia, hyperglycemia, and dyspnea, and the immune-related side effects included pneumonitis, hypothyroidism, and hepatitis. Promising results are also expected from the phase II study evaluating the safety and efficacy of pembrolizumab with pomalidomide and dexamethasone in RRMM. Early evidence of deep, durable responses were observed in this heavily treated population. The ORR was 59% in all cohort of patients, and 50% in patients double refractory to proteasome inhibitors and IMiDs (39). The anti–PD-1 antibody nivolumab, alone or in combination with the CTLA4-blocking antibody ipilimumab or the killer cell immunoglobulin-like receptor–blocking antibody lirilumab, is also under evaluation in a phase I clinical trial in relapsed or refractory hematologic malignancies, including multiple myeloma (NCT01592370).

mAbs.

Direct targeting of the tumor has largely focused on the development of mAbs. This strategy is the most widely used form of cancer immunotherapy today and is a form of passive immunotherapy, as mAbs do not always require the patient's cellular immunity to take an active role in fighting the cancer, such is the case for mAbs capable of inducing complement-dependent cytotoxicity (CDC) and crosslinking-mediated apoptosis. It is considered a truly targeted therapy where the mAb is directed to a single target on a cancer cell, usually an antigen or a receptor site on the cancer cell, or it is directed at a cancer-specific enzyme or protein. Therefore, this approach depends on targets whose expression is relatively restricted to tumor cells and acts by coating tumor cells and promoting antibody-dependent mechanisms of cell death, including antibody-dependent cell-mediated cytotoxicity (ADCC) and CDC (40). For the purpose of this review, we will focus on the two mAbs that have already demonstrated promising clinical activity in multiple myeloma.

Elotuzumab (Elo) is a humanized mAb that specifically targets signaling lymphocytic activation molecule family member 7(SLAMF7)—also known as CS1—a glycoprotein highly expressed on multiple myeloma and NK cells (41). It exerts a dual mechanism of action by directly activating NK cells and tumor cell death via ADCC (42). As a single agent, elotuzumab has shown modest activity (43); recently, however, elotuzumab was combined with lenalidomide and dexamethasone and demonstrated encouraging results. The ELOQUENT-2 trial, a phase III randomized study comparing the efficacy and safety of Len–Dex with or without elotuzumab in RRMM patients, showed that the combination of Elo–Len–Dex demonstrated an ORR of 79% versus 66% in the Len–Dex arm and resulted in an extended progression-free survival (PFS) as compared with the control arm (19.4 months vs. 14.9 months, respectively), reducing the risk of progression or death by 30%. This benefit maintained regardless of patient age, number of prior lines of therapies, previous exposure to lenalidomide, or the presence of high-risk cytogenetics (44). On the basis of these results, elotuzumab was approved by the FDA in November 2015 for use with lenalidomide/dexamethasone in patients with RRMM and one to three prior therapies. A recent update of the ELOQUENT-2 trial also showed that at 3-year follow-up, patients receiving elotuzumab had 27% reduction in risk of progression or death versus lenalidomide/dexamethasone alone and had a median delay of 1 year in time to next treatment (45). Concerning safety profile, the most common side effects were lymphocytopenia, neutropenia, and fatigue. Infusion reactions to elotuzumab occurred in 10% of patients and were of mild grade. In a phase II trial patients who received elotuzumab in combination with bortezomib and dexamethasone showed an ORR of 66% versus 63% in patients treated with bortezomib and dexamethasone alone. The PFS was 9.7 months in the elotuzumab arm versus 6.9 months in the bortezomib arm (46). Infusion reactions occurred in 7% of patients in the elotuzumab arm, and the most common side effects were thrombocytopenia and infections.

Daratumumab is a humanized anti-CD38 mAb that not only targets tumor cells but also mediates the killing of CD38-expressing plasma cells via ADCC, antibody-dependent phagocytosis, CDC, and apoptosis (47). It also has an immunomodulatory mechanism of action due to its ability to induce the depletion of CD38⁺ immunosuppressive cells, which is associated with an increase in Th cells, cytotoxic T cells, T-cell functional response, and T-cell receptor (TCR) clonality (48). CD38 is an attractive target for immunotherapy treatment due to its high and uniform expression on multiple myeloma cells (49) and relatively low expression on normal lymphoid and myeloid cells and in some nonhematopoietic cells (50). As a single agent, in the phase II SIRIUS trial, daratumumab demonstrated an ORR of 29% and a median PFS of 3.7 months in patients with RRMM, all of whom had prior exposure to bortezomib and lenalidomide. The median time to response among responders was 1 month, and the median duration of response was 7.4 months (51). Patients experienced modest infusion-related reactions and manageable hematologic toxicity. On the basis of its favorable toxicity profile and efficacy, daratumumab was approved by the FDA in November 2015 for use in multiple myeloma patients with ≥3 prior therapies. Recent results of a phase I/II study (GEN503) of daratumumab in combination with lenalidomide/dexamethasone showed rapid, deep, and durable responses in RRMM patients. The ORR was 81%, including a 28% VGPR and a 34% complete response (CR)/stringent complete response (sCR), with a median follow-up of 15.6 months. At 18 months, the PFS was 72%, and the OS was 90%. The toxicity profile was similar to that reported by studies of daratumumab monotherapy (52). Two phase III studies of daratumumab are currently ongoing: one of daratumumab in combination with lenalidomide and dexamethasone versus lenalidomide and dexamethasone (MMY3003) and one of daratumumab in combination with bortezomib and dexamethasone (DVd) versus bortezomib and dexamethasone alone (Vd; MMY3004). Preliminary results of the MMY3003 study showed an unprecedented 63% reduction in the risk of progression or death in the daratumumab group compared with the lenalidomide and dexamethasone group. The ORR was 93% in the daratumumab group compared with 76% in the control group. Deep and durable responses were significantly more frequent in the daratumumab group, with higher rates of VGPR or better (76% vs. 44%) and a more than doubling of CR or better (43% vs. 19%). Median PFS had not been reached in the daratumumab arm and was 18.4 months in the control arm. Treatment was well tolerated in the daratumumab group, with adverse events consistent with the known profiles of the drugs in the combination (53). Promising results are also observed in the MMY3004 study, where daratumumab was added to the standard bortezomib and dexamethasone. With a median follow-up of 7.4 months, daratumumab significantly improved median PFS (61% reduction in risk of progression) and TTP for DVd versus bortezomib and dexamethasone. It significantly increased ORR (83% vs. 63%) and doubled rates of ≥VGPR (59% vs. 29%) and ≥CR (19% vs. 9%) for DVd versus Vd, respectively; median duration of response was not reached (NR) versus 7.9 months, respectively. Safety of DVd is consistent with the known safety profile of daratumumab and Vd (54). The combination of daratumumab with pomalidomide and dexamethasone is also being evaluated in an ongoing phase I trial. An early analysis showed rapid initial responses that are deepening over time. The ORR was 71% and 67% in patients double refractory to proteasome inhibitors/IMiDs, and the combination showed a tolerable safety profile (55). Additional trials investigating various daratumumab-based regimens for patients with newly diagnosed multiple myeloma are also ongoing, and results are eagerly awaited.

A summary of additional mAbs currently in clinical development for RRMM in combination with proteasome inhibitor or IMiD-based regimens is shown in Table 1.

CAR T cells.

CAR T cells engineered to target antigens expressed on multiple myeloma cells also represent a promising new area of exploration. They lead to direct multiple myeloma cell killing and T-cell immunity stimulation. Autologous transplantation followed by treatment with CAR T cells against CD19 (CTL019) demonstrated significant activity in a patient with refractory multiple myeloma. It led to a CR lasting longer than previous remissions, but with subsequent relapse (57). Promising results are also coming from CAR T-cell therapy targeting BCMA, the B-cell maturation antigen expressed by normal and malignant plasma cells. Preliminary results of a phase I trial of the CAR-BCMA in patients with advanced multiple myeloma showed strong anti–multiple myeloma activity at higher dose levels, with durable sCR achieved in two patients with a high disease burden and chemotherapy-resistant disease. Substantial but reversible toxicity was observed. This included cytopenias attributable to chemotherapy, fever, and signs of cytokine-release syndrome (58). Additional studies of other CAR T-cell therapies targeting CD38, CD138, and CS1 are currently under evaluation in clinical trials.

Despite promising results, resistance and short duration of response is often noted with CAR-based immunotherapy. Loss of the CAR-specific antigen or limited proliferation of CAR T cells in vivo is often observed due to their inefficient activation or inhibition due to immunosuppressive microenvironment within the tumor stroma (59). This challenge seems to apply even more to multiple myeloma due to its phenotypic heterogeneity and the relative paucity of tumor-specific markers. To overcome these challenges, novel CAR designs are currently being tested, including an introduction of additional motifs from various costimulatory molecules into the intracellular chain of CAR or cotransduction of T cells with genes encoding for essential prosurvival T-cell cytokines (60).

BiTEs.

BiTEs are generated to combine specificities of two antibodies by simultaneously binding to multiple epitopes, one of which involves the activation of T cells via their CD3 molecules (61). The first bispecific antibody generated specifically against multiple myeloma was developed by combining single-chain variable fragments (ScFv) of a mAb that binds normal and malignant plasma cells (Wue-1) and a mAb against CD3 (62). This led to design and development of other BiTEs. A promising molecule, currently under clinical investigation, targets BCMA via a defucosylated antibody that is coniugated to the monomethyl aurastatin F (MMAF). This antibody is currently under investigation in a phase I trial in patients with RRMM (NCT02064387).

Vaccine therapy.

Another major area of investigation is the use of cancer vaccines to elicit a tumor-specific immune response without the need for alloreactive lymphocytes. Various strategies have been examined and can be broadly divided into noncellular approaches using antigen-specific peptides and cellular techniques using tumor lysates and whole-cell DCs (63, 64). Idiotype proteins, derived from the variable region of the clonal immunoglobulin, were some of the first antigenic targets investigated. Unfortunately, due to the poor immunogenic nature of the protein and the low expression of these proteins on the plasma cell surface, this approach did not meet expectations. On the other hand, subsequent identification of tumor-associated antigens such as MAGE, hTERT, WT-1, XBP-1, CS1, and CTA as targets was able to generate cellular responses when used in preclinical studies (65, 66), but the clinical outcome is still lacking. Efforts to enhance the immunogenicity of these vaccines by combining T-cell therapy are currently ongoing.

The second vaccination approach involves patient-derived multiple myeloma cells fused with autologous DCs to take advantage of the ability of DCs to present several antigens from the cell to the host (67). In a phase I and II trial, this approach resulted in the expansion of autologous multiple myeloma–specific T cells, was well tolerated, and demonstrated CRs in a quarter of the patients (68). A National Clinical Trials Network study (BMT CTN 1401) is currently underway, evaluating the efficacy of the DC/tumor vaccine with or without the presence of IMiDs in the post-autologous stem cell transplant setting.

A summary of novel immunotherapeutic targets and treatment options discussed in this revew article is shown in Fig. 2.

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Figure 2.

Overiew of novel immunotherapeutic approaches in multiple myeloma (MM). Shown here are the cellular components of the bone marrow microenvironment and host immunity. The novel immunotherapeutic targets and treatment options discussed in this revew article are highlighted here.