CME
Physicians: Maximum of 1.50 AMA PRA Category 1 Credits™
Released: September 13, 2022
Expiration: September 12, 2023
Shaji Kumar, MD:
As treatments for MM continue to improve, the role of autologous stem cell transplantation (ASCT) as part of initial therapy continues to be examined in a variety of trials. Most recently, the IFM 2009 trial in France showed a PFS improvement with the addition of ASCT to the triplet induction regimen of bortezomib/lenalidomide/dexamethasone along with 2 cycles of consolidation and lenalidomide maintenance for up to 12 months in patients with newly diagnosed MM.68 No difference in OS was seen, suggesting that ASCT could potentially be safely delayed until first relapse.
Shaji Kumar, MD:
The ongoing phase III DETERMINATION trial68,69 is a companion study to the IFM 2009 study, except that patients received maintenance therapy until PD compared with the limited-duration maintenance in IFM 2009.
DETERMINATION is a large, randomized, open-label phase III trial conducted at 56 sites in the United States. In this study, 722 patients with newly diagnosed, transplant-eligible MM who were symptomatic received 1 cycle of bortezomib, lenalidomide, and dexamethasone (VRd) and were then randomized to receive 2 additional cycles of VRd induction therapy followed by stem cell collection, and then either high-dose melphalan plus ASCT or no transplantation. All patients continued VRd as consolidation (2 cycles following ASCT or 4 cycles without ASCT) and then received lenalidomide maintenance until PD. The primary endpoint for the study was PFS. Secondary endpoints included the DoR, time to progression, OS, quality of life, and safety.
Shaji Kumar, MD:
Overall, the patient population was fairly balanced between arms, with a median age of 55-57 years. Approximately one half of the patients had International Staging System (ISS) stage I disease, which was different from IFM 2009, where only one third had stage I disease.71 Of note, nearly 20% of patients in DETERMINATION had high-risk genetics, which included t(4;14), t(14;16), and del(17p).
Shaji Kumar, MD:
The primary endpoint of PFS was met in this trial. The addition of ASCT to upfront VRd was associated with a significant improvement in median PFS from 46.2 months with VRd alone to 67.5 months with ASCT (HR: 1.53; 95% CI: 1.23-1.91; P <.001).
The median PFS reported in the DETERMINATION trial for those who received ASCT was longer than in IFM 2009 (median PFS of 35 months without ASCT vs 47.2 months with ASCT).68 This may reflect the use of continuous maintenance therapy used in the DETERMINATION trial compared with limited-duration maintenance used in the IMF 2009 trial, but with different patient populations it is difficult to say for sure. It is also possible that the significant number of patients who went off study for alternate therapies (as indicated by the shorter EFS), may have artificially prolonged the observed PFS.
Shaji Kumar, MD:
With regard to cytogenetic risk, it is clear that ASCT benefited patients both with standard-risk and high-risk disease. That said, the improvement was particularly striking in patients with high-risk cytogenetics, where VRd alone was associated with a median PFS of 17.1 months compared with 55.5 months for ASCT (HR: 1.99; 95% CI: 1.21-3.26).
In the group of patients with standard-risk cytogenetics, the median PFS improved from 53.2 months with VRd alone to 82.3 months with the addition of ASCT (HR: 1.38; 95% CI: 1.07-1.79). These data highlight the significantly improved outcomes with our current standard therapies, including triplet induction therapy with ASCT followed by consolidation and lenalidomide maintenance until PD.
Shaji Kumar, MD:
The authors also conducted a subgroup analysis for PFS to determine which patients benefited most from the addition of ASCT. Although the numbers were fairly low, it was interesting to note that Black patients who were enrolled on this trial (n = 132) did not seem to benefit as much as White patients (n = 540; HR: 1.07 vs 1.67, respectively).
In addition, patients with ISS stage III MM (n = 96) appeared to derive less of a benefit (HR: 1.14) from ASCT than those with ISS stage I disease (n = 362) (HR: 1.83), again with the caveat of a fairly small number of patients. As mentioned, patients with high-risk cytogenetics (n = 134) had a particularly strong PFS benefit with the addition of ASCT, with an HR of 1.44 with del(17p) and an HR of 2.72 with t(4;14).
Shaji Kumar, MD:
Given the importance of depth of response and its potential relationship to outcomes, the authors also looked at the impact of MRD negativity at the start of maintenance therapy (ie, after ASCT and consolidation). Patients who were MRD negative at the start of maintenance therapy did much better compared with the patients who were MRD positive, regardless of whether they had received ASCT.
The 5-year PFS rate in patients with MRD negativity was 59.2% for VRd and 53.5% with VRd plus ASCT (HR: 0.91). This fairly similar PFS benefit suggests that the treatment that led to the MRD negativity was not as important for long-term PFS as just the ability to achieve MRD negativity in general.
By contrast, in patients who were MRD positive at the end of consolidation, ASCT appeared to facilitate better, more durable PFS outcomes. The median PFS in this group was 33.4 months with VRd alone vs 50.6 months with the addition of ASCT (HR: 1.67).
Shaji Kumar, MD:
In both arms, nearly one half of patients achieved a CR or better (42.0% with VRd alone vs 46.8% with VRd plus ASCT), and almost all patients achieved at least a partial response (95.0% with VRd alone vs 97.5% with VRd plus ASCT).
The 5-year duration of CR or better was marginally higher in the transplant arm, but this was not statistically significantly different (60.6 months vs 52.9 months with VRd alone; P = .7). These results, again, suggest more durability with deeper responses, regardless of ASCT.
However, there was an improvement in the median DoR with ASCT for patients who achieved a partial response or better (38.9 months without ASCT vs 56.4 months with ASCT; P = .003), similar to the PFS outcomes by MRD status.
Shaji Kumar, MD:
The OS was similar between both groups, neither of which reached the median OS rate at this time point. The 5-year OS rate was 80.7% for VRd plus ASCT compared with 72.9% for VRd alone (HR: 1.10; P >.99). Additional follow-up is likely needed to see any differences, if any, in OS with or without ASCT.
Shaji Kumar, MD:
No new safety signals were identified for these treatment strategies compared with previous trials. Among the patients who continued on to lenalidomide maintenance, the median duration of maintenance treatment was slightly longer for patients who received ASCT at 41.5 months compared with 36.4 months for patients who did not receive ASCT.
As expected, significantly higher rates of hematological side effects were seen with ASCT (89.9%) compared with VRd alone (60.5%), including a higher rate of grade 3 or worse treatment-related AEs (P <.001). During maintenance, 26.1% of patients in the VRd arm had grade 3 or worse hematologic events vs 41.9% with the addition of ASCT.
Shaji Kumar, MD:
One of the interesting findings in this study was the incidence of second primary malignancies (SPMs), with slightly more than 10% in each arm. At 5 years, rates of invasive and hematologic SPMs were numerically slightly higher for patients who received ASCT (3.5% vs 1.6% with VRd alone).
Of interest, there were significantly more SPMs of AML and myelodysplastic syndromes observed after ASCT compared with patients who did not receive ASCT: 10 cases vs none (P = .002).
Shaji Kumar, MD:
It is important to place these results in the context of the treatments given as part of the original randomization, as well as what patients received at the time of relapse. Approximately 15% of patients who were assigned to the transplant group did not end up getting an ASCT, which is quite high compared with the IFM 2009 trial in which only 8% of randomized patients did not receive ASCT.71
At the time of relapse, 79.6% in the VRd-alone arm went on to receive subsequent treatment vs 69.6% in the VRd plus ASCT arm. Only 28% of the patients in the VRd-alone arm went on to receive an ASCT after discontinuing trial treatment, as was intended with the delayed transplant approach. With continued follow-up, it is likely that more of these patients will eventually receive an ASCT given the significant heterogeneity of the practice in the United States compared with Europe.
The study also looked at quality-of-life metrics, which demonstrated some decrease in quality of life during the time the patients were going through ASCT; however, the quality of life returned to baseline once the patients recovered from this procedure.
Shaji Kumar, MD:
Results from the DETERMINATION trial confirm the PFS advantage seen with the use of ASCT as a part of initial MM therapy compared with delayed or no ASCT, similar to what was reported in the phase III IFM 2009 trial. In the DETERMINATION trial, patients with newly diagnosed MM who received ASCT after VRd induction and then completed VRd consolidation and continuous lenalidomide maintenance achieved a prolonged median PFS of 67.5 months vs 46.2 months with VRd therapy and continuous lenalidomide maintenance alone. However, even at 5 years, there was no difference in the OS between arms, with a 5-year OS rate of 80% with ASCT vs 73% without ASCT.
One caveat in comparing these results to IFM 2009 is the higher proportion of patients who were randomized to ASCT but did not receive ASCT during the DETERMINATION trial, as well as a lower proportion of patients randomized to no ASCT who then received an ASCT at the time of relapse. Nevertheless, these results confirm a beneficial role for ASCT as part of upfront therapy.
When considering MRD negativity, there was a higher rate of MRD-negative responses at the start of maintenance with the addition of ASCT to VRd: 54.4% vs 39.8%; however, the PFS rate was similar with or without ASCT for patients who did achieve MRD negativity (53.5% with VRd plus ASCT vs 59.2% with VRd alone). These data suggest that some patients may be able to delay or potentially completely avoid ASCT if they do achieve MRD negativity after induction therapy, but there is still work to be done to determine which patients are most likely to benefit from ASCT, especially as more therapies are becoming available for the treatment of MM.
Shaji Kumar, MD:
Currently, lenalidomide maintenance is the standard of care for newly diagnosed MM following ASCT, based on several randomized trials that demonstrated improvement in both PFS and OS with lenalidomide maintenance vs placebo or observation.72 However, those studies also suggested that lenalidomide maintenance is not as efficacious in patients with high-risk MM.
Subsequent studies evaluating combinations of a PI and an IMiD as maintenance therapy have also demonstrated improved outcomes among patients with MM, particularly for patients with high-risk disease. In particular, carfilzomib plus lenalidomide and dexamethasone (KRd) was been shown to improve the depth of response.73 The FORTE trial also assessed extended maintenance with carfilzomib and lenalidomide, and reported a benefit to patients whether or not they received an ASCT.74 As a result of these and other studies, the current practice is to use a PI and an IMiD, typically lenalidomide combined with either bortezomib or carfilzomib, for maintenance therapy in this high-risk patient population.75
Shaji Kumar, MD:
ATLAS is an ongoing, randomized, open-label, phase III study of post-ASCT maintenance therapy in patients with newly diagnosed MM.76 Interim results were presented at ASCO 2022 by Dytfeld and colleagues.
In this study, 180 patients who received induction treatment for no more than 12 months plus a single ASCT were randomized to either standard lenalidomide maintenance or up to 36 cycles of KRd maintenance followed by lenalidomide alone until progression. For patients with standard-risk disease who were randomized to the KRd arm and achieved MRD negativity after 8 cycles of KRd, the therapy was switched to lenalidomide alone until PD. The primary endpoint was PFS from randomization, and the secondary endpoints included MRD negativity at cycles 6 and 12, ORR, very good partial response (VGPR), CR (and stringent CR), and safety.
Conceptually, this study addresses important questions, including whether KRd maintenance can improve PFS over standard lenalidomide maintenance and then if patients with standard-risk disease who achieve MRD negativity can switch to a less-intense maintenance therapy.
Shaji Kumar, MD:
In this study, baseline characteristics were fairly comparable between arms, including approximately 20% of patients with high-risk cytogenetics in both groups. Approximately 65% of patients in both arms received bortezomib, thalidomide, and dexamethasone induction and 15% to 20% received bortezomib, cyclophosphamide, and dexamethasone as induction. Approximately 20% of patients received a different induction regimen. Of note, approximately 90% of patients had already achieved a VGPR or better at study entry.
Shaji Kumar, MD:
In ATLAS, the use of KRd as both consolidation and maintenance therapy was associated with a higher rate of MRD negativity than with lenalidomide maintenance alone (44% vs 27%, respectively). This also translated into a superior median PFS with KRd at 59.0 months compared with 41.1 months with lenalidomide maintenance (HR: 0.56; 95% CI: 0.34-0.93; P = .026). At this interim analysis with a median follow-up of 33.8 months, the median OS was not reached with KRd vs 61.8 months with lenalidomide maintenance.
Shaji Kumar, MD:
Nearly all the patient subgroups analyzed benefited from the use of the KRd combination for consolidation/maintenance vs single-agent lenalidomide maintenance. The benefit in the high-risk patients was lower than anticipated based on previous results (HR: 0.74 vs 0.44 for standard-risk cytogenetics).
Shaji Kumar, MD:
One of the most interesting aspects of this trial is the use of MRD status and cytogenetic risk to guide maintenance therapy. In the group of patients with standard-risk cytogenetics (n = 139), 44% achieved MRD negativity by the end of cycle 6 with KRd vs 26% with lenalidomide (P = .05).
In total, 34 patients with standard risk who became MRD negative during KRd therapy switched to lenalidomide maintenance in accordance with the study design. In this patient subgroup, the median PFS was not reached for both those patients who received KRd and switched to lenalidomide and for those who received only lenalidomide maintenance, but the HR was 0.23 (95% CI: 0.06-0.86) and P = .01 in favor of those who received 6 cycles of KRd before switching to lenalidomide maintenance alone.
Shaji Kumar, MD:
The safety profile clearly showed more grade ≥3 infections (15% vs 6%) and more grade ≥3 cytopenias, especially lymphopenia (8% vs 2%) and thrombocytopenia (13% vs 7%), with KRd compared with lenalidomide alone. In addition, grade ≥3 elevated liver enzymes were seen in 5% vs 0% of patients, respectively. Other grade ≥3 AEs were similar between arms including SPMs.
Shaji Kumar, MD:
Results from ATLAS showed that extended maintenance with a triplet of a PI, an IMiD, and dexamethasone was associated with PFS improvements vs lenalidomide maintenance alone in this analysis. The median PFS was 59.0 months for extended treatment with KRd vs 41.1 months for lenalidomide maintenance (HR: 0.56; P = .026). The follow-up in this study is relatively immature, and additional long-term follow-up will be needed to get a sense of whether this will also improve the OS of patients.
Although some healthcare professionals are already using a combination of PI plus IMiD as a maintenance approach for select patients in clinical practice, it is important to note that the continuous use of dexamethasone in this study is not typically done in routine clinical practice. While MRD-directed, risk-adapted KRd maintenance may be a more effective alternative to lenalidomide maintenance, I think the relatively small number of patients studied in this trial and the lack of OS data, at this point, do not support implementing this approach into routine practice until we have more data.
Shaji Kumar, MD:
Triple-class–exposed patients—those who have previously received an IMiD, a PI, and an anti-CD38 monoclonal antibody—with R/R MM remain in need of a more effective treatment, despite newly approved agents.77-79 BCMA-targeted agents have changed the treatment landscape in this setting, with multiple agents already approved for patients including the antibody-drug conjugate belantamab mafodotin and the CAR T-cell therapies idecabtagene vicleucel and ciltacabtagene autoleucel. Teclistamab is an off-the-shelf bispecific antibody that targets both CD3 on T-cells and BCMA on plasma cells, promoting T-cell–mediated killing of BCMA-positive MM cells. MajesTEC-1 is a first-in-human, open-label, dose-escalation/expansion phase I/II study of teclistamab in patients with triple-class–exposed, R/R MM after at least 3 previous lines of therapy (N = 165).80 The primary endpoint is ORR, with secondary endpoints including CR, VGPR, MRD, PFS, OS, and safety.
Initial results identified 1.5 mg/kg SC once weekly (preceded by step-up doses) as the recommended phase II dose for teclistamab.81 At ASCO 2022, Nooka and colleagues reported updated data from MajesTEC-1.82
Shaji Kumar, MD:
Patients in this study were fairly heavily pretreated with a median of 5 previous lines of therapy and a median of 6 years from diagnosis. The majority of patients had a previous ASCT, and 78% were triple-class refractory, with the majority being refractory to their last line of therapy. High-risk characteristics—del(17p), t(4:14), and/or t(14;16)—were present in 26% of patients. Extramedullary plasmacytomas were seen in 17% of patients at baseline. Most patients were ISS stage I/II (~88%).
Shaji Kumar, MD:
At a median follow-up of 14.1 months, the ORR was 63% with teclistamab, which is consistent with previous reports. The rate of VGPR or better was 59%, and 39% of patients achieved at least a CR, suggesting deep responses with the use of this CD3/BCMA bispecific antibody. Of note, the median relative dose intensity was almost 94%.
In the overall population, 27% of patients achieved MRD negativity and of those with at least a CR, 46.2% were MRD negative. In the MRD-evaluable subgroup (n = 54), 81.5% were MRD negative.
Responses occurred fairly quickly, with a median time to first response of 1.2 months and a median time to best response of 3.8 months. The median DoR at the time of presentation was 18.4 months, which is quite impressive for this group of heavily pretreated patients with MM.
Shaji Kumar, MD:
Subgroup analyses showed that the majority of patients benefited from the therapy irrespective of age, performance status, renal function, or underlying cytogenetic profile. One caveat is that patients with extramedullary plasmacytomas or ISS stage III disease appeared to have derived less benefit, although the number of patients in these subgroups was small.
Shaji Kumar, MD:
The median PFS in this report was 11.3 months, and the median OS was 18.3 months. As mentioned, these are interim data and not yet mature.
Shaji Kumar, MD:
Although no new safety signals were observed in this follow-up analysis, a significant proportion of patients have developed cytopenias, particularly neutropenia (70.9%; grade 3/4 in 64.2%). CRS was also seen in 72% of patients; however, all were grade 1/2 except for 1 patient.
In addition, 76% of patients experienced an infection of any grade (with 45% reported as grade 3/4). As anticipated based on the BCMA targeting of this agent, hypogammaglobulinemia was fairly common (74.5% of patients). Overall, 19 deaths were attributed to AEs, of which 12 were due to COVID-19 and only 5 were considered due to teclistamab-related AEs.
Although no new safety signals have been identified, the high rate of infection must be carefully monitored. It is unclear at this time whether this is related to the patients having such late-stage disease or whether it is due to immunosuppression from the therapy itself.
Shaji Kumar, MD:
As mentioned, grade 1/2 CRS was seen in 72% of patients. CRS was easily manageable, with a median time of onset of 2 days and a median duration of 2 days. In total, 33% of patients had at least 2 CRS events.
Supportive care for CRS was provided in 67% of cases, with 36% receiving tocilizumab, 12.7% receiving low-flow oxygen, and 8.5% receiving steroids. All CRS events resolved without the need for treatment discontinuation or dose reduction.
Shaji Kumar, MD:
In total, 24 patients (14.5%) developed neurotoxicity, which was almost all grade 1/2, and mostly consisted of headaches (8.5%) with dysgeusia, lethargy, and tremor in 2 patients (1.2%) each. ICANS was seen in 5 patients, with 9 events total and 7 events occurring with CRS.
All of these neurotoxic events were easily managed with supportive care measures. The median duration of neurological toxicity was 7 days. No patients needed to reduce the dose or discontinue treatment due to neurotoxicity.
Shaji Kumar, MD:
At a longer median follow-up of 14 months, results from the phase I/II MajesTEC-1 trial clearly demonstrate deep, durable responses with teclistamab in patients with highly refractory MM. The ORR was high at 63%, with 39.4% achieving at least a CR. The median DoR was 18.4 months and the median PFS was 11.3 months. Patients with heavily pretreated MM usually have poor outcomes, but the results in this trial showed improved outcomes, which is very encouraging.
There are AEs reported here that need to be carefully monitored, particularly the potential for infection. Other AEs like cytopenias and CRS seem to be manageable and mostly transient in nature.
Based on these data, the European Commission has recommended conditional marketing authorization (CMA) for teclistamab to treat patients with R/R MM after ≥3 previous therapies, including an IMiD, a PI, and an anti-CD38 antibody, and have demonstrated PD on the last therapy.
With this new approval, we have yet another effective BCMA-targeted agent available for patients with R/R MM. In addition, ongoing studies are evaluating teclistamab combinations in earlier-line MM settings and in patients previously exposed to BCMA-targeted agents.
Shaji Kumar, MD:
In addition to the approved agents that target BCMA, additional research with novel agents is ongoing. As mentioned, BCMA is expressed on malignant myeloma cells (and other B-cells) and CD19 is expressed on malignant myeloma cells and progenitor cells.83.84 Targeting BCMA and CD19 with CAR T-cells is an active area of investigation in MM treatment,85,86 including data from the GC012F dual-targeted autologous therapy. This CAR T-cell therapy was designed using a new transduction platform that may eliminate the need for bridging therapy due to rapid manufacturing in 22-36 hours and was assessed in this first-in-human study, with updated results presented at ASCO 2022.87
In this phase I study, 28 patients with R/R MM were enrolled. All patients had received ≥3 previous lines of therapy and/or were refractory to both PIs and IMiDs, or were primary refractory. Following apheresis and GC012F CAR T-cell manufacturing, patients underwent lymphodepletion with cyclophosphamide and fludarabine on Days -5, -4, and -3 before CAR T-cell infusion. Patients received GC012F at 1 of 3 dose levels: 1, 2, or 3 x 105 cells/kg. The primary endpoint was safety with secondary endpoints including responses, MRD, and pharmacokinetics/pharmacodynamics.
Shaji Kumar, MD:
Patients enrolled in this study had a median age of 58 years, a median time from diagnosis of 4 years, and had received a median of 5 previous lines of therapy. Almost one third had at least 1 extramedullary plasmacytoma. Although most of the patients were refractory to both PI and IMiD, only approximately one third of the patients were refractory to a CD38 antibody. More than 60% of patients were penta-class exposed (including ≥1 PI, ≥1 IMiD, and ≥3 other antimyeloma drugs of any other class) and 86% were refractory to their last therapy.
Shaji Kumar, MD:
As anticipated, cytopenias were the most common hematologic treatment-emergent AE. Neutropenia, all grade ≥3, was reported in 23 of the 28 patients (82%). Likewise, grade 3/4 lymphopenia (64%), leukopenia (79%), thrombocytopenia (57%), and anemia (36%) were commonly reported.
In terms of nonhematologic side effects, patients experienced increased lactate dehydrogenase (61%), hypoalbuminemia (46%), increased aspartate aminotransferase (43%), as well as hypokalemia (64%), hypophosphatemia (32%), and hypocalcemia (25%). However, other than the increased aspartate aminotransferase, these were rarely of grade 3/4 severity.
CRS was seen in a majority of the patients (89%), but it was mostly grade 1/2 with only 2 cases of grade 3 and no grade 4 or 5 events. The median time to onset of CRS was 6 days, with a median duration of 3 days. CRS was well managed with tocilizumab and other supportive care measures. No ICANS of any grade was reported.
Shaji Kumar, MD:
With the caveat of a small number of patients, the ORR was 89%, including 75% of patients who achieved a CR or stringent CR. Of the 27 patients who were evaluated for MRD, all were MRD negative at the time of the assessment. The responses observed in this trial seem to be fairly durable, and the median DoR has not yet been reached.
Pharmacokinetics/pharmacodynamics studies in this trial suggested favorable GC012F CAR T-cell expansion in all patients, with long persistence across all dose levels. The median time to maximum expansion (Tmax) was 10 days (range: 8-14 days).
Shaji Kumar, MD:
These are encouraging results from a first-in-human study of the BCMA/CD19 dual-targeted CAR T-cell therapy GC012F. The results showed that patients with R/R MM who received ≥3 previous lines of therapy had a high ORR (89.3%), with responses occurring rapidly and appearing to be durable (more than 2 years in some patients). As with other CAR T-cell therapies, CRS was reported in the majority of patients, but it was predominantly low grade with no ICANS events. All evaluable patients achieved MRD negativity.
It’s difficult to compare GC012F with the other BCMA-targeted CAR T-cell therapies currently approved for R/R MM (idecabtagene vicleucel and ciltacabtagene autoleucel). This is in part due to the small number of patients in this study, but also because many had not previously received a CD38 monoclonal antibody, suggesting that these patients may not have been as heavily pretreated as in the KarMMa (idecabtagene vicleucel) and CARTITUDE (ciltacabtagene autoleucel) phase II trials.87 Nevertheless, I think the concept of dual-targeted CAR T-cell therapy needs to be explored further.
Shaji Kumar, MD:
In addition to the new BCMA-targeted agents that are currently in development, additional studies are exploring other new targets for MM. One example is an autologous CAR T-cell therapy, OriCAR-017, which targets GPRC5D. GPRC5D is a transmembrane receptor protein predominantly expressed on plasma cells, including MM cells.88 Early data from a phase I study of the GPRC5D-targeted CAR T-cell therapy OriCAR-017 were presented at ASCO 2022 by Huang and colleagues.89
This dose-escalation and dose-expansion study enrolled 10 patients with heavily pretreated MM who were refractory to ≥3 lines of therapy and who had GPRC5D expression on more than 20% of MM cells. The primary endpoint was safety/tolerability, with efficacy as a secondary endpoint.
Patients received escalating doses of OriCAR-017 starting at 1 x 106 cells/kg, then 3 x 106 cells/kg, followed by 6 x 106 cells/kg. One half of those patients had previously received a BCMA-targeted CAR T-cell agent, which is one of the important aspects of this presentation.
These initial safety data for all dose levels are reassuring: no dose-limiting toxicities, no ICANS, no deaths due to AEs, and although CRS was seen in all 10 patients, it was grade 1 in 9 and grade 2 in only 1 patient, with no grade 3/4 CRS.
In terms of efficacy, all patients responded to therapy (ie, 100% ORR), and 6 achieved a stringent CR. At a median follow-up of 175 days, all patients remained progression free without additional therapy needed. Responses are continuing to improve and are independent of previous treatment with BCMA-targeted CAR T-cell therapy, which I think is quite relevant as patients start relapsing from the currently available agents. Finally, all 10 patients became MRD negative by Day 28, and 5 remained MRD negative by Month 6.
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