Alessandra Di Bacco

Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients

Ixazomib is the first investigational oral proteasome inhibitor to be studied clinically. In this phase 1 trial, 60 patients with relapsed/refractory multiple myeloma (median of 4 prior lines of therapy; bortezomib, lenalidomide, thalidomide, and carfilzomib/marizomib in 88%, 88%, 62%, and 5%, respectively) received single-agent ixazomib 0.24 to 2.23 mg/m(2) (days 1, 4, 8, 11; 21-day cycles). Two dose-limiting toxicities (grade 3 rash; grade 4 thrombocytopenia) occurred at 2.23 mg/m(2). The maximum tolerated dose was 2.0 mg/m(2), which 40 patients received in 4 expansion cohorts. Patients received a median of 4 cycles (range, 1-39); 18% received ≥12 cycles. Eighty-eight percent had drug-related adverse events, including nausea (42%), thrombocytopenia (42%), fatigue (40%), and rash (40%); drug-related grade ≥3 events included thrombocytopenia (37%) and neutropenia (17%). Grade 1/2 drug-related peripheral neuropathy occurred in 12% (no grade ≥3). Two patients died on the study (both considered unrelated to treatment). The terminal half-life of ixazomib was 3.3 to 7.4 days; plasma exposure increased proportionally with dose (0.48-2.23 mg/m(2)). Among 55 response-evaluable patients, 15% achieved partial response or better (76% stable disease or better). These findings have informed the subsequent clinical development of ixazomib in multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT00932698.

Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study

BACKGROUND The combination of bortezomib, lenalidomide, and dexamethasone is a highly effective therapy for newly diagnosed multiple myeloma. Ixazomib is an investigational, oral, proteasome inhibitor with promising anti-myeloma effects and low rates of peripheral neuropathy. In a phase 1/2 trial we aimed to assess the safety, tolerability, and activity of ixazomib in combination with lenalidomide and dexamethasone in newly diagnosed multiple myeloma. METHODS We enrolled patients newly diagnosed with multiple myeloma aged 18 years or older with measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and no grade 2 or higher peripheral neuropathy, and treated them with oral ixazomib (days 1, 8, 15) plus lenalidomide 25 mg (days 1-21) and dexamethasone 40 mg (days 1, 8, 15, 22) for up to 12 28-day cycles, followed by maintenance therapy with ixazomib alone. In phase 1, we gave patients escalating doses of ixazomib (1·68-3·95 mg/m(2)) to establish the recommended dose for phase 2. The primary endpoints were maximum tolerated dose for phase 1, and the rate of very good partial response or better for phase 2. Safety analyses were done in all patients who received at least one dose of study drug; efficacy analyses were done in all patients who received at least one dose of study drug at the phase 2 dose, had measurable disease at baseline, and had at least one post-baseline response assessment. This study is registered at ClinicalTrials.gov, number NCT01217957. FINDINGS Between Nov 22, 2010, and Feb 28, 2012, we enrolled 65 patients (15 to phase 1 and 50 to phase 2). Four dose-limiting toxic events were noted in phase 1: one at a dose of ixazomib of 2·97 mg/m(2) and three at 3·95 mg/m(2). The maximum tolerated dose of ixazomib was established as 2·97 mg/m(2) and the recommended phase 2 dose was 2·23 mg/m(2), which was converted to a 4·0 mg fixed dose based on population pharmacokinetic results. Grade 3 or higher adverse events related to any drug were reported in 41 (63%) patients, including skin and subcutaneous tissue disorders (11 patients, 17%), neutropenia (eight patients, 12%), and thrombocytopenia (five patients, 8%); drug-related peripheral neuropathy of grade 3 or higher occurred in four (6%) patients. Five patients discontinued because of adverse events. In 64 response-evaluable patients, 37 (58%, 95% CI 45-70) had a very good partial response or better. INTERPRETATION The all-oral combination of weekly ixazomib plus lenalidomide and dexamethasone was generally well tolerated and appeared active in newly diagnosed multiple myeloma. These results support the phase 3 trial development of this combination for multiple myeloma. FUNDING Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical International Company.

Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma

Proteasome inhibition is an effective treatment strategy for multiple myeloma. With improving survival, attention is increasingly focusing on ease of administration and toxicity profile. Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks. Upon MTD determination, patients were enrolled to 4 different cohorts based on relapsed/refractory status and prior bortezomib and carfilzomib exposure. The MTD was determined to be 2.97 mg/m(2). Dose-limiting toxicities were grade 3 nausea, vomiting, and diarrhea in 2 patients, and grade 3 skin rash in 1 patient. Common drug-related adverse events were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). The observed rate of peripheral neuropathy was 20%, with only 1 grade 3 event reported. Nine (18%) patients achieved a partial response or better, including 8 of 30 (27%) evaluable patients treated at the MTD. Pharmacokinetic studies suggested a long terminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing. This trial was registered at www.clinicaltrials.gov as #NCT00963820.

The Role of Minimal Residual Disease Testing in Myeloma Treatment Selection and Drug Development: Current Value and Future Applications.

Treatment of myeloma has benefited from the introduction of more effective and better tolerated agents, improvements in supportive care, better understanding of disease biology, revision of diagnostic criteria, and new sensitive and specific tools for disease prognostication and management. Assessment of minimal residual disease (MRD) in response to therapy is one of these tools, as longer progression-free survival (PFS) is seen consistently among patients who have achieved MRD negativity. Current therapies lead to unprecedented frequency and depth of response, and next-generation flow and sequencing methods to measure MRD in bone marrow are in use and being developed with sensitivities in the range of 10−5 to 10−6 cells. These technologies may be combined with functional imaging to detect MRD outside of bone marrow. Moreover, immune profiling methods are being developed to better understand the immune environment in myeloma and response to immunomodulatory agents while methods for molecular profiling of myeloma cells and circulating DNA in blood are also emerging. With the continued development and standardization of these methodologies, MRD has high potential for use in gaining new drug approvals in myeloma. The FDA has outlined two pathways by which MRD could be qualified as a surrogate endpoint for clinical studies directed at obtaining accelerated approval for new myeloma drugs. Most importantly, better understanding of MRD should also contribute to better treatment monitoring. Potentially, MRD status could be used as a prognostic factor for making treatment decisions and for informing timing of therapeutic interventions. Clin Cancer Res; 23(15); 3980–93. ©2017 AACR.

Impact of prior therapy on the efficacy and safety of oral ixazomib-lenalidomide-dexamethasone vs. placebo-lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma in TOURMALINE-MM1

Prior treatment exposure in patients with relapsed/refractory multiple myeloma may affect outcomes with subsequent therapies. We analyzed efficacy and safety according to prior treatment in the phase 3 TOURMALINE-MM1 study of ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) versus placebo-Rd. Patients with relapsed/refractory multiple myeloma received ixazomib-Rd or placebo-Rd. Efficacy and safety were evaluated in subgroups defined according to type (proteasome inhibitor [PI] and immunomodulatory drug) and number (1 vs. 2 or 3) of prior therapies received. Of 722 patients, 503 (70%) had received a prior PI, and 397 (55%) prior lenalidomide/thalidomide; 425 patients had received 1 prior therapy, and 297 received 2 or 3 prior therapies. At a median follow up of ~15 months, PFS was prolonged with ixazomib-Rd vs. placebo-Rd regardless of type of prior therapy received; HR 0.739 and 0.749 in PI-exposed and –naïve patients, HR 0.744 and 0.700 in immunomodulatory-drug-exposed and -naïve patients, respectively. PFS benefit with ixazomib-Rd vs. placebo-Rd appeared greater in patients with 2 or 3 prior therapies (HR 0.58) and in those with 1 prior therapy without prior transplant (HR 0.60) versus those with 1 prior therapy and transplant (HR 1.23). Across all subgroups, toxicity was consistent with that seen in the intent-to-treat population. In patients with relapsed/refractory multiple myeloma, ixazomib-Rd was associated with a consistent clinical benefit vs. placebo-Rd regardless of prior treatment with bortezomib or immunomodulatory drugs. Patients with 2 or 3 prior therapies, or 1 prior therapy without transplant seemed to have greater benefit than patients with 1 prior therapy and transplant. TOURMALINE-MM1 registered at clinicaltrials.gov identifier: 01564537.

A phase I/II dose-escalation study investigating all-oral ixazomib-melphalan-prednisone induction followed by single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma

This phase I/II dose-escalation study investigated the all-oral ixazomib-melphalan-prednisone regimen, followed by single-agent ixazomib maintenance, in elderly, transplant-ineligible patients with newly diagnosed multiple myeloma. Primary phase I objectives were to determine the safety and recommended phase II dose of ixazomib-melphalan-prednisone. The primary phase II objective was to determine the complete plus very good partial response rate. In phase I, patients were enrolled to 4 arms investigating weekly or twice-weekly ixazomib (13 28-day cycles or nine 42-day cycles) plus melphalan-prednisone. In phase II, an expansion cohort was enrolled at the recommended phase II ixazomib dose. Of the 61 patients enrolled, 26 received the recommended phase II dose (ixazomib 4.0 mg [days 1, 8, 15] plus melphalan-prednisone 60 mg/m2 [days 1-4], 28-day cycles). Of the 61 enrolled patients, 36 (13 of 26 in the recommended phase II dose cohort) received single-agent ixazomib maintenance (days 1, 8, 15; 28-day cycles). In phase I, 10/38 patients reported dose-limiting toxicities in cycle 1, including grade 3 and/or 4 neutropenia (n=6) and thrombocytopenia (n=4). Complete plus very good partial response rate was 48% (48% at recommended phase II dose), including 28% (22%) complete response or better; responses deepened during maintenance in 34% (33%) of evaluable patients. After median follow up of 43.6 months, median progression-free survival was 22.1 months. Adverse events were mainly hematologic events, gastrointestinal events, and peripheral neuropathy. This study demonstrates the feasibility, tolerability, and activity of ixazomib-melphalan-prednisone induction and single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma patients. clinicaltrials.gov identifier 01335685.

Twice‐weekly ixazomib in combination with lenalidomide‐dexamethasone in patients with newly diagnosed multiple myeloma

Weekly ixazomib with lenalidomide‐dexamethasone (Rd) is feasible and has shown activity in newly diagnosed multiple myeloma (NDMM) patients. This phase 1/2 study (NCT01383928) evaluated the recommended phase 2 dose (RP2D), pharmacokinetics, safety and efficacy of twice‐weekly ixazomib plus Rd in NDMM; 64 patients were enrolled across both phases. Patients received twice‐weekly oral ixazomib 3·0 or 3·7 mg plus lenalidomide 25 mg and dexamethasone 20 mg (10 mg in cycles 9–16) for up to sixteen 21‐day cycles, followed by maintenance with twice‐weekly ixazomib alone. No dose‐limiting toxicities were reported in cycle 1; the RP2D was 3·0 mg based on overall tolerability across multiple cycles. In 62 evaluable patients, the confirmed overall response rate was 94% (68% ≥very good partial response; 24% complete response). Median progression‐free survival was 24·9 months. Responses (median duration 36·9 months for patients receiving the RP2D) deepened during treatment. Grade 3 drug‐related adverse events (AEs) occurred in 64% of patients, including: rash, 13%; peripheral neuropathy, 8%; hyperglycaemia, 8%. There were no grade 4 drug‐related AEs. Thirteen patients discontinued due to AEs. Twice‐weekly ixazomib‐Rd offers substantial activity with promising long‐term outcomes in NDMM patients but may be associated with greater toxicity compared with weekly ixazomib‐Rd in this setting.

Optimizing therapy for del(17p) multiple myeloma

We read with interest the publication by Liu et al. reporting the results from a meta‐analysis of 13 prospective studies evaluating the efficacy of proteasome inhibitor/immunomodulatory drug‐based treatments for newly diagnosed (ND) and relapsed/ refractory (RR) multiple myeloma (MM) patients with chromosome 17p deletion [del(17p)] [1]. In patients with RRMM, progression‐free survival (PFS) was evaluated in seven trials including 1,419 patients, of which 393 had del(17p). The authors state that the PFS of del(17p) RRMM patients treated with single‐agent dexamethasone, lenalidomide+dexamethasone (Rd) or bortezomib+Rd, carfilzomib+Rd, ixazomib+Rd (IRd), elotuzumab+Rd (ERd), or pomalidomide+dexamethasone, was: 1.1, 2‐14.9, 24.5, 15.7, 21.2, and 4.6‐7.3 months, respectively [1]. Based on these results, the authors suggest that combined treatment with carfilzomib or elotuzumab and Rd, or pomalidomide with low‐dose dexamethasone, improves the outcomes of RRMM patients with del(17p) [1]. The meta-analysis of Liu et al. included efficacy data from the phase 3 TOURMALINE‐MM1 study, which demonstrated a 35% improvement in PFS with IRd, compared with placebo‐Rd, in 722 RRMM patients [2]. We would like to point out that in a pre-specified analysis of PFS in 69 RRMM patients with del(17p), median PFS was 21.4 months with IRd (compared with 9.7 months with placebo‐Rd) [3], not 15.7 months, as reported by Liu et al. [1]. In TOURMALINE‐MM1, all cytogenetic analyses were performed at a central laboratory, hence a cut-off value of 5% was appropriately used for defining the presence of the del(17p) genetic abnormality, based on the false‐positive rate (technical cut‐off) of the fluorescence in situ hybridization (FISH) probes used [3]. Subsequent post‐hoc analyses demonstrated that the PFS benefit with IRd vs placebo-Rd was consistent when using different cut-off values for defining the fraction of cells with del(17p); the median PFS in the IRd (vs placebo‐Rd) group was 21.4 months (vs 9.7 and 6.7 months) with a cut‐ off of 5% and 20%, respectively, and 15.7 months (vs 5.1 months) with a cut‐off of 60% [3]. At present, there is no consensus on the appropriate FISH-positivity cut-off value for defining the presence of del(17p) and the International Myeloma Working Group recommends that no specific global cut-off should be applied [4, 5]. Currently, it is not known what minimum percentage of del(17p)‐positive cells is associated with a poor prognosis, or whether this percentage varies depending on the treatment regimen/disease stage [5]. Most recent studies in MM patients with high‐risk cytogenetic abnormalities have used a range of different cut‐off values, from a single cell [6] to a threshold of ≥60% of cells [7], and it is therefore challenging to draw a link between the size of the pool of del(17p)‐positive cells and its impact on clinical outcomes. Therefore, in our opinion, the meta‐analysis from Liu et al. should report that the IRd PFS of del(17p) RRMM patients is 21.4 months, based on the protocol-specified cut-off value of 5% for del(17p) FISH-positivity, and not 15.7 months (based on a 60% cut‐off). Furthermore, Liu et al. did not apply the same threshold when reporting outcomes for other clinical trials, such as the Lonial et al. 2016 study of ERd, which used a cut‐off as low as a single positive cell [1, 6]. While we appreciate the authors’ efforts in conducting the reported meta‐analysis [1], we would like to highlight a major limitation of this study. Cross‐trial comparisons have intrinsic limitations: the trials included in the meta‐analysis differ in many ways, including, but not limited to, the number of patients, inclusion/exclusion criteria, treatment duration, and frequency of assessment. Furthermore, while the authors applied the 60% cut‐off value to identify patients with del(17p), this definition has not been applied equally to all treatment regimens analyzed in the study. As such, no significant conclusions can be made on the relative impact of the different treatment combinations on the outcomes of RRMM patients with del(17p). In summary, we would like to suggest to Liu and colleagues that, in light of our considerations, they re‐evaluate the PFS results reported in their meta‐analysis; in our opinion, the IRd PFS in del(17p) RRMM patients from the TOURMALINE‐MM1 study should be corrected to 21.4 months.