Clinical trial NCT04217967: Ixazomib, Lenalidomide, and Combination for Maintenance in NDMM Patients
Official title: A Multicenter, Open-label, Prospective Study of Ixazomib, Lenalidomide, and Ixazomib in Combination With Lenalidomide for Maintenance Therapy in Patients With Newly Diagnosed Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Multiple Myeloma
Keywords: real-world
dual-drug maintenance
oral regimen
Lead sponsor: Peking Union Medical College Hospital
Sponsor class: OTHER
Collaborators: name: Peking University Third Hospital
name: Beijing Jishuitan Hospital
name: Beijing Chao Yang Hospital
name: Xuanwu Hospital, Beijing
name: Peking University First Hospital
name: Jilin Provincial Tumor Hospital
name: Second Hospital of Shanxi Medical University
name: The First Affiliated Hospital of Shanxi Medical University
name: Tianjin Medical University General Hospital
name: The First Affiliated Hospital of Anhui Medical University
name: Shanxi Bethune Hospital
name: Beijing Hospital
First posted: 2020-01-06
Enrollment: 211
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the real-world efficacy and safety of ixazomib, lenalidomide, or ixazomib in combination with lenalidomide as maintenance therapy in patients with newly diagnosed multiple myeloma in China.

Detailed description: Multiple myeloma (MM), the second most common hematological malignancy, is a clonal plasma cell disorder characterized by the secretion of monoclonal immunoglobulins. The annual incidence of newly diagnosed MM (NDMM) patients is about 2-3/100,000. In the past 20 years, the median overall survival (OS) of MM patients has prolonged from 3 to 5 years to 8 to 10 years since many novel agents developed on the pipeline of treatment. Moreover, multi-drug combination chemotherapy, low-intensity maintenance therapy after achieving a certain effect also contributed to improving the progression-free survival (PFS) and OS in MM patients. Therefore, many international guidelines have explicitly recommended maintenance therapy after first-line regimens until disease progression.

Common maintenance medications include immunomodulatory drugs (IMiDs) such as lenalidomide, thalidomide, ect; proteasome inhibitors (PIs) such as bortezomib. Among them, lenalidomide has the most reliable data as maintenance therapy for prolonging PFS. Although bortezomib maintenance has shown advantages in high-risk MM patients in some clinical trials, it has poor compliance in the real world due to the injection mode of administration and peripheral neuropathy (PN) after long-term use. There is currently no data on the maintenance of large-scale cases in China. The maintenance of regimens in the real world is not standardized, including drug dosage and duration of application. In addition, due to the high cost of bortezomib or lenalidomide for long-term application, domestic thalidomide still accounts for a certain proportion, but its side effects especially PN are very prominent. In addition to the proven efficacy, MM maintenance treatments should preferably include good tolerability, manageable toxicities and administration convenience.

The second-generation PI drug, Ixazomib, was approved in China in May 2018. Based on the data of TOURMALINE MM1 trial and China extended study, ixazomib was approved for the treatment of relapsed and refractory MM. Further more, recent maintenance study after autologous transplantation (MM3) suggested that ixazomib significantly prolonged PFS for 6 months compared with placebo. Because ixazomib is an oral form with a few side effects, especially less PN than bortezomib, safety data and compliance of ixazomib in the real world were comparable as those in the clinical trials.

The survival of patients with multiple myeloma in China is worse than that of western countries. One of the important reasons is irregular follow-up and nonstandard maintenance therapies. Many Chinese MM patients still use traditional maintenance drug thalidomide, which is difficult to apply for a long time due to toxicities especially PN and gastrointestinal reactions. The second generation IMiD drug lenalidomide as maintenance treatment has been increasingly accepted by patients and hematologists. However, due to the low proportion of autologous stem cell transplantation (ASCT) after first-line regimens in China, the efficacy of single-agent maintenance is also limited, especially for high-risk patients. As novel anti-myeloma drugs were rapidly approved and reimbursed in China, a dual oral maintenance regimen of lenalidomide in combination with ixazomib is being explored.

The purpose of this multi-centered study is to evaluate the real world efficacy and safety of the maintenance therapies in Chinese patients with newly diagnosed multiple myeloma (NDMM), non-transplant; which include ixazomib monotherapy, ixazomib combined with lenalidomide, and lenalidomide monotherapy.

Adult NDMM patients who acquire at least partial response (PR) after 4\~9 cycles of front-line regimens including ASCT will be recruited. Those who do not reach a PR after 4 cycles of front-line regimens will be switched to the second regimen for at most 5 cycles. After reaching a PR, these patients will also be recruited to the study. Maintenance therapies will be classified into three groups depending on patients' and doctors' discretion, including ixazomib 4mg day 1, 8,15; lenalidomide 25mg qod day 1\~21; ixazomib and lenalidomide combination with same doses. Front-line maintenance is given till disease progression. Progression free survival and safety issues will be recorded. Drug doses will be adjusted or withdrawn based on the degree of toxicities.

Adjunctive treatments are prophylaxis of herpes zosters with acyclovir, prophylaxis of venous thrombotic events with aspirin, prophylaxis of high-risk infections with sulfanilamide. The doses of lenalidomide are adjusted depending on clearance of creatinine.

Eligibility criteria: Inclusion Criteria:

1. Age older than 18 years;
2. Newly diagnosed MM patients who fulfill the diagnostic criteria of International Myeloma Working Group (IMWG) 2014 standard; transplant-ineligible or transplant eligible yet without intent for ASCT
3. Maintenance treatment will start after first-line treatment or second-line treatment;
4. The total courses of front-line regimens are between 4-9;
5. The clinical efficacy before the enrollment is partial response (PR) or better;
6. Physical performance status (ECOG) score ≤ 2;
7. Patients participate in the study based on his/her own will and voluntarily sign the informed consent form

Exclusion Criteria:

1. Patients who are allergic or intolerant to ixazomib or lenalidomide;
2. patients with severe cardiopulmonary dysfunction;
3. patients with severe hepatic insufficiency, ALT or bilirubin more than 2 times the upper limits of normal range;
4. patients with other malignancies (except for carcinoma in situ);
5. patients with serious bacterial or viral infections, such as HIV or HBV, HCV, etc.;
6. pregnant or lactating women;
7. can not be strictly contraceptive;
8. Psychiatric patients and patients with other serious mental illness that potentially impact signing informed consent and disease consultation and follow-up.

Primary outcomes:
measure: progression-free survival
timeFrame: From date of enrollment until the date of first documented progression, assessed up to 20 months
measure: overall survival
timeFrame: From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months
Secondary outcomes:
Other outcomes:
Locations:
city: Beijing
country: China
facility: PekingUMCH
state: Beijing
Study officials:
affiliation: Peking Union Medical College, department of hematology
name: Junling Zhuang, MD
role: PRINCIPAL_INVESTIGATOR
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