Emerging agents and regimens for multiple myeloma

Novel agents and regimens as well as new technologies for tracing minimal residual diseases (MRD) have substantially improved the prognosis of patients with multiple myeloma (MM), with an increase in median survival from 3–5 years to 8–10 years in the past decade [1, 2]. The goal of treatment for newly diagnosed, transplant-eligible patients is to achieve the best depth of remission and improve the progression-free survival (PFS) and overall survival (OS).

The consensus is that induction therapy followed by autologous stem cell transplantation (ASCT) and maintenance therapy should be the overall management of myeloma, while the quality of life, tolerability, duration of treatment, convenience, and patients’ preference are taken into account [3]. For patients eligible for ASCT, three to four cycles of induction therapy are generally needed before the mobilization of hematopoietic stem cells. Proteasome inhibitors (PIs) and immunomodulator drugs (IMiDs)-based triplet regimens are preferentially considered, such as bortezomib (BTZ) and lenalidomide (Len) plus dexamethasone (DEX) (VRD), BTZ and thalidomide plus DEX (VTD), or cyclophosphamide and BTZ plus DEX (CyBorD). With better depth of remission and survival [4‐6], VRD is currently a standard regimen. The quadruplet regimen of BTZ, Len, cyclophosphamide, and DEX has been found to have increased hematological toxicity but similar efficacy compared to the triplet regimens [7]. Furthermore, with the wide application of cytogenetics-based stratification standards, clinical trials are generally recommended to high-risk patients with the presence of del(17p), translocation t(4;14), t(14;16), t(14;20), 1q21 amplification or p53 mutation; or primary plasma cell leukemia; or the presence of 5 to 20% circulating plasma cells and extramedullary disease. Patients with more than one of the high-risk cytogenetic features are considered to have an “ultra-high-risk” disease. Based on the promising data from randomized trials [8, 9], the MAYO 2020 mSMART guideline recommended induction therapy with monoclonal antibody–based daratumumab (D)-VRD regimen for cytogenetically high-risk patients [10].

For patients ineligible for transplantation, the goal is to achieve deep remission without any serious adverse effects (AEs). Elderly patients who are often complicated with different comorbidities and various impairment of cognitive, physical, and social functions should be thoroughly evaluated before induction therapy. For fit patients, VRD is recommended for initial therapy followed by maintenance therapy with Len, or a BTZ-based regimen for high-risk patients. Daratumumab and Len plus DEX (DRD) is an alternative that has been recently approved for long-term treatment.

In the new drug era, the role of ASCT is still irreplaceable, particularly for patients with high-risk cytogenetic features [11]. ASCT could improve the depth of response, MRD-negativity rate, and PFS, but its benefit in OS needs further evaluation with longer observation time and more cases [12]. However, no consensus has been reached regarding the time for ASCT (early ASCT following induction therapy versus delayed ASCT after relapse) in patients with a standard-risk [12, 13]. Allogeneic hematopoietic stem cell transplant is rarely considered, but is applicable for young patients with high-risk cytogenetics. The significance of the second ASCT is unclear. Hence, more prospective, randomized trials are needed to clarify this in relapsed and refractory MM (RRMM).

Progression of disease is very common even when a complete remission (CR) has been achieved after ASCT. It is important to achieve MRD negativity through maintenance therapy to prolong the response duration and PFS without inducing severe AEs. Len is generally recommended for maintenance therapy [14, 15], and BTZ as well [16, 17], especially in patients with high-risks (e.g., del17p). Studies investigating the response to maintenance therapy with monoclonal antibodies are ongoing. Based on the benefit in PFS demonstrated in the TOURMALINE-MM3 (NCT02181413) study [18], ixazomib, a novel PI, has been included as a category A recommendation in NCCN guidelines for maintenance therapy in transplant-eligible patients with newly diagnosed MM (NDMM). Though the duration of maintenance therapy is still controversial, increasing evidence has suggested that it should be decided according to MRD status.

Currently, the treatment strategies for RRMM are based on the different combinations of conventional drugs and novel drugs, including monoclonal antibodies, PIs, IMiDs, alkylating agents, anthracyclines, and corticosteroids. It is suggested that a triplet regimen is better than a two-drug combination [19]. In addition, immune therapies, such as chimeric antigen receptor T cells (CAR-T), checkpoint inhibitors and vaccines, also play a promising role in the management of MM. Several different classes of these agents were discussed in this review, with a particular focus on the novel immunomodulatory agents. Figure 1 representatively summarizes selected agents, and Tables 1, 2, and 3 summarize key clinical trials.

Antibody–drug conjugates (ADCs), which are composed of a mAb linked to a cytotoxic drug via a biodegradable linker, are among the fastest growing anticancer drugs. A novel promising ADC for MM in clinic is the B-cell maturation antigen (BCMA)-targeted antibody, GSK2857916 (belantamab mafodotin), which is formed by a humanized IgG1 conjugated with a tubulin polymerization inhibitor, monomethyl auristatin F (MMAF). BCMA is a member of the TNF-receptor superfamily expressed only in the plasma cells and mature B lymphocytes [63]. Upon binding to its proliferation-inducing ligand, BCMA promotes MM cell growth and drug resistance [64]. The expression of BCMA in MM cells increases as disease progresses, rendering it an ideal antigenic target.

The multicenter, open-label, phase I study GSK2857916 (DREAMM-1, NCT02064387) enrolled 38 patients in dose escalation phase (part 1) and 35 patients in dose expansion phase (part 2). All patients had been diagnosed with RRMM [65]. In part 1, patients received GSK2857916 (0.03–4.60 mg/kg) intravenously once every 3 weeks for up to 16 cycles. In part 2, patients received the recommended dose of 3.40 mg/kg once every 3 weeks. There was no dose-limiting toxicity in part 1. Corneal symptoms caused by MMAF toxin were common (53% in part 1 and 63% in part 2), including blurred vision, dry eye, and photophobia, all of which were reversible. Two patients discontinued treatment in part 1 because of the corneal events and none discontinued in part 2. The most common grade 3 or 4 toxicities were thrombocytopenia (34% in both part 1 and part 2) and anemia (16% in part 1 and 14% in part 2). Serious AEs occurred in 12 patients, and there was no treatment-related death. In part 2, most patients had been heavily pretreated: 59% had received more than 5 lines of therapy, 89% were refractory to both IMiD and PI, 37% were refractory to daratumumab, and 89% had received ASCT. ORR was 60% in part 2, with sCR 3%, CR 6%, and VGPR 43%. In the updated report, the median PFS was 12 months and mDOR was 14.3 months. These results suggested that GSK2857916 was well tolerated and induced a good response in patients with RRMM [66]. In the phase II DREAMM-2 study (NCT03525678) [67], 196 patients refractory to PIs, IMiDs or anti-CD38 antibody were recruited and were subsequently stratified by previous lines of therapy (≤ 4 vs. > 4) and cytogenetic risk status to receive the ADC at a dose of either 2.5 mg/kg or 3.4 mg/kg, respectively. To date, the ORR was 31% (30 patient, 97.5% CI, 20.8 to 42.6) in the 2.5 mg/kg cohort and 34% (34 patients, 97.5% CI, 23.9 to 46.0) in the 3.4 mg/kg cohort, and the median OS was not reached. Two deaths were potentially treatment related (one case of sepsis in the 2.5 mg/kg cohort and one of hemophagocytic lymphohistiocytosis in the 3.4 mg/kg cohort). Several trials using GSK2857916 are also underway, combining it with IMiDs (NCT03715478), PIs (NCT03544281) and checkpoint inhibitors (NCT03848845).

Besides BCMA, there are many ADCs currently in development, including those targeting CD56 (lorvotuzumab mertansine), CD38, and CD74 (STRO-001) [68]. In a phase I clinical trial of lorvotuzumab mertansine (NCT00346255) [69], 37 patients were enrolled in the dose escalation phase. The maximum tolerated dose was found to be 112 mg/m², which was subsequently used in the dose expansion phase. AEs were seen in 33 patients, including headache, fatigue, paresthesia, neuropathy and increased transaminase. Disease stabilization was the most frequent response in patients (42.9%). Additionally, 5.7% patients achieved PR and 11.4% patients showed minor response. The patients had an mDOR of 15.5 months and PFS of 6.5 months. To date, all of these ADCs are still being tested in clinical trials.

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)/CD28 and the programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) are the major immunosuppressive regulatory molecules. CTLA-4 is an inhibitory receptor expressed on T cells and negatively regulates immunity. Currently, ipilimumab, a humanized anti-CTLA-4 monoclonal antibody, has been approved by the FDA for the treatment of a variety of solid tumors, but no clinical trial of ipilimumab for MM has been reported. A phase I clinical trial of ipilimumab for the treatment of recurrent hematological malignancies after stem cell transplantation enrolled a total of 28 patients, including 1 patient with pulmonary plasmacytoma. The patient with plasmacytoma achieved PR and remained progression free for more than 21 months.

The expression of PD-L1 is not only increased in myeloma cells but also in bone marrow stromal cells. In addition, it is markedly elevated in patients with RRMM [70]. A number of pre-clinical and clinical trials targeting the PD-1/PD-L1 axis are currently underway. Nivolumab and pembrolizumab are two of the major PD-1 inhibitors, while durvalumab is a PD-L1 inhibitor. Early clinical data suggested that the inhibitors alone were not effective. The nivolumab phase 1b study in the treatment of RRMM did not observe a treatment response, and likewise, the pembrolizumab phase 1b trial reported that 93% of the patients discontinued treatment due to disease progression [71]. These studies suggested that blocking PD-1/PD-L1 might need to be combined with other treatment strategies.

KEYNOTE-183 is a randomized, open-label, phase 3 trial that uses POM and DEX with or without pembrolizumab to treat patients with RRMM that had previously received at least two lines of therapy [72]. A total of 249 patients were included and randomly assigned to the pembrolizumab group (n = 125) and the control group (n = 124). With a median follow-up time of 8.1 months, ORR was 34% in the pembrolizumab group versus 40% in the control group and the HR for death was 1.61. Grade 3–5 toxicity increased by 18% in the pembrolizumab group compared to the control group, serious AEs were 63% versus 46%, and treatment terminations caused by AEs were 20% vs. 8%. The immune-related AEs in the pembrolizumab group were mainly pneumonitis, hyperthyroidism, and rash. KEYNOTE-185 evaluated pembrolizumab in combination with Len and DEX in the treatment for patients with NDMM who were ineligible for ASCT. Patients in the pembrolizumab group faced more than double the risk of death than those in the control group. Non-progressive causes of death included pneumonia, intestinal bleeding, and heart failure. In July 2017, the FDA terminated KEYNOTE-183 and185 and multiple other clinical trials using PD-1 and PD-L1 inhibitors in combination with Len and POM due to safety issues (NCT02036502, NCT02726581, and NCT01592370).

Related trials, e.g., on nivolumab, in the treatment of RRMM had also been conducted. However, Checkmate-039 (nivolumab combined with daratumumab, with or without POM and DEX) and Checkmate-602 (nivolumab, elotuzumab, POM and DEX) trials had been terminated by the FDA due to the safety issues of pembrolizumab.

The majority of the current clinical trials focus on the combination of checkpoint inhibitors and IMiDs. However, IMiDs may reduce the expression of PD-1 in T and NK cells as well as the expression of PD-L1 in myeloma cells and myeloid-derived suppressor cells. Therefore, the combination of the two may lead to a decrease in the effector cell targets, which may reduce the corresponding antibody binding. In addition, the downregulation of PD-1/PD-L1 may lead to the compensatory upregulation of other immune checkpoints [73]. Therefore, the use of immune checkpoint inhibitors in the treatment of MM remains challenging. Currently, treatment options using immune checkpoint inhibitors in combination with radiotherapy [74], tumor vaccines [75], chemotherapy and bone marrow transplantation [76], CAR-T [77], and other immune checkpoint inhibitors are being explored.

Recently, another new strategy of immunotherapy using bispecific antibodies and bispecific T-cell engagers (BiTEs) has been shown to have more advantages than monospecific antibodies. These agents have two main binding domains: one is binding to the surface antigen of the tumor cells, and the other is for the immune effector cells, such as CD3 of T cells or CD16 of NK cells. These interactions do not depend on T cell receptor (TCR) specificity and antigen presentation but directly leads to the aggregation of the cells involved, activation of effector cells, and killing of the tumor cells [82]. Bispecific antibodies are classified into IgG-like and non-IgG-like types based on the presence or absence of an Fc region. Typically, IgG-like antibodies are more stable than non-IgG-like types. They have a longer half-life and act through antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, or complement-dependent cytotoxicity through Fc mediation. BiTEs are non-IgG-like and contain two single variable regions on the structure. They have a small molecular weight and short half-life and require continuous infusion to maintain the therapeutic level of the agent [83].

Currently, blinatumomab, a CD3/CD19-BiTE has been approved by the FDA for relapsed and refractory acute lymphoblastic leukemia [84]. MM cells do not express CD19, but in vitro experiments have found that CD19 + B lymphocytes can promote MM cell clonal expansion and may play the role of myeloma stem cells; hence, it seems to be reasonable to use blinatumomab for MM [85]. However, in order to maximize the therapeutic effect of BiTE, the selected target should be expressed only on tumor cells. The BCMA is under intensive focus. The first BiTE used for MM treatment is BI 836,909, which targets CD3 to activate T cells and targets BCMA to selectively induce BCMA-positive MM cells to lyse. Noticeably, its activity is not affected by bone marrow stromal cells, soluble BCMA, or proliferation-inducing ligands. Moreover, BI 836,909 could prolong the survival time in a mouse xenograft model [86]. It was acquired by AMGEN as AMG 420 for a phase I clinical trial for RRMM (NCT02514239) [87]. A total of 42 patients received continuous intravenous infusion at a dose of 0.2–800 µg/day. Each course consisted of treatment for 4 weeks followed by an interval of 2 weeks with no treatment, with a maximum of 10 courses. The patients had a median age of 65 years and had received an average of 4 lines of therapy. During AMG 420 treatment, the patients averaged 2.5 courses and 50% of them developed serious AEs, mainly infection (n = 12) and polyneuropathy (n = 2). Three patients developed grade 2 or 3 cytokine release syndrome (CRS), such as confusion and aphasia, similar to that seen in CAR-T cell therapy. Atypical infections were also observed, such as aspergillosis and fulminant hepatitis. Of the 10 patients who received a dose of 400 µg/day, 5 achieved MRD-negative sCR, 1 VGPR, and 1 PR, with a response rate of 70% and a response duration of 5.6–10.4 months. Therefore, 400 µg/day was determined as the dose for subsequent treatment. Due to the inconvenience of continuous infusion and the possibility of increasing the risk of infection with non-IgG-like bispecific antibodies, current studies are inclined to IgG-like type that can be administered once or twice a week; however, the corresponding toxicity may increase [84]. AMG 701 is a half-life extended BiTE targeting BCMA. Related clinical studies on monotherapy (NCT03287908) or in combination with IMiDs were ongoing. Another bispecific antibody, CC-93269, which binds bivalently to BCMA and monovalently to CD3, was also reported to have a promising efficacy and a manageable safety profile [88].

Although different agents have different structures or binding sites, most BiTEs target BCMA and CD3. Some BiTEs (e.g., AFM26) target BCMA and CD16 to induce NK cell-mediated cell lethality [89]. Thorsten et al. reported that a novel trispecific, tetravalent antibody that simultaneously targeted BCMA, CD200, and CD16A (FcγRIIIa) could significantly increase binding activity and induce NK cell-mediated cell killing [90]. The results are currently limited to in vitro and animal model studies.

Based on the known significant effect of CD38 monoclonal antibody on MM cells, targeting CD3 together with CD38 is expected to be a promising strategy. In vivo experiments showed that AMG 424, an anti-CD38/CD3 XmAb T cell-recruiting antibody, promoted tumor cell killing by T cells without causing excessive release of cytokines even if MM cells expressed low CD38 [91]. In addition, in vitro and in vivo experiments showed that an anti-FcRH5/CD3 T cell-dependent bispecific antibody at picogram concentrations could lead to the accumulation of FcRH5 on MM cells to stimulate the formation of immune synapses and exclude the inhibitory CD45 from the immune synapses, which is necessary for TCR triggering and T-cell activation. Currently, a phase I clinical trial (NCT03275103) is underway [92].

Recently, G protein-coupled receptor class C group 5 member D (GPRC5D) was found to be overexpressed in MM cells. Pilarisetti et al. constructed a GPRC5D/CD3 bispecific antibody, JNJ-64407564, which could recruit CD3 + T cells to aggregate on GPRC5D + MM cells for cell lethality [93]. A phase I clinical trial (NCT03399799) evaluating JNJ-64407564 in RRMM is currently in progress.

CAR-T cell immunotherapy is a new milestone in tumor treatment. Gene editing technology introduced chimeric antigen receptors and costimulatory molecules into T cells. The modified T cells, while have the ability to self-replicate, also carry antigens receptors that specifically recognize tumor cells and execute killing. The selection of the target antigen determines the efficacy of CAR-T cells on MM cells. The choice of antigen is determined by two aspects: (1) whether the targeted antigen is accurately and specifically expressed on the malignant tumor cells. The more accurate and specific the antibody is, the more effective the CAR-T cells are to kill the tumor cells; (2) it should not be expressed in normal cells so that the toxic side effect of CAR-T cells could be prevented. As a clonal malignant tumor, MM could have multiple subclones as the disease progresses. These subclones may have diverse antigens because of their genetic and phenotypic differences. A variety of CAR-Ts against different targets have been used in clinical studies of MM.

With increasing understanding of the mechanisms underlying MM in recent years, novel agents and combinations of existing treatment modalities are providing innovative therapies. In particular, immunotherapies including checkpoint inhibitors, vaccine, BiTEs, and CAR-T cells demonstrated promising efficacy in inducing deep and durable remissions in both NDMM and RRMM. As more novel agents make their way through clinical trials, the efficacy of immunotherapies will need to be assessed in different disease subgroups. It also needs to be clarified whether prior treatment with one immunotherapeutic agent influences the efficacy of subsequent lines of therapy. Cell-based immune therapies may serve as the preferred options for patients with high-risk cytogenetics who are more resistant to standard biological therapies. For these patients, treatment with immune therapies in early disease course may provide significant additional benefits. Nevertheless, high-risk cytogenetics associated with high levels of clonal diversity and cell proliferation may render escape mechanisms, such as loss of antigen expression, increased number of immunomodulatory cells in the microenvironment and upregulation of negative costimulatory molecules. Therefore, the suppressive immune impairments and the mechanisms of resistance to immunotherapies need further exploration. With more approved options, potential synergies among immunotherapeutic agents should be evaluated. For example, BiTE may enhance cytotoxic T cell activity followed by cancer vaccination or CAR-T cell therapy. Future study may come to the treatment algorithms of how to make optimal sequence of treatments and how to choose best treatment when disease progresses, while taking into account prior treatments, toxicities, and patient comorbidities and preferences. Although MM currently remains incurable, the future is bright.