Abstract
MCARH109 is a first-in-class G protein–coupled receptor, class C, group 5, member D (GPRC5D)-targeted CAR T-cell therapy for patients with relapsed/refractory multiple myeloma (RRMM). This phase I clinical trial included 17 patients and determined MCARH109 is safe at a maximum tolerated dose of 150×106 CAR T-cells. In this updated analysis, no new serious adverse events were reported at a median follow-up of 37 months. Overall, 12/17 (71%) patients responded including 7/10 (70%) patients previously treated with B-cell maturation antigen targeted therapy. The median duration of response was 8.6 months (95% CI, 5.7 months - not reached) with two patients sustaining a stringent complete response at the time of last follow-up, 32 months and 41 months respectively. Median overall survival (OS) was not reached and the 3-year OS estimate was 59% (95% CI, 40%−88%). Possible GPRC5D loss via immunohistochemistry was observed in 6/10 (60%) patients at relapse. High-dimensional spectral cytometry-based immune profiling associated an activated T cell phenotype at apheresis with a response to MCARH109.
Introduction
Chimeric antigen receptor (CAR) T-cell therapy is effective in relapsed/refractory multiple myeloma (RRMM).1–4 Two B-cell maturation antigen (BCMA) targeted CAR T-cell products, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel, are FDA-approved for RRMM.5,6 However, despite robust responses, most patients relapse and require alternatively targeted therapies. G protein–coupled receptor, class C, group 5, member D (GPRC5D) is an alternative myeloma antigen.7 Here we present updated analyses of a phase I clinical trial of MCARH109, a first-in-class GPCR5D-targeted CAR T-cell therapy in RRMM, with data regarding ongoing responses, toxicities, and preplanned exploratory immune profiling.8
Methods
Study Design and Endpoints
This was an open-label phase I dose-escalation of MCARH109 using a 3+3 design at four dose levels: 25×106, 50×106, 150×106, and 450×106 CAR T-cells. Inclusion/exclusion criteria were previously described.8 Notably, this trial included 10 patients previously treated with BCMA-targeted CAR T-cells and bispecific antibodies (BsAbs; Table 1). The primary endpoint was safety, and key secondary endpoints included response per International Myeloma Working Group (IMWG) criteria and bone marrow measurable residual disease (MRD) negativity by multicolor flow cytometry (sensitivity: 10−5) as previously described at day 29 and at 1 year follow-up.9,10 Exploratory endpoints included measuring changes to myeloma cell GPRC5D expression was measured via immunohistochemistry (IHC), and correlating results to T cell characteristics. All patients provided informed consent prior to participation in the clinical trial and the study assessments were performed after approval from MSK Institutional Review Board (IRB) and in accordance with an assurance filed with and approved by the Department of Health and Human Services.
Table 1:
Baseline Patient characteristics by BCMA exposure
| Characteristic | No Prior BCMA Therapy (N=7) |
Prior BCMA Therapy (N=10) |
Overall (N=17) |
|---|---|---|---|
| Age, years | |||
| Median (range) | 57.9 (37.6, 76.4) | 63.8 (39.6, 73.5) | 59.6 (37.6, 76.4) |
| Sex, No. (%) | |||
| Female | 3 (42.9%) | 2 (20.0%) | 5 (29.4%) |
| Male | 4 (57.1%) | 8 (80.0%) | 12 (70.6%) |
| High-risk cytogenetics,† No. (%) | |||
| Yes | 5 (71.4%) | 8 (80.0%) | 13 (76.5%) |
| No | 2 (28.6%) | 2 (20.0%) | 4 (23.5%) |
| Extramedullary plasmacytoma, No. (%) | |||
| Yes | 4 (57.1%) | 4 (40.0%) | 8 (47.1%) |
| No | 3 (42.9%) | 6 (60.0%) | 9 (52.9%) |
| Nonsecretory myeloma, No. (%) | |||
| Yes | 2 (28.6%) | 1 (10.0%) | 3 (17.6%) |
| No | 5 (71.4%) | 9 (90.0%) | 14 (82.4%) |
| Prior lines of therapy | |||
| Median (range) | 5.0 (4.0, 8.0) | 6.50 (5.00, 14.0) | 6.00 (4.00, 14.0) |
| Disease refractory to last line of therapy, No. (%) | |||
| Yes | 7 (100%) | 7 (70.0%) | 14 (82.4%) |
| No | 0 (0%) | 3 (30.0%) | 3 (17.6%) |
| Penta-exposed, No. (%) | |||
| Yes | 7 (100%) | 10 (100%) | 17 (100%) |
| No | 0 (0%) | 0 (0%) | 0 (0%) |
| Triple-refractory Disease, No. (%) | |||
| Yes | 7 (100%) | 9 (90.0%) | 16 (94.1%) |
| No | 0 (0%) | 1 (10.0%) | 1 (5.9%) |
| Prior autologous transplantation, No. (%) | |||
| Yes | 7 (100%) | 10 (100%) | 17 (100%) |
| No | 0 (0%) | 0 (0%) | 0 (0%) |
| Prior allogeneic transplantation, No. (%) | |||
| Yes | 3 (42.9%) | 0 (0%) | 3 (17.6%) |
| No | 4 (57.1%) | 10 (100%) | 14 (82.4%) |
| Previous CAR T-cell therapy, No. (%) | |||
| Yes | 0 (0%) | 8 (80.0%) | 8 (47.1%) |
| No | 7 (100%) | 2 (20.0%) | 9 (52.9%) |
| Previous Bispecific antibody therapy, No. (%) | |||
| Yes | 0 (0%) | 2(20%) | 2 (11.8%) |
| No | 7 (100%) | 8(80%) | 15 (88.2%) |
| Bridging therapy, No. (%) | |||
| Yes | 7 (100%) | 9 (90.0%) | 16 (94.1%) |
| No | 0 (0%) | 1 (10.0%) | 1 (5.9%) |
| Responsive to bridging therapy, No. (%) | |||
| Yes | 0/7 (0%) | 1/9 (11.1%) | 1/16 (6.3%) |
| No | 7/7 (100%) | 8/9 (88.9%) | 15/16 (93.7%) |
High-risk cytogenetics is defined by the presence of 1q gain, t(4;14), t(14;16) or 17p deletion.33
Immune profiling correlates
Immune profiling assays were performed via high-dimensional spectral flow cytometry using a 33-color T-cell-focused panel (supplemental information methods). T cell characteristics (Figure S1) were analyzed using algorithm assisted cell clustering with Phenograph.11
Statistical methods
Kaplan-Meier methods estimated overall survival (OS)and duration of response (DOR). DOR was defined from the time of initial response to progression, death, or last follow-up. Median follow-up was calculated using the reverse Kaplan-Meier method.
Results
Safety
Of the 19 patients enrolled, 17 received MCARH109 between 10/22/2020–11/10/2021 (Table 1). The data cut-off for this analysis was 06/30/2024. Among two patients who were not infused with MCARH109, one withdrew consent before manufacturing, and one after manufacturing due to interim disease progression. Dose-limiting toxicities (DLT), CRS and ICANS rates were unchanged from prior report and all events resolved as previously reported.
On-target Off-Tumor Toxicities
Regarding on-target, off-tumor, GPRC5D-related, toxicities, nail changes occurred in 11 (65%) patients. All cases were grade 1 and resolved in 10 patients (91%) without intervention with one patient exhibiting nail discoloration until death. Grade 1 rash occurred in 3 (18%) patients and resolved with observation or topical steroids. Grade 1 dysgeusia occurred in 3 patients (18%) and resolved in 2, with the third experiencing persistent dysgeusia until death, 8.7 months from onset.
Two patients treated at the 450×106 CAR T-cell dose developed a grade 3 neurotoxicity with cerebellar symptoms including dizziness, dysarthria, dysmetria, and ataxia, possibly due to GPRC5D expression in the inferior olivary nucleus.12–14 Both had stable yet persistent symptoms at last follow-up, 31 and 34 months from symptom onset, respectively. Ongoing symptoms include dysarthria, and truncal and appendicular ataxia in both patients. No patients treated at lower doses exhibited cerebellar symptoms.
Anti-myeloma Efficacy
Previously, we reported 12 patients (71%) achieving a partial response (PR) or better. One patient’s response deepened from very good partial response (VGPR) to stringent complete response (sCR) at 13.1 months (Figure 1A). Overall, there were 7 (41%) sCR, 3 (18%) VGPR, and 2 (12%) PR. Among 12 responders, 8 (67%) were MRD-negative. Two patients had ongoing sCR at last follow-up, 32 months and 41 months respectively (Figure 1A). In the 10 BCMA-exposed patients, 7 (70%) responded including 6/8 (75%) BCMA CAR-T treated patients with 3 (38%) achieving sCR. Median follow-up was 37 months (IQR, 34–39m). Median DOR for the entire cohort was 8.6 months (95% CI, 5.7 months -not reached [NR]), including 5/12 (42%) with a DOR of greater than 1 year (Figure 1B). Median OS was not reached, and the 3-year OS estimate was 59% (95% CI, 40%−88%; Figure 1C).
Figure 1:
(A) Swimmer’s plot of individual patient responses over time by dose level. (B) Kaplan-Meier estimate of duration of response and (C) Kaplan-Meier estimate of overall survival
GPRC5D Expression
We previously reported GPRC5D loss by IHC in 4/6 (67%) responders at MCARH109 relapse. Two patients had intact GPRC5D at relapse, albeit with decreased expression from baseline.8 We also reported biallelic loss of GPRC5D in one case and decreased GPRC5D mRNA in the remaining 5 responders at relapse.15 Subsequently, 4 additional MCARH109 responders relapsed, with 2/4 demonstrating possible GPRC5D loss by IHC, giving of a total of 6/10 MCARH109 responders showing GPRC5D expression loss at relapse (Table S1).
Immune profiling correlates
Algorithm-assisted analysis of high-dimensional spectral cytometry data from apheresis samples identified 20 T-cell clusters each comprising ≥ 0.5% of aggregated T-cells (supplementary table 2).11 Patients responding to MCARH109 by IMWG criteria (N=12) had enrichment of CD8+CD45RO+CCR7− effector memory T-cells (TEM, 3.2-fold increase, p=0.0024, q=0.048, Figure 2, S2) when compared to non-responders (N=5). Responders trended toward enrichment of CD8+CD45RA+CCR7− effector memory T-cells re-expressing CD45RA (TEMRA, 3.7-fold increase p=0.041, q=NS). These TEM and TEMRA populations highly expressed HLA-DR and 2B4. Among all CD8+ T cells, MCARH109 responders had higher HLA-DR expression globally than nonresponders (p = 0.0381, Figure S3). No significant differences were identified between responders and nonresponders when analyzing preinfusion CAR T-cells this way.
Figure 2:
(A) Spectral flow analysis was performed on both apheresis products and on post manufacturing CAR T cells prior to infusion. (B) Algorithm assisted analysis of apheresis T cells from all 17 infused patients identified 20 unique T cell clusters, with (C) significant differences notable between MCARH109 responders and nonresponders. (D) MCARH109 responders had enrichment for CD8+ effector memory T cells (TEM) highly expressing HLA-DR (3.2-fold increase, p = 0.0024, q = 0.048), and trended towards enrichment for CD8+ effector memory T cells reexpressing CD45RA (TEMRA) highly expressing HLA-DR (3.7-fold increase, p = 0.041, q = 0.82). Statistical analysis was performed by comparing the relative abundance of each algorithm defined T cell cluster in responders vs nonresponders using individual, unpaired, 2-tailed t tests with strict multiple comparisons testing performed using the Bonferonni correction.
Discussion
MCARH109 is a first-in-class GRPC5D CAR T-cell therapy that is safe and effective in RRMM patients. In this phase I trial, all doses elicited a response and DLTs were only seen at the highest dose, 450×106 CAR T-cells. No new DLTs were observed since our initial report thus 150×106 CAR T-cells remains the maximum tolerated MCARH109 dose.
A grade 3 neurologic disorder with cerebellar symptoms was seen in 2 of 5 patients treated at the highest dose level, with both having stable, persistent symptoms at last follow-up. Other expected GRPC5D-related toxicities including rash, nail changes, and dysgeusia were low-grade and resolved in nearly all patients, which is notably distinct from reports with Talquetamab-treated patients, where on-target off-tumor side effects persist until the time of therapy cessation. This offers a potential advantage to MCARH109, as these symptoms seem to improve as CAR T-cell populations decline over time.
MCARH109 demonstrated a high overall response rate, with 71% of patients achieving ≥PR. Responses were durable in this phase I dose escalation trial with heavily pre-treated relapsed and refractory patients with a median DOR of 8.7 months and 42% of patients maintained a response for ≥1 year. The longest responder had an ongoing sCR at the time of last follow-up (41 months). Importantly, MCARH109 was highly effective in patients previously treated with BCMA targeted therapy, with 75% of patients previously treated with BCMA CAR T-cell therapy responding, thus providing a viable option for BCMA-refractory disease. Other trials investigating GPRC5D CAR T-cell therapies are ongoing.16–20
GPRC5D loss has been reported in patients at relapse after GPRC5D-targeted BsAbs.21–23 However, antigen escape is rare at relapse after BCMA CAR T-cell therapy.23–27 In the phase 2 KarMMa trial, only 4% of evaluable responding patients were suspected to have BCMA loss at relapse after ide-cel.28 In contrast, 60% of MCARH109 patients are suspected to have GRPC5D loss by IHC, indicating antigen escape as a more common event in relapse after GPRC5D CAR T-cells, presumably due to the selective pressure applied by therapy, highlighting the potential benefit of dual-targeted therapy.29,30 Additional studies with more patients are needed to validate the methods for antigen expression including IHC and flow cytometry.
We identified an activated T cell phenotype at the time of apheresis, characterized by an increase in CD8+ TEM populations expressing HLA-DR and 2B4, associated with treatment response (Figure 2). Similar findings have recently been reported with BCMA CAR T-cells, further supporting the relevance of T-cell characteristics at the time of apheresis as predictive of CAR T cell therapy outcomes independent of CAR T cell product and target.31,32
In conclusion, MCARH109 is safe and effective with a maximum tolerated dose of 150×106 CAR T-cells with no new reported toxicities. Responses were deep and durable even in patients with prior BCMA-targeted therapy. In contrast to BCMA CAR-T therapy, antigen escape was common at MCARH109 relapse. Finally, activated T-cell phenotypes at apheresis correlated with a response to MCARH109. A similar GPRC5D CAR T cell therapy, BMS-986393 is currently being evaluated in patients with relapsed and refractory multiple myeloma and prior exposure to BCMA therapies in a multi-center phase II trial (QUINTESSENTIAL trial; NCT06297226).18
Supplementary Material
Figure S2: Algorithm assisted analysis identified that responders had enrichment for CD8 TEM populations with high expression of HLA-DR.
Figure S3: Among CD8+ T cells, MCARH109 responders had higher expression of HLA-DR than MCARH109 non responders
Figure S1: Gating strategy for identifying T cell populations is shown. Light scatter was using to remove debris and identify single cells. Live/dead staining was used to identify living cells and CD3 and CD45 coexpression was used to identify T cells.
Funding Statement:
The clinical trial was funded by Juno Therapeutics, a Bristol Myers Squibb company. All authors from MSKCC are supported by a National Cancer Institute (NCI) Core Grant (P30 CA008748); Eric Jurgens is supported by the NCI T32 training grant (T32 CA9512-34), the American Society of Clinical Oncology (ASCO) Young Investigator Award (YIA), and the International Myeloma Society (IMS); Ross Firestone is supported by ASCO
YIA and the International Myeloma Society; Sham Mailankody is supported by the Scholar in Clinical Research grant from the Leukemia and Lymphoma Society (LLS).
Footnotes
This manuscript is an update of a phase I clinical trial of MCARH109 in relapsed/refractory multiple myeloma with the initial results published on September 28, 2022 (Mailankody et al. GPRC5D-Targeted CAR T Cells for Myeloma. N Engl J Med. 2022). We confirm this manuscript is an original work and has not been published nor is it under consideration elsewhere for publication. The results described in this manuscript were accepted for presentation as a poster abstract at the International Myeloma Society 21st Annual Meeting on September 26, 2024.
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Associated Data
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Supplementary Materials
Figure S2: Algorithm assisted analysis identified that responders had enrichment for CD8 TEM populations with high expression of HLA-DR.
Figure S3: Among CD8+ T cells, MCARH109 responders had higher expression of HLA-DR than MCARH109 non responders
Figure S1: Gating strategy for identifying T cell populations is shown. Light scatter was using to remove debris and identify single cells. Live/dead staining was used to identify living cells and CD3 and CD45 coexpression was used to identify T cells.