Up-front ixazomib in older patients with myeloma

In this issue of Blood, Facon et al report the results of the large randomized Tourmaline 2 trial including 705 transplantation-ineligible patients with newly diagnosed multiple myeloma, in which they show that the addition of oral ixazomib to the standard-treatment doublet of lenalidomide plus low-dose dexamethasone (Rd) results in a clinically meaningful progression-free survival (PFS) benefit.¹ 

It has already been shown that, compared with doublets, triplets including a proteasome inhibitor and an immunomodulator significantly improve PFS in multiple myeloma, both in patients with relapsed disease²  and in newly diagnosed patients (including transplantation-eligible³  and -ineligible patients⁴ ). Therefore, the standard of care is the combination of bortezomib plus Rd (VRd). However, the high incidence of bortezomib-induced peripheral neuropathy often prevents long-term administration. Therefore, evaluating the efficacy and safety of the 2 other approved proteasome inhibitors, carfilzomib and ixazomib, is important

The recently published randomized trial Endurance showed that, in newly diagnosed patients without high-risk cytogenetics, the addition of carfilzomib at a dose of 36 mg/m² to Rd compared with VRd did not improve PFS and was slightly more toxic.⁵  Ixazomib is less neurotoxic than bortezomib and less cardiotoxic that carfilzomib and is administered orally.⁶  Therefore, the combination of ixazomib plus Rd (IRd) might be an attractive alternative to VRd, especially in older patients.

Although the PFS benefit in the ixazomib arm of the Toumaline 2 trial was a clinically relevant 13.5-month improvement (35.3 vs 21.8 months; hazard ratio [HR], 0.83), it did not reach statistical significance (P = .073), and the results in the Rd control arm were relatively modest compared with those in other randomized trials with Rd^4,7,8  (21-34 months; see table). The differences in outcome among Rd-treated patients may be explained by differences in study design and initial patient characteristics. Induction in the Toumaline 2 trial, with 18 28-day IRd cycles, was well tolerated. However, there was a slight increase in early deaths (within 6 months) in the ixazomib arm. Also, PFS was not improved in patients age ≥75 years. These findings may suggest that this triple combination should be used cautiously in elderly frail patients. The impact of the maintenance treatment with a combination of ixazomib and lenalidomide compared with lenalidomide alone cannot be assessed from this report.

Although cross-trial comparisons are always hazardous, the complete response rate with IRd (25.6%) was identical to that achieved in the SWOG VRd trial (24.2%). Although the median PFS was 6 months shorter with IRd, the study population was much older. Compared with the Endurance trial, conducted in patients with only standard-risk cytogenetics and a lower median age, the PFS achieved with IRd was quite similar to that achieved with carfilzomib plus Rd (34.6 months) or with VRd (34.4 months).⁵  Therefore, this all-oral triplet with ixazomib is a viable alternative to other proteasome inhibitor–based triplets, especially when long-term injection treatment or frequent trips to the hospital (especially during the COVID-19 pandemic) are of concern for patients. Interestingly, there was also a significant PFS benefit in patients with high-risk cytogenetics (including amp[1q21]), which confirms the efficacy of ixazomib in this subgroup of patients, as previously shown in relapsed multiple myeloma.⁶ 

In addition to the specific results of the trial, several general questions are pertinent with regard to this study. Firstly, these results highlight the frequent problem faced in the interpretation of the word significance in clinical trials, because “not statistically significant” is often misinterpreted as “not clinically important,” whereas statistical significance, which is affected by the sample size and end points of a study, must be differentiated from clinical relevance or importance.

Secondly, the PFS benefit in the ixazomib arm was due to a higher complete remission rate (26% vs 14%) and a higher response rate of very good partial response or better (63% vs 48%). However, with a median follow-up of >50 months, the overall survival (OS) curves were superimposable. With longer follow-up, would the higher incidence of negative minimal residual disease with ixazomib (15% vs 7%) translate to longer OS? It is much more likely that there will never be an OS benefit with up-front IRd, because the number of active combinations for the treatment of relapse has increased dramatically in the past few years. In particular, OS was slightly better for patients who did not initially receive ixazomib when proteasome inhibitors were used for treatment of first relapse. This may suggest that, if OS is the primary objective, saving proteasome inhibitors for salvage treatment in transplantation-ineligible patients may be a valuable and possibly less expensive alternative. Studies should be designed to evaluate the efficacy and cost-effectiveness of different therapeutic sequencing.

Finally, results of this trial (which was initiated in 2013) should be analyzed in light of more recent randomized trials evaluating the addition of daratumumab to standard treatments for transplantation-ineligible patients with newly diagnosed myeloma. The Alcyone trial showed that the addition of daratumumab to the standard combination of bortezomib, melphalan, and prednisone plus maintenance treatment with daratumumab not only dramatically improved PFS (median, 36.4 vs 19.3 months; HR, 0.42) but also significantly improved OS, with a median follow-up of only 40 months (36-month OS rate, 78% vs 68%; HR, 0.60).⁹  The Maia trial also showed a significant improvement with the addition of daratumumab to continuous Rd, another standard frontline treatment in elderly patients, with a complete remission rate of 47.6% (vs 24.9%) and a 30-month PFS rate of 70.6% (vs 55.6%; HR, 0.56).⁸  A recently updated analysis of this trial confirms that unprecedented PFS rates may be achieved with this approach (60% at 4 years).¹⁰  Therefore, in countries where these combinations will be approved and reimbursed, combinations including daratumumab (or other anti-CD38 antibodies) will likely become the first option for transplantation-ineligible patients with newly diagnosed myeloma.