CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: September 06, 2022
Expiration: September 05, 2023
Jesús F. San-Miguel, MD, PhD:
As the treatments for multiple myeloma continue to improve, the utility of an autologous stem cell transplant (ASCT) as part of initial therapy continues to be examined. In 2020, the phase III IFM 2009 trial in France showed a PFS improvement with the addition of ASCT to induction therapy with bortezomib, lenalidomide, and dexamethasone (VRd) followed by VRd consolidation and lenalidomide maintenance in newly diagnosed myeloma.19 The lack of an OS difference suggests that ASCT can be delayed until first relapse.
The ongoing phase III DETERMINATION trial is a companion study conducted in the United States and has a very similar design to the IFM 2009 trial, with the exception that patients receive maintenance therapy until disease progression instead of the limited-duration maintenance.20 DETERMINATION enrolled 722 transplant-eligible patients with symptomatic, newly diagnosed myeloma after 1 cycle of VRd. They then received 2-3 cycles of VRd induction, randomized to ASCT with melphalan or no ASCT, and then both arms received consolidation with VRd and maintenance with lenalidomide.
The primary endpoint was PFS, with secondary endpoints including duration of response, time to progression, OS, quality of life, and safety.
Jesús F. San-Miguel, MD, PhD:
Overall, the patient population was fairly well balanced between arms, with a median age of 55-57 years and nearly 50% of patients having an Eastern Cooperative Oncology Group performance status of 0/1.20 Of note, one half of the patients had International Staging System (ISS) stage I disease, whereas only one third had ISS stage I disease in the IFM 2009 trial.21 Furthermore, nearly 20% of patients in DETERMINATION had high-risk genetics, which included t(4;14), t(14;16), and del(17p).
Jesús F. San-Miguel, MD, PhD:
In terms of the primary endpoint, the addition of ASCT to upfront therapy was associated with a significant PFS improvement of nearly 21 months compared with VRd alone.20 The median PFS was 67.5 months with the addition of ASCT vs 46.2 months with VRd alone (HR: 1.53; P <.001). The median PFS seen in the ASCT arm is longer than the median PFS of 50 months reported with transplantation in IFM 2009,21 which may reflect the use of continuous maintenance therapy vs limited-duration maintenance.
Jesús F. San-Miguel, MD, PhD:
Analysis of PFS by subgroups showed that, in terms of cytogenetic risk, the addition of ASCT benefited both standard-risk and high-risk patients.20 The improvement was particularly striking in those with high-risk genetics, including t(4;14) and del(17p). In this group, VRd alone was associated with a median PFS of 17 months vs 56 months with the addition of ASCT (HR: 1.99).
It was interesting to note that Black patients did not benefit as much as White patients. Furthermore, those with ISS stage III myeloma appeared to derive less benefit than those with ISS stage I, with the caveat that this is based on a fairly small number of patients.
Jesús F. San-Miguel, MD, PhD:
Nearly one half of the patients were able to achieve a CR with the addition of ASCT (46.8% vs 42.0% with VRd alone), but this was not a significant difference.20 The 5-year duration of CR also was marginally higher in the transplant arm at 60.6% vs 52.9% with VRd alone. This was not a statistically significant difference, but the numerical improvement does suggest good durability of the high-dose melphalan–based consolidation approach. Nearly all patients responded in both arms, with approximately 80% in both arms achieving a VGPR or better.
Jesús F. San-Miguel, MD, PhD:
Given the importance of depth of response and its potential relationship to outcomes, the investigators also evaluated the association between PFS and MRD negativity at the start of maintenance therapy (ie, after ASCT and consolidation).20 As shown here, patients who were MRD negative at the start of maintenance therapy had much better PFS than patients who were MRD positive. The addition of ASCT did not make a significant difference in this group (HR: 0.91), suggesting the treatment that led to the MRD negativity was not as relevant as the fact that these patients were able to achieve MRD negativity.
However, among patients who remained MRD positive at the start of maintenance, the median PFS was substantially longer with the addition of ASCT to VRd at 50.6 months vs 33.4 months (HR: 1.67). This, again, highlights the durable responses possible with ASCT.
Jesús F. San-Miguel, MD, PhD:
OS was nearly identical regardless of whether patients received ASCT.20 The 5-year OS rate was 81% with the addition of ASCT vs 73% with VRd alone (HR: 1.10).
Jesús F. San-Miguel, MD, PhD:
As expected, VRd plus ASCT was associated with significantly higher rates of hematologic toxicity than VRd alone, but no new safety signals were identified.20 For example, neutropenia was seen in 87% of patients with the addition of ASCT vs 43% with VRd only. Other hematologic parameters also were markedly elevated with the addition of ASCT vs VRd alone (thrombocytopenia: 83% vs 20%; anemia: 30% vs 18%).
All grade ≥3 treatment-related AEs (TRAEs), including hematologic grade ≥3 TRAEs, were significantly more frequent with VRd plus ASCT than with VRd alone (both P <.001). Rates of hematologic grade ≥3 TRAEs during maintenance were 26.1% with VRd alone vs 41.9% with VRd plus ASCT. The median duration of maintenance was slightly longer in the VRd plus ASCT arm at 42 months vs 36 months with VRd alone.
Jesús F. San-Miguel, MD, PhD:
One of the interesting findings in this study was the incidence of second primary malignancy. Overall, a second primary malignancy was seen in approximately 10% of patients in each arm.20 There were slightly more invasive and hematologic second primary malignancies in the VRd plus transplant group, but these were not significant differences. However, among patients with hematologic second primary malignancy, significantly more cases of AML/MDS were seen with VRd plus ASCT than with VRd alone (10 vs 0 cases; P = .002).
Jesús F. San-Miguel, MD, PhD:
These results need to be considered in the context of both treatments patients received as part of the original randomization and what they received at the time of relapse. Of note, approximately 15% of the patients assigned to receive ASCT did not transplant, which is quite high compared with the IFM 2009 trial, where only 8% of the randomized patients did not receive ASCT.20,21
When we look at subsequent treatment at the time of relapse, only 28% of the patients who received VRd alone proceeded to undergo transplant, as was intended with the delayed transplant approach. With continued follow-up, it is likely that more patients in this arm will undergo ASCT, given the pronounced heterogeneity of practice in the United States compared with Europe.
Similar rates of immunomodulatory drugs and proteasome inhibitors as subsequent therapy were seen in each arm (~55%), but subsequent monoclonal antibody use was higher in the ASCT arm (21.4% received daratumumab vs 11.3% with VRd alone).
DETERMINATION also showed a transient decrease in global health status during the time the patients were undergoing transplantation. Quality-of-life scores returned to baseline once the patients recovered from the transplant.
Jesús F. San-Miguel, MD, PhD:
In the DETERMINATION trial of patients newly diagnosed with multiple myeloma, the addition of ASCT to VRd triplet induction plus sustained lenalidomide maintenance yielded a significantly prolonged median PFS (67.5 vs 46.2 months with VRd alone) but similar OS (~80% at 5 years).20 At the start of maintenance, 55% of patients in the ASCT arm had achieved MRD negativity vs 40% of patients receiving VRd alone. In the ASCT arm, the 5-year PFS rate was 53.5% with MRD negativity at the start of maintenance vs 50.6% if MRD positive.
The addition of ASCT to VRd induction was tolerable but did cause more TRAEs, including a signal for AML/MDS as second primary malignancies.
One caveat to this study is that the control arm received only 3 more VRd cycles than the ASCT arm. Also, only 28% of patients in the VRd-alone arm received rescue ASCT.
These results confirm the PFS advantage seen in other phase III trials for including ASCT as part of the initial therapy compared with delaying or avoiding stem cell transplant. That being said, some patients may be able to delay or even avoid ASCT if they are benefiting from medical treatment. More work is needed to identify the patients most likely to benefit from transplant, especially as more therapies are becoming available for treatment of multiple myeloma.
Jesús F. San-Miguel, MD, PhD:
Bispecific antibodies have shown promising efficacy that may be enhanced when combined with other antimyeloma therapies.22 The phase Ib TRIMM‑2 study is evaluating teclistamab, an investigational bispecific antibody targeting BCMA x CD3, in combination with the anti-CD38 antibody daratumumab. In preclinical models, daratumumab can lead to T-cell expansion and enhanced cytotoxic T-cell activation. Combining daratumumab with teclistamab may further enhance myeloma cell killing by the patient’s immune system.
TRIMM-2 is evaluating daratumumab plus teclistamab in patients with relapsed/refractory multiple myeloma who have received ≥3 prior lines of therapy (estimated N = 295). In this ongoing, open-label study, patients are receiving SC daratumumab 1800 mg combined with escalating doses of SC teclistamab (1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 3 mg/kg weekly). Of note, 9 patients switched from 1.5 mg/kg weekly to 3 mg/kg every 2 weeks in cycles 4-9.
The primary endpoint is the recommended phase II dose. Secondary endpoints include safety at the phase II dose(s), antitumor activity, and pharmacokinetics/pharmacodynamics.
Jesús F. San-Miguel, MD, PhD:
This analysis included 65 patients, of whom 59% were triple-class refractory, 31% were penta-refractory, and 63% were refractory to daratumumab.22 In total, 8 patients had received prior BCMA-targeted therapy, and most patients (72%) had received stem cell transplantation. Of note, one quarter of patients had high-risk cytogenetics such as del(17p), t(4;14), or t(14;16).
Jesús F. San-Miguel, MD, PhD:
The combination of teclistamab and daratumumab exhibited no overlapping toxicities.22 This regimen was associated with grade 3/4 neutropenia in 42% of patients, grade 3/4 anemia in 28%, and grade 3/4 thrombocytopenia in 25%. The most common all-grade nonhematologic toxicity was cytokine-release syndrome (CRS) in 68%. Diarrhea, fatigue, pyrexia, and nausea each were reported in approximately 30% of patients.
Infections were seen in 68% of patients (grade 3/4: 28%). One patient had a grade 1 immune effector cell–associated neurotoxicity syndrome event during step-up dosing that fully resolved within 1 day. There have been 4 deaths due to AEs, all deemed unrelated to treatment (bacterial pneumonia, sepsis, hepatic failure, and COVID-19).
Jesús F. San-Miguel, MD, PhD:
All cases of CRS in this study were grade 1 (43%) or grade 2 (25%).22 The median time to onset was 2.5 days, with a median duration of 2 days, and all events resolved without treatment discontinuation. Moreover, most CRS events occurred during step-up doses or the first full treatment dose. Supportive care was required in 60% of patients, with tocilizumab being administered to 32%.
Jesús F. San-Miguel, MD, PhD:
At a median follow-up of 8.6 months, among 51 response-evaluable patients, the rate of VGPR or better was 70.6%, including slightly higher CR rates in the weekly cohorts.22
The ORR was similar (73.7%) in patients with prior exposure to anti-CD38 antibodies. Responses were rapid (median time to response: 1 month), were durable, and deepened over time. At the time of this report, 66.7% of responders remain alive and are continuing therapy.
Jesús F. San-Miguel, MD, PhD:
In this early-phase clinical trial, the novel, steroid-sparing immunotherapy combination of teclistamab and daratumumab exhibited no new safety signals and was associated with high response rates in patients with heavily pretreated relapsed/refractory myeloma. The ORR was 76.5%, with >70% of patients achieving a VGPR or better.22 Of note, the ORR was similar in patients with previous anti-CD38 exposure. In total, 67.7% of patients experienced CRS events; all were grade 1/2 and resolved without treatment discontinuation.
Correlative studies have shown that although the proportion of CD38+/CD8+ T-cells declines after initial daratumumab dosing on Day 1 of cycle 1, teclistamab administration led to induction of CD38+/CD8+ T-cells after the first step-up dose. To date, no anti-teclistamab antibodies have been detected.
The favorable safety profile and impressive ORR in this heavily pretreated population—most of whom were refractory to anti-CD38 antibodies—suggest even better efficacy in patients still sensitive to CD38-targeted therapy. The phase III MajesTEC-3 study is evaluating the combination of teclistamab and daratumumab vs either daratumumab plus pomalidomide/dexamethasone or daratumumab, bortezomib, and dexamethasone in relapsed/refractory myeloma (NCT05083169). This study is only including patients who are not refractory to anti-CD38 antibodies.
Jesús F. San-Miguel, MD, PhD:
At EHA 2022, Fernández De Larrea and colleagues23 presented results from an open-label phase I/II pilot study of the BCMA-targeted CAR T-cell therapy ARI0002h in patients with relapsed/refractory multiple myeloma. This trial was conducted in 5 treatment centers in Spain and enrolled 35 patients with ≥2 prior lines of therapy (including a proteasome inhibitor, an immunomodulatory drug, and anti-CD38 therapy) who were refractory to their last line of therapy.
Patients received leukapheresis and then underwent lymphodepletion while their CAR T-cells were being manufactured. Subsequently, the ARI0002h T-cell product was reinfused at 3 x 106 cells/kg using 3 fractions to reduce toxicity (10% on Day 0, 30% on Day 3, 60% on Day 7). A second infusion of ARI0002h at 3 x 106 cells/kg was given at Month 4. The primary endpoints were rates of ORR and CRS.
Jesús F. San-Miguel, MD, PhD:
The median age was 61 years.23 The 30 patients who underwent CAR T-cell infusion had received a median of 4 prior lines of treatment. All were triple exposed, 67% had become refractory, and 87% had previously received ASCT. One third showed high-risk cytogenetics, and 20% had extramedullary disease.
Regarding CAR T-cell production, the median manufacturing time was 11 days.
Jesús F. San-Miguel, MD, PhD:
All patients achieved at least a partial response; 63% achieved a CR or stringent CR and 93% a VGPR or better.23 Of the 26 evaluable patients at Day +100, 24 (92%) were MRD negative and 16 maintained MRD negativity after 1 year.
Of interest, 13 of the 14 patients with soft tissue plasmacytoma responded, including 8 achieving a CR.
At a median follow-up of 17.5 months, the median PFS and OS have not been reached, and 73% remain alive. In total, 24 patients received a second infusion as a booster; 14 of these were already in stringent CR, and 6 improved the depth of response. There were no cases of CRS or neurotoxicity after this second infusion.
The maximum peripheral blood CAR T-cell expansion by polymerase chain reaction (PCR) was 14 days, with a median persistence of 5 months. Three of 9 patients who relapsed still had CAR T-cells detected in blood.
Jesús F. San-Miguel, MD, PhD:
CRS occurred in 90% of patients but was usually grade 1, with no cases of grade ≥3 CRS.23 No cases of immune effector cell–associated neurotoxicity syndrome (ICANS) or late neurotoxicity were observed. The median onset of CRS was 8 days, with a median duration of 4 days. Tocilizumab was used in 74% of patients and corticosteroids in 10%. In total, 3 patients developed macrophage activation syndrome.
Grade 3/4 cytopenias were common, occurring in 52% to 100% of patients, with a median duration of 4-9 months.
Jesús F. San-Miguel, MD, PhD:
Results from this early study of ARI0002h suggested that CAR T-cell production is fast and feasible for patients with relapsed/refractory multiple myeloma, with fractionated dosing being associated with a high ORR and low-grade AEs.23 All patients responded, and 63% achieved a CR.
CRS was reported in 90% of patients, yet most cases were grade 1, and no patient experienced grade ≥3 CRS. In total, 24 of 30 patients received a reinfusion of ARI0002h, with improved response in 25% of patients.
In summary, the production of the academic CAR T-cell product ARI0002h is fast and feasible. This agent is associated with high rates of sustained responses and low-grade toxicity.
Back
