Cilta-cel, a BCMA-targeting CAR-T therapy for patients with multiple myeloma

ABSTRACT

Introduction

Ciltacabtagene autoleucel (cilta-cel), a BCMA-targeting CAR-T therapy, is approved in the United States and Europe for patients with relapsed/refractory multiple myeloma (RRMM) and ≥1 prior line of therapy (LOT), including a proteasome inhibitor and an immunomodulatory drug, and are lenalidomide refractory.

Areas covered

We examine recent long-term data in heavily pretreated RRMM (LEGEND-2, CARTITUDE-1) and earlier LOTs (CARTITUDE-4) compared with standard therapy and discuss the rationale for investigating cilta-cel as frontline therapy for transplant-eligible and transplant-ineligible patients (CARTITUDE-5, CARTITUDE-6).

Expert opinion

CAR-T therapies can improve outcomes for patients with MM across different LOTs. CARTITUDE-1 and CARTITUDE-4 have set a new bar for efficacy, with median PFS of 34.9 months in heavily pretreated patients (CARTITUDE-1) and a 74% relative risk reduction for progression/death versus standard care in patients with 1–3 prior LOTs (CARTITUDE-4), with manageable safety. Response rates were consistent between the two studies: 98% in CARTITUDE-1 and approaching 100% for infused patients in CARTITUDE-4. Cilta-cel could be a key treatment choice for patients with RRMM after first LOT. Clinical trials investigating frontline cilta-cel therapy will provide valuable insights into optimizing treatment pathways with the aim to potentially cure MM.

KEYWORDS:

• B-cell maturation antigen (BCMA)
• chimeric antigen receptor (CAR)-T–cell therapy
• ciltacabtagene autoleucel (cilta-cel)
• lenalidomide-refractory
• multiple myeloma
• newly diagnosed multiple myeloma
• progression-free survival
• relapsed/refractory multiple myeloma

1. Introduction

Multiple myeloma (MM) is associated with periods of remission and relapse as patients cycle through multiple treatment regimens that can be difficult to tolerate and require long periods of continuous dosing. The increased early use of continuously administered anti-myeloma therapies, including immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies until disease progression makes subsequent treatment challenging because patients become resistant to multiple drugs early in the course of their disease [1,2]. Clinical outcomes remain poor in those with relapsed/refractory MM (RRMM) and worsen with each successive line of therapy (LOT) [3,4]. Progression-free survival (PFS) is often <12 months in heavily pretreated patients [3,4], and health-related quality of life worsens with each successive relapse [5]. Thus, patients need effective treatment options both in advanced disease setting and in earlier lines of treatment settings. The emerging treatment landscape includes bispecific antibodies and chimeric antigen receptor (CAR)-T therapies. Whereas bispecific antibodies require chronic administration, CAR-T therapies are given as a single infusion, which can provide patients with the benefit of a treatment-free period. With their high efficacy and treatment-free period in many patients, CAR-T therapies are poised to continue to shape the future of MM treatment.

There are two currently approved CAR-T therapies, ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel). Both target B-cell maturation antigen (BCMA), a member of the tumor necrosis factor receptor family that is involved in B-cell maturation and subsequent differentiation into plasma cells. The selective expression of BCMA on plasma cells and overexpression on MM cells makes it a promising therapeutic target. The cilta-cel construct contains two camelid variable heavy-chain binding domains, and the signaling portion consists of a human CD8 alpha signaling peptide, hinge and transmembrane domains, followed by a human 4-1BB cytoplasmic costimulatory domain connected to a human CD3 zeta cytoplasmic domain [6]. Ide-cel contains one murine, single-chain fragment variable-binding domain for the BCMA antigen, CD8 alpha hinge and transmembrane domain, cytoplasmic 4-1BB (CD137) co-stimulatory domains, and CD3 zeta T-cell signaling element [7,8].

Cilta-cel (CARVYKTI™, Janssen Biotech, Inc.) has recently been approved by the United States (US) Food and Drug Administration and the European Commission for an expanded indication of treatment of patients with lenalidomide-refractory RRMM after at least one LOT, including a PI and an IMiD [9,10]. Initial approval was in heavily pretreated RRMM and was based on results from the phase Ib/II CARTITUDE-1 study, which showed a high overall response rate (ORR) in that population [6,11]. The expanded indication was based on results from the phase III CARTITUDE-4 study, which demonstrated superior cilta-cel efficacy versus standard therapies [12]. We discuss recent data on long-term outcomes of cilta-cel in heavily pretreated patients with RRMM and its efficacy as earlier-line therapy (in lenalidomide-refractory patients with one to three prior LOTs).

2. Cilta-cel has demonstrated long-term efficacy in heavily pretreated RRMM patients

The efficacy and safety of cilta-cel in heavily pretreated MM patients was established in two studies, the first-in-human, phase I LEGEND-2 trial of LCAR-B38M CAR-T cells (generated using the same CAR construct as cilta-cel) and the pivotal phase Ib/II CARTITUDE-1 trial of cilta-cel [11,13]. Primary results from these two studies have been previously published [6,13]. More recently, both studies have reported long-term efficacy and safety data [14,15].

2.1. LEGEND-2

With at least 5 years of follow-up data, LEGEND-2 (NCT03090659, Figure 1(a)), a single-arm open-label study conducted across four centers in China [13], has the longest follow-up of any CAR-T therapy for MM to date [14]. LCAR-B38M CAR-T cells were tested in 74 patients who had prior exposure to a median of three prior LOTs (range: 1–9). Most patients had previously been treated with PIs and IMiDs, but few patients received anti-CD38 therapies as these were not accessible in China at the time. Of 74 patients, 36% had high-risk cytogenetics and 30% had extramedullary disease (EMD). ORR and percent of patients achieving a complete response (CR) were 87.8% (95% confidence interval [CI], 78.2–94.3) and 73.0%, respectively [13,14]. Minimal residual disease (MRD) was assessed at the 10⁻⁴ threshold and an MRD-negative CR rate of 67.6% was observed. At a median follow-up of 65.4 months, median PFS was 18.0 months (95% CI, 10.6–26.6) and median overall survival (OS) was 55.8 months (95% CI, 24.4–non-estimable [NE]) [14]. Promisingly, 16.2% of patients were disease-free for more than 5 years and 44.6% remained alive, exemplifying the high efficacy in this patient population. It is important to note that the median dose received by patients in LEGEND-2 was 0.51 × 10⁶ CAR+ T cells/kg, and most patients were dosed with three split infusions and/or received cyclophosphamide alone as conditioning regimens. Analysis of patient/disease characteristics and treatment history in the 5-year progression-free subset showed that they had less advanced disease and good functional status at baseline, including being more likely to have baseline Eastern Cooperative Oncology Group performance status (ECOG PS) 0, International Staging System (ISS) stage 1, numerically shorter time from diagnosis, fewer prior LOT, immunoglobulin G type MM, no light chain MM, and no EMD versus those who progressed or died [14]. LCAR-B38M CAR-T cells also demonstrated a manageable safety profile. Hematologic adverse events were most common. Cytokine release syndrome (CRS) was reported in most (92%) patients but was mostly grade 1/2, and the incidence of neurotoxicity was 1% [13].

Figure 1. Study design overviews of LEGEND-2 (a), CARTITUDE-1 (b), CARTITUDE-2 (c), CARTITUDE-4 (d), CARTITUDE-5 (e), and CARTITUDE-6 (f). ^a20 patients were enrolled in the initial cohort before the expansion to n = 40, as allowed in the protocol. ^bApproximately 40 and up to 100 patients will be enrolled. ^cAdditional cycle(s) permitted with sponsor approval if an unanticipated delay in cilta-cel manufacturing process occurs.

ASCT, autologous stem cell transplant; BCMA, B-cell maturation antigen; CR, complete response; Cy, cyclophosphamide; DPd, daratumumab/pomalidomide/dexamethasone; DRd, daratumumab/lenalidomide/dexamethasone; D-VRd, daratumumab/bortezomib/lenalidomide/dexamethasone; Flu, fludarabine; IMiD, immunomodulatory drug; ISS, International Staging System; len, lenalidomide; MM, multiple myeloma; NDMM, newly diagnosed multiple myeloma; PD, pharmacodynamics; PI, proteasome inhibitor; PK, pharmacokinetics; PVd, pomalidomide/bortezomib/dexamethasone; Rd, lenalidomide/dexamethasone; R-ISS, revised International Staging System; SCT, stem cell transplant; SD, stable disease; TE, transplant eligible; TNI, transplant not intended; VGPR, very good partial response; VRd, bortezomib/lenalidomide/dexamethasone.

2.2. CARTITUDE-1

CARTITUDE-1 (NCT03548207; Figure 1(b)), was a single-arm, open-label, multicenter study conducted in the US in heavily pretreated patients (N = 97) with prior exposure to a PI, an IMiD, and an anti-CD38 monoclonal antibody who had received at least three prior LOTs [11,16]. The study population had a median of six prior LOTs (range, three to 18), with 42% of patients penta-drug refractory, 88% triple-class refractory, and 99% refractory to their last LOT [6]. Patients underwent lymphodepletion with cyclophosphamide and fludarabine. A single cilta-cel infusion (target dose of 0.75 × 10⁶ CAR+ T cells/kg; median dose, 0.71 × 10⁶ CAR+ T cells/kg [range, 0.51–0.95 × 10⁶]) was administered 5–7 days after start of lymphodepletion. At study close-out, median follow-up was 33.4 months (range, 1.5–45.2) [15]. Median PFS was 34.9 months. To date, this is the longest median PFS reported for FDA-approved therapies in a heavily pretreated RRMM population. Median OS was not reached at data cutoff and survival at 36 months was an estimated 63% [15]. Of 49 patients with samples evaluable for 12-month sustained MRD negativity, 26 were MRD negative at the 10⁻⁵ threshold by next-generation sequencing and 20 also had at least a CR [15]. This high rate of sustained MRD negativity highlights the depth and duration of response to cilta-cel. In addition, sustained MRD negativity was associated with prolonged PFS. The 30-month PFS rate was 54% in the overall CARTITUDE-1 population compared with 75% in those with sustained MRD negativity [15].

In CARTITUDE-1, the most common treatment-emergent adverse events (TEAEs) were hematologic, including neutropenia (grade 3/4: 95%), anemia (68%), leukopenia (61%), thrombocytopenia (60%), and lymphopenia (51%) [15,16]. Treatment-emergent infections occurred in 56 (58%) of patients (19 [20%] were grade 3 or 4) [11]. CRS occurred in 95% of patients (4% grade 3 or 4) and resolved in all but one patient with a grade 5 event (CRS and hemophagocytic lymphohistiocytosis). Neurotoxicities (including immune effector-cell associated neurotoxicity syndrome [ICANS] and other neurotoxicities) occurred in 21 (22%) patients (11 [11%] grade 3 or 4). ICANS occurred in 16 (17%) patients (2 [2%] were grade 3 or 4). Neurotoxicity other than ICANS occurred in 13 (13%) patients, including a total of six cases of movement and neurocognitive TEAEs (MNTs) [16,17]. Second primary malignancies (SPMs) were reported in a total of 20 patients, with 26 events [15]. All SPMs were considered unrelated to cilta-cel as assessed by the treating physicians, with no cases that suggest insertional oncogenesis. However, SPMs are not unexpected in this long-surviving population with prior exposure to autologous transplants, alkylating agents, and lenalidomide, as all are known to carry risk of SPM [18,19]. For example, a meta-analysis of lenalidomide-treated patients with MM reported a risk ratio of 1.42 for developing an SPM [19]. Overall, 35 patients (36%) in CARTITUDE-1 died on study, predominantly due to progressive disease (n = 17; 17.5%) with six deaths (6.2%) considered related to treatment (two due to sepsis/septic shock, and one each due to CRS/hemophagocytic lymphohistiocytosis, lung abscess, respiratory failure, and neurotoxicity) [15]. Follow-up for safety and survival of patients from CARTITUDE-1 is ongoing in the 15-year follow-up study CARTINUE (NCT05201781; MMY4002).

3. Evidence of cilta-cel efficacy in earlier lines of treatment

3.1. CARTITUDE-2

The multicohort CARTITUDE-2 (NCT04133636, Figure 1(c)) phase II study explored efficacy and safety outcomes with cilta-cel in various settings, including early LOT in RRMM. Relevant cohorts included patients refractory to lenalidomide with one to three prior LOTs (Cohort A, n = 20), and those with one prior LOT and early relapse after initial therapy with a PI and IMiD (Cohort B, n = 19) [20]. Early relapse was defined as progression within 12 months after autologous stem cell transplant (ASCT) or from the start of anti-MM therapy for patients who had not received an ASCT. The primary endpoint was MRD negativity at 10⁻⁵. Of 17 patients in Cohort A with MRD-evaluable samples, 100% were MRD negative at 10⁻⁵ sensitivity. ORR was 95%, with 90% of patients achieving at least a CR at median follow-up of 29.9 months [20]. The 24-month PFS rate was 75% (95% CI, 50.0–88.7). In Cohort B, 15 patients (79%) had MRD-evaluable samples, of which 14 (93%) were MRD negative [20]. All patients responded, with 90% achieving at least a CR, at median 27.9-month follow-up. The 24-month PFS rate was 73% (95% CI, 47.2–87.9). Safety was consistent with that seen in CARTITUDE-1 [20].

3.2. CARTITUDE-4

CARTITUDE-4 (NCT04181827, Figure 1(d)) is an ongoing, global, multicenter, phase III randomized clinical trial (RCT) [12] to explore efficacy and safety of cilta-cel in patients at earlier points of treatment for MM compared with those in CARTITUDE-1. Enrolled patients were refractory to lenalidomide, with one to three prior LOTs including a PI and an IMiD, had an ECOG PS ≤ 1, and had no prior CAR-T therapy or previous BCMA-targeted treatment. Importantly, CARTITUDE-4 was the first phase III CAR-T study to include patients after first MM relapse. The primary endpoint in CARTITUDE-4 was PFS. Secondary efficacy outcomes were rates of patients achieving at least a CR, ORR, MRD negativity (10⁻⁵ detection level), OS, time to patient-reported symptom worsening, and safety (adverse events) [12].

Patients were randomized 1:1 to receive cilta-cel or physician’s choice of daratumumab/pomalidomide/dexamethasone (DPd) or pomalidomide/bortezomib/dexamethasone (PVd) as standard of care (SOC) [12]. Patients randomized to cilta-cel received at least one cycle of bridging therapy with physician’s choice of DPd or PVd after apheresis and before lymphodepletion and cilta-cel infusion.

Of the 516 screened patients, 419 were randomized (208 to cilta-cel, 211 to SOC). Of the patients randomized to the cilta-cel group, 176 received cilta-cel as study treatment (32 patients did not receive cilta-cel as study treatment due to disease progression [n = 30] or death [n = 2]). At baseline, the median time since diagnosis was approximately 3 years, and 32% of patients had only one prior LOT. High-risk cytogenetic abnormalities were present in 61% of patients, including gain/amp(1q) (47%), del(17p) (22%), t(4:14) (14%), and t(14;16) (2%); 22% had two or more abnormalities [12]. Soft tissue plasmacytomas were present at baseline in 19% of patients, and 20% had bone marrow plasma cells ≥60%.

Results of CARTITUDE-4 at median follow-up of 15.9 months showed superior efficacy of cilta-cel versus SOC. Cilta-cel significantly prolonged PFS vs SOC in the intent-to-treat population (defined as all randomized patients) (hazard ratio [HR], 0.26; 95% CI, 0.18–0.38; p < 0.001), with a 74% reduction in the risk of progression or death. Median PFS was not reached in the cilta-cel arm (95% CI, 22.8–NE) and was 11.8 months (95% CI, 9.7–13.8) in the SOC arm. At 12 months, an estimated 76% of patients randomized to cilta-cel were alive and progression-free compared with 49% of patients randomized to SOC. Because treatments were the same from randomization until cilta-cel infusion per the study design, the PFS analysis used a prespecified weighted method to focus on events after cilta-cel infusion [12]. This approach can allow for a more accurate estimation of the clinical effect of cilta-cel vs SOC.

In the first 8 weeks of the study, more events of progression or death were reported in the cilta-cel arm than in the SOC arm (22 vs eight), during the time when patients in both arms were receiving the same treatments (before cilta-cel infusion). The reasons for this are not clear, as baseline characteristics were well balanced between study arms.

Analysis of prespecified subgroups showed cilta-cel prolonged PFS over SOC in all subgroups, including patients with one prior LOT (HR 0.35, 95% CI, 0.19–0.66), and those known to be difficult to treat, including patients with soft tissue plasmacytomas (HR 0.39, 0.21–0.75), patients with high cytogenetic risk (for any of four high-risk markers [HR 0.25, 0.16–0.38]; for two or more markers [HR 0.33, 0.17–0.64]), triple-class refractory patients (HR 0.15, 0.05–0.39), and ISS status stage 3 (HR 0.33, 0.11–0.95) [12]. OS data were immature at this interim analysis (HR 0.78, 95% CI, 0.5–1.2, p = 0.26) with 39 deaths in the cilta-cel arm and 46 in SOC arm [12]. Longer follow-up is needed to fully characterize PFS and OS in this study.

Cilta-cel significantly improved response rates vs SOC (84.6% vs 67.3%, risk ratio [RR] 2.2, 95% CI, 1.5–3.1, p < 0.001) and also improved depth of response (at least a CR rate, 73.1% vs 21.8%, RR 2.9, 95% CI, 2.3–3.7, p < 0.001) [12]. Responses to cilta-cel were more durable than with SOC, lasting ≥12 months in an estimated 84.7% of responders (95% CI, 78.1–89.4) with cilta-cel vs 63.0% (95% CI, 54.2–70.6) with SOC [12]. The rate of MRD negativity (at 10⁻⁵ sensitivity) was 60.6% for patients in the cilta-cel arm vs 15.6% for patients treated with SOC (RR, 2.2 [95% CI, 1.8–2.6], p < 0.001). Considering only those with MRD-evaluable samples, rates of MRD negativity were 85.7% vs 32.7% for cilta-cel and SOC, respectively [12].

Patients who received cilta-cel as study treatment (n = 176 of 208 randomized) had a 12-month PFS rate of 89.7%. The ORR in this patient population was 99.4%, including 86.4% of patients who achieved CR or better (68.8% stringent CR, 17.6% CR), and median duration of response was not estimable. The MRD negativity (10⁻⁵ sensitivity) rate was high (n/N, 126/176 [71.6%]).

The safety profile was manageable with appropriate supportive care [12]. Grade 3/4 cytopenias were reported for 94.2% of patients in the cilta-cel arm in CARTITUDE-4 and included neutropenia (89.9%), thrombocytopenia (41.3%), and lymphopenia (20.7%). Most grade 3/4 cytopenias (over 70%) were resolved to grade ≤2 by day 30 (lymphopenia, neutropenia, and anemia) or by day 60 (thrombocytopenia). Cranial nerve palsies were reported in 16 patients infused with cilta-cel, all affecting cranial nerve VII (one each additionally affected cranial nerves III and V) [12]. These were mostly mild to moderate (grade 1 or 2, n = 14; grade 3, n = 2), and most (14/16) had resolved by data cutoff.

Fewer patients reported SPMs in the cilta-cel arm (nine patients, 4.3%) than in the SOC arm (14 patients, 6.7%). SPMs were predominantly cutaneous/noninvasive and hematologic in the cilta-cel arm and cutaneous/noninvasive in the SOC arm. As of the November 2022 data cutoff, in the cilta-cel arm, the three hematologic SPMs observed were acute myeloid leukemia, myelodysplastic syndrome, and peripheral T-cell lymphoma (PTCL). The case of PTCL was CAR positive, and current data are consistent with the presence of a T cell clone in the patient’s apheresis sample that may have had malignant potential before it was engineered into a CAR+ T cell and infused back to the patient [21]. However, tumorigenesis is multifactorial. Given other confounding factors in this case, including other mutations, it is difficult to link the development of this PTCL to a single cause. TCL after CAR-T therapies is a rare, class-wide safety signal. As of December 2023, the US FDA was aware of 22 cases of TCL in over 27,000 doses administered in the U.S. with approved CAR-T therapies for myeloma and other blood cancers [22]. However, given the evidence currently available, the benefits of CAR-T therapy generally outweigh the risks, with the potential for rapid, deep, and durable responses [22,23].

More TEAEs resulting in death occurred in the cilta-cel arm than with SOC (10 vs five) during the study. Many of these events were COVID-19 related (seven with cilta-cel vs one with SOC); six of the seven COVID-19 infections that resulted in death in the cilta-cel arm were diagnosed within 4 months after cilta-cel infusion, when patients were most immunocompromised. The time period for these COVID-19 infections also coincided with the emergence of the omicron variant and the decreasing of COVID-19-related restrictions in some regions. Non-COVID-19-related TEAEs resulting in death included one case each of treatment-emergent neutropenic sepsis, pneumonia, and respiratory failure (occurred prior to cilta-cel infusion) in the cilta-cel arm. One case each of treatment-emergent septic shock, progressive multifocal leukoencephalopathy, respiratory tract infection, and pulmonary embolism resulting in death occurred in the SOC arm.

4. Lessons learned from CARTITUDE-4 and CARTITUDE-1

Informal comparisons of efficacy and safety in CARTITUDE-1 (patients with at least three prior LOTs; 81% lenalidomide-refractory) and CARTITUDE-4 (one to three prior LOTs; 100% lenalidomide-refractory) allow hypothesis generation about the relative efficacy and safety in these populations. Focusing on patients who were infused with cilta-cel as study treatment (n = 97 in CARTITUDE-1, n = 176 in CARTITUDE-4), 12-month PFS rates were 77% and 90%, respectively [11,12]. ORR was 98% in CARTITUDE-1 at 18-month median follow-up [24] and 99% in CARTITUDE-4 at 15.9-month median follow-up [12]. Thus, data from CARTITUDE-4 confirm the anti-myeloma activity of cilta-cel observed in CARTITUDE-1 (Figure 2).

Figure 2. PFS in the as-treated population of CARTITUDE-4 (n = 176) and CARTITUDE-1 (n = 97). ^aCARTITUDE-4 data were re-baselined to begin at time of cilta-cel infusion for patients who received cilta-cel as study treatment, with median follow-up of 13 months. cilta-cel, ciltacabtagene autoleucel; LOT, line(s) of therapy; PFS, progression-free survival.

Potential improved tolerability was observed in earlier-line patients from CARTITUDE-4 compared with patients in CARTITUDE-1 with three or more LOTs. Among patients infused with cilta-cel, incidence of CRS was lower in CARTITUDE-4 than in CARTITUDE-1 (all grade, 76% vs 95%; grade ≥ 3, 1% vs 5%) [11,12]. Incidence of ICANS was also lower in CARTITUDE-4 compared with CARTITUDE-1 (4.5% vs 17%; grade 3/4, 0.6% vs 2%) [11,12]. Finally, the incidence of MNTs, a later-onset neurotoxicity, was lower in CARTITUDE-4 than in CARTITUDE-1 at a similar median follow-up (0.6% at 15.9-month median follow-up vs 5% at 12- and 18-month median follow-ups) [11,12,24]. For MNTs, the explanation for these safety improvements may not only lie in the earlier-line treatment setting; insights from CARTITUDE-1 yielded the development of a set of patient management strategies for minimizing risk of MNTs irrespective of treatment setting [17]. These included enhanced bridging therapy to reduce tumor burden before cilta-cel infusion, early and aggressive treatment of ICANS and CRS, and extended handwriting monitoring for early detection of neurotoxicity symptoms. These strategies were implemented in CARTITUDE-4 and may have contributed to a reduction in the number of MNT cases [12]. Furthermore, bridging therapy to control disease and minimize MNT risk was required in all patients in CARTITUDE-4, whereas it was optional in CARTITUDE-1 and only received by 75% of patients [11].

As demonstrated in clinical trials, most patients who receive cilta-cel are likely to benefit from it; however, results from the CARTITUDE-1 and CARTITUDE-4 studies suggest the critical importance of effective control of tumor burden prior to cilta-cel infusion. In CARTITUDE-4, of the 208 patients randomized to the cilta-cel arm, 30 had disease progression and two died during the bridging therapy period [12]. One caveat of the CARTITUDE-4 study is that it did not include carfilzomib-based combinations as bridging/SOC options because, at the time the study began, the triplet regimens daratumumab/carfilzomib/dexamethasone (DKd) and isatuximab/carfilzomib/dexamethasone (IsaKd) were not approved by regulatory authorities.

5. The current MM treatment landscape and unmet needs

For patients with RRMM, SOC therapy involves multidrug combinations that may include a PI, IMiD, and monoclonal antibodies [25]. However, patients may become refractory to these treatments and those who are refractory to multiple drug classes are more likely to have suboptimal outcomes [3]. Hence, there is an urgent medical need to prolong survival and delay progression in heavily pretreated patients with RRMM. Based on results from the CARTITUDE-1 study, a single infusion of cilta-cel had a high rate and depth of response, with the longest median PFS reported for approved therapies in this heavily pretreated patient population.

5.1. Lenalidomide-refractory MM

Lenalidomide has become a cornerstone of combination therapies for newly diagnosed MM (NDMM) and RRMM; however, its use has led to increased rates of lenalidomide-refractoriness [1], with most exposed patients becoming refractory [26]. Refractoriness occurs as early as first relapse, leading to a growing need for effective, lenalidomide-sparing second-line and later treatments.

Triplet combinations of a steroid plus any two of a PI, anti-CD38 antibody, and an IMiD have shown efficacy in lenalidomide-refractory patients (Table 1) [27–36]. These regimens include DKd, daratumumab/bortezomib/dexamethasone (DVd) and IsaKd, DPd, PVd, and isatuximab/pomalidomide/dexamethasone (IsaPd). Despite the availability of these regimens over the past few years, recent analyses of the early-line lenalidomide-refractory population showed poor patient outcomes and a lack of consistent treatment approaches in real-world (RW) settings [37–40]. For example, a paper examining a mixture of protocol-specified and post-study RW treatments in >900 lenalidomide-refractory patients with one to three prior LOTs from the daratumumab clinical trials showed an ORR of 55.4%, estimated median PFS of 10.0 months (95% CI, 8.8–11.1), and median OS of 27.5 months (95% CI, 24.3–31.4) at median follow-up of 29.7 months [40]. Thus, an unmet need for more effective options in this setting remains, and cilta-cel is currently the only CAR-T therapy that has been evaluated in lenalidomide-refractory patients after first relapse [12]. Indirect treatment comparisons of cilta-cel in CARTITUDE-4 versus DKd and IsaKd indicated that cilta-cel yields superior outcomes in patients with RRMM with two to four prior LOT [41,42]. Its superior efficacy to SOC treatments demonstrated in CARTITUDE-4 suggests that patients may benefit from moving cilta-cel into earlier LOTs. Effective bridging therapy enables better control of tumor burden prior to cilta-cel infusion, which is more feasible in early-relapse patients who have less refractory disease. Additionally, it allows for the necessary time for apheresis and cell manufacture, making administration more controlled in the earlier-line setting. Positive results in CARTITUDE-1 and CARTITUDE-4 set the stage for investigating cilta-cel as frontline therapy, as the data suggest improved tolerability and potentially greater efficacy earlier in the disease course.

Table 1. Efficacy outcomes for cilta-cel vs triplet combinations including lenalidomide-refractory patient subgroup analysis [12,27–36].

	Cilta-cel (CARTITUDE-4)	DVd (CASTOR)	IsaKd (IKEMA)	DKd (CANDOR)	PVd (OPTIMISMM)	IsaPd (ICARIA)	DPd (APOLLO)
Study arm population, n	208	251	179	312	281	154	151
Prior LOTs (per inclusion criteria)	1–3	1 or more	1–3	1–3	1–3	2 or more	1 or more
Median follow-up, months	15.9	40.0	44	27.8	15.9	11.6	16.9
mPFS (95% CI)	NR (22.8–NE)	16.7	35.7 (25.8–44.0)	28.6 (22.7–NE)	11.2 (9.7–13.7)	11.5 (8.9–13.9)	12.4 (8.3–19.3)
ORR, %	84.6	85	86.6	84	82.2	60	69
Lenalidomide-refractory patients, n	208	60	57	99	200	144	120
Lenalidomide-refractory patients mPFS (95% CI), months	NR (22.8–NE)	7.8	NA	28.1 (20.3–NE)	9.5 (8.1–11.3)	11.4	9.9 (6.5–13.1)

CI, confidence interval; D, daratumumab; d, dexamethasone; Isa, isatuximab; K, carfilzomib; LOTs, lines of therapy; mPFS, median progression-free survival; NA, not available; NE, not estimable; NR, not reached; ORR, overall response rate; P, pomalidomide; V, bortezomib.

5.2. Cilta-cel as frontline therapy?

Frontline therapy for patients with MM is determined by risk stratification and transplant eligibility [43]. ASCT with high-dose melphalan was first introduced over 40 years ago [44,45] and remains the gold standard frontline MM treatment for eligible patients. Addition of ASCT to triplet therapy improves PFS [46,47]; however, to date, frontline ASCT has not been shown to improve OS vs other treatment options [46,47]. For the current recommended combination drug regimens with ASCT, 5-year estimates of OS are 81% for bortezomib/lenalidomide/dexamethasone (VRd) [47] and 84% for carfilzomib/lenalidomide/dexamethasone (KRd) [48]. For transplant plus the quadruplet daratumumab-VRd, 4-year OS was 92.7% [49]. Drawbacks to ASCT are toxic adverse effects and a transient but clinically meaningful reduction in quality of life [50].

Patients who are not eligible for ASCT, due to age, comorbidities, disease features, and/or frailty, are a heterogenous group [51]. For transplant-ineligible patients, the triplet therapies VRd and daratumumab/lenalidomide/dexamethasone (DRd) are SOC [25,52]. Median OS was 75 months for VRd and has not been reported for DRd but will be greater than 60 months (60-month OS rate, 66%) [53,54]. Other options for this population include daratumumab/bortezomib/melphalan/prednisone (DVMP; 36-month OS rate, 78%) and KRd (36-month OS rate, 86%) [55,56]. All these combinations are dosed continuously, which may increase the risk of adverse events and reduce adherence [51].

Alternatives to current frontline therapies that confer a long period of PFS and an OS benefit with treatment-free periods and manageable tolerability profile are needed. CAR-T cell therapies may fill this need for both transplant-eligible and transplant-ineligible patients. In addition to CARTITUDE-2 cohorts A and B, the multicohort CARTITUDE-2 study will evaluate the efficacy of cilta-cel in patients with NDMM with less than CR after ASCT frontline therapy (Cohort D), with NDMM for whom transplant is not planned, without prior therapy and classified as high risk per ISS stage III criteria (Cohort E), in patients with NDMM with standard risk (ISS stages I and II) and after initiation of therapy (Cohort F), NDMM patients for whom transplant is not intended (Cohort G), and for NDMM patients who are transplant eligible (Cohort H), with results expected to read out starting in 2024 [57]. Two RCTs are evaluating the efficacy of cilta-cel in NDMM patients. CARTITUDE-5 (NCT04923893, Figure 1(e)) is exploring efficacy of cilta-cel in transplant-ineligible patients with NDMM [58]. Patients in both arms will receive VRd induction treatment, then either a single infusion of cilta-cel without maintenance, or further VRd treatment followed by Rd maintenance treatment. The primary outcome is PFS. CARTITUDE-6 (NCT05257083; Emagine, Figure 1(f)) will compare the efficacy of DVRd induction treatment followed by cilta-cel versus DVRd followed by ASCT and DVRd consolidation in transplant-eligible patients with NDMM [59]. Both arms will then receive up to 2 years of lenalidomide therapy. Primary outcomes will be PFS (measured for up to 10 years) and sustained MRD-negative CR. CARTITUDE-5 and CARTITUDE-6 are expected to read out no earlier than 2026, with CARTITUDE-5 reading out first.

6. Conclusions

The clinical development program for cilta-cel has so far shown that it is efficacious with a manageable safety profile across both early and later LOTs in RRMM. The median PFS of almost 3 years in heavily pretreated patients is longer than the median PFS reported for any other approved anti-myeloma therapy in this patient population. While long-term data from CARTITUDE-4 are needed to fully understand the efficacy benefits in earlier LOT, primary results from the study demonstrated that cilta-cel is superior to SOC, including in subgroups of patients with high-risk disease features. Given the unmet need for therapies with high efficacy, treatment-free interval, and potential for cure, the collective data from these studies provide a strong rationale for the investigation of cilta-cel in NDMM in the CARTITUDE-5 and CARTITUDE-6 studies.

7. Expert opinion

Given the superior efficacy and potential treatment-free interval it can provide, cilta-cel could become a key treatment choice for RRMM for many patients. The long PFS with cilta-cel in later-line settings establishes the expectation for even longer PFS when cilta-cel is used after first relapse. Early use may also allow for more patients to receive cilta-cel treatment; a known challenge with CAR-T therapies is that patients may progress while waiting for CAR-T manufacture. Moving CAR-T therapies earlier in treatment will allow for more options for effective bridging therapy before disease becomes refractory and better treatment sequence planning.

In our view, the most effective treatment should be used early to preserve patient performance status, quality of life, and T-cell fitness for as long as possible. Indirect treatment comparison of cilta-cel and ide-cel has only been conducted in the setting of heavily pretreated RRMM, in which cilta-cel compared favorably to ide-cel [60]. No head-to-head studies have been conducted. Differences in the patient populations in the later-line studies (CARTITUDE-1 and KarMMa-1) and earlier-line studies (CARTITUDE-4 and KarMMa-3), and differences in safety management (i.e. the timing of CRS) differentiate the two therapies. Overall, both CAR-T therapies have led to deep and durable responses and have improved PFS with acceptable toxicities.

Outcomes of CAR-T therapy in practice are impacted by characteristics of RW populations. EMD, high-risk cytogenetics, and ECOG PS ≥ 2 are among the identified prognostic factors for PFS after anti-myeloma CAR-T therapy in RW studies [61,62]. RW treatment of patients with cilta-cel showed an ORR of 89%, with 56% of patients achieving CR or better at median follow-up of 2.3 months. Six-month PFS and OS rates were 79% and 84%, respectively. Over half (57%) of patients did not meet CARTITUDE-1 eligibility criteria, and the RW cohort had more patients with ECOG PS 2–4, high-risk cytogenetics, and EMD than CARTITUDE-1 patients [63]. Similarly, ide-cel efficacy in RW patients was comparable to that in the pivotal trial (median RW PFS, 8.5 months; median KarMMa PFS, 8.8 months) despite most patients not meeting trial criteria [62]. Patients with rapidly progressing disease that cannot be effectively controlled by bridging therapy may not be suitable candidates for CAR-T treatment. However, for appropriately selected patients, the high efficacy, established safety profile, and possibility for an extended treatment-free period (which could improve quality of life) will be an attractive option [64]. In addition to appropriate patient selection, considerations when selecting a particular CAR-T product include the management plan for adverse events, the product familiarity and expertise of the providers at the treatment center, and the availability of the CAR-T therapy.

Increasing equitable and inclusive access for all qualified patients remains a top priority. Manufacturing capabilities for this personalized treatment are being optimized to increase predictability and yield to allow expanded access. Further hurdles to increasing access include physician willingness to refer to a certified treatment center, institutional infrastructure to provide supportive care and monitoring, and cost. Patient preference will also need to be considered when determining the appropriate therapy. Patients may prefer the prolonged treatment-free period offered by CAR-T therapies. However, administration of CAR-T therapies is currently limited to cellular therapy sites, which will impact the available treatment options for individual patients.

Over the next 5 years, we hope to see positive results for cilta-cel in NDMM, and subsequent approval of the CAR-T therapy for these patients. CAR-T therapies will be suited to challenge the role of ASCT in NDMM. To do so, the CARTITUDE-6 study will need to show at least a similar median PFS as was shown in the DETERMINATION study showing the long-term benefit of ASCT plus VRd (approximately 5 and a half years), with less toxicity [47]. The observation that 21% of transplant-eligible and 57% of transplant-ineligible patients do not receive any subsequent treatment after initial therapy highlights the importance of early use of effective treatments [65]. Furthermore, we expect that CAR-T therapies will be an option for patients who are currently considered transplant-ineligible. Overall, increased utilization of CAR-T therapies will increase disease control with less continuous therapy. Other considerations for moving cilta-cel to frontline use include the potential for CRS and ICANS in newly diagnosed patients, further characterization of MNT and SPM risk, and the degree to which debulking will be required for safe cilta-cel administration. These questions await data from CARTITUDE-5 and CARTITUDE-6.

If cilta-cel becomes approved for frontline use and supplants ASCT, the treatment paradigm for MM will shift, and the principal question for treatment sequencing will become what to use after cilta-cel. However, in the meantime, the current indication for cilta-cel in RRMM presents similar questions around sequencing before and after cilta-cel, which are becoming more complex as treatment choices expand. The emerging treatment landscape for MM includes several bispecific antibodies and CAR-T cell therapies that are either approved or in clinical development, with a diversity of targets including BCMA, GPRC5D, and FcRh5 [66–74]. Data are beginning to emerge to inform how to best sequence and combine each of these options and suggest that anti-BCMA therapies do not have optimal efficacy when given sequentially, although many patients can still respond to the second BCMA-targeting therapy [62,63,75,76]. For example, in CARTITUDE-2 Cohort C, heavily pretreated patients with prior exposure to BCMA-directed therapy had an ORR of 60%, compared with 98% in CARTITUDE-1 [16,75]. Thus, the available data suggest that cilta-cel should be sequenced prior to other anti-BCMA therapies for better efficacy outcomes. Data are less promising for retreating with the same CAR-T [77].

Switching therapeutic targets may in theory allow sequential use of targeted therapies without loss of efficacy, but data are currently lacking to support this. For example, sequential use of cilta-cel and talquetamab (which targets GPRC5D) is a potential sequence that deserves clinical study. Preliminary data on use of the GPRC5D-targeting CAR-T MCARH109 in patients with prior BCMA-targeted therapy suggested efficacy but awaits confirmation in a larger cohort [69]. Combination therapy of two agents with different targets is another approach that is beginning to be investigated. Most notably, the phase Ib RedirecTT-1 study (NCT04586426) of combination teclistamab and talquetamab has shown promising initial results, with ORR of 92% [78]. Another possibility deserving study is the use of bispecific antibodies as bridging treatment to control tumor burden prior to treatment with CAR-T. More studies are needed to inform how the various cellular and immune therapies can optimally fit into the evolving treatment landscape.

The ultimate goal is to cure MM by preventing later relapses (i.e. prolonged PFS or sustained MRD negativity). Treatment advances made over recent years make this an increasingly realistic proposition for at least a subset of patients, and cilta-cel will likely have a key role, especially if it moves into NDMM. Together, treatments available now and in the near future will provide a treatment pathway designed for the individual needs of the patient, from NDMM to RRMM, with the aim to cure.

Article highlights

• CAR-T therapies are poised to shape the future of multiple myeloma treatment, as they offer high efficacy and a potentially long treatment-free period for many patients with advanced disease and in earlier lines of therapy, with a manageable safety profile.

• Ciltacabtagene autoleucel (cilta-cel) is a B-cell maturation antigen targeting CAR-T cell therapy which was initially approved by the United States Food and Drug Administration for treatment of patients with relapsed/refractory multiple myeloma with ≥4 lines of therapy and by the European Medicines Agency for triple-class exposed patients with ≥3 prior lines of therapy; the indication in the both United States and Europe was recently expanded to lenalidomide-refractory RRMM after ≥1 line of therapy, including a proteasome inhibitor and an immunomodulatory drug.

• Initial approval was based on results from the phase Ib/II CARTITUDE-1 study, which showed a high overall response rate and durable efficacy in heavily pretreated patients with relapsed/refractory multiple myeloma; median progression-free survival was 34.9 months.

• In the phase III CARTITUDE-4 trial, cilta-cel demonstrated superiority to standard of care in earlier-line patients (lenalidomide-refractory, with one to three prior lines of therapy), with a hazard ratio of 0.26 (p < 0.001) for progression-free survival at median 16 months follow-up.

• This improved efficacy over standard care was also seen in subgroups of patients with high-risk disease features.

• Cilta-cel has shown a manageable safety profile across both early and later lines of therapy in patients with relapsed/refractory multiple myeloma, with potentially greater tolerability in earlier-line patients with respect to cytokine release syndrome and neurotoxicity.

• Given the deep and durable responses and potential treatment-free interval it can provide, cilta-cel could become a key treatment choice for relapsed/refractory multiple myeloma for many patients.

• Cilta–cel is currently being investigated for use as frontline therapy; results are expected starting in 2024.

Declaration of interest

S Jagannath has served in a consulting or advisory role for BMS, Caribou Biosciences, Genentech, Janssen, Karyopharm Therapeutics, Legend Biotech U.S.A. Inc., Regeneron, Sanofi, and Takeda; and has received travel, accommodations, and expenses from BMS and Janssen. CC Jackson, JM Schecter, N Lendvai, and H Sun are current or former employees of Janssen Research & Development. M Akram and N Patel are employees of Legend Biotech U.S.A. Inc. TG Martin has served in a consulting or advisory role for GSK, Pfizer and Legend Biotech U.S.A. Inc.; and has received research funding from BMS, Amgen, Janssen, and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

All authors were involved in the conception of the article, all reviewed and revised the article for important intellectual content, and all authors approved the final submission.

Acknowledgments

Medical writing support was provided by Valerie P. Zediak, PhD, of Eloquent Scientific Solutions, and funded by Janssen Global Services, LLC.

Additional information

Funding

This paper was funded by Janssen Global Services, LLC.