Abstract
In this review we summarize novel clinical data on multiple myeloma (MM) that were presented in the last Annual Meeting of the American Society of Hematology. The MASTER trial showed that a response-adapted approach may effectively guide therapeutic decisions in terms of treatment intensification following autologous transplantation among patients with newly diagnosed MM (NDMM). The ALCYONE study confirmed the superiority of adding daratumumab to the backbone combination of bortezomib, melphalan and dexamethasone among NDMM patients unfit for transplant, which resulted in a significant overall survival benefit. The CANDOR trial showed that the addition of daratumumab to carfilzomib and dexamethasone is associated with a significant benefit in progression-free survival among patients with relapsed/refractory MM after 1 to 3 prior lines of therapy (RRMM). Novel agents including selinexor- and venetoclax-based combinations offer new therapeutic choices for RRMM patients. Furthermore, the tri-specific CC-93269 represents the new generation of highly active T-cell engagers. Chimeric antigen receptor (CAR) T-cell constructs show significant efficacy among heavily pretreated RRMM patients, however the sustainability of responses remains a challenge.
Keywords: multiple myeloma; daratumumab; carfilzomib; bispecific; CAR-T cells;minimal residual disease
Introduction
Novel data and updated results of ongoing studies pertaining to all aspects of the management of patients with plasma cell dyscrasias were presented in the 61st Annual Meeting of the American Society of Hematology (ASH) held in Orlando (Florida, USA), between 7 and 10 of December 2019. In this paper we summarize the most important clinical updates regarding the treatment of patients with multiple myeloma (MM).
Smoldering myeloma
One of the most challenging dilemmas in myeloma therapeutics is the necessity of treating patients with smoldering MM (sMM). Lonial et al have recently shown that lenalidomide monotherapy among patients with intermediate or high risk disease results in a significant delay of symptomatic progression and prevents end-organ damage, as compared with observation.1 Mateos et al presented the results of a more aggressive approach aiming at disease cure for patients at high risk of progression. The GEM-CESAR study recruited 90 transplant-eligible patients with high risk sMM defined as the presence of both bone marrow infiltration by malignant plasma cells ≥10% and M-protein ≥3g/dL; in case of one criterion was present, patients were deemed eligible if they had immunoparesis and more than 95% clonal plasma cells with the the total bone marrow plasma cell compartment. All patients received six cycles of carfilzomib-lenalidomide-dexamethasone (KRd) induction followed by high dose melphalan (HDM) and autologous stem cell transplant (ASCT), two cycles of KRd consolidation and maintenance with lenalidomide-dexamethasone (Rd). The complete response (CR) or better rates after induction, HDM/ASCT and consolidation were 41%, 59% and 70%, respectively. The corresponding minimal residual disease (MRD) negative rates, as assessed by next generation flow (NGF), were 30%, 52% and 57%, respectively, and the trial met its primary endpoint.Interestingly, Quantitative Immunoprecipitation Mass Spectrometry (QIP-MS) was also implemented to assess residual disease burden at the three time points described above and a moderate concordance was found. QIP-MS may supplement NGF, but longer follow up is needed to reach firm conclusions.3 Hematological toxicity and infections were the main adverse events. Following a median follow-up of 32 months (8-128), 98% of the patients remain alive and 93% are progression-free.
The results of three phase 2 studies that applied a non-curative approach is patients with sMM were also reported. Daratumumab monotherapy resulted in an ORR of 46% among patients with high-risk monoclonal gammopathy of undetermined significance (MGUS) and low-risk sMM and it was well tolerated.4 Isatuximab monotherapy resulted in an ORR of 62.5% including a 5% MRD negativity rate at 10-5 among patients with high-risk sMM according to the criteria proposed by PETHEMA.5 Furthermore, the all-oral regimen of ixazomib, lenalidomide and dexamethasone (IRd) was evaluated in the setting of high-risk sMM, according to the criteria proposed by Rajkumar et al.6 The ORR was 93.8% and, importantly, the MRD negativity rate at 10-6 reached at 69%. The regimen was well tolerated and provides the benefit of convenient administration.Should we aim at delaying disease progression or at curing those patients? The jury remains open.
Newly diagnosed MM
Transplant-eligible
The results of several important studies in this field were reported in the last ASH meeting. The MASTER trial may be considered the most novel one, at least in terms of study design.8 Transplant-eligible newly diagnosed MM (NDMM) patients received four cycles of induction consisting of daratumumab and KRd (DaraKRd) with carfilzomib administered at 56 mg/m2 weekly, followed by ASCT. Subsequently, the treatment was adapted according to MRD status assessed by next-generation sequencing (NGS). The MRD was evaluated at pre- specified time points as follows: at the end of induction, post-ASCT, post 4 and 8 cycles of DaraKRd consolidation. Patients with two consecutive MRD negative results at the level of 10-5 received no further treatment. DaraKRd resulted in rapid responses before the end of cycle 2, whereas more than 90% of the patients obtained very good partial response (VGPR) or better by the end of induction. More than 90% of the patients who had reached transplant at the time of analysis achieved CR/strigend CR (sCR) as best response on therapy, as well. Following induction, ASCT and at best response the MRD negative rates were 34%, 70% and 80% at the level of 10-5, respectively, and 28%, 45% and 65% at the level of 10-6, respectively (Figure 1). MRD negative remissions that led to treatment discontinuation were also characterized by imaging MRD negativity. Most frequent adverse events included hematological toxicity and infections.Furthermore, two other response-adapted approaches of administering KRd consolidation were presented. Gavriatopoulou et al selected 39 consecutive patients who were MRD positive post-ASCT. Four cycles of KRd improved the depth of response in 81% of the patients, whereas the MRD negativity rate at the end of consolidation was 68%.9 Noorgard et al administered four cyles of KRd consolidation in 16 patients with a positive fluorodeoxyglucose (FDG)-positron emission tomography / computed tomography (PET/CT) scan post-ASCT. Following consolidation, response improvement was detected in 63% of the patients and 2/8 converted to FDG-PET/CT negativity status.10 Long-term follow up is necessary in order to evaluate the survival outcomes of these response-adapted therapeutic approaches that may serve as a basis for similar clinical trial design for future studies.
Figure 1. Evaluation of MRD and depth of response at pre-specified time points in the MASTER trial.
Following the promising safety results of the phase 2 Griffin trial, updated results for the transplant-eligible NDMM patients were presented. The primary study endpoint was mastitis biomarker met by showing a superiority in terms of CR rate at the end of consolidation for the patients receiving daratumumab, bortezomib, lenalidomide, dexamethasonse (DaraVRd) compared to those receiving VRd (42.4% versus 32%). The VGPR or better rates at the end of consolidation were also in favor of DaraVRd (91% versus 73%, respectively). The depth of response improved over time; among the patients achieving CR or better at the end of consolidation 59% and 24% were MRD negative in the DaraVRd and VRd group, respectively.11 Interestingly, median stem cell yield was 8.1 and 9.4 x 106 cells/kg in the two groups respectively. This observation coincides with the results reported in the CASSIOPEIA trial showing that patients receiving daratumumab-based
combinations may collect a lower yield of stem cells.12 However, both in the Griffin and CASSIOPEIA trials, engraftment times did not differ significantly between the two treatment groups and hematopoietic reconstitution is feasible without compromising patient safety.
The initial results of the phase 2 Cardamon study evaluating the upfront combination of carfilzomib at 56mg/m2 biweekly with cyclophosphamide and dexamethasone (KCd) were presented. At the end of induction, the overall response rate (ORR) was 87.7%, the VGPR or better rate was 59.2% and the rate of MRD negativity was 24.1%. Interestingly, both the VGPR or better and the MRD negativity rates were similar between the standard and the adverse treatment groups.13 Subsequently, patients will either undergo HDM/ASCT or receive KCd consolidation followed by maintenance with carfilzomib.
Although lenalidomide has been well-established as maintenance post ASCT and ixazomib has emerged as a promising alternative option, there are have been reported no results from direct comparison between the two agents. A randomized phase 2 trial compared lenalidomide to ixazomib maintenance among NDMM patients who had received induction, ASCT and IRd consolidation. Following a median follow-up of 11.2 and 12.3 months from randomization, 30% and 18% of the patients have discontinued treatment due to disease progression in the ixazomib and lenalidomide groups, respectively. PFS results are eagerly awaited.
The role of PET/CT in the evaluation of MRD status was assessed in two companion studies. 184 patients included in the CASSIOPEIA trial had evaluable baseline and post- consolidation PET/CT assessments. The CASSIOPET study showed that 64.1% of the patients had achieved a CR based on PET/CT; whereas 102 patients were both MRD negative and in CR according to PET/CT. Double negativity was reported in 66.7% and 47.5% of the patients receiving daratumumab, bortezomib, thalidomide, dexamethasone (Dara-VTd) and VTd, respectively. Furthermore, among the 268 patients with available PET/CT at baseline, the PFS rate for those with negative versus positive results was 100% versus 92.5% at 12 months and 100% versus 87.5% at 18 months,
respectively.15 PET/CT was also performed to evaluate MRD according to the Deauville criteria in the FORTE trial among patients receiving either KRd, with or without ASCT and KRd consolidation, or KCd with HDM/ASCT and KCd consolidation. PET/CT negativity before maintenance was significantly associated with the achievement of CR as best response. There was a strong correlation between the MRD results assessed by PET/CT and multiparameter flow cytometry in the bone marrow.16 Therefore, PET/CT status emerged as a strong predictor of patient outcomes and may also offer important information especially on extramedullary sites complementary to bone marrow MRD assessment.
Another secondary analysis of the FORTE trial tried to determine the factors predicting MRD negativity along with characteristics of patients presenting with an early-relapse. Increased levels of creatinine, percentage of plasma cell invasion of the bone marrow and the presence of deletion 17p at baseline emerged as independent prognostic factors of not achieving a MRD negative status. Regarding early relapses, circulating plasma cells in the peripheral blood, a high LDH level at baseline, along with the inability of attaining MRD negativity were independently associated with an increased risk of early relapse.17 In this context, a novel prognostic system was also proposed based on the characteristics and outcomes of 2528 NDMM patients registered in the Center for Blood and Marrow Transplant Research (CIBMTR) database. Patients were categorized as low NSC 641530 or high risk according to a score system (0-3 versus 4-6, respectively) based on the following characteristics; 1-point variables: bone marrow plasma cells ≥10%, 2 or more prior lines of therapy, presence of standard-risk cytogenetics, induction regimen other than VRd or thalidomide-dexamethasone (Td), 2-point variable: presence of high-risk cytogenetics, 3-point variable: induction with Td. The low-risk group had superior PFS rates at 3 years both in the training (60% versus 27% for the high-risk group) and the validation (51% versus 28% for the high-risk group) cohorts.18 Importantly, the patients including in this analysis had not received carfilzomib- or daratumumab-based combinations as induction treatment.
The combination of elotuzumab with lenalidomide and dexamethasone (EloRd) as induction, consolidation and maintenance was also evaluated in a phase 2 study. Among 52 enrolled patients the ORR was 92% and the VGPR or better rate was 69%, whereas the 18-month median progression-free (PFS) and overall survival (OS) rates were 83% and 89%,respectively.Importantly, the high-risk patients, defined as revised international staging system (RISS) III or with high-risk cytogenetics, had a median PFS and OS of 20.5 and 22 months, respectively, whereas the median PFS and OS have not been reached for the standard-risk patients.19 Similar to the above, the updated analysis according to risk stratification of the NCRI Myeloma XI Trial showed that patients with ISS 2 or 3 and two or more adverse cytogenetic aberrations had significantly inferior outcomes in terms of PFS1, PFS2 and OS.20 However, it has to be noted that most of the patients received cyclophosphamide with dexamethasone and lenalidomide (CRd) or bortezomib or thalidomide, whereas only a subset received carfilzomib with CRd and none received anti- CD38 monoclonal antibodies. Overall, these results highlight the need for more effective treatment strategies regarding the high-risk and the ultra high-risk subgroups of patients.
Bone disease is a hallmark of MM and novel bone-targeting agents are under clinical investigation.21 Among them, the anti-RANKL agent denosumab has shown its non- inferiority compared with zoledronic acid among NDMM patients in a randomized phase 3 study.22 Updated results presented in the last ASH meeting showed a significantly superior PFS for transplant-eligible patients who received denosumab compared with those who received zoledronic acid (HR=0.65, 95%CI: 0.49-0.85). Importantly, the two treatment groups were similar in terms of demographics, baseline disease characteristics and induction regimens.Another important study addressed the issue of setting a chronological age cut-off for offering the option for ASCT in NDMM patients. Data from 15,999 NDMM patients registered in the CIBMTR database were analyzed and showed an increase in the percentage of ASCT performed in patients above 70 years of age between 2013 (15%) and 2017 (28%). Importantly, the multivariate analysis showed that compared to those in the age group of 60-69 years, patients aged 70 years and above experienced similar non-relapse mortality (NRM),PFS and OS. Interestingly, the administration of low melphalan (140mg/m2) was associated with inferior 100-day NRM, 2-year PFS and 2-year OS compared with melphalan at 200mg/m2. However, low melphalan may be considered as a surrogate for frailty and comorbidities.24 Overall, it seems that biological instead of chronological age should better guide our therapeutic decisions in terms of proceeding to ASCT or not.
Ineligible for transplant
One of the most important clinical updates in MM were the OS data from the ALCYONE study. ALCYONE has previously shown the superiority of daratumumab with bortezomib, melphalan and dexamethasone (Dara-VMP) compared with VMP for NDMM patients who are not eligible for ASCT in terms of PFS prolongation.25 Following a median follow up of 40.08 months, median PFS was 36.4 versus 19.3 months for the Dara-VMP and VMP patient subgroups, respectively, whereas the median PFS2 was not reached versus 42.3 months, respectively. Although the median OS was not reached in both subgroups, the estimated OS rate at 42 months was significantly higher in the Dara-VMP group compared with the VMP group (75% versus 62%, HR=0.60, 95%CI: 0.46-0.80, p=0.0003) (Figure 2). Significantly more patients receiving Dara-VMP achieved MRD negativity (28% versus 7%), as well.
Figure 2. Kaplan-Meier curves for PFS and OS favoring Dara-VMP in the ALCYONE study.
The updated results of another important study administrating daratumumab in the upfront treatment of transplant-ineligible patients were also presented. Patients included in the MAIA study were randomized to receive either Dara-Rd or Rd.28 Following a median follow up of 36.4 months, the median PFS was not reached versus 33.8 months in the Dara-Rd versus Rd groups, respectively (HR=0.56, 95%CI: 0.44-0.71, p<0.0001). The median PFS2 was more favorable with the DaraRd regimen (note reached versus 47.3 months with Rd, respectively, p=0.0079), as well. The depth of response was also superior in the DaraRd group, whereas the MRD negativity rates were 29% and 9% in the DaraRd and Rd groups, respectively (p<0.0001).29 Both MAIA and ALCYONE trials show that daratumumab-based triplet or quadruplet combinations may be considered the new standard of care for transplant-ineligible NDMM patients.
The phase 2 HOVON 143 study evaluated the efficacy and tolerability of daratumumab in combination with ixazomib and dexamethasone (Dara-Id) among unfit and frail NDMM patients according to the International Myeloma Working Group (IMWG) frailty index.30 The ORR among unfit (n=23) and frail (n=23) patients were 74% and 78%, respectively. The median PFS was 23 and 12 months for the unfit and frail patients, respectively, whereas the 12-month OS rate was 96% and 74%, respectively. Hematological toxicity was more frequent among the frail patients. Overall, the mortality rate was 2% in unfit patients with a median follow up of 7.1 months and 19% in frail patients with a median follow up of 8.8 months. Infections were a main cause of death among frail patients, who also showed a high early death rate of 12%, as compared with 0% among unfit patients.
The AGMT MM-02 study compared KRd to carfilzomib, thalidomide, dexamethasone (KTd) induction followed by carfilzomib maintenance compared with observation among NDMM who were not eligible for ASCT. Interestingly, carfilzomib was administered biweekly at 20/27mg/m2 for the first two cycles of treatment and weekly at 56mg/m2 thereafter. After a median follow up of 11.7 months, the ORR among 58 included patients in both treatment groups was 96.6%, whereas the CR and VGPR rates were 36.2% and 37.9%, respectively. Among the 17 patients with available data the MRD negativity rate was 47%. The survival rates at 12 and 24 months were 84% and 68%, and 92% and 86%, for PFS and OS respectively. Neither age nor the cytogenetic risk seemed to alter the outcomes. Overall,the most frequent adverse events grade 3 or above were infections and cardiac failure.
The GEM-Claridex is another randomized trial evaluated the combination of clarithromycin and Rd (ClarRd) to Rd among NDMM patients not eligible for ASCT. The depth of response attained with ClarRd was superior to Rd in terms of CR or better rates (20% versus 11%) and VGPR or better (53% versus 37%) rates. However, no differences between the treatment groups were detected regarding the MRD negativity rate, which was below 7% in both, or the median PFS. Interestingly, among patients aged 75 years or above the median PFS was significantly inferior with ClarRd compared with Rd (p=0.03). A high death rate was also detected among older (≥75) patients receiving ClarRd due to infections and cardiovascular events. These results may be partially attributed to an overexposure to steroids on the ground of decreased clearance due to age and clarithromycin co- administration.33 The GEM-Claridex underlines the need for careful consideration and patient selection before administering complex combinations in frail patients with comorbidities.
Irrespective of transplant eligibility
A phase 2 study evaluated the efficacy and safety of Dara-KRd for 8 cycles with weekly carfilzomib at 20/56mg/m2 among NDMM patients. After a median follow up of 8.6 months, the ORR was 100%, whereas the primary endpoint of MRD negativity rate was 77% (23/30).No MRD negative patient progressed, although the follow up was rather limited and the PFS data rather immature. Importantly, no additional toxicities emerged with the weekly Dara-KRd regimen, as compared with the standard biweekly treatment schedule.The combination of daratumumab with bortezomib, cyclophosphamide and dexamethasone (Dara-VCd) has provided promising results as an upfront treatment.35 In the updated analysis of the LYRA study, 86 NDMM patients who received Dara-VCd induction with or without ASCT followed by one year of daratumumab maintenance were included. At the end of induction, the ORR was 87% and the CR or better rate was 12%. Following
maintenance, the ORR was 97% among the patients who underwent ASCT and 83% among those who did not proceed to ASCT, whereas the CR or better rates were 51% and 30%, and the VGPR or better rates were 82% and 70%, respectively. After a median follow up of 24.8 months, the median duration of response, the median PFS and OS had not been reached, regardless of transplantation status. Regarding safety, the adverse events were predictable and manageable.36 Thus, daratumumab maintenance improved the depth of response which was associated with durable PFS and OS.
Another phase 2 study evaluated the efficacy of Dara-IRd with modified dose dexamethasone administered only for the first two cycles among patients with NDMM irrespective of their eligibility for transplant. The ORR among 40 included patients was 95% with a CR or better rate of 25%. The 12-month PFS and OS were 90.4% and 100%, respectively. A low rate of dose reductions was reported, which were mainly due to hematological toxicity and treatment-related rash. There was no impact on stem cell collection and subsequent engraftment, although all 17 patients who underwent ASCT required plerixafor.Furthermore, the primary results of the EMN12/HOVON129 phase 2 study evaluating the efficacy of KRd among newly diagnosed patients with plasma cell leukemia were reported.Following four cycles of KRd induction, the ORR was 93%, whereas the CR or better rate was 33% and the VGPR or better rate was 80%. The majority of the serious adverse events occurred during the first cycle of treatment; however, no deaths were reported during the induction phase, which may be attributed both to the rapid disease control and the supportive measures in case of toxicities.
Relapsed/Refractory MM
The primary analysis of the phase 3 CANDOR study including patients with relapsed/refractory MM (RRMM) following 1-3 prior lines of therapy was presented as a late-breaking abstract.39 Eligible patients were randomized to receive either daratumumab with carfilzomib and dexamethasone (Dara-Kd) or carfilzomib and dexamethasone (Kd) with carfilzomib at 20/56mg/m2 twice weekly. After a median follow up of 16.9 months for the 312 patients in the Dara-Kd group and 16.3 months for the 154 patients in the Kd group, the median PFS was not reached for the Dara-Kd group and it was 15.8 months for the Kd group (HR: 0.63, 95%CI: 0.46-0.85, p=0.0014), and the study met its primary endpoint (Figure 3). Dara-Kd was superior to Kd in terms of PFS both among lenalidomide exposed (HR: 0.52, 95%CI: 0.34-0.80) and lenalidomide refractory patients (HR: 0.45, 95%CI: 0.28-0.74). Furthermore, both the ORR (84.3% versus 74.7%, p=0.0040) and the MRD negative rate at 12 months (12.5% versus 1.3%, p<0.0001) were in favor of Dara-Kd. Regarding adverse events, the rate of treatment discontinuation due to toxicity was similar between the two groups, whereas the rate of grade 3 or higher cardiac failure was 8.5% in the Kd and 3.9% in the Dara-Kd group. However, five treatment-related deaths were reported in the Dara-Kd group which were mainly attributed to severe infections. Therefore, Dara-Kd emerged as a potent therapeutic choice, whereas the benefit-risk profile can be optimized with toxicity surveillance and infection prophylaxis.
Figure 3. Kaplan-Meier curve for PFS favoring the Dara-Kd combination in the CANDOR study.
Another clinical trial evaluated the combination of DaraKRd among patients with primary resistant MM who were not eligible for ASCT. Among the 36 patients recruited in the KYDAR study, the ORR was 91%, whereas the VGPR or better rate was 71%. Hematologic toxicity and infections were the most frequently encountered adverse events. Thus, DaraKRd is a highly effective regimen even in the presence of primary resistant disease.The CARFI clinical trial compared the combination of Kd to observation as maintenance following induction with KCd and salvage ASCT among RRMM patient at first relapse after upfront ASCT who had not received any maintenance.41 The median time to progression (TTP) from the initiation of maintenance was 28.8 and 18.5 for the Kd and the observation group, respectively (HR: 0.42, 95%CI: 0.26-0.68, p=0.0003). The majority of serious adverse events in both groups included infections. Therefore, maintenance may be considered even after a salvage ASCT.
Targeted treatment based on cytogenetics
Venetoclax is a selective BCL-2 inhibitor that promotes MM cell apoptosis and has shown particular activity in patients with RRMM with the cytogenetic translocation t(11;14). In a phase 1/2 study including the aforementioned patient population with 1-9 prior lines of therapy the ORR was 45% and the VGPR or better rate was 26%, whereas the estimated PFS and OS at 9 months were 57% and 71%, respectively. The most common serious adverse event was tumor lysis syndrome.42 These results provide the rationale for further clinical evaluation in a phase 3 clinical trial (CANOVA).
The biomarker analysis from the phase 3 BELLINI trial evaluating the combination of venetoclax with bortezomib and dexamethasone (VenBd) compared with Bd among RRMM patients, was presented in the last ASH meeting.43 Interestingly, although the patients with t(11;14) presented with the highest level of BCL-2 expression, high expression of BCL-2 was not limited only to this cytogenetic subgroup. A significant PFS benefit was reported with VenBd among patients with t(11;14) (HR=0.10, 95% CI: 0.02-0.46, p=0.003) and those with high BCL2 expression (HR=0.26, 95% CI: 0.13-0.51, p<0.001). VenBd was also superior to Bd in terms of PFS (HR=0.26, 95% CI: 0.14-0.48, p<0.001), ORR (88% versus 70%) and MRD negativity rate (19% versus 0) for the combined group of patients with t(11;14) or high BCL2 expression. Although no OS difference was shown between the two treatment groups among patients with t(11;14) or high BCL2 expression, Bd was superior to VenBd in terms of OS among patients without t(11;14) and low BCL2 (HR=3.13, p=0.019). Therefore,biomarker-driven patient selection is highly important for optimizing the efficacy/safety ratio.
Another phase 1/2 study evaluated the efficacy and safety of venetoclax in combination with daratumumab. Venetoclax, daratumumab, dexamethasone (VenDd) was administered in 24 patients with t(11;14) with one or more prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), whereas venetoclax, daratumumab, bortezomib and dexamethasone (VenDVd) was administered in patients with 1-3 prior lines of therapy who were not refractory to PIs irrespective of their t(11;14) status. The ORR was 92% with VenDd and 88% with VenDVd. Interestingly, no tumor lysis syndrome or infection-related death were reported.
Novel agents
Selinexor is an inhibitor of nuclear export protein exportin 1 that has gained regulatory approval for heavily pretreated RRMM patients in combination with dexametheasone based on the results of the STORM trial.45 In the last ASH meeting, the results of the phase 1/2 STOMP trial evaluating the combination of selinexor with pomalidomide and dexamethasone (SPd) among RRMM patients, who had previously received lenalidomide and a PI, were reported.46 The ORR among pomalidomide-naïve patients was 58% and the median PFS was 12.2 months. The dose-limiting toxicities in the phase 1 dose escalation part included fatigue, febrile neutropenia and thrombocytopenia. The adverse events were considered manageable with supportive measures and dose modifications. These results support the subsequent clinical evaluation of the SPd combination.
TAK-079 is a novel anti-CD38 monoclonal antibody which is administered subcutaneously. According to the primary results of the phase 1b study the ORR was 56% and 33% at 300mg and 600mg, respectively, whereas the median PFS was 3.7months at 300mg and it was not estimable at 600mg. Importantly, no dose-limiting toxicities and no infusion-related reactions were reported and the maximum tolerated dose was not determined.47 These promising results serve as a basis for further clinical development of this novel agent.CLR131 is a novel radiotherapeutic that was evaluated in the phase 1/2 CLOVER trial including RRMM patients who were refractory to at least one PI and one IMiD. Among 16 patients the disease control rate was 100%. The ORR among patients receiving the fractionated dose of 37.5 mCi/m2 was 50%; importantly, 80% of these patients were quadra- or penta-refractory. The toxicity was mainly hematological, which showed a predictable kinetic of recovery.48 Based on these results, enrolment is currently ongoing.
Novel immunotherapies
Bispecific antibodies
The novelty of CC-93269 compared to other T-cell engagers lies into its bivalent binding to BCMA along with a monovalent binding to CD3 (2+1 format). In a phase 1 dose-escalation clinical trial, patients with RRMM and 3 or more prior lines of therapy (range 3-12) received intravenous infusions of CC-93269 at doses ranging from 0.15 to 10mg.49 All patients were refractory to their last treatment including 89% refractory to daratumumab, 89% refractory to their last PI and 84% refractory to their last IMiD. The ORR among all 30 patients was 43.3%. The ORR among 12 patients who received 6mg or higher dose of CC-93269 was 83.3%, among which 75% achieved MRD negativity (Table 1). The most frequent adverse events including hematological toxicity and infections, whereas 90% of the patients experienced cytokine release syndrome (CRS), mainly grade 1 or 2 during the first or second infusion. Patients were effectively managed with dexamethasone and tocilizumab; however, one patient suffering from CRS and concurrent infection died. Therefore, CC-93269 is a very promising agent for heavily pretreated RRMM patients, however patient selection according to fitness and appropriate preventive measures should be strongly considered.
Chimeric antigen receptor (CAR) T-cells
CARTITUDE-1 is a United States-based, phase 1b/2 clinical trial evaluating the efficacy and safety of the CAR T-cell JNJ-4528, which has two BCMA-specific single-domain antibodies, among 29 patients with RRMM, who had received at least 3 prior lines of therapy including a PI, an IMiD and an anti-CD38 monoclonal antibody (88% triple-refractory, 36% penta-refractory).
Following 5-7 days after a conditioning regimen consisting of cyclophosphamide 300mg/m2 and fludarabine 30mg/m2 over three days, JNJ-4528 at the targeted dose of 0.75×106 CAR+ cells/kg was administered as a single infusion.50 All patients showed a reduction in paraprotein levels (ORR=100%). Among the 17 patients with evaluable bone marrow sample at day 28 post-infusion, all were MRD negative; 9 at 10-6, 5 at 10-5 and 3 at 10-4 . After a median follow-up of 6 months, 27/29 patients are progression-free.The most frequent adverse events were hematological toxicity and CRS, most of which were grade 1-2; however, there gingival microbiome was also one fatal CRS event. Corticosteroids and tocilizumab were administered for CRS management. Regarding JNJ-4528 kinetics, the peak of post- infusion expansion is variable and is detected around day 10-14. Interestingly, the best responses were independent of peak expansion and peripheral persistence, as well as levels of BCMA expression in MM cells.
LCAR-B38M is an identical CAR T-cell to JNJ-4528 that was evaluated in a first-in- human phase 1 study conducted in China.52 In contrast to JNJ-4528, lymphodepletion was mediated only by cyclophosphamide at 300mg/m2 and the LCAR-B38M administration was performed in three split infusions. The majority of the participants experienced CRS (90%) with a median duration of 9 days (3-57), which was resolved in all but one case. Among 57 enrolled patients with RRMM, the ORR was 88%, whereas 39 patients were MRD negative. Interestingly, there was no association between the best response and BCMA expression level or weight-adjusted CAR+ cells infused. Following a median follow up of 19 months the median duration of response was 22 months and the 18-moht OS rate was 68%. The median PFS was 20 (range 10-28) months, whereas the median PFS for MRD negative patients was 28 (range 20-31) months. The results of the LEGEND-2 study have provided the rationale for further clinical evaluation of such CAR T-cells constructs both in the USA and in China.
CRB-402 is a first-in-human, dose-escalation, phase 1 study evaluating the safety and efficacy of bb21217, which is a next-generation CAR T-cell targeting BCMA based on the construct of bb2121 by adding the phosphoinositide 3-kinase inhibitor bb007 in order to enhance the ability to induce T-cell mediated immunological memory.53 In this way, it is anticipated to achieve durable responses. Patients with RRMM following at least 3 prior lines of therapy including a PI and an IMiD, who presented with at least 50% BCMA expression were considered eligible for inclusion. Bb21217 was administered as a single infusion following lymphodepletion with fludarabine and cyclophosphamide. The recommended dose for a subsequent phase 2 study was determined at 450 x 106. CRS was frequently encountered and was successfully managed in all but one fatal event. The ORR was 83%, whereas all but one evaluable responders were MRD negative. The median duration of response was 11.1 months at the dose level of 150 x 106, whereas the follow up is short for the other cohorts. Although the data are rather immature, 8/10 patients had persistent CAR T-cell in the peripheral blood at month 6 and 2/2 at month 8. Compared to other CAR T-cell constructs, bb21217 presents sustained persistence and durable responses and long-term follow up data are eagerly awaited.
In another first-in-human study conducted in China, a novel BM38 CAR T-cell consisting of a dual target against both BCMA and CD38 was evaluated.54 16 patients with RRMM and at least 2 prior lines of therapy including a PI and an IMiD received lymphodepletion with cyclophosphamide and fludarabine followed by a single CAR T-cell infusion. The majority (91%) experienced CRS (grade 3 or above: 23%) that resolved with supportive treatment and tocilizumab, whereas no neurotoxicity events were reported. Reversible hematological toxicity was also very common. The ORR was 91%, the MRD negative rate was 81% and the 9-month PFS was 79%. Interestingly, all 5 patients with extramedullary lesions showed complete remission. The longest duration of CAR T-cell persistence was more than 450 days. Thus, the bivalent BM38 CAR T-cell achieved deep and durable responses and necessitate further investigation in later stage clinical trials.
CT103A is an anti-BCMA CAR T-cell construct consisting of a fully human scFv, CD8a hinger, and transmembrane, 4-1BB co-stimulatory and CD3z activation domains.55 Among 16 patients with RRMM to 3 or more previous lines of therapy including a PI and an IMiD,the ORR was 100%, whereas all 15 patients evaluable for MRD were negative at 10-4 . The responses were rapid and evident within the first two weeks of infusion. All patients experienced CRS but only one grade 4 case was reported.
Another phase 1 study evaluated the sequential infusion of anti-CD19 and anti-BCMA CAR T-cells in patients with RRMM resistant to a PI and/or an IMiD. 28 patients received lymphodepletion with cyclophosphamide and fludarabine followed by a single infusion of CART- 19 and a split-dose infusion of CART-BCMA.56 Some of them received also thalidomide or lenalidomide maintenance. All patients experienced CRS with two grade 4 events. The ORR was 93%, whereas 41% of the patients achieved CR or better. After a median follow up of 16 (3-28) months, the median PFS and OS were 8 and 16 months,respectively.Overall, CAR T-cell constructs constitute highly effective treatment approaches for patients with RRMM, especially for those with limited therapeutic choices. Although it seems that toxicity is effectively managed, the durability of CAR T-cell persistence remains a challenge.