2021 SOHO article understands the treatment progress of Fahrenheit's macroglobulinemia

Waldenstrom's macroglobulinemia (WM) is a rare subtype of non-Hodgkin's lymphoma characterized by malignant lymphoid plasma cells that accumulate in the bone marrow and other organs and secrete monoclonal IgM
.

The incidence of MYD88 mutation and CXCR4 mutation in WM patients is 90% and 40%, respectively
.

The classic treatment options for WM include the combination of alkylating agents and rituximab, and proteasome inhibitors and rituximab
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The overall response rate (ORR) of these regimens for WM is 90%, and the median progression-free survival (PFS) is 4-6 years
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With the in-depth understanding of the MYD88 mutation signal, Bruton's tyrosine kinase (BTK), an important driver of WM, has become a therapeutic target
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BTK inhibitor (BTKi) ibrutinib has also become one of the effective drugs for the treatment of WM
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The results of a phase II clinical study involving 63 previously treated WM patients showed that the ORR of Ibrutinib monotherapy in WM patients was 90%, and the main response rate was 70%
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The encouraging efficacy of this study prompted the US FDA to approve Ibrutinib for WM patients in 2015
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In addition, the use of ibrutinib in rituximab refractory and naive WM patients reported similar excellent results
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The INNOVATE study included 150 WM patients who were randomly assigned to the treatment group of Ibrutinib plus rituximab or the placebo plus rituximab group
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Compared with patients in the placebo combined with rituximab treatment group, the ibrutinib combined with rituximab treatment group had a higher primary response rate (72% vs 32%) and a higher 30 cases Monthly PFS rate (82% vs 28%).
The results of this study prompted the US FDA to approve Ibrutinib combined with rituximab for the treatment of WM in 2018
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Although the treatment of WM has made great progress, the disease still cannot be cured by standard treatment regimens, and patients usually face recurrence of the disease
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Therefore, there is an urgent need for new drugs
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Three new types of covalent BTKi Zebutinib, Acatinib and Tirabrutinib for the treatment of WM are actively being studied
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The ASPEN study included 201 WM patients who were randomly assigned to the Zebutinib or Ibrutinib treatment group.
The results of the study showed that both drugs were very effective in inducing durable remission in WM patients; Zebutinib and Ibrutinib The primary response rates of patients in the treatment group were 77% and 78%, the primary endpoint of the study was very good partial response (VGPR) rates of 28% and 19%, respectively, and the 18-month PFS rates were 84% and 85%, respectively
.

A clinical study involving 106 patients with WM evaluated the efficacy of acatinib, with an ORR of 93% and a 24-month PFS rate of 80%-90%
.

Another clinical study involving 27 patients with WM evaluated the efficacy of Tirabrutinib, with an ORR of 96% and a major remission rate of 89%
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The results of these studies support the use of covalent BTKi as the standard treatment for WM
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A number of clinical studies of covalent BTKi combined with immunochemotherapy and proteasome inhibitors for the treatment of WM patients are underway
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However, many WM patients develop BTK mutations and subsequently become resistant to covalent BTKi
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A multicenter, phase II study included 26 patients with WM to evaluate the efficacy of non-covalent BTKi Pirtobrutinib.
Among them, 18 patients were previously exposed to covalent BTKi (12 cases progressed, 6 cases were intolerant)
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The results of the study showed that the ORR of pirtobrutinib treatment was 69%, and the incidence of any grade of atrial fibrillation was 1%
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In addition, the BCL-2 inhibitor Veneclax has been proven to be effective and safe in previously treated WM.
In a multi-center, phase II clinical study, 30 WM patients treated with Veneclair had an ORR of 90.
%, the main remission rate was 83%, the VGPR rate was 20%, and the estimated 24-month PFS rate was 74%
.

No atrial fibrillation, peripheral neuropathy, or IgM rebound occurred, and only one case of laboratory-detected tumor lysis syndrome was reported
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A clinical study evaluating the efficacy and safety of ibrutinib combined with Venecla in newly treated WM patients is underway
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CXCR4, PI3K, CD38 and HCK are the treatment targets that have received wide attention in the research of WM treatment
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Studies are currently evaluating the efficacy of the CXCR4 inhibitor Mavorixafor combined with Ibrutinib in the treatment of patients with CXCR4 mutant WM
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The PI3K inhibitor Idelalisib has shown early efficacy in WM patients, but it seems to be associated with a higher incidence of liver toxicity
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A multicenter clinical study evaluating the efficacy and safety of Umbralisib in WM patients has stopped recruiting
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The efficacy of the CD38 monoclonal antibody daratumumab in WM patients is lower than expected
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Dasatinib is a kind of HCK inhibitor, and its related clinical research on the treatment of patients with WM who progressed after covalent BTKi treatment is underway
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In addition, the US FDA granted fast track certification for the phospholipid drug conjugate CLR131 for the treatment of WM patients who have previously received ≥2 treatment options
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In short, the treatment of WM patients continues to move forward
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Many reasons make us optimistic about the prospects for treatment of WM patients
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Reference source: Jorge J.
Castillo.
2021 SOHO.
EXABS-121-MM.
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