CME
Physicians: Maximum of 1.50 AMA PRA Category 1 Credits™
Released: March 21, 2023
Expiration: March 20, 2024
Shaji K. Kumar, MD:
Patients with MM who progress early after first-line treatment and ASCT, especially if they experience a relapse within 12 months of ASCT, have significantly shorter OS compared with those who have a prolonged response to first-line therapy.32-35 BCMA-directed CAR T-cell therapy with idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleucel has continued to demonstrate promising efficacy for patients with R/R MM and are FDA approved for patients with R/R MM after ≥4 prior lines of therapy, including a PI, an IMiD, and a CD38 monoclonal antibody.
The phase II KarMMa trial assessed ide-cel in heavily pretreated patients with R/R MM and was the basis for the FDA approval.36,37 Patients with R/R MM who had received ≥3 previous lines of treatment, including a PI, an IMiD, and a CD38-targeted antibody were treated with ide-cel. The ORR was 73%, with 33% achieving a CR or better, the median PFS was 8.8 months, and the median OS was 24.8 months.
The KarMMa-2 trial is assessing ide-cel in various cohorts of patients with R/R MM. Cohort 2a included patients with functionally high-risk MM with an early relapse within 18 months after first-line induction, ASCT, and lenalidomide maintenance.
Shaji K. Kumar, MD:
KarMMa-2 is a multicenter, open-label, multicohort single-arm phase II trial to assess ide-cel as therapy for patients with R/R MM.38 Enrolled patients underwent leukapheresis to collect their T-cells, which were then modified to express a CAR targeting the BCMA to recognize and attack MM cells. After leukapheresis, patients received lymphodepletion with fludarabine and cyclophosphamide followed by CAR T-cell infusion with ide-cel.
As mentioned, cohort 2a included patients with functionally high-risk MM with an early relapse within 18 months after first-line induction, ASCT, and lenalidomide maintenance. In total, 37 patients were enrolled in this cohort. The primary endpoint of this trial was CR rate. In addition, numerous different secondary endpoints were explored, including ORR, TTP, duration of response (DoR), PFS, OS, and safety.
Shaji K. Kumar, MD:
The median age of the patients in this cohort was 57 years, and the median time from initial diagnosis to screening was 1.6 years. Approximately one third of patients had high-risk genetics, which is expected, given that high-risk genetic abnormalities are one of the underlying drivers of early relapse in MM. Most of these patients received lenalidomide maintenance after ASCT and are considered refractory to an IMiD and a PI, but none was refractory to CD38-targeted therapy.
Shaji K. Kumar, MD:
The ORR with ide-cel in this patient population was 83.8%, which included 46% of patients who achieved CR or better. The median time to response was fast, at 1.0 months, and was similar to the time to response in the KarMMa trial, with patients who had more heavily pretreated R/R MM. The median DoR in this trial was 15.7 months, which is also similar to the patients with more advanced MM.
The median PFS was 11.4 months, but it is worth noting that the PFS is a secondary endpoint and not the primary endpoint of the trial. OS was also a secondary endpoint, but the 2-year OS rate of 84.7% was also an encouraging finding.
Shaji K. Kumar, MD:
The rate of MRD negativity was 68% at 6 months and 53% at 12 months in all evaluable patients. However, the total number of patients was different at each time period because of relatively short follow-up, so it is difficult to get a good sense of the percentage of patients who achieved sustained MRD negativity. With approximately one half of patients progressing within a year of treatment. These data suggest that the durability of response was not as good as hoped with the use of ide-cel in earlier lines of therapy.
A robust CAR T cell expansion was observed in this patient population with Cmax of 286,462 copies/µg. Higher levels of expansion were observed in patients who achieved a CR or better vs those who achieved a less robust response (Cmax: 404,171 vs 217,505 copies/µg). Ide-cel showed durable persistence in the blood, with a median duration of detection of approximately 6 months.
Shaji K. Kumar, MD:
The AE profile in this cohort of patients treated with ide-cel after relapse on first-line therapy was similar to what has been already reported for patients with R/R MM. Neutropenia was reported in 94.6% of patients, and 59.5% of patients had infections. Two patients died because of AEs, both from infection-related AEs.
Cytokine release syndrome (CRS occurred in 83.8% of patients, but most CRS events were grade 1-2.
Shaji K. Kumar, MD:
The rate of CRS and neurotoxicity observed in the Cohort 2a patient population was similar to that seen in the advanced patient population in the overall KarMMa-2 trial. CRS occurred in 83.8% of patients, but the majority of CRS events were grade 1-2. Approximately 22% of patients experienced any-grade neurotoxicity, but no grade 3 or 4 neurotoxicity was observed. This may be attributed to the relatively lower amount of tumor burden in these earlier-stage patients, as compared with patients with more advanced R/R MM who typically have more extensive disease involvement.
However, the occurrence of any-grade CRS or neurotoxicity is still a concern and warrants close monitoring and management, as these AEs can be serious and potentially life threatening.
Shaji K. Kumar, MD:
The investigators concluded that ide-cel is an effective treatment for this high-risk patient population who relapsed within 18 months of starting their first line therapy. The response rates in KarMMa-2 were similar to data from the KarMMa trial in patients with R/R MM who had received ≥3 previous lines of treatment (84% vs 73%, respectively).37,38 However, the median PFS in KarMMa-2 was 11.4 months compared with 8.6 months in KarMMa, and the DoR was also longer in KarMMa-2 (15.7 months vs 10.9 months, respectively).
Based on these results, the KarMMa-2 study provides proof of principle that CAR T-cell therapy can be effective in the earlier lines of therapy for patients with high-risk MM. However, the responses seen in this study were not significantly more durable than those observed in the relapsed setting, which is a disappointing result. This lack of significant improvement in response duration may reflect the underlying biology of the disease in this patient population. It also highlights the need for further research and development to improve the durability of response to CAR T-cell therapy in MM and underscores that there is still much work to be done to optimize this treatment approach for functionally high-risk patients.
Sagar Lonial, MD:
Although the long duration of response observed in this challenging patient population is encouraging, it is also important to consider the limitations of the study and the potential challenges in bringing CAR T-cell therapy earlier in the disease course. T-cell health may not necessarily be better in earlier lines of therapy compared with in later lines of therapy, particularly in patients who have relapsed and have active disease. This could affect the durability of response to CAR T-cell therapy, even when administered earlier in the disease course.
More data are needed to fully understand the potential benefits of CAR T-cell therapy in earlier settings for MM. The upcoming KarMMa-3 study will be an important step in this direction. An additional question to be answered is whether consolidation can help prolong the duration of response for patients who achieve a deep response to CAR T-cell therapy. There is potential to include additional maintenance therapy for some time after CAR T-cell infusion before considering the complete discontinuation of therapy.
Shaji K. Kumar, MD:
Maintenance therapy and clonal suppression will likely play an important role in sustaining the response to CAR T-cell therapy in patients with high-risk MM, whether it is functional high-risk or cytogenetic high-risk. This could involve a combination of approaches, including maintenance therapy with immunomodulatory drugs or other agents, as well as strategies to prevent clonal evolution and the development of treatment resistance. CAR T-cell therapy clearly is an effective way of controlling the tumor initially, but current data suggest that additional therapy is needed to maintain that control over long periods.
Sagar Lonial, MD:
Now that several BCMA-targeted therapies (TT) are approved by the FDA for the treatment of MM, a frequent question is whether sequencing different BCMA-TT is effective. There are limited data on the optimal sequencing of these agents.
The next abstract looks at a real world retrospective study of ide-cel in patients with R/R MM after prior BCMA-TT.39 The study utilized patient-level data from 11 US academic centers and included patients who had undergone apheresis, were treated with ide-cel, and were evaluable for response if Day 30 assessment had occurred. Responses were graded per IMWG response criteria, and safety and survival analysis included patients who died from infection or other ide-cel toxicity before response assessment.
Sagar Lonial, MD:
This retrospective study included 2 groups of patients, one with prior BCMA exposure (n = 50) and one without prior BCMA exposure (n = 153) and compared them with data from the phase II KarMMa trial.36 The baseline characteristics of patients were fairly similar among these 3 groups of patients, with slightly more patients in the KarMMa trial having ECOG performance status of 0/1 and high tumor burden but slightly fewer patients having extramedullary disease.
Sagar Lonial, MD:
In the group of patients who had prior exposure to BCMA-TT, the majority received an antibody–drug conjugate (ADC) (76%; n = 38), 7 received a prior bispecific antibody (14%), and 5 received a CAR T cell therapy (10%). The time from prior BCMA-targeted therapy to current CAR T cell infusion varied significantly, with a median of 202.5 days and a range of 16-1118 days.
The ORR to prior BCMA TT was 21%, with an ORR of 17% for prior ADC, no response for prior bispecific antibodies, and 80% for prior CAR T cell therapy. The authors noted that 5 of 7 patients (71%) who had prior bispecific antibody therapy received a suboptimal dose in clinical trials before the selection of recommended phase II dose (RP2D) for expansion and the patient with no response to previous CAR T-cell therapy received therapy during a phase I trial that did not warrant phase II study.
Sagar Lonial, MD:
In this retrospective study, ORR to ide-cel after exposure to prior BCMA-TT was 74% vs 88% with no prior exposure to BCMA-TT (P = .021). In total, 29% patients achieved CR or better with ide-cel after exposure to prior BCMA- vs 48% with no prior exposure to BCMA-TT (P = .018).
The ORR stratified by type of prior BCMA-TT was 68% for prior ADC, 86% for prior bispecific antibody treatment, and 100% for a prior CAR T-cell therapy.
Sagar Lonial, MD:
In the group of patients who received prior BCMA-TT, the duration of previous BCMA-TT in those who responded to ide-cel was 23 days (range: 1-208 days) vs 63 days (range: 1-370 days) in those with no response (P = .025); however, the time from last BCMA-TT to ide-cel was longer in those who responded to ide-cel (209 days vs 128 days in those with no response; P = .052). Patients who received prior BCMA-TT >6 months before ide-cel infusion had a numerically higher ORR vs those who received prior BCMA-TT ≤6 months before ide-cel infusion (83% vs 60%, respectively; P = .076).
However, the small numbers of patients in these subgroup analyses make it difficult to draw any major conclusions from these data.
Sagar Lonial, MD:
The median PFS with ide-cel after prior BCMA-TT was 3.2 months compared with 9.0 months with no prior BCMA-TT (P = .0002). When assessing PFS by type of previous BCM-TT, the median PFS with a prior ADC was 3.19 months, 2.83 months with a prior bispecific antibody, and not reached with a prior CAR T-cell therapy. The median PFS with no prior BCMA-TT was 9.03 months (P = .0004).
Overall, prior exposure to a BCMA-targeted ADC or bispecific antibody did have a significant impact on PFS. In a multivariate efficacy analysis among all patients, prior BCMA-TT was associated with significantly inferior PFS (HR: 2.91; 95% CI: 1.68-5.04; P <.0001) and OS (HR: 2.94; 95% CI: 1.27-6.82; P = .012).
Sagar Lonial, MD:
No significant difference in safety was demonstrated with ide-cel after prior BCMA-TT vs with no prior BCMA-TT. Any-grade CRS and neurotoxicity were similar between these 2 groups (CRS: 80% vs 86% and neurotoxicity: 17% vs 22%, respectively). Hematologic AEs, including anemia, neutropenia, and thrombocytopenia, were similar as well.
Sagar Lonial, MD:
In this retrospective analysis of patient-level data after ide-cel infusion, it seems that prior BCMA-TT, particularly with an ADC or a bispecific antibody, resulted in a shorter median PFS compared with patients who did not receive prior BCMA-TT. This was an important dataset to help answer the question of sequencing multiple BCMA-targeted therapies for R/R MM, but the number of patients included was small, and additional data are needed to further validate these results.
It is possible that the response to CAR T-cell therapy may be influenced by the number of lines of therapy as well as the type of prior therapies used in addition to other factors such as disease burden and patient characteristics. However, it is also important to note that each patient is unique and may respond differently to different therapies, even within the same class of therapies.
Retreatment with a BCMA-directed therapy after progression on a prior CAR T-cell therapy may be a reasonable option, especially if the patient had a good response to the prior CAR T-cell therapy and the progression occurred ≥12 months after the initial treatment.
In patients who progressed on a prior BCMA-targeted bispecific antibody, it is important to confirm that they still express BCMA before considering treatment with a BCMA-targeted CAR T-cell therapy or consider other treatment options if BCMA expression is lost.
ADCs have a different mechanism of action compared with CAR T-cell therapy or bispecific antibodies and are less reliant on T-cell activation. Although the PFS data in this analysis were similar after prior ADCs vs other BCMA-targeted therapies, I might consider a BCMA-targeted CAR T-cell therapy after a prior BCMA-targeted ADC, knowing that there may be a need for additional therapies to maintain a response over time.
Shaji K. Kumar, MD:
Yes, I agree with your points about defining resistance based on the mechanism of action of the drug rather than the target, and the need to consider the durability of response in evaluating the effectiveness of CAR T-cell therapy. It is also important to keep in mind that the dose of CAR T-cell therapy used in earlier studies may have been suboptimal, and this could have affected the response rates seen in those studies. As CAR T-cell therapy against additional targets are developed, it is also important to keep in mind that somebody who is refractory to CAR T-cell therapy against one target may not respond to a CAR T-cell therapy against another target if given sequentially. We need additional data on each of these types of situations as more patients are treated with BCMA-TT and novel agents as they become available in clinical practice.
Sagar Lonial, MD:
In addition to the various BCMA-directed bispecific therapies that are in clinical trial, other novel targets also are under investigation for R/R MM. One target of interest is G protein–coupled receptor, class C, group 5, member D (GPRC5D), which is expressed on plasma cells including MM clones. The MonumenTAL‑1 study assessed talquetamab, a first-in-class bispecific IgG4 antibody that binds to GPRC5D and CD3 receptors, to treat patients with R/R MM that is refractory or intolerant to established anti-MM therapy.
Data published from the part 1 dose-finding subset of the MonumenTAL-1 trial reported ORR of 64% and 70% at 2 subcutaneous doses of talquetamab.40 In addition, CRS (77%-80%), skin-related events (67%-70%), and dysgeusia (57%-63%) were reported after talquetamab treatment but were primarily low grade. Data from patients treated at the recommended phase II dose (RP2D) were presented at ASH 2022 and included patients with prior CAR T-cell or bispecific antibody treatment.
Sagar Lonial, MD:
The multicenter, open-label phase I/II MonumenTAL-1 trial assessed talquetamab in patients with R/R MM. The phase I portion of the trial included patients who experienced disease progression on established therapies or who could not receive established therapies because of unacceptable AEs, and the phase II portion included patients who had received ≥3 prior lines of therapy that included a PI, an IMiD, and an anti-CD38 antibody. This analysis focused on patients in 3 cohorts based on the RP2D: those who received talquetamab 0.4 mg/kg subcutaneously once weekly, those who received talquetamab 0.8 mg/kg subcutaneously once every 2 weeks, and those who received prior T-cell redirection therapy and then talquetamab at either 0.4 mg/kg once weekly or 0.8 mg/kg once every 2 weeks.41 These RP2Ds included 2-3 step-up doses for all cohorts. The primary endpoint for the phase II portion was ORR.
Sagar Lonial, MD:
The patient characteristics were similar between the groups receiving 0.4 mg/kg subcutaneously once weekly and those receiving 0.8 mg/kg subcutaneously once every 2 weeks.
The median prior lines of therapy were 5 in both cohorts, and 100% were triple class exposed, whereas 70% to 73% were penta-drug exposed, and approximately 15% had prior exposure to belantamab mafodotin (a BCMA-targeted ADC). The refractory status showed a fairly resistant patient population in general.
Sagar Lonial, MD:
The ORR was similar whether talquetamab was given weekly vs every 2 weeks (74.1% vs 73.1%). The ORR was similar among all subgroups examined, including refractory status, except for patients with baseline plasmacytoma. ORR was also similar for both dosing schedules regardless of refractoriness, with an ORR of 72.6% with weekly dosing or 71.0% with every other week dosing in patients who were triple-class refractory or 71.4% with weekly dosing and 70.6% with every other week dosing in patients who were penta-drug refractory.
Sagar Lonial, MD:
The median DoR among responders was good for talquetamab dosing regimens. The median DoR among all responders with once weekly dosing was 9.3 months vs 13.0 months with every other week dosing, although the median follow-up was a bit shorter in that arm (14.9 months with once weekly dosing vs 8.6 months with every other week dosing). The median DoR for patients who achieve CR or better was not estimable at this time, but responses were durable, with the majority of patients remaining in response.
Sagar Lonial, MD:
Patients experienced a range of hematologic AEs, including anemia, neutropenia, lymphopenia, and thrombocytopenia. Of interest, the GPRC5D-targeted bispecific antibody, talquetamab had lower rates of infectious complications (50%-57%) compared with what we have seen with BCMA-targeted bispecific antibodies.
BCMA-directed therapy has been associated with a higher risk of infections because BCMA is expressed not only on MM cells but also on some normal B-cells that play a role in the immune response. This can lead to a depletion of healthy B-cells in addition to the MM cells, making patients more vulnerable to infections. In contrast, GPRC5D is expressed mainly on MM cells and not on normal B-cells, suggesting that it may have a more targeted effect on MM clones and less impact on the immune system.
Sagar Lonial, MD:
The most common nonhematologic AEs with talquetamab were skin and nail-related changes, dysgeusia, rash, anorexia, weight loss, dry mouth, and dysphasia. These AEs are believed to be an on-target effect, meaning that they are related to the mechanism of action of talquetamab and its targeting of GPRC5D. We know that GPRC5D is expressed not only on MM cells but also in the skin, hair follicles, and nail bed as well as in the upper digestive tract, and this may explain some of these AEs.
The severity of these AEs can vary from patient to patient, and in some cases, they can be managed with topical therapy or talquetamab dose modifications. However, in other cases, they may require substantial dose holds or reductions. It is important for healthcare providers to monitor patients closely for these AEs and to provide appropriate supportive care as needed.
Sagar Lonial, MD:
The rate of CRS with talquetamab was similar to what has been shown with other bispecific antibodies, with 72% to 79% of patients experiencing CRS. Most cases of CRS occurred during step-up dosing or during the first full dose of talquetamab and were grade 1/2.
The median time to onset of CRS was 2 days, and the median duration was also 2 days. It is worth noting that in some cases, CRS may require hospitalization or even intensive care. However, with appropriate monitoring and management, most cases of CRS can be effectively managed with tocilizumab, steroids, and supportive care like oxygen supplementation.
Sagar Lonial, MD:
In addition to CRS, 10% to11% of patients receiving talquetamab experienced ICANS, with a 2- to 3-day median time to onset. The majority of ICANS events were grade 1/2 and mitigated with standard prevention and treatment.
It is important for healthcare professionals to closely monitor patients receiving talquetamab for signs and symptoms of ICANS, such as confusion, seizures, or speech disturbances. If ICANS is suspected, treatment may include supportive care, such as corticosteroids, tocilizumab, or antiseizure medications.
Sagar Lonial, MD:
There was no substantial difference in pharmacokinetics, immunogenicity, or pharmacodynamics with 0.4 mg/kg once weekly and 0.8 mg/kg once every 2 weeks talquetamab dosing. These data suggest some flexibility in determining the dosing schedule that will work best for individual patients and their overall frequency of visits to the clinic.
Sagar Lonial, MD:
The authors also included an analysis of talquetamab in patients who had received previous T-cell redirection therapy (n = 51) with either a CAR T-cell therapy (70.6%) or a bispecific antibody (35.3%). The ORR in patients with previous T-cell redirection therapy was 62.7%, with 23.5% achieving CR or better. These data suggest that patients who have progressed on a BCMA-targeted bispecific antibody or CAR T-cell therapy could respond to a bispecific antibody to a different target, like talquetamab, when considering optimal sequencing of therapy.
Sagar Lonial, MD:
The authors concluded that the novel agent talquetamab was highly active with an ORR of 73% to 74% and an ORR of over 60% in patients with prior T-cell redirection therapy. It is encouraging to see that talquetamab appears to be highly active. The median DoR was also impressive, with a duration of longer than 9 months and even longer in patients achieving CR or better.
It is also noteworthy that the rate of discontinuations because of AEs was low, suggesting that talquetamab may be well tolerated by patients. The most common AEs reported besides CRS were skin-related events, nail and upper gastrointestinal tract events, particularly dysgeusia, but also dysphasia and dry mouth.
Ongoing randomized phase III trials will be important in further evaluating the safety and efficacy of talquetamab and determining whether it can be approved by the FDA for use in patients with R/R MM.
Shaji K. Kumar, MD:
The data on talquetamab are interesting and add to the growing body of evidence on the use of bispecific antibodies in MM. The fact that talquetamab targets a different antigen than the currently FDA-approved bispecific antibody, teclistamab could provide another treatment option for patients with R/R MM who are refractory to existing therapies.
The question of sequencing is an important one and will require further investigation to determine the optimal treatment approach for patients. It is possible that a BCMA-targeted bispecific antibody could be followed directly by a bispecific antibody with a different target, but whether using other therapy modalities in the intervening stage before beginning a second bispecific antibody improves response is not yet known.
As you mentioned, the AEs associated with talquetamab can be bothersome, even if they are low grade, and it will be important to weigh the potential benefits of talquetamab against the impact on patients' quality of life.
Sagar Lonial, MD:
Yes, I agree. Understanding the optimal dose and schedule for novel agents like talquetamab is critical for maximizing their efficacy while minimizing potential toxicities. Although AEs like CRS, skin-related events, and dysgeusia are generally manageable with appropriate management strategies, they can still have a significant impact on the quality of life for some patients. As such, healthcare professionals will need to carefully monitor patients receiving these therapies and work with them to manage any AEs as effectively as possible.
Shaji K. Kumar, MD:
Another interesting novel class of agents being investigated in R/R MM are cereblon-modulating agents (CELMoDs). These agents, including iberdomide and mezigdomide, are similar to more traditional IMiDs in that they all modulate the immune system and promote the destruction of MM cells, but they differ in their mechanism of action and chemical structure. CELMoDs directly modify the activity of cereblon by binding to it and induce degradation of specific proteins, which leads to the suppression of the immune system. CELMoDs have also been designed to be more potent and specific in their activity to reduce off-target AEs.
Both iberdomide and mezigdomide have shown activity in patients with R/R MM, including those who are refractory to lenalidomide and pomalidomide.42,43
The CC-92480-MM-001 study is a phase I/II dose expansion trial evaluating mezigdomide plus dexamethasone in patients with R/R MM who have received ≥3 previous lines of therapy and are refractory to lenalidomide, pomalidomide, a PI, and an anti-CD38 monoclonal antibody. At ASH 2022, an analysis of the dose expansion cohort of the CC-92480-MM-001 study was presented.44 This heavily pretreated group of patients was treated with mezigdomide 1 mg on Days 1-21 of a 28-day cycle along with dexamethasone 40 mg weekly. The primary endpoint was ORR with secondary endpoints, including safety, time to response, DoR, and PFS.
Shaji K. Kumar, MD:
In total, 101 patients were enrolled on this study, and all patients were previously treated with an IMiD, a PI, and a CD38-targeted monoclonal antibody. Patients had a median of 6 prior lines of therapy, and all patients had triple-class refractory disease. In addition, 29.7% of the patients previously received a BCMA-TT, including an ADC (21.8%), a bispecific antibody (7.9), or a CAR T-cell therapy (3.0%).
This cohort of patients was comparable to what we have seen for the trials of bispecific antibody and CAR T-cell therapy.
Shaji K. Kumar, MD:
The ORR in the dose expansion cohort of patients receiving mezigdomide plus dexamethasone was 40.6% in all patients. In patients with prior BCMA-TT, the ORR was similar at 50.0%. In patients with plasmacytomas, including extramedullary soft tissue–only disease and soft tissue bone-related plasmacytomas, the ORR was a bit lower at 30.0%.
Shaji K. Kumar, MD:
The median PFS with mezigdomide plus dexamethasone was 4.4 months (95% CI: 3.0-5.5). However, this was a heavily pretreated patient population.
Shaji K. Kumar, MD:
The median DoR was 7.6 months (95% CI: 5.4-9.5) among the 40% to 50% of patients who responded to therapy. The median DoR was 9.2 months for patients who achieved VGPR or better, whereas the median DoR was 5.1 months for patients who achieved partial response.
Shaji K. Kumar, MD:
The median follow-up at this analysis was 7.46 months and 9.9% of patients remained on therapy. Most patients who discontinued the study treatment did so because of progressive disease (60.4%), whereas discontinuation because of AEs was fairly low (5.9%). There were 8 patient deaths on this study, with 5 patient deaths related to AEs, primarily infection related with 1 death related to COVID-19.
Shaji K. Kumar, MD:
Treatment emergent hematologic AEs were common with mezigdomide plus dexamethasone, particularly neutropenia (77.2% any grade) and thrombocytopenia (42.6% any grade). Grade 3/4 neutropenia occurred in 75.3% of patients, grade 3/4 anemia occurred in 35.7% of patients, grade 3/4 thrombocytopenia occurred in 27.8% of patients, and grade 3/4 febrile neutropenia occurred in 14.9% of patients.
Common treatment-emergent nonhematologic AEs included infections, fatigue, and some gastrointestinal toxicities. Overall, 65.3% of patients experienced infections, with 34.6% having grade 3/4 infections.
Based on these data, careful consideration should be given to combining mezigdomide with other MM therapies that may exacerbate these toxicities, particularly other agents that may also increase the risk of hematologic AEs.
Shaji K. Kumar, MD:
The investigators concluded that mezigdomide plus dexamethasone is an effective therapy in patients with late stage R/R MM after multiple prior lines of therapy. I tend to agree but think we will need to better understand the hematologic AEs associated with mezigdomide, particularly if we combine this CELMoD with other anti-MM drugs, particularly a CD38-targeted monoclonal antibody, which also has a higher risk of hematologic toxicity and infections.
Sagar Lonial, MD:
Based on these preliminary data, mezigdomide seems to have promising activity but I agree that the dosing is going to be important for minimizing toxicity, particularly if mezigdomide is combined with other agents. When considering the AE profile of pomalidomide or lenalidomide, it is similar. It seems that iberdomide may have fewer AEs than mezigdomide, particularly in the rate of neutropenia, but mezigdomide seemed to have significant activity in extramedullary disease.
Moving forward, determining the optimal timing and sequencing of treatment with CELMoDs and other immune therapies will be important to maximize their effectiveness and minimize AEs. For example, the idea of using CELMoDs to maintain T-cell health following treatment with bispecific antibodies or CAR T-cell therapy is an interesting idea and may allow us to prolong the antitumor immune response.
Overall, there is still much to learn about the optimal use of CELMoDs and other immune therapies in the treatment of MM. However, the potential benefits of these approaches are significant, and continued research and development in this area is likely to lead to further improvements in patient outcomes.
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