In multiple myeloma, certain cytogenetic abnormalities, such as t(4;14), t(14;16), and del(17p), are considered high risk and are associated with worse prognosis. Patients with these high-risk cytogenetic abnormalities, as well as those who are elderly and transplant ineligible, have not experienced the same degree of improved survival outcomes that other patients have seen with recent advances in the treatment of multiple myeloma. To date, no treatment regimen has demonstrated sustained and consistent survival beneﬁts in elderly, transplant-ineligible patients with high-risk cytogenetic abnormalities and newly diagnosed multiple myeloma. Thus, there is an unmet need to identify effective treatment options for these patients and achieve outcomes parity with standard-risk patients. In this review, we assessed clinical trials of both doublet and triplet regimens for newly diagnosed multiple myeloma that included elderly, transplant-ineligible patients with high-risk cytogenetic abnormalities and that provided outcomes data stratiﬁed by cytogenetic risk status. We concluded that regimens containing an IMiD agent as the foundation of therapy, combined with agents that have synergistic mechanisms of action— including novel therapies—may in future investigations help overcome the poor prognosis of high-risk cytogenetic abnormalities in this vulnerable patient population. Introduction (PFS) in patients lacking both t(4;14) and del(17p) abnormalities was 24 vs 14 months for patients with t(4;14) Multiple myeloma (MM) is a highly heterogeneous malig- and 11 months for patients with del(17p) (P < 0.001) . nancy characterized by a variable disease course [1, 2]. Similarly, median overall survival (OS) in patients without Speciﬁc cytogenetic abnormalities confer poor outcomes in either abnormality was 50 vs 32 months for patients with t patients with MM , including t(4;14), t(14;16), and del (4;14) and 19 months for patients with del(17p) (P < 0.001). (17p), which are well validated high-risk prognostic factors Greater understanding of the molecular biology and [4, 5]. The International Myeloma Working Group (IMWG) development of novel therapies for MM has resulted in molecular classiﬁcation lists these abnormalities as estab- improved survival in recent decades [7, 8], but not all lished markers that are essential testing for all patients with patient subgroups have beneﬁted equally. Improvements in MM . In a retrospective study using data from the outcomes for patients with high-risk cytogenetic abnorm- Intergroupe Francophone du Myelome database for patients alities and elderly patients have not been as great as in aged >65 years (median, 72 years) with newly diagnosed transplant-eligible patients who do not have high-risk MM (NDMM; N = 1890), median progression-free survival cytogenetic abnormalities [3, 9]. Indeed, although overall response rates (ORRs) are often similar between patients with high-risk and standard-risk cytogenetic abnormalities [10–12], this has not always correlated to similar survival * Herve Avet-Loiseau outcomes. Moreover, elderly patients with NDMM and email@example.com high-risk cytogenetic abnormalities who are not eligible for transplant remain in need of treatment regimens that provide Unite de Genomique du Myelome CHU Rangueil, Toulouse, France long-term beneﬁts to PFS and OS with minimal toxicity. To date, no treatment regimen, including those containing Service des Maladies du Sang, Hôpital Claude Huriez, Lille, France lenalidomide or bortezomib, has demonstrated sustained 1234567890();,: 1234567890();,: 1268 H. Avet-Loiseau, T. Facon Table 1 Select trials of doublet and triplet regimens in patients with transplant-ineligible NDMM and high-risk cytogenetic abnormalities Trial Patient population Regimens N Median age High-risk cytogenetics Response by cytogenetics PFS and OS by cytogenetics (range), y Retrospective study NDMM Rd vs RD 100 HR: 67 (48–78) HR (n = 16): hypodiploidy, del ORR: HR vs SR, 81 vs 89%; Median PFS: HR vs SR, 18.5  SR: 63 (32–78) (13q), del(17p), t(4;14), t P = 0.56 vs 36.5 mo; P < 0.001 (14;16), or plasma cell labeling ≥ VGPR: HR vs SR, 38 vs 45%; index ≥3% P = 0.36 Ph III E4A03 [16, 17] NDMM Rd vs RD 445 HR: 62 126 pts with FISH; HR (n = 21): ORR: HR vs SR, 75% vs 77% Median PFS: HR vs SR, 11 vs SR: 66 t(4;14), t(14;16), or del(17p) ≥ VGPR: HR vs SR, 30 vs 46% 29 mo; P = 0.047 deletions OS: HR vs SR hazard ratio, 3.48 [95% CI, 1.42–8.53]; P = 0.004 Ph III FIRST [18, 19] NDMM TI Rd continuous 1623 73 [94% ≥ 65 y] 762 pts with FISH; 19% HR [t ORR: HR patients: 77% (Rd Median PFS: HR: Rd vs Rd18 vs MPT (4;14), t(14;16), or del(17p)] continuous) vs 67% (Rd18) vs 68% continuous, 8.4 mo (MPT) Rd18, 17.5 mo SR patients: 81% (Rd continuous) vs MPT, 14.6 mo 80% (Rd18) vs 71% (MPT) SR: Rd continuous, 31.1 mo ≥ VGPR: HR patients: 30% (Rd Rd18, 21.2 mo continuous) vs 35% (Rd18) vs 11% MPT, 24.9 mo (MPT) Median OS: HR: Rd SR patients: 49% (Rd continuous) vs continuous, 29.3 mo 47% (Rd18) vs 39% (MPT) Rd18, 24.3 mo MPT, 35.5 mo SR: Rd continuous, 69.9 mo Rd18, 68.7 mo MPT, 53.6 mo Ph III, SWOG S0777 NDMM without RVd vs Rd 471 63 [43% ≥ 65 y] 316 pts with FISH; 33% HR [t NR Median PFS: HR: RVd, 38 mo  intent for (4;14), t(14;16), or del(17p)] Rd, 16 mo immediate ASCT P = 0.19 t(4;14): RVd, 34 mo Rd, 15 mo P = 0.96 Ph III VISTA [11, 12] NDMM TI VMP vs MP 682 71 [97% ≥ 65 y] 168 pts in VMP with NR Median OS in VMP arm only: cytogenetics data; 15% HR [t HR vs SR cytogenetics: 40.0 (4;14), t (14;16), or del(17p)] mo vs not reached; P = 0.399 Ph III Spanish Elderly NDMM VMP vs VTP 260 HR: 72 232 pts with cytogenetics data; ORR after induction: HR, 79% Median PFS: HR vs SR, 24 vs GEM05MAS65 [29, SR: 72 HR (n = 44): t(4;14), t (14;16), SR, 82% 33 mo; P = 0.04 30] [100% ≥ 65 y] and/or del(17p) SR (n = 188) Median OS: HR vs SR, 38 mo vs not reached; P = 0.001 Ph III GIMEMA  NDMM TI VMPT → VT vs 511 71 [96% ≥ 65 y] 376 pts with cytogenetics data; NR PFS: VMP → VT vs VMP in VMP 16% t(4;14), 4% t(14;16), 15% pts with HR CAs hazard ratio, del(17p) 0.98 [95% CI, 0.58–2.10]; P = 0.215 Front-line therapies for elderly patients with transplant-ineligible multiple myeloma and high-risk. . . 1269 Table 1 (continued) Trial Patient population Regimens N Median age High-risk cytogenetics Response by cytogenetics PFS and OS by cytogenetics (range), y Ph II Spanish Elderly NDMM Sequential or 242 NR [100% ≥ 174 pts with FISH; ORR: Sequential (HR vs SR) 74 vs Median PFS: sequential (HR vs GEM2010 [32, 33] alternating VMP 65 y] HR (n = 32): t(4;14), t (14;16), 79% SR) 29.5 vs 31.5 mo; P = 0.9 and Rd and/or del(17p) SR (n = 142) Alternating (HR vs SR) 69 vs 86% Alternating (HR vs SR) 24 vs 33 mo; P = 0.03 Median OS: sequential (HR vs SR) 46 vs 63 mo; P = 0.1 Alternating (HR vs SR) 38.4 mo vs not reached; P = 0.002 Ph III  NDMM TI MPT-T vs MPR- 668 MPT-T: 72 367 pts with FISH; NR PFS and OS: no signiﬁcant R (33% ≥ 76 y) HR (n = 174): del(17p), difference in treatment with MPR-R: 73 t(4;14), gain(1q21) MPT-T vs MPR-R for all (34% ≥ 76 y) analyzed subgroups (HR CAs) Median PFS: gain(1q21) (MPT- T vs MPR-R) 17 vs 19 mo del(17p) (MPT-T vs MPR-R) 15 vs 15 mo t(4;14) (MPT-T vs MPR-R) 12 vs 14 mo Median OS: gain(1q21) (MPT- T vs MPR-R) 39 vs 50 mo del(17p) (MPT-T vs MPR-R) 41 vs 35 mo t(4;14) (MPT-T vs MPR-R) 23 mo vs not reached Retrospective NDMM TI CyBorD vs 122 CyBorD: 76 t(4;14), t(14;16), and p53 del, 21 NR Median PFS: HR vs SR, 11.8 institutional study  VMP vs Vd VMP: 73 pts (17%) vs 15.9 mo; P = 0.002 Vd: 77 Median OS: HR vs SR, 22.4 vs 39.7 mo; P = 0.029 ASCT autologous stem cell transplant, CA cytogenetic abnormality, CyBorD cyclophosphamide, bortezomib, dexamethasone, FISH ﬂuorescent in situ hybridization, HR high risk, MP melphalan, prednisone, MPR-R melphalan, prednisone, lenalidomide, followed by lenalidomide maintenance, MPT melphalan, prednisone, thalidomide, MPT-T melphalan, prednisone, thalidomide, followed by thalidomide maintenance, NDMM newly diagnosed multiple myeloma, NR not reported, ORR overall response rate, OS overall survival, PFS progression-free survival, ph phase, pt patient, Rd lenalidomide plus low-dose dexamethasone, RD lenalidomide plus high-dose dexamethasone, Rd18 lenalidomide plus low-dose dexamethasone for 18 cycles, RVd lenalidomide, bortezomib, dexamethasone, SR standard risk, TI transplant ineligible, TTP time to progression, Vd bortezomib, dexamethasone, VGPR very good partial response, VMP bortezomib, melphalan, prednisone, VMPT bortezomib, melphalan, prednisone, thalidomide, VT bortezomib, thalidomide Per preliminary analyses from available data at trial entry 1270 H. Avet-Loiseau, T. Facon and consistent survival beneﬁts in these patients. Addi- Doublet regimens: Rd and Vd tionally, the relatively smaller number of elderly patients with NDMM and patients with high-risk cytogenetic Lenalidomide–low-dose dexamethasone (Rd) and abnormalities who are enrolled in prospective clinical trials bortezomib-dexamethasone (Vd) are identiﬁed as doublet has limited the quantity of available data. However, useful regimens for the treatment of transplant-ineligible NDMM data can be gathered from large trials that include these in recent treatment guidelines [1, 7]. The NCCN guidelines patient subgroups. recognize Rd as a preferred category 1 regimen, whereas Vd The purpose of this review is to assess the available is listed in the “Useful in Certain Circumstances” category data for doublet and triplet regimens in elderly patients . In the ESMO guidelines, Rd is listed as a “ﬁrst option,” with transplant-ineligible high-risk NDMM and identify whereas Vd is not recognized . The ESMO guidelines treatment options with the potential to overcome the recognize melphalan-prednisone (MP) as an “other option,” poor prognosis associated with high-risk cytogenetic but the NCCN guidelines note that melphalan-containing abnormalities. regimens are not standard of care in transplant-ineligible patients [1, 7]; therefore, this review did not consider MP. In NDMM trials examining doublets, efﬁcacy outcomes in Methodology high-risk patients have typically lagged behind those patients with standard-risk cytogenetic abnormalities To identify data regarding the use of doublet and triplet (Table 1). In a retrospective study of patients who received regimens in the treatment of elderly patients with transplant- either Rd or lenalidomide–high-dose dexamethasone (RD) ineligible NDMM and high-risk cytogenetic abnormalities, as initial therapy (N = 100), outcomes were stratiﬁed by we reviewed clinical trials of regimens recommended or high-risk vs standard-risk cytogenetic abnormalities, with preferred by the National Comprehensive Cancer Network high-risk cytogenetic abnormalities deﬁned as presence of (NCCN) and European Society for Medical Oncology del(17p), t(4;14), t(14;16), hypodiploidy, plasma cell (ESMO) guidelines as treatment options for patients with labeling index ≥3%, or monoallelic loss of chromosome 13 transplant-ineligible NDMM [1, 7]. We also performed a or its long arm . Fifty patients (50%) proceeded to SCT literature search to ﬁnd NDMM studies or subanalyses that after induction. ORR was similar in patients with high-risk included data stratiﬁed by cytogenetic risk status and patient cytogenetic abnormalities (n = 16; median age 67 years) age. Using the PubMed database, we searched for data and those with standard-risk cytogenetic abnormalities published between 2010 and 2017 and the keywords (n = 84; median age 63 years); 81 vs 89%, respectively “lenalidomide or bortezomib” and “myeloma” and “risk.” (P = 0.56). However, PFS was signiﬁcantly longer in the Additionally, we conducted searches for abstracts accepted standard-risk group vs the high-risk group (36.5 vs by the European Hematology Association, American 18.5 months, respectively; P < 0.001). In an analysis that Society of Clinical Oncology, and American Society of censored data from patients who underwent SCT, the PFS Hematology congresses between 2015 and 2017, using the ﬁndings were similar to those in the overall analysis: terms “myeloma,”“transplant,” and “cytogenetics.” After 36.9 months for standard-risk patients vs 18.5 months for applying additional criteria—newly diagnosed, elderly, high-risk patients (P = 0.002). No safety data were reported transplant ineligible, and outcomes by cytogenetic risk in this publication. stratiﬁcation—10 trials were identiﬁed, which together had The open-label, phase 3 E4A03 study (N = 445) com- data on treatment outcomes in approximately 650 patients pared RD with Rd in patients with NDMM . The with NDMM and high-risk cytogenetics (Table 1). We median age of patients in the RD group was 66 years (53% reported efﬁcacy data by cytogenetic status, but reported ≥65 years) and was 65 years (51% ≥65 years) in the Rd safety data for the overall trial populations as most of the group. Eligible patients could receive SCT after the ﬁrst reviewed trials did not provide these data by cytogenetic four cycles of therapy; those who underwent SCT (n = 167; status. In consideration of the narrow criteria and to avoid 38%) discontinued the study per protocol. After a median overlooking relevant data, clinical trials with a median follow-up of 12.5 months, Rd was superior to RD for OS patient age of <65 years (non-elderly) were included as (P = 0.0002) and was associated with less toxicity. Jacobus long as patients ≥65 years of age (elderly) were also et al. performed a subanalysis on the clinical signiﬁcance of included in the trial. This age limit was chosen to deﬁne cytogenetic risk status in this study population . elderly in this review because 65 years of age is commonly Fluorescent in situ hybridization (FISH) analysis data were used as a cutoff for stem cell transplant (SCT) eligibility, available for 126 patients, with 21 classiﬁed as high risk although it must be acknowledged that transplant may be a based on the presence of t(4;14), t(14;16), or del(17p). ORR treatment option for ﬁt patients older than 65 years of age as was similar in the two cytogenetic abnormality risk groups well [13–15]. (75% for standard risk and 77% for high risk), whereas the Front-line therapies for elderly patients with transplant-ineligible multiple myeloma and high-risk. . . 1271 standard-risk group had a longer median PFS (29 vs 15.9 months; P = 0.002) and median OS (22.4 vs 11 months; P = 0.047) and a higher 2-year OS rate (91 vs 39.7 months; P = 0.029). The most common AE across all 76%) vs the high-risk group. Overall, toxicities were cohorts was peripheral neuropathy (42.8% in the CyBorD reported more frequently with RD than Rd. Signiﬁcantly group, 66% in the VMP group, and 55% in the VD group; more patients in the RD group had grade ≥3 non- P = 0.03). hematologic toxicities than patients in the Rd group (65 vs In the reviewed studies, median PFS for high-risk 48%; P = 0.0002), including deep vein thrombosis or pul- patients treated with doublets ranged from 8 to monary embolism (26 vs 12%; P = 0.0003) and hypergly- 19 months, compared with a range of 21 to 37 months in cemia (11 vs 6%; P = 0.09). Rates of neuropathy were standard-risk patients. It must be noted that, in both the similar between the treatment groups (2 vs 2%; P = 0.1). retrospective study by Kapoor et al. and the E4A03 study, More patients in the RD group (27%) discontinued treat- substantial proportions of patients proceeded to SCT. ment due to adverse events (AEs) than patients in the Rd Nevertheless, these data demonstrate that current doublet group (19%) . regimens are suboptimal, because neither Rd nor Vd alone The phase 3 FIRST trial compared Rd continuous vs Rd is enough to overcome the poor prognosis associated with for 18 cycles (Rd18) vs MP-thalidomide (MPT) in high-risk cytogenetic abnormalities in patients with transplant-ineligible patients with NDMM (N = 1623) . NDMM, most of whom were elderly and not eligible for Across all treatment arms, the median age was 73 years. In transplant. However, triplet regimens containing novel the Rd continuous and Rd18 groups, 94% of patients agents, as discussed below, may better improve survival were aged ≥65 years, and in the MPT group, 95% of outcomes in this patient population. patients were aged ≥65 years. For patients with high-risk cytogenetic abnormalities, Rd continuous resulted in a numerically higher ORR than both MPT and Rd18 (77 vs Triplet regimens 68 vs 67%, respectively), but did not demonstrate a sig- niﬁcant improvement in PFS or OS vs MPT . In patients Elderly patients with MM are a heterogenous population, with standard-risk cytogenetics, ORRs were 81, 71, and and they range from ﬁt to frail [21, 22]. Frail elderly patients 80%, respectively. Despite the similar ORRs observed in may not be able to tolerate triplet regimens as well as those patients with high-risk and standard-risk cytogenetics, PFS who are not frail may be able to. With that noted, the NCCN was worse in high-risk patients. The 4-year PFS rates were MM guidelines recommend triplet regimens over doublet 34.7, 11.8, and 15.3%, respectively, for patients with regimens in patients who can tolerate them . An IMWG standard-risk cytogenetics, compared with 3.0, 10.0, and consensus statement on the treatment of MM with high-risk 0%, respectively, for patients with high-risk cytogenetic cytogenetic abnormalities recommends a triplet regimen abnormalities. These data further indicate that the Rd that includes a proteasome inhibitor, an IMiD agent, and doublet alone is unable to overcome the poor PFS prognosis dexamethasone for the treatment of patients with NDMM associated with high-risk cytogenetic abnormalities. As and high-risk cytogenetic abnormalities . Despite the reported in the initial publication, MPT was associated with limited efﬁcacy of Rd or Vd alone in patients with high-risk higher rates of hematologic AEs than Rd continuous and cytogenetic abnormalities, promising results have been Rd18 . There was a higher frequency of grade 3/4 demonstrated in patients with relapsed or refractory MM neutropenia reported with MPT (45%) than with either Rd and high-risk cytogenetic abnormalities using Rd or Vd as a continuous (30%) or Rd18 (26%). In the Rd continuous backbone regimen [23–27]. group, 32% patients had grade 3/4 infections vs 22% with The open-label, multicenter, phase 3 SWOG S0777 trial either Rd continuous or 17% with MPT . compared Rd with RVd in patients with NDMM without Although limited data exist for Vd in randomized stu- intent for immediate autologous SCT (ASCT) . The dies, Vd has been examined in elderly patients with median age of patients in both treatment groups was 63 transplant-ineligible NDMM. Jimenez-Zepeda et al. con- years; 43% of the patients evaluable for efﬁcacy were ≥65 ducted an institutional study examining the use of years of age. Median follow-up was 55 months. Patients cyclophosphamide-bortezomib-dexamethasone (CyBorD), treated with RVd had signiﬁcantly longer median PFS than bortezomib-MP (VMP), and Vd in transplant-ineligible those treated with Rd (43 vs 30 months; P = 0.0018). Data NDMM (N = 122) . The median age at diagnosis for from FISH analyses conducted at trial entry were available patients in the study was 76, 73, and 77 years, respectively. for 316 patients; 33% had ≥1 high-risk cytogenetic High-risk cytogenetic abnormalities, deﬁned as t(4;14), t abnormality—either t(4;14), t(14;16), or del(17p). Among (14;16), or p53 del, were identiﬁed in 21 patients overall evaluable high-risk patients (n = 44), there was numerical (17%). Compared with standard-risk patients, high-risk superiority in the RVd group compared with the Rd group patients had signiﬁcantly shorter median PFS (11.8 vs for median PFS (38 vs 16 months), but this was not 1272 H. Avet-Loiseau, T. Facon signiﬁcant (P = 0.19). A similar treatment difference in with that of VMP in patients with transplant-ineligible median PFS was seen in patients with t(4;14) speciﬁcally (n NDMM (N = 511) . The median age of the study = 17): 34 months in the RVd group vs 15 months in the Rd population was 71 years, with 96% aged ≥65 years. FISH group (P = 0.96). Overall, 75% of patients in the Rd group data were available for 376 patients; 15% had del(17p), experienced grade ≥3 AEs vs 82% in the RVd group. 16% had t(4;14), and 4% had t(14;16). There was no sig- Patients treated with RVd had a greater frequency of grade niﬁcant PFS beneﬁt with VMPT followed by VT vs VMP ≥3 neurologic toxicity than patients treated with Rd (33 vs among high-risk patients (HR, 0.98 [95% CI, 0.58–2.10]) or 11%; P < 0.0001). standard-risk patients (HR, 0.69 [95% CI, 0.46–1.02]), The phase 3 VISTA trial compared the efﬁcacy of VMP suggesting that adding a fourth agent to induction therapy with that of MP for the treatment of NDMM (N = 682); the may not provide added beneﬁt over a triplet regimen. The study population was elderly, with a median age of 71 years frequency of grade 3/4 hematologic AEs was similar and 97% of patients ≥65 years . Of patients with FISH between the VMPT followed by VT and VMP groups (47 data who were treated with VMP (n = 168), 15% were vs 41%; P = 0.20). However, VMPT followed by VT was considered high risk due to presence of t(4;14), t(14;16), or associated with more frequent grade 3/4 nonhematologic del(17p). In patients treated with VMP, OS trended longer AEs (46 vs 33%; P = 0.003); grade 3/4 cardiologic events among the standard-risk patients than the high-risk patients were reported in 10% of patients in the VMPT followed by (median OS, not reached vs 40.0 months; hazard ratio (HR), VT group vs 5% in the VMP group (P = 0.04). 1.346 [95% conﬁdence interval (CI), 0.674–2.687]; P = The phase 2 Spanish study GEM2010 (N = 242) com- 0.399) . As reported in the initial publication, there was pared sequential vs alternating VMP with Rd in patients no statistical difference in time to progression between with NDMM . There were 233 patients who were patients treated with VMP who had high-risk cytogenetic evaluable for safety and efﬁcacy, and all were aged abnormalities and those who had standard-risk cytogenetics ≥65 years. FISH data were available for 174 patients . (median time to progression, 19.8 vs 23.1 months; HR, Of these patients, 32 had high-risk cytogenetic abnormal- 1.297 [95% CI, 0.55–3.06]; P = 0.55) . In the VMP ities, whereas 142 had standard-risk cytogenetic abnormal- group, 91% of patients had a grade ≥3 treatment-emergent ities. Between high-risk and standard-risk patients, ORRs AE vs 80% in the MP group . Neutropenia was the most did not differ signiﬁcantly. High-risk and standard-risk common grade 3/4 AE in either treatment arm, and was patients had similar ORRs in both the alternating treatment reported in 12% of patients receiving VMP and 11% of arms (69 and 86%, respectively) and the sequential treat- patients receiving MP. ment arms (74 and 79%). In the alternating treatment arm, In the phase 3 Spanish GEM05MAS65 trial, patients patients with high-risk cytogenetic abnormalities had a aged ≥65 years with NDMM were treated with either VMP shorter median PFS than those with standard-risk cytoge- or bortezomib-thalidomide-prednisone (VTP) as induction netic abnormalities (24 vs 33 months; P = 0.03); patients regimens (N = 260) ; patients were then randomized to with high-risk cytogenetic abnormalities also had shorter maintenance with bortezomib-prednisone or bortezomib- median OS than those with standard-risk cytogenetic thalidomide (VT). FISH analysis data were available for abnormalities (38.4 months vs not reached; P = 0.002). In 232 patients ; 19% had high-risk cytogenetic abnorm- the sequential treatment arm, however, there was no sig- alities (n = 44), deﬁned as t(4;14), t(14;16), or del(17p). niﬁcant difference between standard-risk and high-risk The median age of both standard- and high-risk patients was patients in their median PFS (31.5 vs 29.5 months, 72 years. ORR after induction was similar between the respectively; P = 0.9) or median OS (63 vs 46 months, standard-risk and high-risk groups (82 vs 79%), regardless respectively; P = 0.1). Safety data were reported by age of treatment. The high-risk group had a signiﬁcantly shorter group . More patients >80 years of age (63%) dis- median PFS from ﬁrst randomization (24 vs 33 months; P continued the trial due to toxicity or informed consent = 0.04) and median OS (38 months vs not reached; P = withdrawal than patients aged 65–75 (30%) or those aged 0.001) compared with standard-risk patients. Neutropenia 75–80 years (30%). was reported more frequently with VMP than VTP (39 vs A multicenter, randomized phase 3 trial by Zweegman 22%; P = 0.008), as was thrombocytopenia (27 vs 12%; P et al. examined MPT followed by thalidomide maintenance = 0.0001) . As for nonhematologic toxicities, VMP was (MPT-T) vs MP-lenalidomide followed by lenalidomide associated with a higher incidence of infections than VTP (7 maintenance (MPR-R) in patients with transplant-ineligible vs 1%; P = 0.01) but a lower incidence of cardiac events (0 NDMM (N = 668) . In the MPT-T arm (n = 318), the vs 8%; P = 0.001). During the maintenance phase, there median age of patients was 72 years (33% aged ≥76 years), were no grade ≥3 hematologic AEs. and in the MPR-R arm (n = 319), median age was 73 years The phase 3 GIMEMA trial compared the efﬁcacy of (34% aged ≥76 years). FISH was performed in 73% of bortezomib-MPT (VMPT) followed by VT maintenance patients in the MPT-T arm and 78% in the MPR-R arm, Front-line therapies for elderly patients with transplant-ineligible multiple myeloma and high-risk. . . 1273 Table 2 Key challenges in the treatment of patients with multiple myeloma with high-risk cytogenetic abnormalities Challenge Explanation Inconsistent deﬁnitions for high-risk The lack of consensus on precisely which CAs are considered high risk leads to variable inclusion of CAs CAs in clinical studies, complicating data interpretation by clinicians Limited data Past clinical trials have not consistently included patients with high-risk CAs. In studies that do include these patients, a full subanalysis may not be executed, and the small number of patients with high-risk CAs makes it difﬁcult to compare outcomes with SR patients or overall study populations High cost of testing for CAs Standard bone marrow examination, required for FISH analysis, has become more expensive  Heterogeneity of CAs Multiple CAs impart poor prognosis. Treatments may help overcome an aspect of the poor prognosis imparted by one CA but not others, or may help in TE patients but not TI patients; this requires careful consideration of therapy Lack of treatment guidelines Although the NCCN and ESMO MM guidelines both recognize cytogenetic abnormalities as prognostic factors, neither provides categorized treatment recommendations for patients with TI NDMM and high- risk CAs [1, 7] CA cytogenetic abnormality, ESMO European Society for Medical Oncology, FISH ﬂuorescent in situ hybridization, MM multiple myeloma, NCCN National Comprehensive Cancer Network, NDMM newly diagnosed multiple myeloma, SR standard risk, TE transplant eligible, TI transplant ineligible with presence of del(17p), t(4;14), or gain(1q21) being reported in the SWOG S0777 trial, which was the only classiﬁed as high risk. The MPT-T arm had 87 standard-risk reviewed trial that included the recommended triplet regi- patients and 88 high-risk patients, whereas the MPR-R arm men by the IMWG (a proteasome inhibitor, IMiD agent, had 106 standard-risk patients and 86 high-risk patients. In and dexamethasone). This further suggests that elderly subanalyses of MPT-T vs MPR-R for both OS and PFS patients with high-risk cytogenetics may beneﬁt from based on age and cytogenetic risk status, no statistical dif- regimens that combine novel agents. ference in outcomes between the treatment groups was found across any of the investigated subgroups. In the overall population, there was no statistical difference in PFS Discussion and future strategies with MPT-T (20 months) vs MPR-R (23 months). Out- comes data for patients with high-risk cytogenetic Over half of patients with myeloma are considered elderly abnormalities were provided for each cytogenetic abnorm- (≥65 years), with a median age at diagnosis of 69 years, and ality individually, with each abnormality negatively approximately 15–20% of patients newly diagnosed with impacting PFS (P < 0.01). Among patients in the MPT-T myeloma have high-risk disease, including the presence arm, PFS was 17, 15, and 12 months for gain(1q21), del high-risk cytogenetic abnormalities among other prognostic (17p), and t(4;14), respectively, and 19, 15, and 14 months features [35, 36]. Advanced age may preclude many of for patients treated with MPR-R. Findings from the FIRST these patients from receiving SCT, which is commonly trial support these data and show that MPT cannot over- reserved for patients <65 years of age [13–15]. These come the adverse PFS prognosis of high-risk cytogenetic patients are routinely seen in clinical practice, but they are abnormalities. The rate of grade 3/4 AEs was 81% in the underrepresented in clinical trials, making treatment deci- MPT-T group vs 86% in the MPR-R group (P = 0.13). sions difﬁcult. Elderly patients with NDMM and high-risk Grade 3/4 hematologic AEs were more frequently reported cytogenetic abnormalities need effective and tolerable with MPR-R vs MPR-T, including neutropenia (64 vs 27%; treatment regimens to help them overcome the poor prog- P < 0.001), thrombocytopenia (30 vs 8%; P < 0.001), and nosis imparted by their high-risk cytogenetic status, but anemia (14 vs 5%; P < 0.001). there are many challenges in the treatment of these patients In the reviewed trials that examined triplet regimens, (Table 2). Additionally, the fragmented data from a limited median PFS for patients with high-risk cytogenetic number of trials demonstrate that no therapeutic modality in abnormalities ranged from 12 to 38 months. Among the NDMM has consistently shown improvements in PFS for studies that included data for standard-risk patients, median elderly patients with high-risk cytogenetic abnormalities, PFS ranged from 32 to 33 months. Although these are and these patients have not achieved survival outcomes limited data, the reported median PFS range for high-risk parity with standard-risk patients in clinical trials. Lenali- patients reached a longer period (38 months) than that noted domide and bortezomib have emerged as cornerstones of from the doublet trials (19 months). Notably, the longest MM care, but the above review of the limited data available reported median PFS (38 months) in patients with high-risk with doublet regimens demonstrate that neither Rd nor Vd cytogenetic abnormalities was achieved with RVd, as alone is enough to mitigate the poor prognosis of high-risk 1274 H. Avet-Loiseau, T. Facon cytogenetic abnormalities. However, because some novel trials examining triplet regimens containing the Rd or Vd agents have great tolerability and synergistic mechanisms of backbone with newer agents (carﬁlzomib, elotuzumab, action (MOAs), patients may beneﬁt from regimens that use daratumumab, and ixazomib) for the treatment of relapsed a combination of these novel agents [19, 37]. Indeed, a 2016 or refractory MM have shown promising results in patients consensus statement by the IMWG recommends that with high-risk cytogenetic abnormalities, and we patients with NDMM and high-risk cytogenetic abnormal- eagerly anticipate the results of such combinations in ities receive a triplet regimen containing a proteasome NDMM studies [23–27]. The available data suggest that inhibitor, dexamethasone, and lenalidomide or pomalido- using an IMiD agent as the foundation of combination mide . Going forward, it will be important to further therapy with drugs that have synergistic MOAs may over- explore the efﬁcacy of such triplets and identify the optimal come the poor outcomes imparted by high-risk cytogenetic regimens for these patients. abnormalities. Multiple factors make interpretation of data from high- risk patients difﬁcult. Risk stratiﬁcation in MM remains ﬂuid, and the lack of consistency in the methods used to Conclusion stratify patients into cytogenetic risk categories confounds interpretation of the data. The IMWG has identiﬁed multi- No treatment regimen for transplant-ineligible NDMM has ple criteria used by different methods to assess risk status been consistently shown to improve outcomes in patients involving various factors . The existence of multiple with high-risk cytogenetic abnormalities. Incorporating methods and the inconsistency of clinical study adherence promising emerging agents—such as monoclonal anti- to them has resulted in a potential for variability in results bodies, checkpoint inhibitors, and vaccines —in com- and data interpretation. Furthermore, cytogenetic abnorm- bination regimens with synergistic MOAs may beneﬁt alities are often not considered as inclusion criteria in most patients with transplant-ineligible NDMM and high-risk clinical trial protocols and outcomes by cytogenetic risk are cytogenetic abnormalities in future investigations. How- often exploratory in nature. Discrepancies among risk ever, to better identify optimal regimens for these patients, stratiﬁcation guidelines are limiting; there is no direct way further consensus is needed to consolidate and reﬁne risk to compare patients across risk groups with the different assessment guidelines, which should improve analytical and methods, and not all high-risk groups impart the same design uniformity among clinical trials. It must also be prognosis. Additionally, cytogenetic data analyses are often considered that the age cutoff in this review of ≥65 years to not performed at one centralized facility, even among deﬁne elderly patients was based on the standard conven- patients within the same study. Further, there is a lack of tion that SCT is generally reserved for patients aged <65 prospective trial data that inform the use of available years. In practice, treatment decisions for patients with methodologies to comprehensively proﬁle patients and high-risk cytogenetic abnormalities should be based on select regimens that will provide the most beneﬁt. clinical assessment of each patient’s frailty; combination Another challenge in the interpretation of data for regimens including the previously mentioned emerging patients with transplant-ineligible high-risk NDMM is agents are not likely to be tolerable for frail patients but may identiﬁcation of the optimal efﬁcacy endpoint. High-risk be good options for ﬁt elderly patients. Per the recom- and standard-risk patients have similar response rates to mendations of the IMWG consensus statement, further treatments, but despite this, there is still disparity in their NDMM clinical trials, especially those evaluating novel survival outcomes. Clinical trials commonly rely on PFS agents, should continue to enroll these patients and either and OS, but other endpoints may be valuable. Chakraborty conduct appropriate post hoc risk-stratiﬁed outcomes ana- et al. have determined that depth of response and minimal lyses or directly apply risk-stratiﬁed treatment . Finally, residual disease are relevant endpoints for certain high-risk data for elderly patients and high-risk patients should be patients . Additionally, data from high-risk patients and reported not only in the context of the overall study popu- elderly patients are often reported for the entire study lation but also for each treatment arm. population rather than for each individual treatment arm. Acknowledgements The study was funded by Celgene Corporation. Although this facilitates identiﬁcation of overall trends, We thank Shawn Vahabzadeh, PharmD, and Kerry Garza, PhD, for such as worse outcomes overall for high-risk patients, it medical writing assistance, and Thea Gray for medical editing assis- makes it difﬁcult to ascertain the effect of treatment. The tance, sponsored by Celgene Corporation. small number of patients with high-risk cytogenetic abnormalities included in clinical trials presents another Compliance with ethical standards challenge: making statistically signiﬁcant conclusions with small populations is more difﬁcult than it is with larger Conﬂict of interest HA-L declares that he has no conﬂict of interest; standard-risk or intention-to-treat populations. 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Published: Mar 28, 2018