Ixazomib-based frontline therapy in patients with newly diagnosed multiple myeloma in real-life practice showed comparable efficacy and safety profile with those reported in clinical trial: a multi-center study

Substantial improvement in outcomes of multiple myeloma (MM) has been observed over the past decades [1], and the treatment paradigm for MM has been considerably evolved [2]. For newly diagnosed MM (NDMM), induction therapy with multi-agents combination has become a standard of care, with numeral phase 3 trials showing superior survival benefit using triplet or quadruplet regimens containing proteasome inhibitor bortezomib [3‐5]. Besides, the concept of continuous or long-term therapy in MM has been widely accepted, since maintenance therapy or continued initial therapy demonstrated obvious prolonged survival [6, 7]. In this context, the proteasome inhibitor bortezomib has become one of the backbone agents in the frontline treatment for MM; however, the non-oral administration and concerns in side effects including peripheral neuropathy hampered its long-term use in the real-world setting, with a median duration of treatment of only 6 months for bortezomib-based frontline therapy [8].

Ixazomib is the first oral proteasome inhibitor approved for the treatment in MM patients who have received at least one prior therapy in over 60 countries. The all-oral combination of weekly ixazomib plus lenalidomide and dexamethasone (IRd) has demonstrated durable efficacy and well-tolerated toxicities in phase 3 trial TOURMALINE-MM1 [9, 10] and in real-life practice [11].

The all-oral triplet regimen of IRd exhibited favorable efficacy with an acceptable toxicity profile in NDMM, according to the results of a phase 1/2 study (NCT01217957) [12, 13], with an overall response rate (ORR) of 92%. Besides, the ixazomib-based all-oral regimen combined with cyclophosphamide and dexamethasone (ICd) has shown promising efficacy in phase 2 studies [14, 15]. Furthermore, all-oral regimens, including IRd combination, have been suggested as possible options during the pandemic of COVID-19 in different consensus or opinions [16‐19], owing to the fact that using an oral regimen may help to reduce the risk for virus exposure and infection. However, effectiveness and tolerability of novel agent for MM treatment in routine clinical practice often differ from the results reported in registered clinical trials [8, 20, 21], and the published data on frontline treatment with ixazomib-based regimes in large phase 3 trials and in the real-world setting are limited. Herein, we report the real-world data of the initial effectiveness and safety profile of ixazomib-based frontline therapy in patients with NDMM from 14 centers in China, in hopes of providing informative data to help therapeutic decision-making.

This is a national, multi-centric, retrospective, observational study analyzing data collected from 85 patients with NDMM, who received ixazomib-containing regimen as induction therapy in real-life routine practice. Patients were treated at 14 different medical centers in China between August 2018 and April 2020, since ixazomib was officially approved by the China Food and Drug Administration in April 2018.

For inclusion in the present study, patients had to be diagnosed with MM by the 2014 criteria of International Myeloma Working Group (IMWG) [22] and previously untreated before receiving at least one cycle of ixazomib therapy. The records including demographics, disease characteristics, molecular cytogenetic subtype, treatment exposure, treatment response, treatment duration, adverse events (AEs), and survival outcome were retrieved and analyzed.

The main objectives of this analysis were to determine the ORR (partial response (PR) or better) and the proportion of patients with CR or very good PR (VGPR) of frontline ixazomib-based regimens in real-life setting. Secondary endpoints included estimation of progression-free survival (PFS), overall survival (OS), and the response rate within patient subgroups categorized by cytogenetic risk stratification defined by fluorescence in situ hybridization (FISH) [23] or metaphase cytogenetics. High-risk cytogenetic abnormalities (CA) included del 17, t(4;14), t(14;16).

The other primary objective of this study was to assess the safety profile of frontline ixazomib therapy, including the occurrence rate of common AEs and severe AEs, the duration of ixazomib treatment exposure, and the rate and reasons for drug discontinuation.

The study was approved by the institutional ethics committee (B2019-228R) and conducted in accordance with the 1964 Helsinki declaration and its later amendments. Patient care and evaluation were determined by their own treating physicians and effected by the patients’ own preference.

All 85 patients with symptomatic MM received at least one ixazomib-based therapy. Ixazomib-containing regimens analyzed in this study were listed as follows: IRd regimen (ixazomib 4 mg on days 1, 8, and 15, lenalidomide 25 mg on days 1–21, dexamethasone 40 mg weekly, every 28 days), Id regimen (ixazomib 4 mg on days 1, 8, and 15, dexamethasone 40 mg weekly, every 28 days), and Id regimen in combination with other chemotherapeutic agents or monoclonal antibody (ITd, Id plus daily thalidomide 100 mg; ICd, Id plus weekly oral cyclophosphamide 300 mg/m²; IAd, Id plus doxorubicin 9 mg/m² IV d1–4; DId, Id plus daratumumab administered IV at 16 mg/kg weekly for 8 weeks, followed by every other week for 8 doses, and then every 4 weeks). Selected patients received long-term single-agent ixazomib maintenance after up to 12 cycles of ixazomib-based induction therapy. Patients received continuous ixazomib-based treatment until disease progression, intolerable toxicity, or patient/physician decision to end treatment. Dose modifications of studying drugs for toxic effects were recorded. Interruption of treatment for stem cell collection or stem cell transplantation (SCT) was allowed.

Response assessment and safety evaluation were done in patients every month according to the 2016 IMWG response criteria [24]. A bone marrow aspiration/biopsy was required to confirm a complete response (CR).

This multi-center, retrospective, observational study highlights the real-world efficacy, feasibility, and tolerability of ixazomib-based frontline therapy in patients with NDMM.

Importantly, the results of this analysis are comparable with those of the phase 1/2 clinical trial of IRd in NDMM (NCT01217957) [12, 13].

Findings from our real-world cohort reflected the outcome of a broader general patient population, which was older than that included in the phase 1/2 trial (NCT01217957) [12, 13] (median age 67 versus 66 years), and tended to have more advanced stage diseases (ISS II–III 74% versus 57%, p = 0.000) and worse ECOG performance status (ECOG PS > 2 25% versus 0%, p = 0.000) (Table 5). Near half of patients (45%) received IRd regimen as in the phase 1/2 clinical (NCT01217957); about 30% of patients received doublet regimen of ixazomib plus dexamethasone, mostly the elderly (median age 75 years) who might not be able to tolerate triplet regimens; the rest of patients (25%) received triplet regimen of Id plus other chemotherapeutics or monoclonal antibody. Yet despite these differences in baseline characteristics and treatment exposure, treatment response and survival outcomes in our study were comparable with the trial (NCT01217957) findings, with an ORR of 95%, ≥ VGPR rate of 66%, and a 12-month PFS of 86% in our cohort compared with 88%, 58%, and 88% in the phase 1/2 trial (NCT01217957) [12, 13], respectively (Table 5). Besides, there was no statistically significant difference in treatment response between different ixazomib-based regimens. The results suggest that the ixazomib-based triplet and doublet combination as frontline therapy could be active in a broader real-world population. Of note, despite the promising efficacy results in our whole cohort, we still observed a relatively inferior treatment outcome in those who have high-risk CA and those who were ineligible for clinical trial. Although more than 86% of the patients with high-risk CA achieved disease response, only one-third achieved a deeper response of ≥ VGPR (Table 3). Besides, an inferior PFS was observed in the patients with high-risk CA and those who were ineligible for clinical trial (Fig. 2 B, F), with a 12-month PFS of 76.6% and 77.4%, respectively, which was lower than the data reported in the NCT01217957 trial (88%) [12, 13]. The possible reasons for these discrepancies may lie in the fact that the patients ineligible for clinical trial were older, with worse ECOG performance status and lower transplantation rate. In fact, patients with age more than 75 years and ECOG PS > 2 did demonstrate inferior PFS in our cohort (Fig. 2 D, E).

Safety profile was compatible with the previously published phase 1/2 trial (NCT01217957) [12, 13]. Grade ≥ 3 AEs were reported in 29% of the present cohort within follow-up, and 14% discontinued ixazomib due to AEs in the absence of disease progression. However, the lower grade ≥ 3 AE rate (29%) reported here is likely to be attributed to a reporting bias due to the retrospective nature of this study. Despite the potential bias, these findings still reflected that ixazomib-based regimens are well-tolerated. Of note, no grade > 2 PN was observed in our cohort. This finding was encouraging, especially in the consideration that PN has been one of the major concerns when using proteasome inhibitor and the reported incidence of bortezomib-induced PN was 40% [25]. Despite the lower > 3 AE rate and high response rate in our cohort, we observed high discontinuation rate (14% vs. 8%) in our data. Unlike in strictly controlled and well-managed clinical trials, the treatment endurance may be rather low in real-life practice, since physicians may be less motivated to encourage their patients on the need to continue treatment in routine practice, and patients in real-life may tend to give up a therapy despite few side effects.

In our real-world cohort, ten patients received single-agent ixazomib maintenance after induction. None of the patients discontinued ixazomib maintenance due to AEs, and all but the one who had disease progression remained on maintenance therapy until the date of the last follow-up. The favorable tolerability observed in our cohort highlighted the feasibility of maintenance therapy with ixazomib. The SCT rate in our cohort was only 15.4% in patients who were evaluated as transplantation-eligible (ages 18–64 years, ECOG 0–1, without severe comorbidities). This data was quite consistent with the reported SCT rate (14.4%) in another large real-world study of 940 Chinese NDMM patients [26], and it did reflect the real situation in China. The possible reasons for the low SCT rates include fears for transplant, financial concerns (many fees for SCT, including melphalan, were not covered by health insurance), limited drug accessibility (melphalan has just commercially entered China in 2019), shortage of qualified medical service (only large reference centers or specialized centers have the ability to perform SCT), and disturbance on routine medical service during COVID.

The ixazomib-based all-oral regimens, including IRd, ICd, and ITd, have demonstrated promising efficacy, safety, and tolerability in rigorously controlled clinical trials for NDMM [12‐15, 27, 28]. Besides the greater convenience brought by the oral administration, the NDMM patients who received all-oral regimens have been shown to have lower economic burden of illness, less activity impairment, and lower productivity loss [29]. These facts together explained the reason for choosing ixazomib-based regimens as frontline therapy in selected real-world patients. More importantly, all-oral therapy may be able to help in decreasing the exposure to and infection with COVID-19 [16].

Indeed, real-world data are emerging for the use of ixazomib in RRMM, but such data in the frontline treatment setting with ixazomib are still limited. The findings in the present study are encouraging. Although the follow-up was fairly short (median 10.3 months), as ixazomib was just introduced in China in April 2018, our real-world data did demonstrate that the ixazomib-based regimens were active in routine practice for NDMM. On the basis of this analysis and the other co-factors that should be taken into consideration when making treatment decisions NDMM patients in routine practice, ixazomib-based regimen would be an optimal alternative as frontline therapy.

In conclusion, herein we reported the data from the first real-life, multi-center study on the effectiveness and safety profile of ixazomib-based frontline therapy in NDMM.