ABSTRACT
Objective
Treatment strategies for relapsed/refractory MM are particularly complex. In particular, patients who are refractory to the three classes of therapies have limited therapeutic options and poor survival. Fortunately, promising treatments are emerging, but their incorporation into existing treatments still needs to be defined. We will describe the latest trends and emerging developments in the field of therapies for RRMM by analyzing the most recent clinical data and new technologies in drug development.
Methods
Pubmed, Embase and Cochrane Library were searched to select eligible studies, the clinical data of new promising treatments were reviewed. The key results of the most recent clinical trial were summarized in Table.
Results
A total of 13 studies were included in the final analysis involving anti-BCMA CAR T-cell therapy, Combined CAR T-cell therapy, antibody-drug conjugates, bispecific Ab therapy and CELMoDs. The key efficacy and side effects of treatments were summarized.
Conclusions
There is great promise for a set of next-generation of rescue therapies, including CAR T-cell therapy, bispecific antibodies, antibody-drug conjugates, and novel PROteolysis Targeting Chimeras. Emerging new treatments for MM provide more choices for relapsed/refractory multiple myeloma (RRMM). The optimal therapy for each patient should be based on disease-related factors, such as previous therapies, duration of response to prior drugs, clinical and biochemical features of relapse, and the relationship of patient comorbidities with known AE profiles of the different therapies.
Introduction
Multiple myeloma (MM), the second-most frequent hematologic tumor, is an incurable malignancy of the plasma cells, although several available treatments can provide remission and prolong survival [Citation1]. In 2021, about 34,920 new cases will be diagnosed with MM and 12,410 people will die from MM in the U.S. The current 5-year survival rate (47%) is much better than in 1999 (31%) [Citation2]. The availability of advanced agents, including proteasome inhibitors (PIs), immunomodulatory imide drugs (IMiDs) and monoclonal antibodies (MoAbs), are responsible for these substantially improved outcomes [Citation3]. However, these conventional therapies are not curative and nearly every patient will eventually relapse and face a poor prognosis [Citation4]. In addition, relapsed MM is typically characterized by genetic alterations that lead to subclonal evolution, making it more resistant to treatment. Consequently, patients experience shorter durations of remission and eventually develop relapsed/refractory MM (RRMM) [Citation5].
The treatments available for RRMM have become more complex, and most of these patients receive drug combinations that include PIs, IMiDs and/or MoAbs, with histone deacetylase inhibitors and/or alkylating agents [Citation6,Citation7]. The recent regulatory approval of belantamab mafodotin (a B cell maturation antigen [BCMA antibody drug conjugate ADC) and selinexor (a selective inhibitor of nuclear export) may fill an unmet need for treatment of myeloma that is refractory to PIs IMiDs [Citation8],and anti-CD38 MoAbs [Citation9]].
Despite these emerging treatment options, RRMM remains largely incurable, and additional novel therapies are needed. According to extensive studies of the molecular and cellular biology of this cancer, several new approaches have entered early clinical trials, including CAR T-cell therapy, ADCs, and Bispecific Ab therapy. These new approaches broaden the therapeutic options and pave the path for more effective treatments and rational combination approaches for RRMM. In this review, we will describe the latest trends and emerging developments in the field of therapies for RRMM by analyzing the most recent clinical data () and new technologies in drug development, including PROteolysis Targeting Chimeras (PROTACs).
Table 1. Clinical trials with different drug modalities in the RRMM setting.
Main context
Chimeric antigen receptor (CAR) T-cell therapy
CAR T-cell therapy is new class of immunotherapy used to treat multiple cancers, especially hematologic malignancies, in which T lymphocytes are genetically engineered with a synthetic receptor that specifically recognizes a tumor antigen [Citation10]. The U.S. Food and Drug Association (FDA) and the European Medicines Agency (EMA) recently approved CD19-targeted CAR T-cell therapy to treat relapsed refractory acute B lymphoblastic leukemia and diffuse large B cell lymphoma [Citation11,Citation12]. Because MM derives from B cell hematological malignancies, several studies administered CAR T-cell therapies that target CD19, kappa light chain, and BCMA to RRMM patients, and the results indicated that single BCMA-targeted CAR T-cells were more effective than non-BCMA-targeted therapy [Citation13]. CAR T-cell therapy with a BCMA target alone had overall response rate (ORR) of 82%, whereas the non-BCMA therapy had an ORR of 43% [Citation14].
The expression of BCMA is primarily in normal/abnormal plasma cells, mature B cells, and plasmacytoid dendritic cells (PDCs), but not in normal haemopoietic stem cells, naive B cells, memory B cells, and other non-haemopoietic cells [Citation15]. Several studies reported promising results from anti-BCMA CAR T-cell therapy [Citation16–18]. Here, we review available BCMA-targeted CAR T-cell therapies currently in clinical testing, bb2121/bb21217 and LCAR−B38M/JNJ-4528.
bb2121/bb21217
bb2121 contains a lentiviral CAR construct with a murine scFv, a CD127 (4-1BB) co-stimulatory motif, and a CD3z signaling domain. The Phase I CRB-401 study showed that bb2121 had promising efficacy and tolerability in RRMM patients who received intensive previous treatments. In particular, 76% of patients had a median duration of clinical response that was more than 10 months without receiving continuous MM therapies [Citation19,Citation20].
The efficacy and safety of bb2121 (idecabtagene vicleucel [ide-cel]) in RRMM patients is being evaluated in the pivotal multi-center Phase II KarMMa study. All 128 enrolled patients received more than 3 prior regimens and were refractory to the last therapy. These patients received bb2121 (ide-cel), consisting of 150 × 106–450 × 106 CAR T-cells. During a median follow-up of 13.3 months, the ORR was 73% overall, 50% in the low-dose group (150 × 106 cells), 69% in the medium-dose group (300 × 106 cells), and 82% in the high-dose group (450 × 106 cells). Overall, 42 of 128 patients (33%) had complete response (CR) or a stringent CR (sCR). A total of 67 patients (52%) had a very good partial response (VGPR) or better. The median progression free survival (PFS) time was 8.8 months overall (2.8 months in the low-dose group, 5.8 months in the medium-dose group, 12.1 months in the high dose group). The median overall survival (OS) time was 19.4 months. Analysis of toxicities indicated the most frequent types were neutropenia (91%), anemia (70%), and thrombocytopenia (63%). Besides, 84% of these patients had cytokine release syndrome (CRS), mostly of grade 1 or 2 and 7 patients (5%) had adverse events (AEs) of grade 3 or higher [Citation21]. Treatment with bb2121 thus led to deep (VGPR ≥ 50%) and durable response in RRMM patients who were heavily pretreated. The efficacy and safety of bb2121 were similar to the reports in prior trial data, and support a favorable benefit-risk profile in the tested dose range. Researchers recently initiated a phase III randomized study comparing bb2121 with the most advanced triplet regimen for patients with RRMM. Thus, bb2121 could be the first CAR T-cell therapy for RRMM to be approved by the FDA.
In addition, Bluebird Bio initiated the Phase I trial CRB-402 with bb21217, the next-generation anti-BCMA CAR T-cell therapy. bb21217 is similar to bb2121, but a phosphoinositide 3-kinase inhibitor (bb007) was added during ex vivo T-cell expansion [Citation22]. Phase I CRB-402 study has shown that for all 72 patients treated, the ORR was 69%, with 36% achieving a CR. The median duration of response (DOR) was 23.8 (16.8-34.2) months for all patients. bb21217 persisted in the circulation longer term than unselected CAR T-cells. Presence of memory like markers in drug product and in peak expansion samples is associated with superior clinical outcomes [Citation23,Citation24].
Ciltacabtagene autoleucel
Ciltacabtagene autoleucel (Cilta-cel; LCAR-B38M, Legend Biotech) is the most clinically advanced CAR construct targeting BCMA that was developed in China. Cilta-cel incorporates human scFvs with ‘dual-epitope’ specificity, thus allowing the binding to two BCMA extracellular domains. The ongoing Phase I/II LEGEND-2 trial (NCT03090659) includes 57 RRMM patients who received infusional Cilta-cel (median dose: 0.5 × 106 cells/kg) and recorded follow-up for a median of 8 months. The ORR was 88%, the CR was 74%, the VGPR was 4%, and the partial response (PR) was 11%. The median PFS time for all treated patients was 20 months. Moreover, cilta-cel had an acceptable safety profile after a median follow-up of 19 months, and provided deep (CR ≥ 70%) and durable patient responses [Citation25]. A Phase II confirmatory study of cilta-cel recently began in China (CARTIFAN-1, NCT03758417).
The ongoing CARTITUDE-1 study (NCT03548207), a Phase Ib/II clinical study of Cilta-cel (JNJ-4528, identical to LCAR-B38M) is being conducted in the U.S. The results demonstrated that Cilta-cel provided early and deep responses and had a manageable safety profile in patients with RRMM [Citation26,Citation27]. 97 patients (29 in phase I and 68 in phase II) received a cilta-cel infusion. The ORR was 97%, 67% achieved sCR. The median time to first response was only 1.0 months, and the median time to CR or better was 1.8 months. Responses improved over time, in that the 12-month PFS was 77%. The most frequent AEs were CRS (94.8%), neutropenia (90.7%), anemia (81.4%), and thrombocytopenia (79.4%). CAR T-cell neurotoxicity occurred in 21% patients [Citation28]. The longer-term (median 24 months) follow up results were recently presented at the 63th American Society of Hematology (ASH) Annual Meeting in December 2021. The ORR remained at 98%, with higher sCR rates (83%). Two-year PFS and OS rates were 60.5% and 74%, respectively. No new safety signal was observed. All these data from the CARTITUDE-1 study suggested an early and durable response and a tolerable safety profile for cilta-cel.
In February 2019, the FDA approved JNJ-4528 for use as an orphan drug, and in April 2019, the EMA granted JNJ-4528 a PRIority Medicines (PRIME) designation.
Combination CAR T-cell therapy
Data from anti-BCMA CAR T-cell studies are encouraging, however, some RRMM patients did not respond or experienced relapse soon after treatment. This may be because a small fraction of CD19-expressing MM clones are myeloma-like stem cells or less-differentiated myeloma cells [Citation29,Citation30]. Thus, a Phase II trial of a combination of CAR T-cell therapy with humanized anti-CD19 and anti-BCMA CAR T-cells (ChiCTR-OIC-17011272) [Citation31] is examining safety and efficacy in patients with RRMM. After lympho-depletion using fludarabine and cyclophosphamide, patients received infusions of humanized anti-CD19 CAR T-cells at a dose of 1 × 106 cells/kg and murine anti-BCMA CAR T-cells at the same dose. After a median follow-up of 179 days, the ORR was 95%, the sCR was 43%, the CR was 14%, the VGPR was 24%, and the PR was 14%. Notably, 81% of these patients achieved minimal residual disease-negativity. The safety profile was consistent with that reported for other CAR T-cell therapies; CRS was the most frequent AE (90%), and hematological toxicity was the most common serious AE (95%) [Citation31].
Another Phase I trial is examining the effect of a bispecific CAR T-cell therapy against CD38 and BCMA in RRMM patients (ChiCTR1800018143) [Citation32]. Among the 16 patients who received treatment at the most recent cut-off, 87.5% responded to treatment and achieved measurable residual disease (MRD) in the bone marrow, including 50% with sCR, 12.5% with VGPR, 25% with PR, and 75% with PFS at 9 months [Citation32].
CAR natural killer cell therapy
Despite the remarkable progress in development of CAR T-cell therapies for treating RRMM, there are certain limitations of this approach, especially on-target off-tumor toxicity and CRS, which can be serious safety concerns [Citation32,Citation33]. To overcome these concerns, some researchers are examining the application of natural killer (NK) cells as alternative vehicles for CAR engineering. NK cells are CD3−CD56+ innate lymphocytes that play an essential role in host defense against pathogenic infection and tumorigenesis [Citation34]. In contrast to T cells, NK cells eliminate tumor cells in the absence of antigen priming, and are not limited by the expression of major histocompatibility complex (MHC) molecules on target cells [Citation35,Citation36]. Therefore, tumor cells that are resistant to T-cell clearance via enrichment of MHC I-deficient clones remain susceptible to NK cells [Citation37]. In addition, NK cells have unique biological characteristics and a well-established safety profile.
Therapeutic NK cells can be harvested from various sources, such as umbilical cord blood, peripheral blood, hematopoietic stem cells, pluripotent stem cells, and the NK-92 cell line [Citation38]. Chu et al. reported that adoptive transfer of CS1-specific CAR NK-92 cells inhibited the proliferation of IM9 MM cells and efficiently prolonged the life span of MM xenograft mice [Citation39]. Therefore, CS1 is a potential target for CAR-expressing cells, and allogeneic or autologous transplantation of CS1-CAR-expressing NK cells appears to be an encouraging option for MM treatment. A current Phase II trial in China (NCT03940833) is investigating the effect of CAR NK cells in MM patients. In particular, this study is examining the safety and feasibility of anti-BCMA CAR-NK 92 cells in RRMM patients. Although currently in the early stage of development, CAR NK-therapy appears to be a promising strategy for overcoming the immunosuppressive environment in MM.
Antibody–drug conjugates
ADCs are an emerging therapeutic class of drugs that may also be effective against MM. An ADC consists of a MoAb conjugated to a potent cytotoxin via synthetic linkers that selectively targets tumor cells [Citation33].
Belantamab mafodotin
Belantamab mafodotin (Belamaf; GSK2857916) is the first-in-class MM ADC. It consists of an antibody that targets BCMA and is conjugated to maleimidocaproyl monomethyl auristatin-F (mcMMAF). Pre-clinical research indicated that this ADC selectively induced significant anti-MM activities, in that it bound to BCMA, was internalized by these cells, and then released the mcMMAF via proteolytic cleavage, resulting in cell cycle arrest and apoptosis [Citation34]. Belamaf induced responses in intensively pretreated RRMM patients who were resistant to bortezomib, dexamethasone, IMiDs, and daratumumab. In August, 2020, the FDA approved belantamab mafodotin as a monotherapy for RRMM adults who received at least four prior therapies.
This approval was based on data collected from an open-label, multicenter study, the pivotal DREAMM-2 trial (NCT 03525678). This study examined 196 RRMM patients who continued to deteriorate despite receiving the current standard of care. These patients received 2.5 mg/kg (n = 97) or 3.4 mg/kg (n = 99) of intravenous (IV) belantamab mafodotin as a single agent every three weeks. The results demonstrated that a dose of 2.5 mg/kg resulted in deep and durable activity and had a manageable safety profile for up to 13 months in these heavily pretreated RRMM patients [Citation35]. Patients who received 3–6 prior treatments had an ORR of 34%, and patients who received 7 or more previous treatments had an ORR of 30%. The DOR in the two groups was 11.0 and 13.1 months, and the median PFS was 2.9 and 2.2 months, respectively. The most common AEs in these two groups were keratopathy (33%, 27%), thrombocytopenia (17%, 20%), anemia (11%, 31%), and decreased lymphocyte count (11%, 14%).
The multimodal mechanism of action, efficacy, and safety profile of belantamab mafodotin, as well as the preclinical data, indicated a possible synergistic benefit when used in combination with IMiDs and PIs. A Phase I study evaluated the efficacy, safety, and tolerability of belantamab mafodotin in combination with PIs, an IMiD drug enhancing T-cell and NK cell-mediated immunity, and dexamethasone in RRMM patients [Citation36]. The ORR was 86.2% (6 with PR, 15 with VGPR, and 4 with sCR). The treatment-emergent AEs were considered acceptable and consistent with the known safety profiles of belantamab mafodotin and PIs. These results demonstrated that belantamab mafodotin provided clinically meaningful efficacy and had a manageable safety profile when administered to patients with RRMM.
Bispecific Ab therapy
Administration of bispecific antibodies (bsAbs), synthetic antibodies that bind two different antigens, is another immunotherapeutic approach that can enhance the interaction between myeloma cells and immune effector cells, including T-cells and NK cells [Citation37]. In the case of MM, a bispecific T-cell engager (BiTE) that targets BCMA on MM cells and CD3 on T cells leads to an interaction of T cells and MM cells, cytolytic synapse formation, and eventually tumor lysis [Citation38]. To date, preclinical studies of BiTEs have had promising results, and early clinical data show encouraging efficacy of bsAbs in the treatment of RRMM.
AMG 701
The Phase Ib AMG 420 study (NCT02514239) is the first clinical proof-of-principle study for anti-BCMA BiTE therapy in RRMM patients. These researchers infused AMG 420 as single-agent into 42 patients with RRMM. The response rate was 70% (7 of 10) at the maximum tolerated daily dosage of 400 µg, and 5 patients had sCR. However, AMG 420 requires continuous infusion because of its short half-life [Citation39].
A recent study is evaluating AMG 701, a similar BiTE that has an extended half-life (Amgen, NCT03287908). In total 75 patients received AMG 701 at doses from 5 µg to 12 mg. The ORR was 36% (16/45) at doses of 3–12 mg; at doses of 1.6 mg and below there was only 1 response in a patient with low baseline level of soluble BCMA (sBCMA). The median time to response was 1.0 month, the median duration of response was 3.8 months, and the maximum duration of response was up to 23 months. AMG 701 had a favorable pharmacokinetic (PK) profile, in that exposure increased with dose. The baseline sBCMA levels were determined as an indicator of exposure to AMG 701 free drug. At higher doses, even in patients with higher baseline levels of sBCMA, there were encouraging initial responses [Citation40].
CC-93269
CC-93269 is an Ig-like BiAb that asymmetrically targets BCMA via two binding sites and CD3 via one binding site. The interim data from a phase I dose titration study in RRMM patients (CC-93269-MM-001, NCT03486067) showed the ORR was 43.3% and the CR/sCR was 16.7%. The response was also dose-dependent, in that the ORR was 88.9% with a CR/sCR of 44.4% in patients who received the higher dose of 10 mg. Almost all patients (96.7%) had treatment-emergent adverse events (TEAEs), and the majority of grade or higher 3 TEAEs were hematologic abnormalities with neutropenia; 11 patients (36.7%) had anemia and 5 (16.7%) had thrombocytopenia. The most common non-hematologic TEAEs of any grade were CRS (n = 23, 76.7%) and infections (n = 17, 56.7%) [Citation41].
Although the pooled results from early trials of BiTEs look promising, larger scale studies with long-term follow-up are needed to assess their benefit-risk profiles and toxic potential.
GPRCIT005D × CD3
GPRCIT005D, an orphan G protein-coupled receptor of family C, group 5, member D, is highly expressed in MM cells, but has very limited expression in normal tissues [Citation42]. Talquetamab (JNJ-64407564) is a first-in-class bispecific antibody that binds to GPRCIT005D and CD3 to stimulate T cell-mediated clearance of GPRCIT005D+ MM cells and primary MM cells in vitro [Citation43]. An ongoing phase I dose-escalation study of talquetamab (NCT03399799) showed the ORR for IV doses of 20–180 µg/kg was 78%, and the ORR for subcutaneous (SC) doses of 135–405 µg/kg was 67%. The most frequent AEs were anemia (50%), CRS (47%), neutropenia (45%), and lymphopenia (40%). The encouraging clinical responses suggest this agent has potential for use in the development of monotherapy and combination therapies [Citation44,Citation45].
CELMoDs (cereblon E3 ligase modulators)
Proteins targeted by CELMoD agents play an essential role in cell proliferation, differentiation, and apoptosis and are dysregulated in hematologic malignancies, including MM. Preclinical studies demonstrated that the multifunctional protein cereblon (CRBN) was necessary for the immunomodulatory and anti-myeloma effects of two IMiD agents, lenalidomide and pomalidomide. These IMiDs bind to CRBN to induce ubiquitination and degradation of two transcription factors, IKZF1 (Ikaros) and IKZF3 (Aiolos) in MM cells [Citation46]. IMiDs have recently been applied to generate bifunctional proteolysis targeting chimeras (PROTACs) by targeting other proteins for ubiquitination and proteasomal degradation via the CRBN E3 ligase.
Iberdomide (IBER; CC-220)
Iberdomide, a potent, high affinity, CRBN E3-ligase modulator (CELMoD), showed significant activity against IMiD-resistant myeloma cells in preclinical studies [Citation47]. Compared with IMiDs, the binding affinity of IBER to CRBN was 20-fold higher and it also appeared to be more effective than IMiDs in degrading Ikaros/Aiolos. Furthermore, IBER can better circumvent drug resistance than IMiD.
A preclinical study demonstrated that IBER led to significant substrate degradation, and when combined with PIs led to significantly increased tumoricidal activity. When PIs were used in combination with IBER rather than IMiD, there was greater substrate degradation and enhanced apoptosis [Citation47].
Clinically, even in the presence of PIs, IBER can cause a rapid decrease in substrate levels, and the level decreases further with repeated administration. This indicates that simultaneous administration of PI has minimal effect on IBER-mediated substrate proteasome degradation [Citation47]. Ongoing phase 1/2 dose-escalation studies of IBER that combined with different treatments for RRMM patients (CC-220-MM-001; NCT02773030) are examining its efficacy profile in patients who have resistance to lenalidomide and pomalidomide. The results from IBER in combination with Dexamethasone (DEX) showed that the ORR was 26.2%, with 1 (0.9%) sCR, 8 (7.5%) VGPR, and 19 (17.8%) PR; the clinical benefit rate (CBR) was 36.4% and disease control rate (DCR) was 79.4%. Median DOR was 7.0 (4.5–11.3) months, median PFS was 3.0 (2.8–3.7) months, and median OS was 11.2 (9.0–not reached) months [Citation48]. Overall, IBER + DEX demonstrated a favorable tolerability profile and good clinical activity in these heavily pretreated RRMM patients.
CC-92480
CC-92480 is more potent CELMoD agent that has enhanced antiproliferative activity in MM cell lines, including those resistant to lenalidomide and pomalidomide [Citation49]. This drug is currently in phase 1/2 development in RRMM patients. The phase 1 multicenter, dose-escalation trial CC-92480-MM-001 (NCT03374085) is examining the dose-dependent pharmacodynamic activity of CC-92480 in the range of 0.1 mg to 1.0 mg. The ORR was 21.1%, with 1 CR, 6 VGPRs, 9 PRs, and 4 MRDs. The majority of responders were dual-IMiD-refractory (10/ 16, 63%). CC-92480 combined with dexamethasone had a favorable activity and safety profile in MM patients who were heavily pretreated. The TEAEs were mainly related to myelosuppression [Citation50].
Future perspectives – PROteolysis Targeting Chimeras
The ubiquitin-proteasome pathway is a validated target for treating RRMM [Citation51], as indicated by the FDA approval of bortezomib [Citation52], carfilzomib [Citation53], and ixazomib [Citation54]. However, these therapies are frequently associated with off-target effects, and patients can develop drug resistance [Citation55–57]. PROteolysis Targeting Chimera (PROTAC) is a promising and powerful technology that has attracted great attention in the field of drug target discovery. A PROTAC targets a protein of interest and then ‘hijacks’ the cell’s endogenous ubiquitin-proteasome pathway so that it degrades that protein. Recent research reported that PROTACs which recruit CRBN E3 ligase can simultaneously mediate recruitment of neosubstrates, similar to IMiDs [Citation58]. The first-wave of PROTAC drugs are now entering clinical trials for cancer.
Bromodomain and extra-terminal proteins
Bromodomain and extra-terminal (BET) proteins are considered ‘epigenetic readers’ of acetylated histones. These proteins employ tandem bromodomains that bind to acetylated lysine residues (Kac) at the tail of the amino-terminal regions of histones [Citation59]. Proteins in the mammalian BET family (BRD2, BRD3, BRD4, and BRDT) regulate gene transcription by recruiting transcriptional factors and chromatin regulators to specific genomic locations [Citation59]. The highly specific and potent small molecule inhibitors of BET proteins (BETi), such as JQ1 and I-BET151 (quinolone-based BET protein inhibitor), bind to the Kac binding pocket of the bromodomains and block their interactions with histones [Citation60]. Preclinical studies demonstrated that BETi mediated antitumor effects in refractory hematological malignancies, including myeloma [Citation61]. Moreover, expression of MHC class I chain-related protein A (MICA) is enhanced by BET-induced protein degradation via the heterologous dual-function PROTAC probe in human myeloma cell lines, and this renders MM cells more susceptible to degranulation by NK cells. These findings provide a new perspective on the immune cell-mediated antitumor activities of BETi and the regulation of NK cell-activating ligand expression in MM. The development of a BETi using NK cells is a possible option for treatment of RRMM.
Histone deacetylases
Histone deacetylases (HDACs) are a class of proteases whose primary functions are modification of chromosome structure and regulation of transcription [Citation62]. Dysregulation of HDACs is common in malignancies, and their inhibition can suppress cancer cell proliferation and promote apoptosis. Thus, therapeutic administration of HDACs has shown some promising effects in treatment of various malignant tumors, including MM [Citation63–65]. In fact, the FDA approved the HDAC inhibitor (HDACi) panobinostat (Farydak®) in 2015 for the treatment of MM. However, when transferring single agent application of HDACi into clinical trials, there was only a limited effect on MM cells, probably due to its low penetration of tumor tissues [Citation66,Citation67].
Conversion of an HDACi into an isoform-selective HDAC PROTAC enhanced the potency and minimized off-target toxicities [Citation68–70]. In 2019, Tang and coworkers described their development of a multifunctional HDACIT006 degrader in which they tethered a CRBN ligand with the selective HDACIT006 inhibitor nexturastat A. The resulting molecule had synergistic antiproliferative effects in MM [Citation68].
Rpn13
Some studies investigated the effect of targeting Rpn13, because this 19S regulatory component of the proteasome captures ubiquitinated proteins as a substrate for degradation by the 20S proteasome [Citation71,Citation72]. Furthermore, Rpn13 is involved in signaling pathways of immune responses [Citation73], has high expression in MM cells, and is important in regulating the proliferation and survival of MM cells [Citation73]. Studies of inhibitors and RNA interference indicated that Rpn13 was a suitable target for treatment of MM [Citation74]. Chauhan et al. designed the first Rpn13 degrader, WL40, by linking the Rpn13 covalent inhibitor RA190 with a CRBN ligand. They reported that binding of Rpn13 with RA190 blocked the recognition of polyubiquitinylated proteins for subsequent proteasomal degradation. WL40 triggered potent anti-myeloma activity, led to bortezomib resistance, suppressed the growth of xenograft human MM cells, and increased survival [Citation74].
Although PROTACs are a promising and advanced technology, the efficacy and pharmacodynamic and pharmacokinetic characteristics in patients with RRMM are uncertain.
Conclusions
Emerging new treatments for MM have already led to changes in the standard clinical interventions used for patients with RRMM. Naked mAbs, ADCs, and BiAbs, and anti-CD38 MoAbs have ORRs of about 20–30% in heavily pretreated RRMM patients; ADCs have ORRs up to 60% (belantamab mafodotin); BiAbs have ORRs up to 90% (high dose CC-93269); and CAR T-cell therapy can have an ORR of 100%. The off-target toxicity of ADCs could limit their application, and although BiAbs are very effective, a high infection rate limits their combination with other drugs.
The anticipated approvals of other novel therapeutic agents, such as CAR T-cells that target BCMA and BiTEs, may fulfill unmet needs in this area. Utilizing NK-cell based immunotherapy for treatment of MM remains an attractive and under-researched area, and combinations of CAR-NK cell therapy with other drugs may improve patient response. Trials with larger cohorts that assess individual patient NK cell profiles may help to identify patients who respond best to these interventions.
There are a plethora of therapeutic choices for RRMM, and the optimal therapy for each patient should be based on disease-related factors, such as previous therapies, duration of response to prior drugs, clinical and biochemical features of relapse, and the relationship of patient comorbidities with known AE profiles of the different therapies.
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