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Subjects:
Hematology
Multiple Myeloma (MM) remains a difficult to treat disease mainly due to its biological heterogeneity. The biological diversity translates into a wide range of clinical outcomes from long-lasting remission in some patients to very early relapse in others. In NDMM transplant eligible (TE) patients, the incorporation of mAb as daratumumab in the induction regimens, followed by autologous stem cell transplantation (ASCT) and consolidation/maintenance therapy, has led to a significant improvement of PFS and OS.; however, this outcome remains poor in ultra-high risk MM or in those who did not achieve a minimal residual disease (MRD) negativity. Several trials are exploring cytogenetic risk-adapted and MRD-driven therapies in these patients. Similarly, quadruplets-containing daratumumab, particularly when administered as continuous therapies, have improved outcome of patients not eligible for autologous transplant (NTE).
- multiple myeloma
- minimal residual disease
- monoclonal antibodies
- CAR T cell
1. Introduction
Although MM currently remains an incurable disease, therapeutic strategies developed over time have led to impressive improvement in overall survival (OS), suggesting that some patients could be considered cured [1]. However, both inter-patient and intra-patient heterogeneity constitute the biggest obstacle in treating and curing MM, even though innovative approaches to either newly diagnosed or in relapsed/refractory patients have tried to overcome them. In upfront settings, continuous or long-term therapies including mAbs as daratumumab have recently shown to induce deep and sustained responses [2,3,4]; however, it remains unclear what the optimal duration of treatment may be or how to minimize toxicities. In this regard, MRD status has shown to be not only a predictor of progression free survival (PFS) and OS but also an extremely valid biomarker to design MRD-driven therapies and to guide the duration of treatment. Although ASCT still plays a significant role in patients who are eligible, in the near future the unprecedented responses seen with quadruplet combinations including mAbs could modify this paradigm. However, moving novel effective drugs as proteasome inhibitors (PIs), immunomodulatory agents (IMiDs) and mAbs in the upfront setting means that the number of patients becoming early refractory to them is growing [5]. Luckily, newly developed immunotherapies like conjugated antibodies, bispecific antibodies or CAR T cell therapies are representing a turning point in the management of heavily pre-treated and refractory MM patients, despite many issues regarding their use that still need to be solved.
2. Improvements in Risk Stratification
Despite the application of validated risk stratification systems, the category of intermediate risk MM now includes a very heterogeneous group of patients [6], characterized by vastly different prognoses, opening the challenge to build a more exhaustive risk stratification model [7].
The three-stage classification International Staging System (ISS) [8], which combines serum β2-microglobulinemia and albumin, depicting disease burden, has proven to be the simplest, most powerful and reproducible staging system and demonstrated to be more effective in comparison to the Durie and Salmon one [9]. Revised-ISS (R-ISS) incorporated two further prognostic factors: the presence of high risk genetic mutations [del(17p), t(4;14), or t(14;16)], assessed by fluorescence in situ hybridization (FISH), and lactate dehydrogenase level (LDH), as representative of disease burden [10]. It is currently used to prognosticate NDMM patients, it can predict early post-transplant relapse and have an independent prognostic effect on post-relapse survival after an early relapse [11]. The main limitation of the R-ISS was that 62% of patients were classified as intermediate-risk (R-ISS II), possibly including patients with different risk levels of progression/death. Recently, D’Agostino et al. validated an improvement of R-ISS in R2-ISS [12], whereas Abdallah published the Mayo Additive Staging System (MASS) [13], by adding 1q gain/amplification among the high risk cytogenetic features and considering the prognostic meaning of each single baseline risk feature in an additive fashion. D’Agostino et al. [12] validated R2-ISS in 10,843 NDMM patients, enrolled in clinical trials from 2005 to 2016, in the context of the HARMONY Project, and identified four groups of patients: R2-ISS I (19.2%), II (30.8%), III (41.2%) and IV (8.8%), redeploying intermediate-risk population in two different and more precise stages. Outcomes were significantly different among these groups, above all between the two intermediate groups, both in TE (OS 140 months in R2-ISS II and 75 months in R2-ISS III) and in NTE (OS 66 months in R2-ISS II and 52 months in R2-ISS III) patients, and independently of the upfront therapy they have received. This new score considered ISS and LDH, as previously, but it took a step forward regarding the karyotype by considering del(17p), t(4;14) and the role of the combination of different adverse cytogenetic features [14]. It did not account t(14;16) that was listed among the unfavourable high-risk chromosomal abnormalities by IMWG [15,16,17], because it was demonstrated to be significant in terms of OS, but not PFS, rare and usually present together with other adverse prognostic features [18,19,20]. Differently from previous scores, abnormalities of 1q were included in the R2-ISS, as also recommended by NCCN MM Panel [21], without a distinction between gain (3 copies) and amplification (>3 copies), although this would further improve the risk stratification. It was recently described that amp1q and its main clone position could be significantly associated with prognosis results, in comparison with gain1q [22,23,24,25], even if the biological meaning of amp1q remains difficult to determine. A recent retrospective experience confirmed the greater role of the association of high risk feature rather than a single one, but also the size of high risk clone influenced prognosis [26]. M-Smart MM risk stratification guideline by Mayo Clinic proposed an innovative concept, with patients possessing two of the high risk genetic abnormalities defined as “double hit” and having any three as “triple hit” MM [27]. Both phenotypes were considered ultra-high-risk disease characteristics, having observed that they correlated with aggressive clinical presentations, high early mortality and poor outcomes even in real life settings [9,28,29,30]. With these innovations—whose applications still have some difficulties when applied to the clinical practice setting because of the heterogeneity among labs and the lack of techniques’ standardization—a guideline update is needed.
3. Current and Future Role of Immunotherapy in the Upfront Setting
Triplet-based regimens as induction therapy in TE patients have been found to be more effective than doublets [67], but, in the 2021 ESMO guidelines [68], only VRD (bortezomib, lenalidomide, dexamethasone) regimen is still recommended as first option in these patients. The phase III PETHEMA/GEM2012 trial evaluating VRD for 6 cycles followed by ASCT conditioned with busulfan plus melphalan vs. melphalan, reported ≥ VGPR, CR and MRD negativity (by NGF) rates of 66.6%, 33.4% and 35% after induction, respectively [69,70]. The other first option as upfront therapy recommended for TE patients is Dara-VTD (daratumumab, bortezomib, thalidomide, dexamethasone) regimen, approved after results from the phase III CASSIOPEIA trial [2] comparing VTD vs. Dara-VTD as induction (4 cycles) and consolidation (2 cycles) after ASCT. Adding daratumumab to VTD increased response rates (at least VGPR after consolidation 83% vs. 78%, p = 0.024; at least CR 39% vs. 26%, p < 0.0001) and quality of response, being 64% (vs. 44%, p < 0.0001) the rate of MRD negativity at level of 10−5 in patients receiving Dara-VTD. The last update of the CASSIOPEIA study [71] showed, after a follow-up of 44.5 months, a median PFS not reached in Dara-VTD group vs. 51.5 months in VTD one (HR = 0.58, p < 0.0001) with no difference in term of OS, not reached in both arms. Daratumumab has been explored in combination with other triplets as VRD, KRD (carfilzomib, lenalidomide, dexamethasone) and IRD (ixazomib, lenalidomide, dexamethasone). Scholars are waiting for the results of Phase III EMN PERSEUS trial of Dara-VRD vs. VRD as induction and consolidation in 690 TE patients, but randomized phase II GRIFFIN study has already shown that Dara-VRD leads to a 55% reduction in the risk of disease progression and death compared with VRD since, after a median follow-up of 49.6 months, 3-year PFS was 89% in Dara-VRD group vs. 80.7% in VRD one (HR = 0.45, p = 0.0324) [72]. In the MASTER phase II study [73], in which TE patients received 4 Dara-KRD cycles as induction, ASCT and up to 8 cycles of Dara-KRD as consolidation on the basis of MRD status, 80% reached MRD < 10−5 comparable with 71% obtained after 8 cycles of Dara-KRD in the phase 2 MANHATTAN trial [74]. The randomized phase II ADVANCE study, comparing Dara-KRD vs. KRD, will better clarify the role of daratumumab added to KRD. Quadruplet Dara-IRD has been explored in the phase II IFM 2018-01 study including only standard risk cytogenetics patients and reporting a rate of MRD negativity (10−5) of 51.4% after consolidation with 4 cycles of Dara-IRD (preceded by 6 cycles as induction and ASCT) [75].
4. Autologous Stem Cell Transplantation in Light of New Therapies
The introduction of increasingly more effective regimens has questioned the role of upfront ASCT in TE patients and several trials tried to address the issue. Considering those most recently published, the phase III IFM 2009 study [84] demonstrated that in patients receiving 3 VRD cycles as induction followed by ASCT and 2 VRD cycles as consolidation, median PFS was significantly longer if compared with that of patients treated with 8 cycles of VRD, being 47.3 months vs. 35 months (HR = 0.70, p = 0.0001). Phase III US DETERMINATION trial [85], with the same design of IFM 2009 study except for the duration of lenalidomide maintenance that was one year in the IFM trial and until progression in the DETERMINATION one, confirmed the superiority of upfront ASCT in TE patients in term of PFS. The EMN02/HO95 trial [86] in which patients were randomized after a 3–4 VCD induction regimens to receive either 4 cycles of VMP or ASCT, demonstrated the superiority of ASCT over VMP with median PFS of 56.7 vs. 41.9 months, respectively (HR = 0.73, p = 0.0001). Using carfilzomib instead of bortezomib in the triplet induction regimens, KRD plus ASCT was compared with KRD without ASCT and with KCD plus ASCT in the phase III UNITO-MM-01/FORTE trial [87]. A significantly higher proportion of patients who received KRD vs. KCD as induction (4 cycles) achieved at least VGPR, so the primary endpoint of study was met (70% vs. 53%, OR 2.14, p = 0.0002). Remarkably, after a median follow-up of 51 months among patients who were treated with KRD as induction and consolidation (4 cycles), those who underwent ASCT had a significantly longer PFS compared to those receiving additional 4 cycles without ASCT (KRD12) (4-year PFS = 69% vs. 56%, HR = 0.61, p = 0.0084), whereas no significant PFS difference was found between KCD plus ASCT vs. KRD12. The last recently published randomized phase II CARDAMON study [88] showed 2-years’ PFS of 75% in the ASCT group vs. 68% in the KCD group, failing to demonstrate a non-inferiority of KCD compared with ASCT. However, of the above-mentioned studies, only EMN02/HO95 trial reported a significant benefit of ASCT over VMP consolidation in term of OS since after an extended median follow-up, 75-month OS was 69% in the ASCT group vs. 63% in the VMP group (HR = 0.81, p = 0.034). It is reasonable to think that the use of induction/consolidation therapy regimens, that are more effective than VCD/VMP used in the EMN study, could make the role of early ASCT not so certain. The development of innovative BCMA-targeted immunotherapies as CAR T cells and bispecific antibodies, recently approved for RRMM patients, paved the way for exploring them in upfront setting. In the ongoing phase III EMagine/CARTITUDE-6 trial [89], that is comparing a cellular therapeutic approach with CAR T cells with conventional ASCT, NDMM patients are randomized to receive either 6 cycles of Dara-VRD followed lymphodepletion and a single cilta-cel infusion or 4 cycles of Dara-VRD as induction followed by ASCT and 2 cycles of Dara-VRD consolidation.
5. Pros and Cons of Continuous vs. Fixed-Duration Therapy
In both TE and NTE MM patients, long-term therapies aim to prolong the duration of response, allowing to delay occurrence of a relapse that represents a virtually unavoidable event in the course of this haematologic disease. Continuous frontline therapy represents one of the ways to apply this therapeutic approach. In patients without intent for immediate ASCT, US SWOG 0777 trial [92] compared 8 VRd cycles vs. 8 Rd cycles as induction followed by Rd maintenance until progression (median duration of Rd maintenance was 17.1 months). After a median follow-up of 84 months, median PFS was 41 months for VRd and 29 months for Rd (p = 0.003), whereas OS was not reached and 69 months, respectively. Remarkably, VRd significantly improved OS in patients younger than 65 years (HR = 0.640, p = 0.028), but not in those ≥ 65 years old (HR = 0.769, p = 0.168). As described above, longer PFS has been reported with continuous D-Rd evaluated in the MAIA trial [4], showing an improved PFS vs. Rd in all subgroups of patients including those ≥ 75 years in whom median PFS was 54.3 vs. 31.4 months for Rd [80]. Unlike D-Rd regimen, representing a continuous therapy, D-VMP regimen, explored in the ALCYONE study [3], is characterized by an induction with 9 cycles of D-VMP (vs. VPM) followed by daratumumab monotherapy administered every 4 weeks until progression, leading to a median PFS of 37.3 months, definitely lower than that reported with continuous D-Rd. In TE patients, a continuous therapy can be applied with consolidation and maintenance after ASCT. It is undeniable that using as consolidation the same triplet or quadruplet combinations administered as induction, quality and depth of response can be significantly improved as reported by recent trials. In the phase III PETHEMA/GEM2012 trial [69], comparing IV busulfan plus melphalan vs. melphalan as conditioning regimes, the CR rate increases from 33.4% after 6 VRD cycles to 50.2% after 2 VRD consolidation cycles after ASCT with MRD negativity at level of 3 × 10−6 went from 28.8% to 45.2%.
6. High Risk Multiple Myeloma and Risk-Adapted Therapies
The extreme biological and clinical heterogeneity of MM makes this disease very difficult to treat in different patient groups. As described above, the presence of t(4;14), t(14;16) and del(17p), taken into account in the R-ISS score [10], to which it can be added 1q gain/amplification (1q21+) and del(1p) identifying patients with HR MM characterized by a median OS ranging from 3 to 5 years [14]. It has to be emphasized that, unlike t(11;14) for which venetoclax, a BLC2 inhibitor, demonstrated significant efficacy in RRMM setting [106], for patients with all other HR cytogenetic abnormalities currently there are no specific available therapies. However, relevant conclusions can be drawn from retrospective analyses of carried out trials and from ongoing risk-stratified studies. In regard to triplet induction regimens, in the phase III DETERMINATION trial [85], median PFS of HR patients who underwent VRD induction and consolidation after ASCT was 55.5 vs. 82.3 months in SR. In the pre-planned cytogenetic subgroup analysis of FORTE trial [107], KRD plus ASCT resulted in higher rate of 4-years’ PFS compared with KCD plus ASCT and KRD12 in all cytogenetic risk groups. Noticeably, in patients receiving KRD plus ASCT 4-years PFS was 82% vs. 67% (HR = 1.89, p = 0.11) in patients with 0 or 1 high risk cytogenetic abnormalities (defined as the presence of t(4;14), t(14;16), del(17p) or 1q (gain or amp)), respectively. This suggests that this therapeutic approach could abrogate also adverse effect of 1q gain/amplification. In patients with 2 or more high risk cytogenetics abnormalities (HRCA) 4-year PFS resulted to be 55%, significantly lower than that of patients with 0 HRCA (HR = 2.7, p = 0.020). Recently, two retrospective studies compared outcome of HR MM patients receiving VRD or KRD induction followed by ASCT. The first study by MD Anderson Cancer Center [108] included 121 patients with HR cytogenetics defined as t(4;14), t(14;16), del(17p) or 1q (gain or amp), who received a median of 4 VRD or KRD cycles followed by ASCT. After a median follow-up of 34.4 months, 3-year PFS was 53.5% and 64% for KRD and VRD group, respectively (p = 0.25), with no difference reported for OS, not reached for either group (p = 0.30). The second study evaluated 154 NDMM HR patients treated at Memorial Sloan Kettering Cancer Center [109], who, after induction with VRD or KRD, received early ASCT (77 patients) or no early ASCT (77 patients). In the subgroup of patients undergoing early ASCT, 5-year PFS from ASCT was 24% for VRD and 60% for KRD (HR = 0.49, p = 0.04) with 5-year OS of 53% and 87%, respectively (HR = 0.39, p = 0.09). Patients who received more than six induction cycles had longer PFS and OS in multivariate analysis. Moreover, a recent retrospective analysis from MD Anderson Cancer Center [110] reported median PFS and OS of 22.9 months and 60.4 months, respectively, in 79 MM patients harboring t(4;14) and receiving triplets as induction (mainly VRD regimen) followed by ASCT and maintenance, confirming the poor outcome of these HR patients in the real-life setting.
7. Minimal Residual Disease (MRD) in the Era of New Drugs and MRD-Driven Therapies
The introduction of three-drug and, more recently, four-drug combinations as induction and consolidation post ASCT allowed for the achievement of deep responses never seen before. However, despite these results, most patients continue to relapse suggesting that obtaining even a sCR does not lead to a disappearance of disease, low burden of which can be detected by immunophenotypic and molecular methods. Minimal (or measurable) residual disease (MRD) status has emerged as one of the most potent factors affecting PFS and OS in MM. In the meta-analysis by Munshi et al. [119] including 8098 MM patients, obtaining MRD negativity improved PFS (HR = 0.33, p < 0.001) and OS (HR = 0.45, p < 0.001), with a significant OS improvement seen in all settings of patients (NDMM and RRMM), regardless of cytogenetics, method of MRD measurement or sensitivity thresholds of it. However, the highest improvements in PFS and OS were observed with MRD negativity at level of 10−6 (HR = 0.22, p < 0.001; HR = 0.26, p < 0.001, respectively). Currently, Next-Generation Flow (NGF) that, using an 8-colour 2 tube panel, is able to reach a sensitivity between 10−5 and 10−6 and represents one of the most appropriate methodologies to detect bone marrow MRD, as recommended by the International Myeloma Working Group [120]. This method requires more than 5 million cells’ sample and assessment within 24–48 h, but it can be done in a few hours. Using time-dependent analysis, patients with undetectable MRD before maintenance post ASCT (NGF at 3 × 10−6 limit) had an 82% reduction in the risk of progression or death (HR = 0.18, p < 0.001) and an 88% reduction in the risk of death (HR = 0.12, p < 0.00) in the PETHEMA/GEM2012MENOS 65 trial [121].
MS represents a promising method to detect MRD and it has the not negligible advantage to require peripheral blood instead of bone marrow, allowing simple longitudinal evaluations. Patients with MS negativity at different time points (after induction, prior maintenance and one year of maintenance) had an improved PFS in the GMMG-MM5 trial [50]. Noticeably, CR patients who were MS positive before maintenance had a median PFS of 1.7 vs. 4 years in MS negative CR patients (HR = 2.46, p < 0.001).
Several studies either explored or are studying treatments tailored according to MRD response. The single arm, multicenter phase II MASTER trial [73,129] is the first to demonstrate the possibility to discontinue treatment without impact on outcome. After 4 cycles of Dara-KRD as induction followed by ASCT, 123 TE patients received 0, 4 or 8 cycles of Dara-KRD as consolidation based on MRD status, assessed by NGS (<10−5) after induction, ASCT and during each 4-cycle block of Dara-KRD consolidation. Patients who achieved two consecutive MRD negative assessments, at the above-mentioned time points, discontinued therapy and entered MRD surveillance (MRD-SURE), whereas patients without 2 consecutive negative MRD assessments after consolidation underwent lenalidomide maintenance. MRD negativity after MRD-directed consolidation was 81% and, after a median follow-up of 34.1 months, 3-year PFS was 91%, 87% and 51% in patients with 0, 1 and ≥2 HRCA, respectively, with 3-years OS of 96%, 91% and 75%. Notably, in patients with 0 or 1 HRCA that discontinued therapy after 2 MRD negative results, 2-year PFS was 91% and 89%, respectively. An even higher risk of progression or death has been found in patients with ≥2 HRCA. Despite reaching MRD negativity, 2-year PFS from treatment cessation was 54%, suggesting that in these patients alternative strategies should be explored as consolidation therapy. Ongoing randomized phase II MASTER-2 trial will evaluate, after 6 cycles of Dara-VRD as induction, ASCT vs. 3 additional cycles of Dara-VRD, in MRD negative patients after induction whereas positive patients will undergo ASCT followed by teclistamab plus daratumumab vs. daratumumab plus lenalidomide.
8. Sequential Therapy in Relapsed/Refractory MM in Light of New Immunotherapeutic Strategies
Natural history of MM is characterized by a continuous succession of remissions and relapses, and the approval of new mAbs in frontline setting are introducing the problem of choosing a correct treatment strategy in RRMM setting, since refractoriness status is one of the principal features to be considered for selecting successive therapies [131]. Data from randomized clinical trials are in support of continuous therapy in RRMM setting, like in NDMM patients, improving survival outcomes, while early progression after fixed duration therapy diminishes quality of life due to several relapses and cumulative toxicity.
For non-lenalidomide-refractory RRMM patients, lenalidomide-based regimens may be used, that could be mAb-based (daratumumab-lenalidomide-dexamethasone, elotuzumab-lenalidomide-dexamethasone) or PIs-based (carfilzomib-lenalidomide-dexamethasone, ixazomib-lenalidomide-dexamethasone, bortezomib-lenalidomide-dexamethasone) [132]. Daratumumab-lenalidomide-dexamethasone (Dara-Rd) triplet demonstrated a significant survival benefit vs. the comparator doublet (Rd) in the recent OS analysis of the phase III POLLUX trial. After a median follow-up of 79.7 months, median OS was 67.6 vs. 51.8 months, respectively, independently of previous lines of therapy (LOT) (1–3 in enrolled patients) even if OS benefit seemed lower beyond the third line of therapy, high cytogenetic risk and age, being the triplet beneficial also in patients with ≥65 years [133].
For lenalidomide-refractory and PI-sensitive RRMM patients, mAbs- or PI-based treatments may be employed. Phase III IKEMA trial randomized 302 RRMM patients with a median of 2 prior LOT to receive isatuximab-carfilzomib-dexamethasone (Isa-Kd) vs. carfilzomib-dexamethasone (Kd). Recent updates confirmed the significant benefit of the triplet compared to the duplet, which a median PFS of 35.7 vs. 19.2 months and 33.5% vs. 15.4% MRD negativity, respectively [134]. Facon et al. have recently published a subgroup analysis of IKEMA trial, confirming the PFS advantage of Isa-Kd in early (24.7 vs. 17.2 months, HR = 0.662) rather than in late relapse (42.7 vs. 21.9 months, HR = 0.542). This advantage was confirmed also for the depth of response [135]. Median PFS was 38.2 vs. 29.2 months in Isa-Ks vs. Kd arms, respectively, in the group of patients with 1 prior line of therapy; whereas it was 29.2 vs. 17 months, respectively, in patients who received >1 prior line of therapy [136].
For lenalidomide-refractory and PI-sensitive RRMM patients, mAbs- or PI-based treatments may be employed. Phase III IKEMA trial randomized 302 RRMM patients with a median of 2 prior LOT to receive isatuximab-carfilzomib-dexamethasone (Isa-Kd) vs. carfilzomib-dexamethasone (Kd). Recent updates confirmed the significant benefit of the triplet compared to the duplet, which a median PFS of 35.7 vs. 19.2 months and 33.5% vs. 15.4% MRD negativity, respectively [134]. Facon et al. have recently published a subgroup analysis of IKEMA trial, confirming the PFS advantage of Isa-Kd in early (24.7 vs. 17.2 months, HR = 0.662) rather than in late relapse (42.7 vs. 21.9 months, HR = 0.542). This advantage was confirmed also for the depth of response [135]. Median PFS was 38.2 vs. 29.2 months in Isa-Ks vs. Kd arms, respectively, in the group of patients with 1 prior line of therapy; whereas it was 29.2 vs. 17 months, respectively, in patients who received >1 prior line of therapy [136]. As for safety, the most common, any-grade, non-hematologic AEs in Isa-Kd were infusion reactions (45.8%), diarrhea (39.5%), hypertension (37.9%) and upper respiratory tract infections (37.3%). Isa-Kd has been approved by regulatory agencies for the treatment of RRMM with ≥1 prior LOT. Daratumumab-carfilzomib-dexamethasone (Dara-Kd), recently approved by FDA and EMA, demonstrated a median PFS of 28.6 months compared to 15.2 months of the comparator arm Kd, in the phase-3 CANDOR trial, whose characteristics could be similar to the IKEMA trial ones. The most common AEs in the Dara-Kd group were thrombocytopenia (25% vs. 16%), hypertension (21% vs. 15%) and pneumonia (18% vs. 9%) [137]. Phase III CASTOR trial [138] recently demonstrated a significant OS advantage of the triplet daratumumab-bortezomib-dexamethasone (Dara-Vd) compared to bortezomib-dexamethasone (Vd) alone, in 498 RRMM patients with a median of 2 prior LOT after a median follow-up of 72.6 months. Median OS was 49.6 vs. 38.5 months, respectively, and the benefit of the triplet was confirmed independently from age, cytogenetic risk and lenalidomide-refractoriness, OS being higher in patients with MRD negativity. Moreover, authors showed that the advantage of the triplet was highest for patients who have received 1 prior LOT (HR = 0.56), dropping for whom have received 2 lines (HR = 0.87) and so on for more LOT (HR > 1 for ≥3 lines of therapy). The most common (≥10%) grade 3/4 AEs with Dara-Vd vs. Vd were thrombocytopenia (46.1% vs. 32.9%), anaemia (16.0% vs. 16.0%), neutropenia (13.6% vs. 4.6%) and pneumonia (10.7% vs. 10.1%) [138]. Daratumumab-pomalidomide-dexamethasone (Dara-Pd) is a recently approved triplet by regulatory agencies for the treatment of RRMM with ≥1 previous line of therapy [139]. Recent OS updates from phase III APOLLO trial demonstrated a significant OS advantage for this triplet compared to the doublet pomalidomide-dexamethasone (Pd) with a median OS of 34.4 vs. 23.7 months, in a population of 304 RRMM patients with a median of 2 prior LOT (range 1–5), whose 79.6% was lenalidomide-refractory. The most common grade 3/4 AEs was neutropenia (68% vs. 51%) whereas pneumonia were reported in 15% vs. 8% of patients and lower respiratory tract infections in 12% vs. 9%, respectively [140]. Pomalidomide-based triplet isatuximab-pomalidomide-dexamethasone (Isa-Pd) was approved for the treatment of RRMM patients with ≥2 previous lines of therapy, on the basis of results of the phase III ICARIA trial, having randomized 307 RRMM patients to receive the triplet vs. Pd. Isa-Pd demonstrated a median OS of 24.6 vs. 17.7 months, compared to the doublet, after a median follow-up of 52.4 months. Additionally, PFS2 and TNT showed continuous benefit with Isa-Pd vs. Pd, without inducing more resistant disease refractory to subsequent treatments. The most common grade 3/4 AEs in the isatuximab group vs. the control group were neutropenia (50% vs. 35%), pneumonia (23% vs. 21%) and thrombocytopenia (13% vs. 12%) [141,142]. Pomalidomide has been also combined to elotuzumab, anti SLAMF7 mAb, in the phase III ELOQUENT-3 trial, demonstrating a significant OS improvement over Pd (median OS 29.8 vs. 17.4 months), beyond the PFS advantage already demonstrated (median PFS 10.3 vs. 4.7 months), and it was maintained across all the subgroups [143,144]. Elo-Pd has been approved for the treatment of RRMM with ≥2 prior LOT. Data from a phase-2 study evaluating efficacy of Elo-Pd in daratumumab-exposed RRMM patients, which were <5% in ELOQUENT-3 trial, showed a PFS of 3.7 months, demonstrating lower efficacy of this triplet in daratumumab-exposed patients. Interestingly, patients who received Elo-Pd immediately following progression on daratumumab obtained significantly longer PFS than patients who got Elo-Pd ≥ 1 line after daratumumab failure; however, they were less heavily pre-treated [145]. Daratumumab-refractoriness is the actual primary challenge for clinicians who treat MM patients [5]. Considering that daratumumab-containing regimens currently represent a standard in TE and NTE patients as above-mentioned, the number of these patients is rapidly increasing. There are limited data on the outcomes of patients relapsing after first-line daratumumab-based therapy and mechanisms of resistance are poorly understood, but re-treatment with anti-CD38 seems to be ineffective [146]. Recent data from the French real life EMMY study reported better but not exciting results when patients were re-treated with anti-CD38 in the early lines of therapy (second and third). Further investigations are needed to answer this challenging question [147]. Therefore, despite the impressive results of mAbs in RRMM, patients continue to relapse and have a dismal outcome [148,149]. Consequently, researchers have combined the specificity of mAbs with a cytotoxic drug, creating a sophisticated delivery system to transport a lethal payload directly to the tumor cells. The selected and most developed target has been BCMA, the B cell maturation antigen expressed at high levels in plasma cells and plasma blasts, but not in other tissues.
9. Precision Medicine and Next Generation Therapies
Venetoclax (Ven) is a potent and selective oral BCL-2 inhibitor with demonstrated anti-myeloma activity in pts with t(11;14), thus making it the first example of precision medicine in MM.
The phase III BELLINI trial, randomizing RRMM patients with 1–3 prior lines of therapy between venetoclax-bortezomib-dexamethasone vs. bortezomib-dexamethasone showed better outcomes for the venetoclax-bortezomib-dexamethasone arm, although increased mortality was observed in the venetoclax group, reflecting a higher incidence of death related to infection [106]. A phase 1/2 trial is evaluating venetoclax in association to dara with/without bortezomib in t(11;14) RRMM patients, part 3 of this study has been recently updated demonstrating an ORR of 95%, 100% and 62% for the Ven400Dd, Ven800Dd, and DVd arms, whereas the ORR for the combined Ven arms was 98%. VenDd demonstrated deep responses that appear to be durable; data are not mature and follow-up is ongoing [234].
Iberdomide (CC-220) is an orally available CELMoDs (cereblon E3 ligase modulator) agent that binds to the cereblon E3 ubiquitin ligase complex leading to greater degradation of Ikaros and Ailos than lenalidomide and pomalidomide. It has been investigated in the phase I/II CC-220-MM-001, with 31.9% ORR and a manageable safety profile, and phase III EXCALIBER-RRMM studies with different treatment combinations in RRMM patients. Iberdomide-dexamethasone combination recently showed encouraging efficacy and safety in patients with triple-class-exposed (ORR 36.8%) or triple-refractory RRMM and prior anti-BCMA therapy in specific cohorts of CC-220-MM-001 trial [235].
Mezigdomide (CC-92480) is another potent CELMoD, that has a significantly higher degradation efficiency compared to either lenalidomide or pomalidomide, having shown a 55% ORR in a heavily pre-treated RRMM population enrolled in the phase I CC-92480 trial [236]. Efficacy data in triple-class refractory RRMM, including patients with prior BCMA-targeted therapies are promising, showing 40% and 50% ORR, respectively [237]. Selinexor is a first-in-class, selective exportin-1 inhibitor, that is approved in the EU and USA for the treatment of adult patients with MM who have received at least one prior therapy. Approval of the selinexor-bortezomib-dexamethasone (XVd) regimen was based on the phase III BOSTON trial, in which 195 patients received XVd vs. 207 twice-weekly Vd, with a median PFS of 13.93 vs. 9.46 months, respectively [238]. The phase I/II STOMP trial, which showed an ORR of 78% in RRMM patients treated with Xd-carfilzomib, recently confirmed this advantage also in triple-refractory patients (ORR 67%) [239].
This entry is adapted from the peer-reviewed paper 10.3390/cancers15082203
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