(UPDATE) Ixazomib Update

Commentary by Shaji K. Kumar, MD, Multiple Myeloma Co-Site Editor for JNCCN 360

Professor of Medicine, Mayo Clinic, Rochester, Minnesota

Proteasome inhibitors continue to represent an important component of the various treatment combinations used for patients with newly diagnosed or relapsed multiple myeloma. Since the initial approval of ixazomib (Ninlaro), the first oral proteasome inhibitor to be introduced for treatment of multiple myeloma, various studies have examined the utility of this drug in several settings (ie, newly diagnosed myeloma and relapsed disease), in various combinations, and as a single agent in the maintenance setting. Although all phase III clinical trials with the drug have not met their primary endpoints, the data so far demonstrate activity, allowing us to develop all-oral combination regimens for myeloma without sacrificing the inclusion of the proteasome inhibitor class of drugs. This is particularly relevant for older patients, who often find it difficult to travel to the clinic on a weekly basis for injectable drugs.

DISCLOSURES

Dr. Kumar has received clinical research support/data safety monitoring board from AbbVie, Allogene, Amgen, Bristol Myers Squibb, Carsgen, Janssen Pharmaceutica Products, Kite Pharma, MedImmune, Merck & Co, Roche Laboratories, Sanofi-Aventis U.S., Takeda Pharmaceuticals North America, and Tenebio. He has also served on a scientific advisory board or as a consultant or expert witness for AbbVie, Inc., Amgen Inc., Celgene Corporation, Cellectar, Genecentrix, GlaxoSmithKline, Jannsen Pharmaceutica Products, LP, Molecular Partners, Oncopeptides, Roche Laboratories, Inc., Sanofi-Aventis U.S, and Takeda Pharmaceuticals North America, Inc.

Managing Multiple Myeloma Today

Despite enormous advances in the management of newly diagnosed multiple myeloma, patients eventually develop progressive/relapsed disease.¹ Relapsed disease typically acquires additional genomic alterations that render it more resistant and refractory to each subsequent salvage therapy.

The aims of myeloma treatment are to control the disease, prolong survival, reduce disease-related symptoms, and improve quality of life.² The impact of a specific treatment on quality of life for patients with multiple myeloma depends not only on the depth of response but also on the toxicities associated with individual therapy. Efficacy and safety also depend, to a large degree, on a patient’s individual tolerance, biologic robustness, and comorbidities.

Although a number of classes of agents are available to clinicians for managing patients with relapsed or refractory myeloma, proteasome inhibitors (eg, bortezomib, carfilzomib, ixazomib) have played a critical role in the initial management of the disease, as well as in the relapsed setting.³ Among them, ixazomib is currently the only oral proteasome inhibitor approved for use in these patients.⁴ The ability of patients to take their medication at home minimizes office visits and increases the convenience and attractiveness of the regimen. Ixazomib is a capsule taken once a week for 3 weeks of a 4-week cycle.⁴ Recent trials have yielded additional data regarding the use of ixazomib at various stages of myeloma disease evolution.

Treatment of Newly Diagnosed Multiple Myeloma

A recent ongoing clinical trial (ClinicalTrials.gov identifier NCT01850524) was designed to evaluate the addition of ixazomib to lenalidomide and dexamethasone in newly diagnosed transplant-ineligible patients with multiple myeloma.⁵ Although the initial results did not meet the threshold for statistical significance, the efficacy observed and the safety profile were generally consistent with the existing prescribing information.

Given the increasing interest in developing quadruplets that include multiple classes of drugs, a phase II study evaluated ixazomib in combination with daratumumab, lenalidomide, and an abbreviated course of dexamethasone (40 mg intravenously weekly for no more than two cycles) in 40 patients with newly diagnosed multiple myeloma.⁶ The primary objective of this study was to determine the rate of complete response. The overall best confirmed response rate among all 40 patients was 95%, including 10% stringent complete responses, 5% complete responses, and 23% near-complete responses. CD34-positive cell collection was completed in 17 patients at the time of data cutoff.

Another recent study focused on the use of induction therapy with ixazomib, thalidomide, and dexamethasone. Most dimensions of quality of life assessed, notably health-related quality of life, physical functioning, and emotional well-being, remained relatively stable during exposure to the treatment regimen.⁷ However, although the study centered on pain reduction, many patients experienced increasing neuropathy. Indeed, the 43 patients who started maintenance therapy had significantly less fatigue and somewhat less pain but significantly more neuropathy than those who discontinued treatment earlier.

Maintenance Therapy for Myeloma

The phase III TOURMALINE-MM3 trial examined the role of ixazomib maintenance after single autologous stem cell transplantation.⁸ This trial demonstrated a significant improvement in progression-free survival with ixazomib maintenance used as a single agent after autologous stem cell transplantation. Another ongoing phase III study of the safety and efficacy of ixazomib, the TOURMALINE-MM4 trial (NCT02312258), was designed to compare single-agent ixazomib maintenance versus placebo in patients with newly diagnosed multiple myeloma who were not treated with stem cell transplantation. In November 2019, it was announced that the TOURMALINE-MM4 trial had met its primary endpoint of prolonging progression-free survival compared with placebo.⁹

Additional studies are evaluating ixazomib maintenance in combination with other available agents. For example, a phase II trial has demonstrated the feasibility and activity of long-term ixazomib/lenalidomide therapy as maintenance after autologous stem cell transplantation.¹⁰ The doublet improved responses in 45% of patients, and the median progression-free survival has not been reached after a median follow-up of more than 3 years. Only 6% of patients discontinued ixazomib due to toxicity, providing further evidence of its feasibility as a component in long-term treatment approaches.

Results from the phase II HOVON-126/NMSG 21.13 trial did not show an improvement in progression-free survival with ixazomib maintenance treatment compared with placebo.¹¹ However, according to the authors, the sample size was small, partly due to toxicity associated with thalidomide used in combination during induction therapy; randomization was allowed in just 55% of all patients and in 40% of the oldest and most frail patients. Of note, for those patients who were randomly assigned, ixazomib maintenance seemed to be well tolerated, irrespective of age and frailty.

Treatment of Relapsed Disease

Over the past few years, ixazomib, in combination with other agents, has shown significant activity in relapsed or refractory multiple myeloma. For example, ixazomib in combination with lenalidomide and dexamethasone was shown to be more effective compared with lenalidomide and dexamethasone in relapsed multiple myeloma in the phase III TOURMALINE-MM1 study.¹² An ongoing study aims to compare the effect of ixazomib plus dexamethasone versus pomalidomide plus dexamethasone on progression-free survival in participants with relapsed and/or refractory multiple myeloma (NCT03170882). These patients had received at least two prior lines of therapy, including lenalidomide and a proteasome inhibitor, and were refractory to lenalidomide but not refractory to proteasome inhibitors. The study is expected to be completed in December 2020.

Ixazomib has been studied in combination with other immunomodulatory drugs such as pomalidomide and thalidomide, as well as with alkylating agents such as cyclophosphamide and melphalan. In one phase I/II trial, ixazomib was combined with pomalidomide and dexamethasone in 32 lenalidomide-refractory patients with multiple myeloma.¹³ In the phase I portion of the study, 4 mg of ixazomib was determined as the recommended phase II dose, with standard doses of pomalidomide. With a median follow-up of 11.9 months, 48% achieved at least a partial response, with 5 patients (20%) achieving a very good partial response. The most common adverse events (≥ grade 2) were anemia, neutropenia, thrombocytopenia, and infections.

Researchers also studied the combination of ixazomib, thalidomide, and dexamethasone in patients with relapsed disease. In the phase II trial,⁷ treatment consisted of eight cycles of ixazomib, 4 mg, on days 1, 8, and 15, every 28 days; thalidomide, 100 mg/d on days 1 through 28; and dexamethasone, 40 mg, on days 1, 8, and 15, every 28 days. Patients aged 75 or older required a 50% dose reduction of thalidomide to 50 mg/d, dexamethasone to 20 mg, and ixazomib to 3 mg. Maintenance treatment with ixazomib therapy consisted of 4 mg, on days 1, 8, and 15 of a 28-day cycle, and was given for 1 year.

Safety

As with many other proteasome inhibitors, ixazomib is associated with its share of side effects.³ As such, it is vital for oncologists/hematologists and their care teams to educate patients about what to do should they occur. Although there is no cure for multiple myeloma, patients should understand that drug-related symptoms can be addressed.

Thrombocytopenia is common with ixazomib and can sometimes be serious. Clinicians should speak with patients about symptoms of low platelet counts, including bleeding and bruising and should consider platelet transfusions if platelet counts are too low.

Gastrointestinal issues, such as diarrhea, constipation, nausea, and vomiting are common and may be severe with ixazomib. Patients should be instructed to call their care teams if they develop any of these symptoms, as effective treatment options are available.

Ixazomib is also associated with neurologic adverse events. Patients should be queried about new or worsening symptoms, including tingling, numbness, pain, a burning feeling in the feet or hands, or weakness in the arms or legs. In a recently concluded trial, preliminary data indicated continuous treatment with ixazomib, in combination with lenalidomide and dexamethasone, did not increase the incidence of grade ≥ 3 neuropathy.¹⁴

Patients treated with ixazomib may also observe edema and should be prompted to inform their health-care teams if they develop swelling in their arms, hands, legs, ankles, or feet, or if they note sudden weight gain. In addition, dermatologic reactions are possible with ixazomib; patients should call attention to any a new or worsening rash.

Some patients treated with ixazomib may experience thrombotic microangiopathy, which may be associated with thrombocytopenia, anemia, purpura, or renal failure. Patients should seek medical help immediately if they develop any of the following signs or symptoms during treatment with ixazomib: fever, bruising, nose bleeds, tiredness, or decreased urination.

Other common side effects with ixazomib therapy include back pain, skin pain (ie, shingles), neutropenia, and ophthalmic conditions including blurred vision, dry eyes, and conjunctivitis.¹⁵ Necrotizing cutaneous vasculitis may occur with ixazomib treatment, but it is extremely rare.¹⁶ 

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