1019622 research-article20212021 TAH0010.1177/20406207211019622Therapeutic Advances in HematologyA Oriol, L Abri Therapeutic Advances in Hematology Review The role of idecabtagene vicleucel in Ther Adv Hematol 2021, Vol. 12: 1–16 patients with heavily pretreated refractory DOI: 10.1177/ https://doi.org/10.1177/20406207211019622 https://doi.org/10.1177/20406207211019622 20406207211019622 multiple myeloma © The Author(s), 2021. Article reuse guidelines: sagepub.com/journals- permissions Albert Oriol , Laura Abril, Anna Torrent, Gladys Ibarra and Josep-Maria Ribera Abstract: The development of several treatment options over the last 2 decades has led to a notable improvement in the survival of patients with multiple myeloma. Despite these advances, the disease remains incurable for most patients. Moreover, standard combinations of alkylating agents, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies targeting CD38 and corticoids are exhausted relatively fast in a proportion of high-risk patients. Such high-risk patients account for over 20% of cases and currently represent a major unmet medical need. The challenge of drug resistance requires the development of highly active new agents with a radically different mechanism of action. Several immunotherapeutic modalities, including antibody–drug conjugates and T-cell engagers, appear to be promising choices for patients who develop resistance to standard combinations. Chimeric antigen-receptor- modified T cells (CAR-Ts) targeting B-cell maturation antigen have demonstrated encouraging efficacy and an acceptable safety profile compared with alternative options. Multiple CAR-Ts are in early stages of clinical development, but the first phase III trials with CAR-Ts are ongoing for two of them. After the recent publication of the results of a phase II trial confirming a notable efficacy and acceptable safety profile, idecabtagene vicleucel is the first CAR-T to gain regulatory US Food and Drug Administration approval to treat refractory multiple myeloma patients who have already been exposed to antibodies against CD38, proteasome inhibitors, and immunomodulatory agents and who are refractory to the last therapy. Here, we will discuss Correspondence to: Albert Oriol the preclinical and clinical development of idecabtagene vicleucel and its future role in the Institut Josep Carreras, changing treatment landscape of relapsed and refractory multiple myeloma. Carretera de les Escoles, Carretera del Canyet, s/n., Badalona, Barcelona 08916, Spain Keywords: B-cell maturation antigen, chimeric antigen receptor modified T cells, aoriol@iconcologia.net idecabtagene vicleucel, relapsed and refractory multiple myeloma Clinical Hematology Department and Clinical Trial Unit, Institut Català Received: 14 March 2021; revised manuscript accepted: 4 May 2021 d’Oncologia at Hospital Germans Trias i Pujol, Badalona, Spain Laura Abril Introduction relapse have shifted accordingly from lenalido- Anna Torrent The use of combinations of new drugs with differ- mide or bortezomib-based triplets to carfilzomib Gladys Ibarra Clinical Hematology ent mechanisms of action for the treatment of or pomalidomide-based alternatives.5–10 Despite Department and Clinical multiple myeloma (MM) in the last decade has these advances, most patients are expected to Trial Unit, Institut Català d’Oncologia at Hospital dramatically prolonged life expectancy of relapse, and a proportion of them will develop Germans Trias i Pujol, patients.1 These combinations, triplet or even resistance to several drugs relatively early in the Badalona, Spain quadruplet regimens, of proteasome inhibitors course of disease. Patients who are refractory to Josep-Maria Ribera Clinical Hematology (PIs), immunomodulatory agents (IMIDs) and PIs, IMIDs, and anti-CD38 MoAbs, also desig- Department and Clinical monoclonal antibodies (MoAbs) have emerged as nated triple-class refractory MM, have poor prog- Trial Unit, Institut Català d’Oncologia at Hospital game-changer agents,2,3 particularly when used in nosis with median overall survival (OS) of less Germans Trias i Pujol, association with high-dose therapy and autolo- than 1 year.11 The benefit of triplet combinations Badalona, Spain Josep Carreras Leukemia gous stem-cell transplantation (ASCT).4 As a in patients relapsing soon after contemporary Research Institute, consequence, combinations for MM patients at frontline treatments is limited in time, even when Badalona, Spain journals.sagepub.com/home/tah 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Hematology 12 based on drugs to which the patient was not prednisone, and bortezomib,26 or the addition of exposed in the previous line.12 Therefore, effica- daratumumab to the prior standard lenalidomide cious and well-tolerated therapeutic options for and dexamethasone,26 improved the complete the treatment of triple-class refractory MM remission (CR) rates to almost 50% and extended remains an unmet need. Several novel immuno- the PFS to 3 years or more.26,27 This last trial therapeutic approaches have been developed tar- included continuous treatment with both lena- geting these population. Bispecific antibody lidomide and daratumumab up to progression.27 T-cell engagers (TCEs), antibody–drug conju- For patients intolerant to any of these continuous gates (ADCs) and chimeric antigen receptor- treatment alternatives, ixazomib, an oral PI, has modified T cells (CAR-Ts) have demonstrated also proved better than placebo as maintenance encouraging early efficacy in clinical trials.13–16 therapy.28 Standard-risk patients and the patients Most of these agents are targeting B-cell matura- achieving the deepest responses are those benefit- tion antigen (BCMA). The present review will ting most from optimized frontline treatment discuss preclinical and clinical data that led to the strategies, and there is already evidence of a pro- regulatory approval of idecabtagene vicleucel portion of them being disease-free for more than (ide-cel; bb2121), the first available CAR-T 10 years following high-dose melphalan.29 Still, against BCMA for the treatment of relapsed and the projected proportion of ‘operationally cured’ refractory MM patients who have received at least patients is under 20% and most of individuals are three prior therapies including an anti-CD38 expected to relapse at some point. The patient MoAb, a PI, and an IMID. profile at relapse is also changing as a conse- quence of upgrading frontline treatment strate- gies. In contrast with patients that relapsed a Limits of standard treatment for decade ago, relapse occurs after exposure to a multiple myeloma combination of different drug classes. More The combination of IMIDs, PIs, antiCD38 importantly, patients relapse while still receiving MoAbs, and dexamethasone has become stand- one or more drugs as maintenance. Time to ard treatment of MM in the frontline and in the relapse after initial treatment is already defining relapse setting. Bortezomib, thalidomide and subgroups of patients with a different prognosis dexamethasone (VTD) became standard front- and a dramatically different likelihood of response line induction treatment after proving its superi- to salvage treatment. Primary refractory patients, ority over bortezomib and dexamethasone17 or and patients relapsing early (less than 1 year) after thalidomide and dexamethasone.18,19 Also, lena- initial therapy, including ASCT, will be of an lidomide, bortezomib, and dexamethasone exceptionally high risk. A second group, includ- (VRD) is superior to lenalidomide and dexameth- ing the largest proportion of standard-risk asone alone20 and constitutes an adequate induc- patients, will relapse after a relatively prolonged tion in the transplant setting.4,21 The addition of disease-free period while on treatment with lena- MoAbs to both backbones also has a positive lidomide. Despite the heterogeneity of situations impact in depth of initial response and progres- at relapse, subsequent treatment is essentially sion-free survival (PFS).22,23 Similarly, the addi- based on prior bortezomib- or lenalidomide expo- tion of daratumumab or isatuximab to VRD or sure and, more importantly, on bortezomib- or carfilzomib, lenalidomide, and dexamethasone lenalidomide refractoriness. A growing propor- (KRD) backbones is being explored in several tion of patients exposed to both drugs and mostly ongoing trials. High-dose melphalan and autolo- refractory to lenalidomide is expected in follow- gous stem-cell transplantation (ASCT) is a stand- ing years. Refractoriness should be viewed more ard procedure for all patients who are fit enough,4 as a continuous variable than a category in any and tandem ASCT may also benefit at least a patient previously exposed to an agent in combi- subset of patients.24 After ASCT, the current nation therapy. The safer choice at relapse is maintenance standard with lenalidomide25 is likely to be an alternative combination based in, already being challenged in ongoing trials with at least one, but optimally two, drugs to which the two drug maintenance combinations including patient is still naïve. The most promising combi- PIs or MoAbs. In the non-transplant setting, the nations are likely to be anti-CD38 MoAbs with addition of continuous daratumumab up to pro- the next-generation PI carfilzomib5,6 or immu- gression to the prior standard melphalan, nomodulatory agent pomalidomide.8,10 Also, the 2 journals.sagepub.com/home/tah A Oriol, L Abri et al. combination of pomalidomide, carfilzomib and proliferation-inducing ligand (APRIL) and/or the dexamethasone (KPD) has been explored30,31 B-cell-activating factor of the tumor necrosis factor and may be the adequate option for patients family (BAFF) to activate growth and survival refractory to a frontline combination including a signaling cascades.39 BCMA expression is upregu- MoAb until progression. Median PFS with anti- lated during MM pathogenesis and the evolution CD38 MoAbs in combination with carfilzomib from monoclonal gammopathy of undeterminate and pomalidomide are in the 1–2 year range. It significance to active MM.40 Surface BCMA is may be anticipated that patients who relapsed modulated by γ-secretase (GS), a multi-subunit soon after a frontline triplet or quadruplet combi- protease that mediates protein cleavage, resulting nation are those likely to benefit less from these in release of a soluble BCMA (sBCMA) fragment alternative triplets in the second line. composed of the extracellular domain and part of the transmembrane region.41 Soluble BCMA is Bortezomib and lenalidomide have become mainstay considered a marker of tumor burden and increased agents of initial MM treatment and consequently levels are associated with worse outcomes.42 combinations of carfilzomib, pomalidomide and Relatively mature results with anti-BCMA ADCs13 MoAbs provide the best chances of success in the and TCEs14 have been recently communicated. salvage setting. However, the use of different tri- plet therapies up to progression both in first and Belantamab mafodotin is an anti-BCMA immu- second line implies that patients suffering a sec- noconjugate using an antimitotic agent, mono- ond relapse will have already exhausted most of methyl auristatin as a payload.43 Results of the the currently available therapeutic resources. phase I trial in which patients, PI and IMID New agents with different mechanisms of action exposed and mostly refractory (97% to PIs and such as venetoclax or selinexor32,33 offer most 94% to IMIDs),43,44 showed a 60% overall benefit in combination with PIs or IMIDs; in response rate (ORR) and a median PFS of consequence, their place in the salvage treatment 12 months.44 Results of the subsequent phase II remains to be determined. Until recently, availa- trial included also anti-CD38 exposed, were less ble data for immunotherapeutic agents, includ- striking,13 with a 31% ORR, a 7% CR rate and a ing ADCs, TCEs, and CAR-Ts were derived median PFS of 3 months, highlighting the major from relatively small phase I trials, and had to be prognostic relevance of prior exposure and resist- considered with extreme caution. Recent data ance to prior drugs in RRMM. Belantamab mafo- provide solid evidence that immunotherapy is dotin presented a characteristic corneal toxicity in likely to offer much more benefit than other up to 72% of patients.45 Thrombocytopenia (35% alternatives, at least in the triple-class refractory grade 3) was the most common hematological setting. toxicity. Several trials are exploring belantamab mafodotin in combination with PIs and IMIDs in a less refractory population. Current immunotherapeutic options Immunotherapy is rapidly evolving in this sce- AMG-420 was the first bispecific TCE targeting nario. Because of its alternative mechanisms of BCMA and CD3 that proved capable of inducing action, they probably are the optimal choice after selective lysis of BCMA-positive MM cells, activa- failure of IMIDs, PIs, and naked MoAb combina- tion of T cells and release of cytokines and T-cell tion therapies. BCMA, a protein belonging to the proliferation with negligible impact on BCMA- tumor necrosis factor receptor (TNFRS17) is a negative cells.46 The drug will be no further devel- transmembrane protein that critically regulates oped because of the need to use a continuous B-cell proliferation and survival,34 as well as matu- infusion. However, a number of longer-life con- ration and differentiation into plasma cells.35,36 Its structs are being explored that can be given on a limited distribution in normal tissue, almost exclu- weekly or bi-weekly basis. Results of the largest sive presence in terminally mature plasma cells and phase I dose-finding trial with an ongoing expan- its overexpression in myeloma plasma cells37 have sion cohort have been communicated recently.14 revealed BCMA as a most attractive target for Teclistamab was explored in 128 patients with immunotherapeutic approaches.37,38 Furthermore, heavily treated MM in increasing intravenous and BCMA plays an important role in MM patho- subcutaneous doses. Most participants were tri- genesis and pathophysiology by engaging the a ple-class exposed (95%) or refractory (79%), and journals.sagepub.com/home/tah 3 Therapeutic Advances in Hematology 12 a relevant proportion of them were penta-drug the 16 patients treated with the highest dose level. exposed or refractory, 70% and 38%, respectively. CRS after CAR-T-cell infusions was a major disad- At the most active dose levels the ORR was 65%, vantage of the procedure; 6 out of 16 patients including a 20% CR rate with minimal residual receiving the highest dose level required vasopres- disease (MRD) negativity at a 10−6 sensitivity sors, and grade 3 or higher CRS was associated level. Median time to first response was 1 month, with a high tumor burden. It was also noted that and the median duration of response (DOR) had CAR-T persistence was of importance to prevent not been reached at the time of communication. or delay relapse. The NCI CAR-T used a CD28 Teclistamab had a favorable safety profile with co-stimulatory domain.54 Vector design elements mostly hematological toxicity. Cytokine-release appear to be important factors in the activity of syndrome (CRS) appeared in 53% of individuals; CAR-Ts. Several studies suggested that 4-1BB co- severity was up to grade 2, and generally with ini- stimulation may offer some advantages over CD28, tial doses only. Frequency and severity of CRS more specifically a significant survival increase has was similar with subcutaneous and intravenous been suggested.55 CAR constructs using CD28 co- formulations. All patients received prophylactic stimulatory domains are associated with a more medication, and several step-up doses were rapid activation than 4-1BB containing CAR vec- explored to minimize CRS. Neurotoxicity was tors due to a faster increase in levels of T-helper- infrequent (5% of patients), although 2% of cell-2-like cytokines.56 Such rapid activation of patients had grade 3 or higher (all of them in the CAR-T cells using the CD28 co-stimulation path- intravenous cohorts). Other constructs targeting way may make these cells more prone to cause an BCMA47–50 or other plasma cell-surface antigens, early-onset CRS. When comparing CAR con- such as GPRC5D,15 have shown similarly inter- structs with identical single-chain variable frag- esting results, although in smaller samples or with ments (scFvs) in tumor treatment models, shorter follow up (Table 1). When analyzed as a 4-1BB-containing vector-transduced T cells devel- whole, it is apparent that several anti-BCMA oped into more central memory-like T cells with TCEs under clinical development will be likely to enhanced respiratory capacity, increased fatty-acid have a notable efficacy and maintain durable oxidation, and enhanced mitochondrial activity responses. They are also expected to have a man- than CD28 co-stimulatory-containing vectors.57 ageable CRS and will be able to maintain adequate However, such comparisons must be viewed with plasma levels with once-weekly infusions or less. caution in the absence of direct comparisons in humans of identical CARs containing either CD28 Finally, several genetically modified T cells to or 4-1BB, as many other variables may contribute express a chimeric antigen have been developed to the persistence or exhaustion of T cells. against BCMA51–53 and have shown impressive Moreover, the scenario may be dramatically modi- results. The first fully published phase II trial, fied with the availability of third-generation prod- including relatively mature data in a number of ucts incorporating more than one co-stimulatory patients with sufficient follow up is the KARMMA domain. In any case, these observations clearly sug- trial with ide-cel.16 Different immunotherapeutic gest the critical influence of T-cell metabolism on approaches may be more adequate for different the function of T cells and, consequently, in CAR- patient profiles. The main differences among T-cell clinical efficacy. Friedman et al. sought to immunotherapeutic approaches are summarized produce a series of anti-BCMA CAR-encoding in Table 1. lentiviral vectors (LVVs) to generate anti-BCMA CAR-T cells.58 Anti-BCMA CAR LVVs were rep- lication defective, self-inactivating, third-genera- Idecabtagene vicleucel development tion human immunodeficiency virus type 1 (HIV-1) based, pseudotyped with the vesicular stomatitis Preclinical data virus–glycoprotein envelope protein. Four different The National Cancer Institute (NCI) was the first anti-BCMA CARs were constructed using distinct to provide the proof of principle that CAR-T cells anti-human BCMA MoAbs shown to have high targeting BCMA were able to induce responses in specificity to human plasma cells. Sequences from patients with MM.50 A phase I trial of their CAR- the MoAbs were used to construct scFvs (in orien- T-cell product in MM patients resistant to stand- tation VL-linker-VH), which were assembled into a ard therapies was able to induce responses in 13 of CAR architecture using a CD8α extracellular hinge 4 journals.sagepub.com/home/tah A Oriol, L Abri et al. Table 1. Advantages and disadvantages of different immunotherapeutic approaches in the treatment of relapsed and refractory multiple myeloma: comparison of characteristics and treatment requirement of different anti-BCMA modalities. Antibody-drug T-cell engager (TCE) CAR-T cell conjugate (ADC) Efficacy For Better response rates Higher response rates than ADCs Against Lower response rate than TCEs or CAR-Ts Safety For No CRS, no Limited CRS neurotoxicity Against Ocular toxicity Uncertainties in long Higher CRS and neurotoxicity term use Deeper thrombocytopenia rates than TCEs Prolonged cytopenias Applicability For Off the shelf Off the shelf One-time intervention Only one infusion every 3 weeks No hospitalization required Applicable in small centers Data on combinations and earlier use in the course of disease Against Ophthalmologist Weekly infusions Not applicable in small centers requirement Continuous treatment Hospitalization required Manufacturing delay, need for bridging therapy or use in stable disease Continuous treatment Hospitalization required BCMA, B-cell maturation antigen; CAR-T, chimeric antigen-receptor-modified T cells; CRS, cytokine-release syndrome. and transmembrane domain followed by 4-1BB more favorable expression than other constructs (CD137) co-stimulatory domain and CD3ζ T-cell despite similar transduction efficiency;58 addition- signaling elements (Figure 1). The study proved ally, given a similar CAR expression, T cells in that the specific scFv used to target the CAR-T which constructs differed only in their scFv domain cells also affects T-cell-effector function. Preclinical displayed significantly different cytokine release in studies proved that the bb2121 vector presented co-culture assays and different lytic activity.58 journals.sagepub.com/home/tah 5 Therapeutic Advances in Hematology 12 Figure 1. Chimeric antigen receptor structure of idecabtagene vicleucel. Consequently, T-cell activity is also influenced by bb2121 had complete tumor elimination and long- scFv affinity and a relationship between scFvs with term survival (up to day 85 post-CAR-T treat- lower binding constants and enhanced activity has ment), in contrast to mice treated with control been observed.59 bb2121 was selected for addi- CAR-T cells, vehicle treated or treated with borte- tional studies due to its gene transfer efficiency, zomib. CAR+ T cells were observed in peripheral antigen-specific cytokine release, and cytolytic blood starting at day 2 and markedly increased at activity of anti-BCMA CAR-T cells, anti-tumor 11 days after adoptive transfer, and then declining activity of bb2121 was confirmed in a wide panel of over the next 3 weeks. Post CAR-T cell infusion, cell lines. Activity could be observed in cell lines sBCMA levels precipitously declined in parallel with as few as 222 BCMA molecules/cell. with tumor regression. The levels of sBCMA post Consistent with prior reports showing absence of day 8 were at or near the background detection BCMA expression in healthy precursor bone-mar- level of this assay. There was no apparent inhibition row cells, no activity against normal donor bone- of the product by soluble BCMA protein. marrow cell lines was observed. In vivo activity of BB2121 also demonstrated proving rapid expan- After these preclinical data, centralized manufac- sion and MM-cell clearance in mice xenografts, turing of bb2121 was developed to launch a phase despite the presence of soluble BCMA protein. I multicenter clinical trial to evaluate the safety and Mice received a single intravenous administration efficacy of bb2121 for relapsed refractory MM (5 × 106 CAR+ T cells/mouse). Mice treated with [ClinicalTrials.gov identifier: NCT02658929]. 6 journals.sagepub.com/home/tah A Oriol, L Abri et al. Phase I trial: CRB-401 The most common toxicity was hematological; The phase I open-label trial was conducted in the neutropenia grade 3 or higher was observed in United States and consisted of a dose-escalation 85% of the patients. Within a month, most patients and a dose-expansion phase.60 The primary end- recovered absolute neutrophil count and platelet point was safety, and the main secondary end- count to grade 1 (97% and 65%, respectively); point was ORR. The trial included adult patients however, a proportion of patients presented with a good performance status and adequate delayed recovery from cytopenias. CRS was organ function, measurable disease, and at least observed in 76% of individuals, 70% grade 1–2. three previous lines of therapy, including a PI and No patient presented CRS higher than grade 3. an IMID, or disease refractory to both drug CRS had a median time to onset of 2 days (range classes. The dose-escalation phase also required 1–25) and a median duration of 5 days (range 50% or more BCMA expression in marrow 1–32). CRS correlated with the CAR-T-cell dose plasma cells. Levels of BCMA expression were and a higher peak of CAR-T-cell expansion. In not necessary in the dose-expansion phase but patients requiring treatment, the most common previous exposure to daratumumab and refracto- approach was tocilizumab; only four patients also riness to the most recent line of therapy were received glucocorticoids. CAR-T expansion did required. Thirty-six patients were enrolled and not appear to be negatively affected by use of toci- underwent leukapheresis. No minimum absolute lizumab or glucocorticoids. Neurologic adverse lymphocyte count was required to proceed to events occurred in 42% of patients, mostly grade apheresis. The manufacturing of bb2121 was suc- 1–2. One patient presented grade 4 neurologic tox- cessful for 100% of the patients but three of them icity starting 11 days after the infusion and requir- progressed before bb2121 infusion. Bridging ing 1 month for resolution. Infections affected 42% therapy during manufacturing was allowed but of patients; none grade 4 or 5.60 had to be stopped at least 14 days before the start of lymphodepletion. Bridging therapy was given The ORR was 85%, with 45% of the patients hav- to 14 patients (42%), mostly with dexametha- ing a CR (9%) or stringent CR (36%). Both sone, daratumumab, bortezomib or bendamus- response rate and DOR appeared to be dose tine and all treated patients still had measurable dependent; very good partial responses (PRs) or disease after the completion of bridging therapy better were observed only with doses of at least and before the start of lymphodepletion. 150 × 106 CAR-T cells. Response did not appear to Lymphodepletion consisted of fludarabine 30 mg/ be influenced by baseline sBCMA or BCMA m2/day and cyclophosphamide 300 mg/m2/day on expression in myeloma cells. Although the number days −5, −4, and −3, infusion of bb2121 on day 0 of patients did not allow exploration of prognostic ranged from 50 × 106 to 800 × 106 total CAR-T factors, the authors suggested that patients with a cells in the dose-escalation phase, and then high-risk cytogenetic profile, who did not have 150 × 106 to 450 × 106 cells in the expansion CRS and who had received 150 × 106 or fewer phase. Up to 20% deviation from assigned dose CAR+ T cells presented less in vivo CAR-T-cell was allowed in the actual product to be infused. expansion and lower response rates. Median time The final bb2121 CAR-T cell product had a to achieve a PR or better was 1 month. Tumor highly variable proportion of CD4 and CD8 T responses were also seen within the first month in cells, with a median of 85% (from 42 to 98) most patients with extramedullary disease. Only 18 CAR-T CD4 and 13% CAR-T CD8+ cells. The patients could be evaluated for MRD status; 16 characteristics of the 33 patients who finally who had a response and 2 who presented less than received bb2121 were those expected in a rela- a PR; only 3 were MRD negative at the 10−6 level. tively fit relapsing–remitting MM (RRMM) pop- Typically, full clearance of M protein to achieve a ulation. The median age was 60 years, 45% had a CR could be delayed in some patients despite rapid high-risk cytogenetic profile, and 27% had bone-marrow clearance of plasma cells. Moreover, extramedullary disease. The median time since early MRD negativity was observed in patients with diagnosis was 5 years, and the median number of detectable M component with later evolution to previous regimens was eight. Almost 80% of CR. At a median follow up of 11 months, 17 patients were exposed to bortezomib, carfilzomib, patients (52%) suffered disease progression, of lenalidomide, pomalidomide, and daratumumab, whom 6 had achieved a CR. The median PFS was 79% were refractory to both a PI and an IMID, 11.8 months. Patients having detectable CAR-T and 18% were penta-refractory.60 cells were 96%, 86%, 57% and 20% at 1, 3, 6 and journals.sagepub.com/home/tah 7 Therapeutic Advances in Hematology 12 12 months, respectively. Blood CAR-T-cell levels 35% of individuals, respectively. Baseline expres- were higher in patients who responded than in sion of BCMA was evaluable in 110 tumor sam- those who did not have response. Overall, 85% of ples, and 97% of them had ⩾50% BCMA-positive patients with heavily pretreated relapsed or refrac- plasma cells. All patients had detectable levels of tory MM presented a response that lasted a median sBCMA at baseline. CAR-T-cell doses were 150, of 10.9 months, and 40% of the patients were free 300, and 450 × 106 in 4, 70 and 54 patients, respec- of progression at 12 months, without any subse- tively. The ORR was 73% and the CR rate was quent therapy. Importantly, response appeared to 33%. The median time to response was 1 month, be independent of tumor BCMA expression. and the median time to CR, 2.8 months. MRD Toxicity was manageable, and the use of tocili- negativity was evaluated in bone marrow by next- zumab or glucocorticoids to treat CRS did not generation sequencing with a cutoff of 10–5 nucle- appear to negatively affect CAR-T-cell expansion ated cells. The 33 patients with a CR and evaluable or treatment response. The high rate of deep MRD achieved an MRD-negative status at a sensi- responses did not translate into continuous remis- tivity level 10−5, representing 26% of the total sion for all patients warranting a deeper analysis of treated population. Response rates were generally the relapse mechanisms, particularly in patients consistent in subgroups of patients, including those achieving an MRD-negativity status.60 with high and low tumor BCMA expression, aggressive disease features, high tumor burden or triple- or penta-refractory disease. As observed in Phase II trial: KARMMA trial the prior study, responses were correlated with the The phase I results prompted a pivotal phase II trial doses of CAR-T cells; the ORR was 50%, 69%, (KARMMA) [ClinicalTrials.gov identifier: and 82%, respectively, and the CR rate was 25%, NCT03361748] to confirm the observed efficacy 29%, and 39%, respectively, for 150, 300, and and safety of ide-cel (bb2121) in triple-class- 450 × 106 cell doses. Maximum CAR-T-cell expan- exposed RRMM.16 The KARMMA trial was, sion occurred at a median of 11 days, and, again, again, a single-arm study for patients who had had higher expansion and exposure was associated with at least three prior regimens, including an IMID deeper response. Median DOR was 10.7 months agent, a PI, and an anti-CD38 antibody, and were for the full cohort, and 11.3 months at the 450 × 106 refractory to their last treatment. Other inclusion dose. Similarly, the median PFS was 8.8 months in criteria were similar to those of the expansion the full cohort, and it increased to 12.1 months at cohort of the prior phase I trial. The trial design the 450 × 106 dose. CAR+ T cells were detected in also allowed bridging therapy, restricted to drug 29 of 49 (59%) and 4 of 11 (36%) patients at 6 and classes that patients had previously received, up to 12 months post-infusion, respectively. 14 days before lymphodepletion. Target doses of ide-cel were 150, 300 and 450 × 106 CAR+ T Levels of sBCMA appeared to be an adequate sur- cells. The primary study endpoint was ORR and rogate of MM tumor mass. Baseline sBCMA levels secondary endpoints included CR rate, MRD sta- were elevated in all patients at baseline, and tus, time to response, DOR, PFS and OS, along decreased rapidly post-infusion, particularly in with safety, pharmacokinetics, and immunogenic- responders, with nadir values achieved within the ity. The trial enrolled 140 patients, of whom 12 first 3 months. Higher expansion was associated (9%) discontinued prior to ide-cel infusion, includ- with deeper reductions of sBCMA. Undetectable ing 1 manufacturing failure. Most patients (88%) sBCMA levels were associated with depth of received bridging therapy during the manufactur- response (63% of patients with PR, 95% with CR). ing period, but only five (4%) presented a response. Duration of undetectable sBCMA correlated also After completion of bridging therapy, all patients with durability of tumor response. The 450 × 106 maintained measurable disease. Ide-cel infusion dose was associated with longest time to rebound of could be performed to 128 patients who had sBCMA from undetectable levels. Rising sBCMA received a median of six prior antimyeloma regi- levels (>40 ng/ml) at the time of disease progression mens, 84% were triple-refractory, 60% were penta- were observed in 69 of 71 (97%) patients. In 16 exposed (bortezomib, carfilzomib, lenalidomide, responders with evaluable bone-marrow biopsies at pomalidomide, and daratumumab) and 26% progression, 15 (94%) retained BCMA-expressing penta-refractory. High-risk cytogenetics and tumor cells. Loss of tumor BCMA expression was extramedullary disease were present in 39% and suspected in three patients and in one of them, 8 journals.sagepub.com/home/tah A Oriol, L Abri et al. bi-allelic genomic loss of BCMA on chromosome Neurotoxicity was not reported in patients receiving 16p was subsequently confirmed.61 A similar case of the 150 × 106 dose while it affected 17% and 20% homozygous loss of BCMA expression has been of patients at doses of 300 and 450 × 106 CAR-T reported in a patient in the phase I CRB-401 trial cells. Out of 44 patients (34%) who died during the who was unsuccessfully treated at relapse, 9 months study, 3 (2%) died within 8 weeks after infusion after the first infusion.62 Although homozygous loss from adverse events considered ide-cel related of BCMA genes is extremely rare, the 16p mono- (bronchopulmonary aspergillosis, gastrointestinal somy, leading to a heterozygous BCMA-deficient hemorrhage, and CRS). Most deaths in the study phenotype is relatively common and it has been sug- (n = 27) were related to myeloma progression. gested that it may be a mechanism leading to resist- ance to anti-BCMA therapies.61 At the time of analysis, OS was immature, with 66% of patients Idecabtagene vicleucel ongoing trials still censored, 78% of patients were alive at Ide-cel is currently being explored in three addi- 12 months, and the estimated median OS was tional trials. KARMMA-2 [ClinicalTrials.gov 19.4 months [95% confidence interval (CI), identifier: NCT03601078] is a multicohort phase 18.2–non-evaluable]. The protocol allowed ide-cel II trial evaluating the efficacy and safety of ide-cel retreatment for patients meeting disease progression in refractory MM, including less heavily treated criteria, and 28 patients were retreated with ide-cel, subjects conveying a bad prognosis; that is, MM of whom 6 (21%) achieved a second response rang- having progressed within 18 months of frontline ing from 1.9 to 6.8 months’ duration. treatment, including ASCT (cohort 2a), or not (cohort 2b), or subjects with inadequate response The safety profile observed in the phase I trial was to ASCT (cohort 2c). KARMMA-4 [ClinicalTrials. also confirmed. With the exception of hypogamma- gov identifier: NCT04196491] is a phase I trial globulinemia and infections, most adverse events exploring ide-cel in high-risk (R-ISS 3) newly diag- occurred within the first 2 months after infusion. As nosed patients following standard induction. expected, grade 3 or 4 hematologic toxicity was Finally, KARMMA-3 [ClinicalTrials.gov identi- common, neutropenia (89%), anemia (60%), and fier: NCT03651128] is a phase III trial attempting thrombocytopenia (52%), and usually short-lived, to enroll approximately 381 subjects with RRMM although in a proportion of patients, grade 3 or 4 having received two to four prior lines of treatment neutropenia (n = 52) or thrombocytopenia (n = 62) and randomize them in a 2:1 ratio to either ide-cel persisted over 1 month after infusion. Serious bleed- or one of several salvage treatments of choice. ing events were observed in three patients, including cerebral hemorrhage (after myeloma progression), gastrointestinal, and conjunctival. Infections Idecabtagene vicleucel efficacy in the occurred in 88 individuals (69%), although grade 3 competitive landscape or 4 in only 28 (22%). CRS occurred in 107 patients Patients who are refractory to PIs, IMIDs, and (84%) and reached grade 3 in 5 (4%); 1 patient anti-CD38 MoAbs have a dismal prognosis. A (<1%) had grade 4, and there was 1 CRS-related recent cohort sudy11 described the characteristics death (<1%). Median time to onset of CRS was of these patients and observed an ORR of 31% 1 day (range, 1–12 days) with a median duration of after anti-CD38 MoAb failure. Responses were 5 days (range, 1–63 days). For most individuals typically short-lived, with a median PFS of (52%) CRS could be adequately managed with 3.4 months and a median OS of 9.3 months. tocilizumab. CRS was also related to the dose of Some agents with new mechanisms of action have CAR-T cells; any-grade CRS was observed in 50%, been explored in the setting of triple-refractory 76% and 96% of patients at doses of 150, 300, and MM, including the recently approved exportin-1 450 × 106 CAR-Ts, respectively. Grade ⩾3 CRS inhibitor selinexor,63 the peptide–drug conjugate was not common, affecting 6% of patients at doses melflufen (melphalan flufenamide)64 and the of 300 or 450 × 106. Neurotoxicity was also reported ADC belantamab mafodotin.13 Selinexor in 18% of patients, but there were no reports of achieved a PR or better in 26% of patients; the grade 4–5. Neurotoxicity typically followed CRS, median DOR was 4.4 months, the median PFS particularly if CRS appeared early and had a higher 3.7 months, and the median OS 8.6 months.63 intensity. The median time to any neurotoxicity The ORR of melflufen in triple-refractory MM event was 2 days, and its median duration, 3 days. patients was 26%, with a median DOR of journals.sagepub.com/home/tah 9 Therapeutic Advances in Hematology 12 Table 2. Efficacy and safety profile of new agents in the treatment of advanced relapsed and refractory multiple myeloma. Selinexor63 Melflufen64 Belamaf13 Teclistamab14 Talquetamab15 Ide-cel16 Cilta-cel65 Efficacy ORR, % 26 29 31 69 69 73 97 CR, % <2 1 8 26 19 33 67 PFS, months 3.7 4.2 2.8 – – 8.8 77% at 12 months OS, months 8.6 11.6 13.7 – – 19.4 88% at 12 months Safety Neutropenia, % 40 82 20 57 47 91 91 Grade ⩾3 21 79 12 46 31 89 91 Thrombocytopenia, % 73 82 24 40 32 63 79 Grade ⩾3 58 76 19 22 13 52 60 CRS, % – – – 55 54 84 95 Grade ⩾3 – 0 3 5 4 Neurotoxicity, % – – – 5 6 18 21 Grade ⩾3 – 0 2 3 10 Other Fatigue 73% – 71%, ocular – – – – GI 72% keratopathy Belamaf, belantamab mafodotin; Cilta-cel, ciltacabtagene autoleucel; CR, complete response; CRS cytokine-release syndrome; GI, gastrointestinal; Ide-cel, idecabtagene vicleucel; ORR, overall response rate; OS, overall survival; PFS, progression-free survival. 5.5 months, a median PFS of 4.2 months, and off-treatment time of manufacture are not an median OS of 11.6 months.64 The results of option. belantamab mafodotin, as previously discussed, are in the same range.13 Although direct compari- Finally, other CAR-T products will be available sons are difficult because patient characteristics shortly. Ciltacabtagene autoleucel (cilta-cel, pre- differed slightly among these three trials and viously LCAR-B38M) is an anti-BCMA CAR-T between these and the KARMMA trial, ide-cel is characterized by having two different heavy-chain likely to represent a major step forward in com- variable domains which recognize separate parison with previously available agents (Table epitopes of the BCMA antigen.66 Its phase I clini- 2). Current data show that TCEs targeting cal trial with 57 patients obtained an ORR of 88% BCMA or other molecules can achieve responses and a CR rate 68%; additionally, 63% of patients in around two thirds of patients,14,15 although CR achieved MRD negativity. The median PFS was rates appear to be lower than those reported for 15 months.66 Results of a subsequent phase Ib/II ide-cel and other CAR-Ts (Table 2); available trial (CARTITUDE-1) in 97 patients have been data come from dose-finding phase I trials, and communicated recently.65 In this analysis cilta-cel may prove better in patients at the recommended obtained an impressive PR and CR rate, 97% and phase II dose. Additionally, responses may 67%, respectively, and a 12-month PFS and OS deepen over time with continuous treatment. If of 76.6% and 88.5%, respectively. Orvacabtagene TCE results are confirmed in robust trials with a autoleucel (orva-cel), a fully human CAR-T, sufficient follow up, they may provide a more delivered in a fixed 1:1 CD4/CD8 ratio, also convenient alternative to ide-cel or other CAR-Ts, showed interesting results, with a 91% ORR and particularly in patients where bridging therapy or 39% CR rate but a still-short follow up.52 Other 10 journals.sagepub.com/home/tah A Oriol, L Abri et al. CAR-T products are being tested in clinical trials with respect to alternatives are confirmed. On the and have reported similar, but still immature, other hand, prolonged neutropenia and thrombo- results. Additionally, allo-CAR-Ts are also being cytopenia may affect over a third of patients and explored in the clinical setting;67 such agents are may be challenging in some patients. The severity expected to combine the efficacy of autologous and specific characteristics of long-term immuno- CAR-Ts with the convenience of ‘off the shelf’ suppression after treatment with ide-cel or other availability. Despite the observation of deep CAR-Ts and TCEs remain a matter of concern responses in very advanced and refractory patients, for both treatment modalities. there is no apparent plateau in the PFS curves of MM patients treated with CAR-Ts, and conse- quently, durability of the product may emerge as a Future perspectives key factor in defining the best choice, in terms of Important challenges need to be addressed in efficacy. Current data do not allow determination future development of CAR-T-cell strategies in of whether there will be major differences in terms MM. Current limitations are both product related, of efficacy among different CAR-T products. including lack of expansion/early exhaustion,68 and disease related, including issues such as BCMA shielding and dynamic BCMA expression Idecabtagene vicleucel safety in the after infusion, the development of other survival competitive landscape mechanisms by the malignant cell, and the mye- From the safety point of view, anti-BCMAs loma-induced alterations of the microenviron- appear to present less toxicity than anti-CD19 ment to create an immunosuppressive milieu.42,69 CAR-Ts used in other B-cell malignancies. Ide- cel demonstrated a consistent manageable safety Several strategies are under evaluation to prevent profile in phase I and II trials.5,16 The CRS was escape of MM cells, to minimize a potential frequent (84% in the phase II trial) but mostly immune rejection, and to modify the microenvi- low grade with grade ⩾3 events observed in ⩽6% ronment. Combinatorial antigen-recognition of patients at all doses. Only two patients in the approaches may be able to circumvent antigen KARMMA trial experienced CRS grade 4 or 5 shielding. The combination of a CAR-T against (one each). Onset of CRS was within the first BCMA with another CAR-T against CD19 has week of infusion, mostly (median 1 day), and its already been explored in early clinical trials.70 The median duration was 5–6 days, regardless of grade development of bi-specific CAR-Ts may be even in less severe cases, but it lasted a median of more effective to prevent disease progression asso- 11 days in patients with maximum grade ⩾3. ciated to loss of BCMA expression. Bicistronic vec- Early use of tocilizumab may have prevented tors encoding two CARs avoid the challenge of most severe forms of CRS. Similarly, neurotoxic- parallel manufacturing separate CAR-T-cell prod- ity was reported in 18% of patients in the ucts, while providing superior efficacy. Several KARMMA trial but half of them had a grade 1 CAR-Ts combining receptors against BCMA and and none grade 4 or 5. All neurotoxic events GPRC5D,71 SLAMF7,72 or CD1973 are in early occurred in the proximity of CRS events, either development. Also, dual-targeting of BCMA and overlapping with CRS or within the following the transmembrane activator and CAML interac- week. There were no late events, and this may tor (TACI) on MM cells has successfully been represent a differential characteristic with cilta-cel reported by use of an APRIL-based CAR in mouse where delayed-onset neurotoxicity was described models and in ex vivo primary myeloma cells, in up to 12% of individuals.65 Management of including BCMA-negative MM cells.74 While tar- ide-cel neurotoxicity in the KARMMA trial geting more than one antigen has the potential to involved the use of corticoids in 10 patients (43%) increase CAR-T-cell efficacy and reduce the risk of and tocilizumab in 3 (13%). The use of corticoids antigen scape, it increases the risk of on-target, off- had no apparent impact on the ORR or DOR. tumor toxicities; therefore, such strategies should CRS and neurotoxicity appear to be more fre- be compared in a randomized fashion with stand- quent and severe with CAR-Ts than those ard single-antigen CAR therapy before implemen- reported for TCEs. In any case, the applicability tation. Increasing BCMA expression on the plasma of CAR-Ts or TCEs is not likely to be limited, cell surface might also improve the efficacy of with improved expertise in the management of BCMA CAR-T cells, and preliminary data have CRS and neurotoxicity if differences in efficacy shown that GS inhibitors could reduce the cleavage journals.sagepub.com/home/tah 11 Therapeutic Advances in Hematology 12 of BCMA.41,75 Administration of an oral GS inhibi- Finally, immunotherapy may also be critically tor with BCMA CAR-T cells is being explored.76 affected by the worsening immune dysfunction that occurs with disease progression. Quality of Increasing the CAR-T-cell durability is still the CAR-Ts is likely to depend more on the T-cell most critical factor for improving current results. In quality at time of apheresis than on the actual an attempt to reduce the proportion of senescent T manufacturing process. It is likely that the great- cells, a recently developed anti-BCMA CAR-T, est benefit of these agents will only be seen when bb21217, used the same CAR molecule as ide-cel incorporated earlier into the treatment strategy. but added a phosphoinositide-3-kinase inhibitor Given that PFS benefit of any conventional treat- during ex vivo culture to enrich the drug product ment triplet in patients suffering early relapses for memory-like T cells. The CRB-402 after front line therapy will probably be below [ClinicalTrials.gov identifier: NCT03274219] 12 months, such patients are a potential target for ongoing phase I trial is investigating whether this earlier use of ide-cel. Consolidation of upfront procedure has a clinically relevant impact on out- therapy in high-risk disease not achieving immu- comes. The trial design is similar to that of the ide- nophenotypic CR is also an adequate target for cel phase I trial, and researchers plan to enroll 74 immunotherapy. The ongoing KARMMA 2, 3 patients, including 50 in an expansion cohort. The and 4 ide-cel trials are exploring the potential results of the first 46 patients have been communi- advantage of earlier CAR-T therapy after a lym- cated recently.77 The safety profile appears to be phocyte apheresis in a less immunocompromised similar to those of other CAR-T products, with a patient. Additionally, the infusion of CAR-Ts slightly delayed onset of CRS (median 3 days). while still in response or at biological relapse, Despite the enrichment procedure being effective, may increase safety, maximize efficacy, and patients with a reported response were 55%, includ- reduce the risk of full-blown progression before ing 18% with CR or better, and the median DOR infusion. was 12 months. However, the presence of T-cell markers associated with memory, and the absence of T-cell markers associated with senescence in the Conclusions product, correlated with peak expansion and DOR, Ide-cel is the first CAR-T product to be approved supporting the hypothesis that enrichment for for the treatment of MM, representing a major memory-like T cells may result in more durable advance in the immunotherapeutic approach to CAR-T cells and improved clinical outcomes. the disease and covering a major and emerging clinical need, that of triple-refractory patients. Lack of CAR-T-cell persistence is not only The median PFS of almost 1 year after a single dependent on the choice of an optimal co-stimu- administration, a relatively acceptable safety pro- latory domain or the proportion of CD4/CD8 or file, and the possibility of avoiding continuous memory/effector cells. The targeting moieties of treatment in heavily exposed patients may out- the CAR often display reduced stability and are weigh the convenience of other ‘off the shelf’ therefore at risk of oligomerization or clustering, alternatives. Current trials will determine if ide- leading to continuous off-target signaling and cel and other CAR-T products should move for- development of an exhausted T-cell phenotype. ward to treat high-risk patients earlier in the Refined targeting moieties, such as small mono- course of disease. meric proteins, might diminish CAR structure related tonic signaling. One such CAR-T-cell Acknowledgements product, P-BCMA-101, has already reported The authors acknowledged all the components of early clinical results,78 Additionally, P-BCMA-101 the CAR-T team at Institut Català d’Oncologia, makes use of the piggyBacR transposon-based Badalona, and all the staff at the Clinical Trial deoxyribonucleic acid modification, and it is Unit. Particularly, Cristina Vazquez and Olga speculated that viral-free generation of the system Fernandez for their special involvement in the may favor the development of a T-stem-cell CAR-T trials. memory phenotype.78 The clinical relevance of strategies to specifically engineer products of a Conflict of interest statement desirable T-cell-subset composition remains AO has served in board or consulting for unclear, as follow-up periods of early trials are Celgene/BMS, Amgen, GSK, Sanofi and still too limited to assess durability of responses. Oncopeptides. 12 journals.sagepub.com/home/tah A Oriol, L Abri et al. Funding a randomised, multicentre, open-label, phase 3 The authors received no financial support for the study. Lancet 2019; 394: 2096–2107. research, authorship, and/or publication of this 9. Dimopoulos MA, Dytfeld D, Grosicki S, article. et al. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl J ORCID iDs Med 2018; 379: 1811–1822. 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