For multiple myeloma (MM) patients who are refractory to proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 agents, the prognosis is poor. After each relapse, treatment regimens result in progressively lower response rates, shorter response durations, and increasing drug resistance, thereby diminishing the number of treatment options. This demonstrates the urgent need for alternative treatments for patients with advanced illness following refractory/multiply relapsed MM. Therapies that target B-cell maturation antigen (BCMA) are of particular interest in heavily pretreated patients. These therapies are a more recent addition to the MM armamentarium and could offer novel options for these particularly difficult-to-treat patients.
BCMA, a receptor that is expressed on the surface of malignant cells but is absent from healthy naïve and memory B cells, is an ideal therapeutic target. In fact, two BCMA-directed therapies were recently approved for specific subgroups of MM patients: the antibody-drug conjugate belantamab mafodotin and the chimeric antigen receptor (CAR) T-cell therapy idecabtagene vicleucel are now indicated for patients with relapsed/refractory MM (RRMM) who have received at least four prior lines of therapy. Many other BCMA-targeted treatments are progressing in clinical trials.
At the 18th International Myeloma Workshop (IMW), held September 8–11 in Vienna, Austria, clinical updates on two BCMA-directed immunotherapeutic classes (CAR T-cell therapy and T-cell engager therapy [also known as bispecific antibodies]) were presented—and the MMRF was there to capture this information to bring it back to share with the broader MM community.
CAR T-Cell Therapy: Longer Follow-Up; Durable Responses
CAR T-cell therapy is a form of engineered immune cell therapy that has generated considerable interest as a potential myeloma treatment because of its potential for eliciting responses in most patients (response rates >90%), including those in whom myeloma has relapsed despite many prior therapies. Data presented at IMW focused on two CAR T-cell therapies, providing key updates to data presented at meetings earlier this year and late last year.
Idecabtagene vicleucel (ide-cel; bb2121)
Ide-cel is a BCMA-directed CAR T-cell therapy and the first CAR T-cell therapy to be approved for MM patients. The initial results from the KarMMa phase 2 trial, published here, were the basis for the approval of ide-cel in patients with RRMM who had received four or more prior lines of therapy, including an IMiD, a PI, and an anti-CD38 monoclonal antibody. At IMW, Dr. Larry Anderson from The University of Texas Southwestern Medical Center presented updated data from KarMMa. In this update, 128 of the 140 enrolled patients who had received a median of six (3–16) prior regimens (including IMiD, PI, and anti-CD38 monoclonal antibody) and were refractory to their last regimen (84% were triple- and 26% were penta-refractory) received treatment with ide-cel at 150─450 × 106 CAR+ T cells. At a median follow-up of 24.8 months, the overall response rate (ORR) was 73%. The median duration of response was 10.9 months and median progression-free survival (PFS) was 8.6 months; both increased with higher doses. In patients who achieved a complete response or better (≥CR), median duration of response and PFS was 21.5 months and 22.4 months, respectively. Median overall survival (OS) was 24.8 months with the estimated 24-month OS rate at 51%. All subgroups had an ORR ≥48% (including those with high tumor burden, extramedullary disease, and revised International Staging System stage III disease). Cytokine release syndrome (CRS) occurred in 84% (any grade) and was mainly grade 1 or 2; five (4%) patients had grade 3, one had grade 4, and one had grade 5 CRS (at the 300 × 106 dose). Neurotoxicity occurred in 18% (any grade), with 4% of patients experiencing grade 3. Ultimately, these results did not differ from what has been previously published. Based on these data, the investigators concluded that ide-cel yielded deep, durable responses in heavily pretreated RRMM patients, with a favorable clinical benefit-risk profile across the target dose range.
Ide-cel continues to be studied in several clinical trials.
Ciltacabtagene autoleucel (cilta-cel; JNJ-4528)
Cilta-cel is another BCMA-targeted CAR T-cell therapy; it contains two BCMA-targeting single-domain receptors. Excitement for this drug is growing because the US FDA has granted it a priority review for use in treating RRMM—it may be approved by the end of this year!
In the meantime, updates from two different trials of cilta-cel were reported at this meeting. The first (CARTITUDE-1) is a phase 1/2 trial investigating the use of cilta-cel in patients who had three or more prior lines of therapy (or were double-refractory to a PI and IMiD) and received an anti-CD38 antibody. Initial results from this trial were reported here. Updated results were presented by Dr. Sundar Jagannath at the Mount Sinai Hospital in New York City. As of February 11, 2021, 97 patients had been treated with a single infusion (target dose 0.75 × 106/CAR+ T cells/kg[range 0.5-1.0× 106]); patients had received a median of six prior lines. The ORR was 97%, with 80.4% achieving a stringent complete response (sCR) and 94.8% achieving a very good partial response or better (≥VGPR). Of the 61 patients evaluable for minimal residual disease (MRD), 91.8% were MRD negative (10-5). The median duration of response was 21.8 months and median PFS was 22.8 months. The estimated 18-month PFS and OS rates were 66% and 80.9%, respectively. CRS occurred in 95% patients (4% grade 3/4), and neurotoxicity occurred in 21% of patients (10% grade ≥3). During this study, 21 deaths occurred after cilta-cel infusion: 10 due to disease progression, 6 related to treatment, and 5 due to adverse events unrelated to treatment.
The second trial (CARTITUDE-2) is a phase 2 trial in patients with a median number of three or fewer prior lines of therapy. In this presentation, Dr. Adam Cohen from the University of Pennsylvania reported on 20 patients who had received a median of two (1–3) prior regimens (all patients were exposed to a PI, IMiD, and dexamethasone; 95% received alkylating agents; 65% received daratumumab; 95% were refractory to their last therapy; and 40% were triple-class refractory). All patients received a single infusion with cilta-cel at 0.75 × 106 CAR+ T cells/kg. At a median follow-up of 5.8 months, ORR was 95% with 75% achieving ≥CR and 85% ≥VGPR. Of the 4 patients evaluable for MRD assessment, 100% were MRD negative (10-5). The median duration of response was not yet reached. CRS occurred in 85% (10% grade 3/4). Neurotoxicity occurred in 20% (all grade 1/2). One death from COVID-19 occurred.
Cilta-cel will continue to be investigated in other populations of myeloma patients, in earlier-line settings, and as outpatient treatment.
Relapse From CAR T-Cell Therapy
Though CAR T-cell therapy is highly effective, patients can relapse after this treatment due to lack of long-term persistence of CAR T cells in patients. Two studies presented at IMW focused on relapse after CAR T-cell therapy. One presentation summarized clinical outcomes; the second presentation described an investigation of a unique way to sustain a response to CAR T-cell therapy.
Life After CAR T!
A retrospective single-center analysis evaluated the clinical outcomes of 31 MM patients who relapsed after CAR T therapy (after a median of 74 months [22-282]). Most of the patients had been extensively pretreated (a median of five [1-18] prior lines of therapy), and 90% of patients had previously received an autologous stem cell transplant (ASCT). The majority of patients had been exposed to and were refractory to most MM agents, such as lenalidomide, bortezomib, carfilzomib, alkylating agents, and daratumumab or isatuximab. Some patients (13%) had previously received a non–BCMA-targeted bispecific antibody. The median time to subsequent treatment following relapse on CAR T-cell therapy was 34 days (0-378). Most patients had two subsequent treatment lines; the most common was chemotherapy (V-DECP or VD-PACE, 34%). Twelve patients had a stem cell boost and five patients were treated with a bispecific antibody immediately following CAR T relapse, whereas 11 patients received this treatment at any point after CAR T relapse. Following CAR T relapse, 48% of patients responded to the treatment regimen that followed CAR T-cell therapy. The median time to progression after this post-CAR T relapse treatment was 104 days (62 days for second line after CAR T cells). Durable responses (>120 days) occurred in 20 patients with treatments that were either selinexor-based, non–BCMA-targeted bispecific antibody-based, stem cell boost-based, or venetoclax-based. The median OS after relapse on CAR T was 496 days. Ultimately, the results suggested that there is “life after CAR T,” because patients who relapse after CAR T-cell therapy can receive and respond to other treatments that are available.
Investigators from Canada showed that low BCL2L1 gene expression (the gene that encodes BclxL) is a consistent feature of relapsing patients, based on their analysis of serial blood and marrow samples from 10 patients who had been treated with anti-BCMA CAR T cells. From their findings, the investigators designed a second-generation CAR construct to increase BclxL expression in an effort to armor engineered CAR T-cells from inactivation and death (ie, lack of persistence). They compared the antimyeloma activity and persistence of these new armored CAR T cells with those of unarmored CAR T cells in vitro and in vivo. The viability and cytotoxicity of armored CAR T cells were superior to unarmored CAR T cells, providing justification for a novel approach to overcome relapse due to lack of CAR T-cell persistence.
Bispecific Antibodies: Potential New Options for Heavily Pretreated Patients
Another option for stimulating a patient’s T cells—that is, T cell–activating immunotherapies—that is currently under investigation is the use of bispecific antibodies. Comprising two antigen-recognition domains designed to recognize CD3 expressed on T cells and a myeloma cell surface antigen, bispecific antibodies recruit T cells to MM cells and cause T-cell proliferation and MM cell lysis. Many bispecific antibodies target BCMA, and there are other bispecific antibodies that target other myeloma cell surface proteins. Preliminary data on two of these agents were reported at IMW.
Elranatamab and Talquetamab
The MagnetisMM-1 trial is a phase 1 trial investigating the safety and efficacy of elranatamab—a BCMA × CD3 bispecific antibody—as a single agent. Thirty patients who had been exposed to a median of eight prior treatments (87% were triple-class refractory, 97% had received anti-CD38 therapy, and 23% had received prior BCMA-targeted antibody-drug conjugate or CAR T-cell therapy) received elranatamab subcutaneously at varying doses. ORR was 70% at doses ≥215 μg/kg (83% at the recommended phase 2 dose of 1,000 μg/kg). All patients with ≥CR achieved MRD negativity. Three quarters of patients who had prior BCMA-targeted therapy responded to treatment; CRS was seen in 73% (grade ≤2) and 20% neurotoxicity (grade ≤2).
Talquetamab is one of several new bispecific antibodies that binds to a different target on myeloma cells, in this case GPRC5D. A phase 1 trial evaluated varying doses of talquetamab administered intravenously or subcutaneously in patients with RRMM. One group at IMW presented results on a subset of patients (n=30) who received talquetamab subcutaneously at 405 μg/kg, which is considered the phase 2 recommended dose. Patients receiving treatment had previously received a median of 5.5 (2–14) prior lines of therapy. Most patients were triple-class/penta-drug exposed or refractory and 21% had prior BCMA-directed therapy. Treatment resulted in a 70% ORR (65% in triple-refractory and 84% in penta-refractory patients). CRS occurred in 79% of patients (4% grade 3) and neurotoxicity in 7% (grade ≤2). Skin-related side effects occurred in 77% of patients.
The results from both trials support the further clinical development of these agents.
Biallelic Loss of BCMA: Implications for BCMA-Directed Therapy
Researchers at the Dana-Farber Cancer Institute presented their analysis of over 2,000 myeloma patients to determine the frequency of BCMA deletion (del16p). They observed del16p in approximately 9% of newly diagnosed patients. High-risk chromosomal deletion events del1p and del17p (TP53) were more likely to be observed in patients with loss of BCMA. Additionally, patients with a loss of BMCA had increased mutational load than did those without loss of BCMA. The researchers concluded that del16p should be assessed in patients who may receive BCMA-directed therapy and that the association of del16p with other chromosomal losses such as del17p raises the question of the role of BCMA-targeted therapy in high-risk MM patients.
Support for this activity has been provided through a donation from Amgen; educational grants from GlaxoSmithKline, Karyopharm Therapeutics, and Oncopeptides; and a sponsorship from Johnson & Johnson Health Care Systems, Inc.
For further IMW analysis, please check our other blog here, here and here.