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Maintenance therapy has demonstrated to be key to prolonging survival and disease control and can be used following induction therapy or after autologous stem cell transplantation (auto-SCT). To date, the immunomodulatory drug (IMiD®), lenalidomide, is the only approved agent for maintenance therapy in patients with newly diagnosed multiple myeloma (NDMM) after auto-SCT.1 Effective as it can be, some patients develop resistance to lenalidomide, minimizing its use. Moreover, lenalidomide discontinuation due to toxicity has been observed in a significant subset of patients with MM in clinical trials.1 Currently, there are no approved post-induction maintenance agents for transplant-ineligible patients with NDMM.2
Overall, there is a lack in variation of maintenance agents with favorable safety profiles for the efficient management of MM for all patient populations. One non-IMiD candidate with a different mode of action is the proteasome inhibitor (PI), ixazomib.1,2 The potential of ixazomib as post-induction maintenance therapy for transplant-ineligible patients with NDMM is being investigated in the placebo-controlled phase III clinical trial, TOURMALINE-MM4 (NCT2312258).2 In November 2019, preliminary reports announced that the trial had met its primary endpoint of prolonging progression-free survival (PFS).
During this year’s European Hematology Association (EHA) Annual Congress2 and the American Society of Clinical Oncology (ASCO) Annual Meeting,3 the results of the TOURMALINE-MM4 trial were reported, indicating the clear survival benefit of ixazomib in the transplant-ineligible patients with NDMM setting. We hereby summarize the latest up-to-date results from the TOURMALINE-MM4 trial presented at EHA 2020.2
Table 1. Patient baseline characteristics from the phase III TOURMALINE-MM4 trial2
CR, complete response; ECOG PS, Eastern Cooperative Oncology Group Performance Status; IMiD, immunomodulatory drug; ISS, International Staging System; PI, proteasome inhibitor; PR, partial response; VGPR, very good partial response * Frailty status was determined on the basis of four components: age, the Katz Index of Independence in Activities of Daily Living, the Lawton Instrumental Activities of Daily Living Scale, and the Charlson Comorbidity Index Scoring System. † High risk cytogenetics include t(4;14); t(14;16) and del(17p). |
||
Characteristic |
Ixazomib (n = 425) |
Placebo (n = 281) |
Median age, years (range) |
72 (42–89) |
73 (52–90) |
Age ≥ 75 years, % |
37.6 |
39.1 |
ISS stage at diagnosis, % |
||
I |
26.4 |
23.5 |
II |
38.8 |
40.6 |
III |
34.8 |
35.9 |
ECOG PS at study entry, % |
||
0–1 |
95.5 |
95.0 |
2 |
4.2 |
5.0 |
Frailty status*, % |
||
Fit |
40.5 |
39.9 |
Unfit |
34.6 |
34.9 |
Frail |
24.0 |
24.2 |
High-risk cytogenetics†, % |
17.4 |
17.1 |
High-risk cytogenetics + amp 1q21, % |
35.3 |
32.4 |
Induction therapy containing, % |
||
PI |
82.6 |
81.9 |
IMiD |
32.2 |
33.5 |
PI + IMiD |
15.5 |
15.7 |
Response at study entry |
||
CR |
22.6 |
22.1 |
VGPR |
39.5 |
39.9 |
PR |
37.9 |
38.1 |
Table 2. Significant PFS benefits of ixazomib across subgroups2
Patient subgroup |
Median PFS, months |
HR (95% CI); p value* |
|
|
Ixazomib |
Placebo |
|
All |
17.4 |
9.4 |
0.659 (0.542–0.801); p < 0.001 |
Response to initial therapy CR or VGPR PR |
25.6 10.2 |
12.9 6.5 |
0.576 (0.499–0.765); p < 0.001 0.756 (0.566–1.010); NS |
Pre-induction ISS stage I or II (n = 465) III (n = 241) |
17.4 16.6 |
10.6 7.8 |
0.641 (0.503–0.816); NS 0.695 (0.499–0.967); p = 0.030 |
Age at randomization < 75 years (n = 432) ≥ 75 years (n = 274) |
17.7 16.7 |
9.3 10.6 |
0.615(0.480–0.788); NS 0.738 (0.537–1.014); p = 0.060 |
CI, confidence interval; CR, complete response; HR, hazard ratio; ISS, International Staging System; NS, not significant; PFS, progression-free survival; PR, partial response; VGPR, very good partial response * Statistical significance is indicated by bold font. |
Regarding safety, the overall rates of treatment-emergent adverse events (TEAEs) were similar across the two arms, with the rates of serious TEAEs (ixazomib, 22.1% vs placebo, 16.7%) and discontinuations due to TEAEs (ixazomib, 12.9% vs placebo, 8.0%) being slightly higher in the ixazomib arm vs the placebo arm
The results of the phase III TOURMALINE-MM4 trial indicate that post-induction ixazomib lead to a clear benefit for transplant-ineligible patients with NDMM, with an 8 month increase in median PFS and a 34.1% reduction in risk of progression or death when compared with placebo. Interestingly, ixazomib even led to PFS improvements in patients with advanced age or disease stage.
During the EHA 2020 panel discussion, Meletios A. Dimopoulos answered questions from fellow experts on the results of the TOURMALINE-MM4 trial. He clarified that they did perform a subgroup analysis for high-risk patients and that ixazomib led to a significant PFS benefit in this subpopulation too.
Regarding the heterogeneity of the induction therapies that the enrolled patients had received prior to the trial, Meletios A. Dimopoulos highlighted that further subgroup analyses revealed that patients who had received an IMiD-based induction therapy benefitted more from ixazomib. This can be further supported by the results of another trial presented at EHA 2020, which showed that induction therapy with ixazomib-based triplets leads to high overall response rates in elderly patients with NDMM.4 Whether the different induction therapies influenced the ixazomib-mediated PFS benefit in TOURMALINE-MM4 is still unclear as such subanalysis was not performed.
Lastly, Meletios A. Dimopoulos commented on the future of ixazomib as maintenance therapy in comparison to lenalidomide-based therapies. He pinpointed that ixazomib cannot substitute lenalidomide but is very well tolerated and could be used as an alternative treatment in patients who are lenalidomide intolerant. Moreover, he mentioned that ixazomib could provide a great agent for combination therapies in patients with progressive disease stage or high-risk features, since lenalidomide is not very effective in these settings. The combination of ixazomib and lenalidomide could also be considered in the future as maintenance therapy in these difficult-to-treat patient subpopulations.
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