The potential of ixazomib, a second-generation proteasome inhibitor, in the treatment of multiple myeloma

Abstract

The therapeutic armamentarium for multiple myeloma has recently benefited from the addition of several new agents (including second-generation proteasome inhibitors, monoclonal antibodies and histone deacetylase inhibitors). This review will focus on ixazomib, an orally bioavailable second-generation proteasome inhibitor. Specifically, we will review the preclinical data, clinical trial experience, potential indications as well as unanswered questions pertaining to this new agent in multiple myeloma.

Introduction

Multiple myeloma (MM) remains a malignancy for which no consistently curative treatment exists. Despite best efforts, the most effective therapeutic agents only delay the inevitable progression of this disease, typically associated with debilitating end-organ damage. With the challenges imposed by evolving drug resistance, there is a continued and unmet need to expand the therapeutic arsenal against this disease.

One of the most significant therapeutic advances in the past 15 years for the treatment of MM has been the introduction of proteasome inhibitors (PIs). Bortezomib (BTZ), the first-in-class PI, has become the backbone for the majority of front-line regimens in MM care.^1–5 The success seen with BTZ primed the development of second-generation PIs seeking to improve on activity while minimizing the toxicities, most notably peripheral neuropathy (PN). This success has also encouraged the exploration of PIs as therapeutic options in other disease states, including primary systemic amyloidosis and in certain lymphomas, although the scope of this review will remain focused on MM alone. BTZ-induced PN, however, remains the main limitation to the use of this agent in the clinic. In addition, while the delivery of BTZ via subcutaneous injection appears to reduce but not eliminate the incidence of severe grade 3 and higher PN, the biweekly and even the weekly dosing schedule still remain tedious for patients.

The development of carfilzomib (CFZ), a second-generation PI, represented significant progress towards a less neurotoxic and potentially more efficacious PI. Unlike BTZ, CFZ demonstrated irreversible inhibitory kinetics. While the incidence of grade 3 PN was markedly diminished with CFZ, other aspects of the BTZ toxicity profile, including the incidence of thrombocytopenia, lymphopenia, herpetic zoster reactivation, and fatigue persisted, with a small percentage of patients developing cardiotoxicity rarely seen with the first-generation PI. Furthermore, CFZ, delivered as twice weekly infusions on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle, is more cumbersome than BTZ given as four twice weekly subcutaneous injections over a 21-day course. Yet the clinical benefit rates seen with CFZ in a variety of combinations clearly outperformed that of BTZ. Single-agent CFZ recaptured responses in 23.7% of BTZ-refractory patients,⁶ while CFZ in combination with lenalidomide (LEN)/dexamethasone (DEX) or cyclophosphamide/DEX achieved deeper and more durable responses than those seen in comparative BTZ-based regimens.^4,7–10 The clinical experience with CFZ culminated in the Endeavor trial, which compared BTZ and DEX with CFZ and DEX and noted a superiority of the latter in terms of efficacy and a lower incidence of neurotoxicity.¹¹ Additional trials which cemented the role of CFZ included the ASPIRE trial (which resulted in approval by the US Food and Drug Administration (FDA) of this agent in patients after failure of first-line therapy) as well as the experience with CFZ in combination with LEN and DEX in newly diagnosed myeloma, which resulted in unprecedented complete response (CR) rates.^12,13

The recent approval of ixazomib for the treatment of MM in the refractory/relapsed (RRMM) setting introduces the first orally bioavailable PI option. Ongoing clinical investigations exploring ixazomib in the refractory/relapsed, as well as the upfront and maintenance settings are generating exciting data. This review will offer perspectives on the preclinical and clinical data and delve into the potential roles ixazomib can assume in the further optimization of clinical management of patients with MM.

Preclinical studies

Proteasome function is an integral regulator of intracellular signaling. Impairment of protein degradation and recycling dependent on the proteasome disrupts critical survival pathways regulating cell cycle, cell differentiation, and apoptosis dependent on the rapid turnover of signaling mediators to control checkpoint mechanisms.¹⁴ BTZ, a small-molecule reversible inhibitor, was the first-in-class PI approved for the treatment of both MM and mantle cell lymphoma.^2,3,15–18 BTZ effectively targets the 20S proteasome subunit, binding to the NH₂-terminal threonine side chain of the catalytic β subunit, preferentially to the β5 site directing the chymotrypsin-like activity.¹⁹ However, the relative inefficacy of BTZ in the solid tumor setting, thought to be due to poor tissue penetration, as well as the neurotoxicity defined a need for second-generation PIs with improved pharmacokinetics and therapeutic index.

Ixazomib, developed initially as MLN9708, is another potent yet reversible boronate-containing PI. Compared with BTZ, ixazomib demonstrates a shorter dissociation half life with the 20S proteasome and this is believed to contribute to its superior tissue penetration.²⁰ Considering proteasomes are highly concentrated in red blood cells, it is presumed that more durable binding, as seen with BTZ, results in trapping of the drug in circulation, thus contributing to poorer tissue distribution. MLN9708 is designed as a stable citrate ester that immediately hydrolyzes to MLN2238, the biologically active form, in aqueous solution or plasma (Figure 1). Structurally, MLN2238 is a dipeptidyl leucine boronic acid and, like BTZ, preferentially binds the β5 subunit of the 20S proteasome with a measured IC₅₀ (half maximal inhibitory concentration) of 3.4 nmol/L, although also binding the β1 and β2 sites at higher concentrations. However, the measured dissociation rate for ixazomib from the proteasome is approximately sixfold faster than that for BTZ, with a dissociation half life of 18 min as compared with 110, and preclinical assessments clearly demonstrated improved drug activity outside the circulatory system corresponding to a concomitant drop off in inhibitor activity in the blood.²⁰ Ultimately, this translated to improved tumor control in in vivo animal studies. Kupperman and colleagues demonstrated the superiority of MLN2238 over BTZ in suppressing tumor growth in xenograft models of prostate cancer and lymphoma, with a statistically significant overall survival (OS) benefit (54 versus 33 days) in mice challenged with OCI-Ly7 lymphoma cells.²⁰ Comparisons between MLN2238 and BTZ in xenograft models of MM were similarly impressive, with MLN2238 demonstrating a stronger capacity than BTZ to promote tumor regression and improve survival in mice engrafted with MM.1S cells.²¹ Finally, in a murine spontaneous MM model, the double-congenic iMyc^Cα/Bcl-X_L mouse, MLN2238, was equally protective in comparison to BTZ but was significantly better in protecting against osteolytic bone disease.²²

Figure 1.

Molecular structures of ixazomib and bortezomib.

Phase I studies

Ixazomib entered early clinical testing in the form of two phase I clinical trials run simultaneously, exploring two different dosing regimens. Kumar and colleagues²³ implemented a weekly dosing schedule, 3 weeks out of 4 in a 28-day cycle up to 12 cycles, in a 3+3 dose-escalation scheme with doses ranging from 0.24 to 3.95 mg/m². In a simultaneous phase I trial, Richardson and colleagues²⁴ explored a twice weekly dosing schedule resembling that used with BTZ, with escalating doses ranging from 0.24 to 2.23 mg/m² given on days 1, 4, 8 and 11 on a 21-day cycle for up to 12 cycles. In both dosing strategies, ixazomib was well tolerated, although with slightly different toxicity profiles.

In the trial looking at once weekly dosing, 60 patients were enrolled: 32 in the dose-escalation phase and another 28 in the expansion cohorts. Inclusion criteria mandated measurable disease and a minimum of two prior lines of therapy that must include exposure to BTZ, an IMiD and corticosteroids in any combination. The patient population had an average age of 64 years, a median of four prior lines of therapy, and 20% were considered to have high-risk disease by either international staging system (ISS) staging or the presence of high-risk cytogenetic features. The maximum tolerated dose (MTD) identified in the escalation phase was 2.97 mg/m², after two grade 3 events were observed at the 3.95 mg/m² dosing cohort, one subject developing grade 3 nausea, vomiting and diarrhea (also seen in one patient at the 2.97 mg/m² dosing tier), and a second subject developing a grade 3 erythema multiforme rash, both of which led to dose interruption. Of note, the rash resolved when the drug was held and did not recur when the patient resumed ixazomib at a lower dose. The expansion phase of the trial included four cohorts of patients defined based on prior exposure to PIs: relapsed/refractory, relapsed but not refractory to prior BTZ treatment, PI naïve, and prior CFZ exposure. Grade 3 and higher adverse events (AEs) were seen in 53% of the total patient populations; the most common grade 3 and higher AEs seen in at least 20% of the expansion cohorts were thrombocytopenia (39%), neutropenia (26%) and diarrhea (23%). Importantly, only one patient developed PN higher than grade 2. Among the 50 evaluable patients, 20% demonstrated a best overall response of, minimal response (MR) or better, including one very good partial response (VGPR) and eight partial responses (PRs). In these patients, median duration of response was 7.3 months, with the only group appearing to have shorter benefit being those in the CFZ-exposed cohort.

The second phase I study evaluated twice-weekly dosing of ixazomib in 60 patients as well. Enrollment criteria among the two studies were identical, contributing to highly similar characteristics of the respective patient populations, although this second study included slightly more BTZ-refractory patients. Following a twice-weekly dosing schedule, the MTD identified in the dose-escalation phase was 2.0 mg/m². Two patients at the 2.23 mg/m² dosing cohort developed grade 3 and higher AEs, including a grade 3 macular erythematous rash that resolved with standard supportive measures allowing for continuation at a lower dose, and a grade 4 thrombocytopenia treated with a platelet transfusion. The expansion phase was similarly divided into the four treatment-defined cohorts. There was slightly more toxicity associated with the twice weekly dosing. While thrombocytopenia was again the most common grade 3 and higher AE (48%) in the expansion cohorts, other grade 3 and higher AEs occurring in at least 20% of the cohorts included nausea (45%), fatigue (40%), rash (38%), vomiting, diarrhea and pyrexia (all 20%). Again, drug-related AEs were typically adequately managed with standard supportive measures. No PN higher than grade 2 was seen with twice-weekly dosing. Among 55 evaluable patients, 17% achieved a best overall response of MR or better, including one CR, one VGPR and six PRs. As anticipated, responses were more likely in the BTZ-naïve and BTZ-relapsed arms than in the BTZ-refractory cohort.

In essence, both studies identified thrombocytopenia and gastrointestinal (GI) toxicity as prevalent AEs; however the twice-weekly regimen also demonstrated a higher incidence of fatigue and rash. With relatively similar response rates seen in the two studies, toxicity guided the selection of a weekly dosing scheme as the optimal regimen. However, this remains somewhat speculative considering the determination was based on two relatively smaller studies, enrolling only 120 patients collectively, and less than 70 treated at the respectively determined maximally tolerated doses. It remains less clear whether either dosing regimen could potentially be superior in terms of depth or duration of response.

A third phase I/II study (technically a phase II design as there was a minimal dose-determining component) evaluated the combination of ixazomib, LEN and DEX in Asians with RRMM.²⁵ In this trial, 43 patients with one to three prior lines of therapy were included. The phase I aspect of this trial was designed to start at an expected optimal ixazomib dose of 4 mg, allowing for tiered reductions to 3 mg and 2.3 mg dosing in the setting of intolerance. Nonetheless, the dose-finding component of this study, the first six patients enrolled, established adequate tolerability of the 4 mg ixazomib dosing. Thus, ixazomib was given orally at 4 mg on days 1, 8 and 15 in combination with LEN 25 mg given on days 1–21 and DEX 40 mg given on days 1, 8, 15 and 22 of a 28-day cycle. As with the previous studies, thrombocytopenia, along with neutropenia and diarrhea, were the most prevalent grade 3 and higher toxicities associated with the regimen. Overall response rate (ORR) to ixazomib in combination with LEN/DEX was 65%, including 9% CRs, 14% VGPRs and 83% demonstrated at least a MR with a median duration of response measured at 12.9 months. While 74% of these patients had received BTZ previously, BTZ refractoriness was an exclusion criterion for this study. While it is difficult to compare across trials, especially when conducted during a different time period, the response rate of BTZ/LEN/DEX appeared comparable to that of ixazomib/LEN/DEX.¹⁰ Similarly, the ORRs to LEN/DEX in patients with one to three prior lines of therapy appear to be similar (approximately 60%).^26,27

Phase II studies

With two phase I studies providing convincing evidence for the single-agent efficacy of ixazomib in RRMM, a phase II trial was designed to further clarify a role for ixazomib in the treatment of RRMM.²⁸ As opposed to the two prior phase I studies evaluating single-agent ixazomib, this study incorporated DEX as a partner agent in patients demonstrating a suboptimal response to initial single-agent ixazomib therapy, defined as a lack of a minor response after the completion of two cycles, lack of a PR by completion of the fourth cycle of therapy, or evidence of disease progression at any time. Furthermore, this study targeted a patient population that was largely PI naïve, and specifically defined as having relapsing disease after at least one prior line of therapy (median two). Seventy-two percent of the participants in this study were naïve to BTZ, while 59% had previously undergone autologous transplant. The median age of the patients enrolled was 69 years. Ixazomib was given at a higher dose of 5.5 mg weekly on days 1, 8 and 15 of a 28-day cycle, and DEX 20 mg was added on days 1, 2, 8, 9, 15 and 16 in patients demonstrating a suboptimal response. Overall, 34% of patients in this study achieved at least a PR, while one patient achieved a CR and another achieved a stringent CR. Notably, while this ORR may be in line with early trials exploring BTZ/DEX,^2,15 it is significantly inferior to that seen with current BTZ/DEX studies, regardless of prior BTZ exposure,^11,29–31 suggesting that ixazomib may not be a more effective PI than BTZ. Six of these 11 responses were attained only after the addition of DEX. DEX was initiated in 67% of the patients, 51% for not meeting planned response objectives on single-agent ixazomib and another 16% at the time of disease progression. Response rates were similar irrespective of prior BTZ exposure. Median event-free survival (EFS) was 11.5 months, while median duration of response in patients achieving at least MR was 17.4 months. While DEX was added only in patients demonstrating suboptimal responses, the decision to use a higher ixazomib dose, and to select a primarily PI-naïve patient population, confound the ability to draw any direct conclusions as to which of these factors may be contributing or responsible for the noted improvement in response rate.

It is important to note, however, that the addition of steroids correlated with a small but significant reduction in overall GI toxicity that may have interfered with the measure of true EFS. Nonetheless, only three patients discontinued treatment for toxicity-related reasons. Thrombocytopenia remained the most common AE, and fatigue, nausea and diarrhea were the other most common grade 3 toxicities. Furthermore, it is noteworthy that the decision for a weekly dosing regimen chosen for the phase II study was motivated by a difference in GI toxicity that may no longer exist when ixazomib is combined with DEX, thus potentially reviving discussions as to the optimal therapeutic dosing schedule.

With proven efficacy as an orally dosed PI for the treatment of RRMM, ixazomib was a logical candidate to be evaluated for its potential utility as both a front-line agent in newly diagnosed MM (NDMM), as well as in the maintenance therapy setting after autologous stem cell transplant (ASCT). The results of a combined phase I/II trial published by Kumar and colleagues provided key insights into these questions.²³ But with the mounting support for triple drug regimens in the upfront setting of NDMM, this trial additionally presented strong evidence arguing for the safety and efficacy of combining ixazomib with LEN/DEX. The phase I aspect of this study tested ixazomib in escalating doses (ranging between 1.68 and 3.95 mg/m²) on days 1, 8 and 15, in combination with a fixed dose of LEN at 25 mg orally on days 1–21 and DEX at 40 mg on days 1, 8, 15 and 22. This was continued for up to 12 28-day cycles while patients eligible for ASCT were allowed to interrupt treatment for stem cell mobilization after three cycles, and could proceed to ASCT after the sixth cycle. The study enrolled 65 patients, 15 into the phase I and 50 into the phase II aspects, and characteristics of the population were generally an accurate representation of the standard MM population in terms of age and sex, although high-risk patients were slightly underrepresented. The dose-escalation phase determined the maximum tolerated ixazomib dose to be 2.97 mg/m², however a decision was made to proceed with a dose of 2.23 mg/m² for the phase II portion of the protocol, one dose level lower than the MTD, in an effort to optimize the balance between efficacy and toxicity, anticipating extended drug exposure with utilization in both induction and maintenance capacities. Body surface area (BSA)-based dosing was converted to a fixed dose of 4 mg based on population pharmacokinetic studies supporting the feasibility of such a conversion.³² In the expansion phase, this regimen was well tolerated, with grade 3 or higher AEs reported in 63% of patients; the most common toxicities were rash (17%), neutropenia (12%), fatigue (9%) and thrombocytopenia (8%). Of note, 6% of the treatment population developed significant grade 3 and higher PN, which had largely not been noted in all prior studies. In 64 evaluable patients, 58% achieved a VGPR or better response, including 27% CRs and 11% stringent Complete Response (sCRs), while the ORR was 92%. Importantly, these response values remained consistent when these parameters were assessed in the 24 patients aged 65 and older. Furthermore, response rates and depth of response were comparable to those reported with BTZ, LEN and DEX in the EVOLUTION study.⁴ Neither the median duration of response nor the median OS had been reached at the time the study results were published. A second phase I/II study looked at the combination of ixazomib, LEN and DEX using a twice-weekly dosing schedule.³³ This study enrolled 64 patients, 50 of whom went onto the phase II aspect once the recommended phase II dosing was established at 3.0 mg for the twice weekly schedule. More frequent scheduling resulted in similar efficacy, with an ORR (⩾PR) of 93%, including 24% CR (of which 14% were sCR) and with 67% of responses VGPR or better in the 58 evaluable patients. Furthermore, the median time to initial response was 0.69 months and the median duration of response was ongoing at the time of reporting but exceeding 5.9 months. However, increased dosing frequency was associated with increased toxicity in terms of rates of rash and PN. Further studies have focused on the weekly dosing.

Phase III studies

In a well designed and well balanced international phase III clinical trial, the TOURMALINE-MM1 study enrolled 722 patients with RRMM having measureable disease after one to three prior lines of therapy to receive LEN and DEX either in combination with ixazomib or with placebo.³⁴ Patients were randomized in a 1:1 ratio, further stratified based on number of prior lines of therapy, prior PI exposure and ISS staging. The primary endpoint in this study was progression-free survival (PFS), with prespecified secondary endpoints to include OS in the intention-to-treat and del(17p)-positive populations, ORR, rate of CR and VGPR, duration of response, time to progression, and PFS specifically in patients with high-risk cytogenetics.

The addition of ixazomib to LEN/DEX extended the median PFS from 14.7 to 20.6 months. Of relevance, a preplanned comparison of the two regimens in a subset of patients with high-risk cytogenetics, defined as the presence of del(17p), t(4;14) or t(14;16), suggested that the addition of ixazomib can compensate at least partially for the presence of high-risk disease; PFS in the ixazomib versus placebo arms was 21.4 months versus 9.7 months, respectively. ORRs between the two groups were roughly the same at 78% versus 72%, while the depth of response appears to be only marginally better with ixazomib, with 48% achieving a VGPR or better, compared with 39% in the placebo arm. The lack of separation between the two study arms in terms of depth of response may reflect a limited efficacy of ixazomib but could also represent, in part, an unexpectedly strong performance by the placebo arm, as the VGPR and higher rates for LEN/DEX here are notably higher than reported in previous studies. The ixazomib arm produced more CRs (12% versus 7%). Median OS was not reached in either group. Grade 3 and higher thrombocytopenia seen in the earlier clinical data also appeared to be somewhat more prevalent in the ixazomib arm (19% versus 3%). Neutropenia was the most common grade 3 and higher AE but was equally present in both arms. Incidence of rash, GI toxicities and fatigue that manifest as grade 3 and higher toxicities in the phase I and II studies were rather infrequent and did not appear to vary between the treatment groups significantly. PN of any grade was noted in 27% of patients receiving ixazomib versus 22% of those in the LEN/DEX arm, of which 2% in each group were considered grade 3. Although the study avoided a direct comparison between ixazomib and BTZ, thus leaving an essential question unaddressed, the TOURMALINE-MM1 trial emphasized the utility of ixazomib in the treatment of MM, while additionally demonstrating the efficacy and tolerability of an all-oral treatment regimen.

The results of the TOUMALINE-MM1 trial paved the way for approval of ixazomib by the US FDA in November 2015 for the treatment of RRMM in combination with LEN/DEX. The European Medicines Agency has been more reluctant to issue similar approval for ixazomib, citing lack of sufficient evidence of clinical benefit and a reduction in differences between the two arms with longer follow up, although the agency has recently recommended conditional approval, thus raising optimism that the oral PI will soon be available in Europe as well.

Maintenance

Maintenance therapy is widely accepted as an integral component in MM care, aimed at balancing extended duration of disease control following induction with or without ASCT therapy with quality-of-life measures. The intergroupe francais du myeloma (IFM) and cancer and leukemia group B (CALGB) studies have clearly demonstrated the benefit of LEN maintenance.^35,36 Although other agents including BTZ have demonstrated efficacy in a maintenance capacity,^8,37–39 BTZ has not been used in the maintenance setting to nearly the same degree as LEN. Convenience is undoubtedly a factor contributing to a preference for oral LEN. But additionally, LEN has been thoroughly evaluated in the maintenance setting, whereas data supporting BTZ maintenance are less clear, leaving unanswered questions about optimal dosing schedules and the relative importance of maintenance BTZ versus other variables introduced by the trial designs. Important considerations in defining an ideal maintenance regimen center on ease of administration, limited toxicity and durable effect. LEN, demonstrating dramatic improvements in PFS as an oral agent with high degree of tolerability, is currently the most frequently used agent in the maintenance setting. Furthermore, its diminished efficacy in high-risk MM⁴⁰ raises the awareness for the need for better options. BTZ, when explored as a combined induction/maintenance option, demonstrated a slightly more favorable capacity to overcome the poor prognostic implications associated with high-risk cytogenetic features,³⁷ although at the expense of injections every 2 weeks that limited convenience. Combining BTZ and LEN in the maintenance setting for patients exhibiting high-risk cytogenetics further improved upon survival outcomes (32-month median PFS and 93% 3-year OS), but again at the expense of convenience and toxicity. As an orally bioavailable drug, ixazomib may be particularly advantageous in this setting, offering a combination of convenience and improved efficacy especially in patients contending with MM with high-risk features. .

In the phase II trial described by Kumar and colleagues, patients who completed 12 cycles of induction therapy with ixazomib, LEN and DEX were allowed to continue on maintenance consisting of ixazomib alone following the same 28-day cycle.²³ The feasibility of ixazomib maintenance is also presently being explored in a single-arm phase II study as part of a maintenance regimen in combination with LEN at standard maintenance dosing of 10 mg daily with escalation to 15 mg after 3 months as tolerated.⁴¹ Preliminary results from 65 patients enrolled suggest the combination is well tolerated and safe, while providing an estimated 2-year PFS of 83% with median PFS not having been reached yet.

There are currently two phase III trials exploring ixazomib in the maintenance setting. The TOURMALINE-MM3 and -MM4 trials will compare ixazomib with placebo as maintenance therapy after ASCT and without ASCT, respectively. The TOURMALINE-MM3 study will enroll approximately 652 patients who have achieved at least a PR after ASCT, comparing weekly ixazomib versus placebo control in terms of impact on PFS as a primary endpoint. Similarly, TOURMALINE-MM4 explores the therapeutic potential of weekly ixazomib versus placebo maintenance in nontransplant-eligible patients with NDMM who have achieved at a minimum a PR with induction therapy; this protocol is anticipated to enroll 761 patients, again with a primary outcome measure of PFS. Accrual is ongoing and expected to continue for at least 2 more years. Results are highly anticipated to provide strong support for the use of ixazomib in the maintenance setting. Unfortunately, using a placebo arm rather than comparing ixazomib with LEN, considered the current standard-of-care maintenance agent, inevitably weakens the potential impact of these trials.

Optimizing PI use

Ixazomib holds tremendous upside as the newest approved PI and the first with an oral route of delivery. The treatment of MM has changed dramatically, as has the expected durability of responses, with the inclusion of BTZ and subsequently CFZ in the therapeutic armamentarium. BTZ has become the backbone of the majority of induction regimens. Furthermore, evidence suggesting that BTZ is more effective and durable in disease with high-risk features raises the issue as to the importance of continuing BTZ in the maintenance setting when high-risk features are present.^42–44 CFZ appears to be a more potent PI compared with BTZ, demonstrating the ability to recapture therapeutic responses in 23% of BTZ-exposed patients with RRMM as a single agent⁶ and more recently demonstrating superior depth and duration of response in a head-to-head comparison in patients with RRMM.¹¹ However, the dosing frequency and schedule of each of these drugs, especially when factoring in the need for parenteral delivery, undoubtedly increases the degree of inconvenience when incorporating these two agents into treatment plans. While both BTZ⁴⁵ and CFZ⁴⁶ have been shown to maintain safety and efficacy given in weekly dosing schedules, this still does not compare to the convenience of an oral agent. This becomes even more challenging in the maintenance setting. The preclinical data would suggest that ixazomib should demonstrate increased clinical potency over BTZ and should translate to a minimum equivalence in efficacy. The improved tissue distribution seen with ixazomib in comparison to BTZ in the preclinical models further supports the expectation for improved clinical efficacy.²⁰ Direct comparisons of ixazomib and BTZ have not been made in the clinical setting, which has now been done between BTZ and CFZ.¹¹ Furthermore, although it stands to reason, there is limited direct evidence that ixazomib retains the improved outcomes BTZ has produced in high-risk disease such as is associated with del(17p) and t(4;14) mutations.⁴⁷ Nonetheless, as the only approved orally dosed PI, ixazomib makes a strong case as a convenient option for maintenance therapy, alone or possibly in combination with LEN.

With three PIs now available, the optimal sequencing will need to be determined. Certainly, data suggest that CFZ consistently demonstrates the highest potency in the clinical setting.¹¹ Although direct comparisons have not been examined clinically, ixazomib and BTZ appear to elicit similar rates of overall responses and similar depths of response when evaluated in similar patient populations. Guidelines are beginning to identify CFZ as the optimal choice for induction in high-risk disease. The exact role for ixazomib among the three PIs remains to be definitively established, although there are indications that it may be the ideal choice for incorporation of PIs into maintenance regimens.

Future directions

As an orally dosed medication, ixazomib fills an important void in the therapeutic options for myeloma management. While CFZ, by all indications, appears to be the more potent PI, the dosing schedule poses an inconvenience that can be difficult to address for many patients. Clinical investigations are under way to explore the feasibility of consolidating the CFZ dosing to a weekly schedule,⁴⁶ but this still requires three weekly intravenous infusions over a 4-week cycle. Similar modifications in the dosing of BTZ led to the acceptance of a weekly dosing schedule to improve convenience and possibly reduce toxicity, including neutotoxicity,⁴⁸ but much as with CFZ, the agent requires parenteral delivery thus mandating multiple clinic visits per cycle. The convenience of ixazomib should extend the utilization of the PI, particularly in the context of maintenance therapy where convenience and toxicity minimization are assigned similarly strong priority as therapeutic efficacy. With evidence now supporting the early initiation of systemic therapy in patients with high-risk smoldering myeloma,^13,49 ixazomib may also prove to be a good addition to this emerging therapeutic niche.

The single-agent efficacy of ixazomib seen in the early phase trials is promising and indicative of the potential this drug holds. But the acceptance of the importance of triple drug therapies in the induction phase of treatment emphasizes that the true potential of ixazomib may lie in the optimal combination partner. In this regard, there are now data accumulating to support the efficacy and tolerability of ixazomib with various partners (Table 1^50–55). In combination with logical candidates like pomalidomide, cyclophosphamide and panobinostat, ixazomib is proving to be an exciting therapeutic option.

Table 1.

Ixazomib-based regimens in clinical development.

Regimen	Regimen	Phase	n	Target population	Best response
Ixazomib Dexamethasone50	Ixa 4.0/5.5 mg on days 1, 8 and 15 Dex 40 mg on days 1, 8, 15 and 22	II	71	RRMM (not BTZ refractory)	5.5 mg: ORR 51% (8 VGPR, 1 sCR) 4.0 mg: ORR 31% (7 VGPR, 1 CR)
Ixazomib Panobinostat Dexamethasone51	Ixa 4 mg on days 1, 8 and 15 Pano 20 mg on days 1, 3, 5, 15, 17 and 19 Dex 20 mg on days 1, 2, 8, 9, 15 and 16	I	11	LEN/BTZ-exposed RRMM	ORR 27% (3 MR)
Ixazomib Cyclophosphamide Dexamethasone52	Ixa 4 mg on days 1, 8 and 15 Cy 300/400 mg on days 1, 8, 15 and 22 Dex 40 mg on days 1, 8, 15 and 22	II	70	NDMM	ICd 300: ORR 80%; CR+VGPR 27% ICd 400: ORR 73%; CR+VGPR 23%
Ixazomib Cyclophosphamide Dexamethasone53	Ixa 4 mg on days 1, 8 and 15 Cy 300/400 mg on days 1, 8, 15 and 22 Dex 40 mg on days 1, 8, 15 and 22	I/II	51	NDMM	ICd 400: ORR 78%; CR+VGPR 38%
Ixazomib Pomalidomide54	Ixa 4 mg on days 1, 8 and 15 Pom 4 mg on days 1–21 Dex 40 mg on days 1, 8, 15 and 22	I / II	17	LEN/BTZ refractory	ORR 62% (7 PR, 1 VGPR)
Ixazomib Pomalidomide55	Ixa 3 mg on days 1, 8 and 15 Pom 4 mg on days 1–21 Dex 40 mg on days 1, 8, 15 and 22	I/II	21	RRMM, LEN refractory	ORR 40%

BTZ, bortezomib; CR, complete response; LEN, lenalidomide; MR, minimal response; NDMM, newly diagnosed multiple myeloma; ORR, overall response rate; RRMM, refractory/relapsed multiple myeloma; VGPR, very good partial response; ICd, Ixazomib Cyclophosphamide Dexamethasone; sCR: stringent Complete Response.

While ixazomib is the first oral PI to achieve FDA approval, oprozomib (OPZ) is a second orally dosed PI currently in clinical trials in the setting of MM. OPZ is a structural analog of CFZ, similarly exhibiting irreversible binding kinetics to the 20s proteasome subunit. Two dosing strategies are being evaluated including a 2/7 schedule administered on days 1, 2, 8 and 9, and a 5/14 schedule administered on days 1–5 of 14 day cycles. In an analysis of the Phase IB portion of a Phase 1b/2 study looking at single agent OPZ, 34 RRMM patients received OPZ testing both dosing schedules, with a cumulative ORR of 35.2% seen, and with a toxicity profile similar to other oral PI including mainly GI and hematologic AEs.⁵⁶ In a similarly designed study combining OPZ with DEX enrolling 35 RRMM patients, the majority of which had prior BTZ exposure, ORR in the 2/7 was similarly measured at 35.5% whereas decreased treatment exposure was suggested as an explanation for a lesser response rate seen in the 5/14 arm.⁵⁷ While depth of response was greater in the first study, with several patients achieving ⩾VGPRs in contrast with the OPZ-DEX trial, this is likely related to heavier prior BTZ exposure in the OPZ-DEX study. GI toxicity appeared to be reduced with the addition of DEX. However, delays in the clinical development of oprozomib have helped establish ixazomib as the sole orally dosed PI currently available to MM patients.

Finally, the arena of myeloma therapy has recently begun to undergo a revolutionary change with the advent of effective immunobiologics. The IMiD drugs helped demonstrate the importance of the immune system and the ability to augment its response to MM. We now have two antibody-directed therapies in elotuzumab^58,59 and daratumumab^60–62 approved for the treatment of MM. And furthermore, the near future will see the likely addition of several more therapeutic antibodies directed against CD38 or other MM surface antigens, or directed at immune modulation, such as the checkpoint inhibitor pembrolizumab.⁶³ The integration of ixazomib into regimens containing these immunobiologics will be an extremely important next step in the optimization of our utilization of this PI.

Conclusion

As the third PI approved for the treatment of MM, ixazomib is a welcome addition to the growing treatment options. The potential advantages ixazomib brings as an orally dosed agent should help define a niche among the three PIs, particularly in the maintenance setting, but also potentially in the elderly or frail patient populations in which limitations in access to transportation can pose challenges to keeping frequent clinic appointments that are required for administration of parenteral agents. The acceptable toxicity profile, notably with less PN, will define an additional important patient population in MM needing additional treatment options. While CFZ may be a more potent PI, ease of administration clearly favors ixazomib, such that ixazomib should unquestionably retain its relevance and utility in the context of MM patient care.