The final analysis of the TOURMALINE-MM1 research is released, come and watch!

Introduction TOURMALINE-MM1 research results are quick to see! As an annual academic event in the field of hematology, the annual meeting of the European Society of Hematology (EHA) will be held this year in the form of an online conference on June 9-17
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At this EHA meeting, the final analysis of the TOURMALINE-MM1 study to be announced has attracted the attention of doctors! The TOURMALINE-MM1 study is an international multi-center, randomized, double-blind, placebo-controlled phase III clinical trial conducted in 147 medical centers in 26 countries around the world
.

A total of 722 patients with relapsed and/or refractory multiple myeloma (RRMM) were enrolled in the study, and they were randomly assigned to ixazomib-lenalidomide-dexamethasone (IRd) (360 cases) according to 1:1 Or placebo-lenalidomide-dexamethasone (pRd) (362 cases) treatment until the disease progresses or intolerable toxicity appears [2]; the study is based on the number of previous treatment regimens (1 vs 2/3), protease The exposure of PIs and ISS disease stages (ISS-Ⅰ/ISS-Ⅱ vs ISS-Ⅲ) were stratified [1,2]
.

The final analysis of TOURMALINE-MM1 aims to report the overall survival (OS) of the intention-to-treat (ITT) population and the OS of related subgroups.
The results of the study were published on EHA this year (Abstract No.
EP963)
.

Take a look at the latest detailed data of the TOURMALINE-MM1 study.
The results show that the median follow-up is about 7 years (85 months)
.

The median number of treatment cycles for patients in the IRd group and pRd group were 18 and 16, respectively
.

At the last follow-up, a total of 32% of patients were alive, and 4% of patients in each group were still receiving treatment
.

In the ITT population, the median OS of the IRd group and the pRd group were 53.
6 months and 51.
6 months, respectively (HR 0.
939, P=0.
495, Figure 1).
The benefit of IRd compared with pRd was not statistically significant, but this In the Phase 3 study of combined lenalidomide + dexamethasone in the treatment of RRMM patients so far, the treatment group and the placebo group have achieved the longest OS
.

Figure 1 Another important result of the OS outcome study of the ITT population and high-risk cytogenetic abnormal subgroups is that in the predetermined subgroups with poor prognostic risk characteristics, IRd has OS benefit compared with pRd (lower HRs)
.

The subgroups include the following: In addition, in patients with standard-risk cytogenetic characteristics, IRd has also been observed to have an OS benefit compared with pRd (HR 0.
875)
.

During the 7-year follow-up, no new/additional safety issues were found, and the incidence of new primary malignancies in the two groups was similar (10% in the IRd group and 12% in the pRd group) [1]
.

Extension: Why are the benefits of OS in patients with IRd inconsistent? Seeing the above data, we can't help but wonder why the OS benefit of IRd patients is inconsistent? Researchers believe that it is the imbalance of follow-up treatment (including the widespread use of PI and new monoclonal antibodies) that interferes with the interpretation of OS [1]
.

Studies have shown that most patients (92% in the IRd group and 85% in the pRd group) are still blind when entering the next-line treatment.
The proportion of blind patients receiving PI or non-PI regimens for the next-line treatment is similar in the two groups, but Unblinding greatly affects next-line treatment decisions
.

The data show that the proportion of patients in the IRd group (72%) and the pRd group (70%) who received ≥1 follow-up anticancer treatment is similar, but on the one hand, patients in the pRd group started follow-up treatment earlier than those in the IRd group; on the other hand, Among the IRd and pRd patients who received ≥1 follow-up treatments, the proportions of patients receiving daratumumab were 25% and 34%, and the proportions of patients receiving proteasome inhibitor (PI) were 72% and 77%, respectively , The proportion of patients undergoing autologous stem cell transplantation is 4% and 10%, respectively
.

Compared with patients who received PI after pRd treatment, patients who received PI after IRd treatment had less OS benefit
.

What are the reasons for the benefit of IRd treatment in high-risk patients? Although some MM patients can get long-term remission, and even a very small number of cases will be cured, the prognosis of high-risk patients is still very poor and there are unmet medical needs [3]
.

Ajeeta B.
Dash et al.
's exploratory analysis for the TOURMALINE-MM1 study showed that in the subgroup of RRMM patients amplified by 1q21, the activation of the non-classical NF-κB pathway increased; the addition of ixazomib to the Rd program can be a non-classical NF-κB pathway Patients with increased activation of RRMM, including high-risk patients with 1q21 amplification and t(4;14), provide greater progression-free survival (PFS) benefits [4]
.

The results of this study may explain the underlying mechanism of the clinical benefit of IRd therapy in the subgroup of RRMM patients
.

Conclusion PIs are the cornerstone drugs for RRMM treatment, but PI for injection may be restricted by the burden of treatment and the need to go to a clinic/hospital [1]
.

As the first oral PI, ixazomib has better treatment convenience and patient compliance.
It has been approved in China in combination with Rd for MM patients who have received at least one previous treatment [5]
.

The final analysis of the TOURMALINE-MM1 study showed that, due to the influence of subsequent treatment, although the OS benefit of IRd compared with pRd in the ITT population was not statistically significant, it was in subgroups with poor prognostic factors (including high-risk cytogenetic abnormalities).
The OS benefit of IRd in the group is greater
.

This result still has important guiding value for clinical precision treatment
.

Reference [1]https://library.
ehaweb.
org/eha/2021/eha2021-virtual-congress/325721/paul.
g.
richardson.
final.
analysis.
of.
the.
phase.
3.
tourmaline-mm1.
study .
html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Asearch%3Dtourmaline-mm1+final+analysis%E2%80%AF[2] Moreau P, Masszi T, Grzasko N, et al.
Oral Ixazomib, Lenalidomide, andDexamethasone for Multiple Myeloma[J].
N Engl J Med.
2016;374(17):1621–34.
[3] Corre J, Munshi NC, Avet-Loiseau H.
Risk factors in multiple myeloma: is it time for a revision[J].
Blood.
2021 Jan 7;137(1):16-19.
[4] Dash AB, Zhang J, Shen L, et al.
Clinical benefit of ixazomib plus lenalidomide-dexamethasone in myeloma patients with non- canonical NF-κB pathway activation[J].
Eur J Haematol.
2020 Sep;105(3):274-285.
[5] Ishazomi Citrate Capsules Chinese Drug Instructions.
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