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Results from the TOURMALINE-MM4 trial: Ixazomib for maintenance

Jul 31, 2020

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. 1Effective 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. 1Currently, 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. 1,2The 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). 2In November 2019, preliminary reports announcedthat the trial had met its primary endpoint of prolonging progression-free survival (PFS).

During this year’s European Hematology Association (EHA) Annual Congress 2and the American Society of Clinical Oncology (ASCO) Annual Meeting, 3the 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

Study design 2

  • Multicenter, placebo-controlled, randomized, double-blind, phase III trial in adult patients with NDMM who did not undergo auto-SCT and who had received 6–12 months of standard of care induction therapy with a response of ≥ partial response
  • N = 706 patients were randomized (≤ 60 days from last induction therapy) 3:2 to receive either ixazomib or placebo for a maximum of 2 years or until disease progression or unacceptable toxicity. Treatments were administered in 28-day cycles with the following dosing:
    • Ixazomib (n = 425): 3 mg on Days 1, 8, and 15 of Cycles 1–4, increased to 4 mg during Cycles 5–26. If tolerated, dosing was increased to 4 mg during Cycles 1–4
    • Placebo (n = 281): Days 1, 8, and 15 of each cycle
  • The primary endpoint of the trial was PFS from randomization, as determined by an Independent Review Committee
  • Secondary endpoints included overall survival, time-to-progression, quality of life, and long-term safety
  • Patient baseline characteristics were well balanced between the two arms and are shown in Table 1

Table 1 . Patient baseline characteristics from the phase III TOURMALINE-MM4 trial 2

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

Results 2

  • With a median follow-up of 21.1 months, median PFS from randomization was significantly higher in the ixazomib arm when compared with the placebo arm (17.4 vs9.4 months, respectively; HR, 0.659; 95% CI, 0.542–0.801; p < 0.001), as shown in Table 2
  • A significant 34.1% reduction in the risk of progression or death was observed in the ixazomib arm vsplacebo
  • At 24 months from randomization, the rates of PFS were 39.2% and 24.1% for ixazomib and placebo, respectively
  • When PFS was landmarked to the date of initiation of induction therapy, ixazomib still led to a significantly longer median PFS when compared to placebo: 26.3 vs20.3 months, respectively; HR, 0.650; 95% CI, 0.534–0.791; p < 0.001
  • The ixazomib-mediated PFS benefits across the total cohorts and in different patient subgroups are shown below in Table 2
    • Notably, patients with CR or very good partial response had a significantly longer PFS with ixazomib compared with placebo. Moreover, ixazomib led to statistically significant PFS benefit even in patients with ISS Stage III and aged ≥ 75 years old
  • Median time-to-progression was also significantly increased with ixazomib compared with placebo (17.8 vs9.6 months, respectively; HR, 0.655; 95% CI, 0.537–0.799; p < 0.001)
  • Overall survival data were not mature enough for reporting

 

Table 2 . Significant PFS benefits of ixazomib across subgroups 2

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

  • Of note, 30.8% of patients needed a dose reduction of ixazomib due to TEAEs
  • The most commonly reported ixazomib-related TEAEs were
    • nausea
    • vomiting
    • diarrhea
    • rash
    • peripheral neuropathy
    • pyrexia
  • There were no significant differences in the incidence of new primary malignancies or on-study deaths between the two arms
  • Quality of life scores were not significantly different between the two arms

Conclusion

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.

EHA panel discussion on TOURMALINE-MM4 results 2

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. 4Whether 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.

  1. Dimopoulos MA, Gay F, Schjesvold F, et al .TOURMALINE-MM3 study group. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial.  Lancet. 2019;393(10168):253-264. DOI: 1016/S0140-6736(18)33003-4
  2. Dimopoulos MA, Spicka I, Quach H, et al. Ixazomib vs placebo maintenance for newly diagnosed multiple myeloma patients not undergoing autologous stem cell transplant: The Phase III TOURMALINE-MM4 trial. Oral abstract #S200. 25th EHA Annual Congress; Jun 12, 2020; Virtual.
  3. Dimopoulos MA, Spicka I, Quach H, et al. Ixazomib vs placebo maintenance for newly diagnosed multiple myeloma patients not undergoing autologous stem cell transplant: The Phase III TOURMALINE-MM4 trial . J Clin Oncol.2020;38(2020): suppl; abstr 8527. DOI: 1200/JCO.2020.38.15_suppl.8527
  4. Mina R, Larocca A, Corradini P, et al. Ixazomib with either dexamethasone, cyclophosphamide-dexamethasone, thalidomide-dexamethasone or bendamustine-dexamethasone followed by ixazomib maintenance in elderly newly diagnosed myeloma patients. Oral abstract #S202. 25th EHA Annual Congress; Jun 12, 2020; Virtual.