Ixazomib in treatment of relapsed/refractory multiple myeloma: A case review from Hong Kong
The oral proteasome inhibitor ixazomib is approved in Hong Kong in combination with lenalidomide and dexamethasone for the treatment of patients with MM who have received at least one prior therapy.1 A pivotal and global TOURMALINE-MM1 trial demonstrated that ixazomib-based triple therapy significantly prolonged the progression-free survival (PFS) in adult patients with R/R MM who have received one to three prior therapies.2 Dr. Justin Li, Resident at Tuen Mun Hospital, shared a case of a R/R MM patient who was treated successfully with the triple therapy of ixazomib, lenalidomide and dexamethasone.
In MM, the oncogenesis of a malignant plasma cell is initiated in the germinal center of lymph nodes. MM is the second most prevalent hematological malignancy in the United States (US) and Europe.3 In Hong Kong, the incidence rate of MM is 1.7 per 100,000 persons and is most common amongst those aged 65 or older.4 Despite continuous progress in the development of new and increasingly effective agents, the disease remain incurable for most patients and a vast majority will experience multiple relapses inevitably. In addition, due to the acquisition of additional genetic mutation and emergence of resistant clones, the disease becomes more resistant with each relapse, resulting in progressively shorter duration of response with each subsequent line of salvage treatment used.5 Dr. Justin Li commented, “The management of R/R MM is diverse. It depends on many factors, such as patient’s comorbidities, nature of relapse, presence of high-risk cytogenetic abnormalities and response to previous treatments.”
Ixazomib is the first orally administered second-generation proteasome inhibitor approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to be used in combination with lenalidomide and dexamethasone for the treatment of patients suffering from R/R MM.5,6 The efficacy of ixazomib plus lenalidomide and dexamethasone in the treatment for patients with R/R MM who had received one to three prior therapies was evaluated in the randomized, double-blind, placebo-controlled, multinational, and phase 3 TOURMALINE-MM1 trial.2 This triple therapy regimen significantly prolonged PFS and improved overall response rate (ORR) compared with placebo plus lenalidomide and dexamethasone.2 The patient presented in this case review was treated with this triple combination and had remained in response for up to 4 years. The long-term administration of this therapy was well-tolerated.
The patient is a 65-year-old retired ship repair worker who suffers from hypertension, diabetes mellitus, obstructive sleep apnea and benign prostatic hyperplasia. He presented initially with bone pain and weight loss in June 2014. Blood tests showed mild anemia with hemoglobin level of 9.7mg/dL, reversed albumin to globulin ratio and serum IgA kappa paraprotein of 20g/L. He had normal renal function and calcium levels, but skeletal survey revealed lytic lesions over the skull. Bone marrow examination later confirmed this patient to be suffering from International Staging System (ISS) stage II symptomatic IgA kappa MM. He did not have any high-risk cytogenetic abnormalities detected by fluorescence in-situ hybridization (FISH). Treatment was initiated with bortezomib, thalidomide and dexamethasone in July 2014 achieving a partial response with paraprotein level decreased to 3g/L and he later underwent an autologous stem cell transplantation in January 2015.
In April 2017, the patient experienced lower rib pain and laboratory tests showed evidence of disease progression, with paraprotein level rising to 11g/L, a gradual drop in hemoglobin level, and a slow rise in globulin level again. Clonal plasmacytosis was evident in bone marrow examination. Second-line treatment options were discussed, and the patient was started on ixazomib, lenalidomide and dexamethasone since June 2017. However, during the first cycle, he experienced an episode of varicella zoster reactivation that required intravenous antiviral therapy. The patient also experienced grade 1 diarrhea, which was managed with symptomatic treatment; grade 2 anemia, and grade 4 thrombocytopenia and neutropenia, which only required the use of granulocyte colony stimulating factor injection but not blood product transfusion. In view of these hematological adverse events (AEs), the dosage of lenalidomide was reduced. The patient subsequently underwent 21 cycles of therapy until June 2019 with good tolerability. The treatment was continued for several cycles with the proteasome inhibitor, an alkylating agent and steroid after he ran out of funding for the use of lenalidomide. He was then eventually maintained on the proteasome inhibitor and steroid alone in view of a stable control of his paraprotein level. The alkylating agent was reintroduced 10 months later due to a slight increasing trend of his paraprotein level, which have since then been stabilized. Our team plans to keep the current treatment regimen for the time being and to consider switching back to maintenance therapy should the disease remain stable. In case the patient progressed, alternative salvage therapy regimen including the use of monoclonal antibodies would be considered. Dr. Li emphasized, “This case is important as R/R MM is usually difficult to control, but the patient in this case has remained under good control for almost 4 years now.”
The incorporation of ixazomib in the lenalidomide and dexamethasone combination has shown efficacy in controlling the disease for this patient, as seen similarly in the TOURMALINE-MM1 trial. In the trial, PFS was significantly longer (20.6 months vs. 14.7 months) (Figure 1), and the risk of disease progression or death was 26% lower in the ixazomib group versus placebo group.2
The ORR (78% vs. 72%) and corresponding rates of very good partial response or above (48% vs. 39%) were improved in the ixazomib group compared with placebo group.2 The median time to response was 1.1 months with ixazomib and 1.9 months with placebo, and the corresponding median duration of response was 20.5 months and 15.0 months respectively.2 The rates of serious AEs were similar in the two treatment arms.2
In a separate regional expansion of the TOURMALINE-MM1 study in China, similar improvement in PFS was seen with ixazomib.7 The overall survival (OS) was improved with ixazomib (25.8 months) versus placebo (15.8 months).7 The most frequent AEs were thrombocytopenia, neutropenia, and anemia.7 Most importantly, in the subset of R/R MM patients with high-risk and standard-risk cytogenetics, ixazomib was associated with a consistent PFS benefit.8
Furthermore, the patient-reported quality of life was similar in both groups. Physical, emotional and social function domains were maintained with ixazomib.9 The addition of ixazomib to the lenalidomide and dexamethasone combination significantly improved the efficacy while maintaining quality of life, reflecting limited additional toxicity attributable to ixazomib.9 This finding supports the feasibility of long-term administration of such combination.9 Similarly, this case demonstrates the sustainability of ixazomib combinations as the patient has received ixazomib for nearly 4 years with manageable AEs. Dr. Li also added, “The patient is receiving an all oral drug combination, giving the advantage of sparing the patient from additional frequent hospital visits for injections and has certainly improved patient compliance, tolerance and quality of life.”
The EMA has stated that the additional PFS of 5.9 months observed with ixazomib compared to placebo is clinically meaningful.6 The benefit-risk ratio for ixazomib in the combination with lenalidomide and dexamethasone was considered positive.6 Dr. Li commented that the AEs experienced by the patient presented were comparable to those observed in the TOURMALINE-MM1 trial. Most of them were tolerable and manageable with symptomatic treatment with only a minority requiring dose reduction of ixazomib in real-life practice. On top of its proven clinical benefit, the benefit of its all oral combination with better tolerability and acceptance amongst patients certainly outweighs the potential adverse events in the use of ixazomib with lenalidomide and dexamethasone. Dr. Li also highlighted that with better accessibility to ixazomib, the outcomes for R/R MM treatment in Hong Kong are positive.
Ixazomib is the first orally administered proteasome inhibitor approved for patients with R/R MM, and the Ixazomib-based triple therapy with lenalidomide and dexamethasone is an effective regimen, with a manageable side effect profile. In the TOURMALINE MM1 trial, ixazomib-based triple therapy has demonstrated superior and prolonged PFS in R/R MM patients, including those with high-risk cytogenetic abnormalities. The patient reported in this case review tolerated the therapy well for up to 4 years and his quality of life was well maintained. The combination of ixazomib with lenalidomide and dexamethasone represents an important salvage treatment option for patients with R/R MM who have previously received at least one prior therapy.
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