Regimen Protocols IRD or RID: Ixazomib citrate/lenalidomide/dexamethasone Constituents of Regimen: ixazomib, lenalidomide, dexamethasone Other Names of Regimen Constituents and Unique Ingredient Identifier (UNII): Ixazomib citrate: MLN9708; proteasome inhibitor MLN9708, UNII: 46CWK97Z3K Lenalidomide: CC-5013, CC5013, CDC 501, IMID-1, Revlimid, UNII: F0P408N6V4 Dexamethasone: Decadron, Dex, UNII: 7S5I7G3JQL Common Names or Abbreviations for Regimen: IRD, RID Mechanism(s) of Action: Ixazomib is a reversible proteasome inhibitor. It preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome. Ixazomib induced apoptosis of multiple myeloma (MM) cell lines in vitro. This agent demonstrated in vitro cytotoxicity against myeloma cells from patients who had relapsed after multiple prior therapies, including bortezomib, lenalidomide, and dexamethasone. The combination of ixazomib and lenalidomide demonstrated synergistic cytotoxic effects in multiple myeloma cell lines. In vivo, ixazomib demonstrated antitumor activity in a mouse multiple myeloma tumor xenograft model. U.S. FDA-Approved Indication(s): Ixazomib is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. 1 Approval was based on outcomes of the pivotal international, randomized, doubleblind, placebo-controlled clinical trial TOURMALINE-MM1, of 722 patients designed to evaluate the superiority of ixazomib plus lenalidomide and dexamethasone over placebo plus lenalidomide and dexamethasone in adult patients with relapsed and/ or refractory multiple myeloma. 2 It was announced earlier, February 10, 2015, that the TOURMALINE-MM1 trial achieved its primary endpoint of improving progression-free survival (PFS) at the first pre-specified interim analysis. In the trial, patients treated with investigational ixazomib plus lenalidomide and dexamethasone lived without their disease worsening for a significantly longer time compared to patients who received placebo plus lenalidomide/dexamethasone. 3 1
NCCN Recommended Use(s): IRD is recommended as primary therapy for transplant candidates; primary therapy for non-transplant candidates; and therapy for previously treated multiple myeloma. NCCN Preferred Regimen or Other: Both 4 Preferred Regimen: IRD is a preferred regimen as therapy for previously treated multiple myeloma. Note: This recommendation is consistent with U.S. FDA-approved indication. Other: IRD is not a preferred regimen, but is listed under other regimens as a primary therapy for transplant candidates and as a primary therapy for non-transplant candidates. Note: This recommendation is outside of the U.S. FDA-approved indication at this time. NCCN Category of Evidence 4 : IRD as a preferred regimen for previously treated multiple myeloma is a category 1 recommendation. IRD as listed under Other regimens as a primary therapy for transplant candidates and as primary therapy for non-transplant candidates is a category 2A recommendation. Dose Schedule: Newly diagnosed, untreated MM: Ixazomib 4 mg/day PO on days 1, 8, and 15 for up to twelve 28-day induction cycles; lenalidomide 25 mg/day PO on days 1 21 for up to twelve 28-day induction cycles; and dexamethasone 40 mg/day PO on days 1, 8, 15, 22, for up to twelve 28-day induction cycles. Note: Dose modifications of all three drugs were permitted for toxic effects. Patients were allowed to interrupt therapy so they could undergo stem cell collection after 3 cycles and discontinue for autologous stem cell transplant (ASCT) after 6 cycles. After primary induction therapy, maintenance with oral ixazomib was given on days 1, 8, and 15 every 28 days until progression at the last tolerated dose of induction therapy. 5,6 TOURMALINE MM-2 is the ongoing phase III part of this study. Relapsed/Refractory MM [TOURMALINE-MM1, Phase III study]: Ixazomib 4 mg/day PO on days 1, 8, and 15 on a 28-day cycle; lenalidomide 25 mg/day PO on days 1-21 on a 28-day cycle; dexamethasone 40 mg/day PO on days 1, 8, 15, and 22 on a 28-day cycle. Treatment was administered until disease progression. 2 IRD or RID: Ixazomib citrate/lenalidomide/dexamethasone
Safety: There are no black box warnings for ixazomib as the drug is not yet FDA approved. Black box warnings for lenalidomide and dexamethasone exist however. Common side effects and warnings include: Black box warnings for lenalidomide include embryo-fetal toxicity, hematologic toxicity, and venous and arterial thromboembolism. The most common side effects of lenalidomide in MM ( 20%, per Celgene package insert, Revlimid, 2015) 7 include fatigue, neutropenia, constipation, diarrhea, muscle cramps, anemia, pyrexia, peripheral edema, nausea, back pain, upper respiratory tract infection, cough, dyspnea, dizziness, thrombocytopenia, tremor, insomnia, decreased appetite, and rash. Additional warnings and precautions for lenalidomide in MM are rare, but should be considered, and include: Allergic reactions: Hypersensitivity, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis. If these occur, lenalidomide should be discontinued. Tumor lysis syndrome (TLS): Cases of TLS have been reported. Monitor for if disease burden high. Hepatotoxicity: Hepatic failure (including fatalities) has occurred. Liver function should be monitored. If hepatotoxicity is suspected, lenalidomide should be stopped. Second primary malignancies (SPMs): A higher incidences of SPMs were observed in controlled trials of patients with multiple myeloma receiving lenalidomide. Patients should not become pregnant when taking lenalidomide. Two reliable methods of contraception should be used while on therapy. IRD Fifty patients were enrolled in the phase II study of IRD as primary induction therapy in newly diagnosed, untreated multiple myeloma 5 ; 29 patients discontinued the study to proceed to transplant. All patients reported at least one drug-related event [65 patients (100%)]. In the total phase I/II study group, 49 (75%) patients had at least one adverse event (AE) of grade 3. Grade 3 or higher AEs related to any drug were reported in 41 (63%) patients, including skin and subcutaneous tissue disorders in 11 (17%) patients, neutropenia in 8 (12%) patients, and thrombocytopenia in 5 (8%) patients; drug-related peripheral neuropathy of 3 occurred in 4 (6%) patients. Five patients discontinued because of adverse events. Phase I/II safety profile of IRD (phase I, phase II and modified intention-to treat populations). 6 3 IRD or RID: Ixazomib citrate/lenalidomide/dexamethasone
AEs led to dose reductions in 37 (57%) patients, including eight (53%) of 15 in the dose-escalation cohort and 29 (58%) of 50 in the phase II cohort. The most common AEs resulting in dose reductions included skin and subcutaneous tissue disorders (13 patients, 20%), fatigue (9 patients, 14%), diarrhea (5 patients, 8%), peripheral neuropathy not elsewhere classified (5 patients, 8%), insomnia (4 patients, 6%), and increased body weight (4 patients, 6%). AEs leading to discontinuation of study treatment were reported in five patients. The only grade 4 drug-related adverse events were thrombocytopenia in two (3%) patients (one each in phase I and phase II), and neutropenia in two (3%) patients (both in phase II), all during induction with ixazomib/lenalidomide/dexamethasone. Two patients in the phase II cohort died during the study, one due to respiratory syncytial viral pneumonia that was thought to be related to treatment, and one due to cardiorespiratory arrest that was not thought to be related to treatment. Only treatment-emergent peripheral neuropathy (PN) of any type was observed in 28 (43%) patients; four reported PN at baseline. o PN was grade 1 in most patients (17, 26% patients), with grade 2 reported in 7 (11%) patients o Grade 3 PN was reported in 4 (6%) patients; one painful grade 3 PN Of 39 separate PN events, 19 (49%) [17 grade 1, and 2 grade 2] had resolved at the time of last follow-up (median 1.4 months [IQR 0.7-3.4]). Drug-related AEs. 6 4 IRD or RID: Ixazomib citrate/lenalidomide/dexamethasone
5 IRD or RID: Ixazomib citrate/lenalidomide/dexamethasone
Required Supportive Care/Prophylaxis: Patients on this regimen are at an increased risk for pneumonia, varicella zoster virus (VZV) or shingles reactivation, venous thromboembolic events (VTE), and PN. The following recommendations should be considered: Pneumococcal infections are common in patients with multiple myeloma. Pneumococcal vaccination should be completed at the time of diagnosis and repeated in 5 years to minimize preventable illness (link to CDC guidelines: http://www.cdc.gov/vaccines/vpd-vac/pneumo/vacc-in-short.htm). Antiviral prophylaxis with acyclovir or valacyclovir to prevent herpes zoster infections is recommended for patients receiving proteasome inhibitors. Thromboprophylaxis with aspirin or low molecular weight heparin is advised in patients receiving immunomodulatory drug regimens due to the high incidence of venous thrombosis observed. Patients should be educated as to the signs and symptoms of PN and report the onset or worsening of PN symptoms immediately. Dose reduction or discontinuation of ixazomib may be warranted. Bisphosphonates (zoledronic acid or pamidronate) are intended to decrease the risk of skeletal related events and should be considered in all patients with MM receiving first-line therapy, regardless of presence of osteolytic bone lesions on conventional radiography. Dental health should be evaluated at baseline and an ongoing basis to assess for osteonecrosis of the jaw. Serum creatinine levels should be obtained prior to each bisphosphonate dose. Periodic 24-hour urine monitoring should be performed to assess for renal damage secondary to bisphosphonate use long term. Tailoring of Regimen: No specific data on the use of ixazomib in the elderly or other special populations has yet been reported. Lenalidomide should be dose-reduced in patients with renal impairment. Steroids such as dexamethasone should be administered in lower doses in the elderly to prevent steroid-associated psychosis. Primary and Secondary Efficacy Outcomes: Fifty patients were enrolled in phase II study reported at American Society of Hematology (ASH). 6 Overall responses (ORR) were observed in 59 of 64 (92%, 95% CI: 83-87) patients; when patients who went on to autologous stem-cell transplant were excluded, the ORR was 88% (37 patients): Responses of very good partial response (VGPR) were observed in 37 (58%; 95% CI: 45-70) patients, and complete response (CR) in 17 (27%; 95% CI: 16-39). The median duration of response for the entire cohort had not been reached, with responses reported durable for up to 2 years. The estimated 1-year PFS was 88% (95% CI: 74-95) and the 2-year PFS was 67% (95% CI: 27-85). The median overall survival (OS) had not been reached; estimated 1-year OS was 94% (95% CI: 84-98). 6 IRD or RID: Ixazomib citrate/lenalidomide/dexamethasone
Patients 65 years treated in the phase II part of the study: o ORR: 88% (21 patients) [95% CI: 68-77] o CR or near-cr (ncr): 38% (9 patients) o VGPR: 33% (8 patients) o PR: 17% (4 patients) o 1-year PFS: 73% (95% CI: 49-87) o 1-year OS: 83% (95% CI: 62-93) Maintenance therapy with ixazomib in the phase I/II study of newly diagnosed, untreated multiple myeloma patients who received IRD: To date, the overall best confirmed/unconfirmed responses included: CR in 52% (11 patients), ncr in 62% (13 patients), and VGPR in 71% (15 patients), and 29% (6 patients) partial response (PR). The median time to first response ( PR) was 0.99 months (range 0.92 5.78) and to best response was 7.46 months (range 1.02 24.74). 33% of patients improved their response during maintenance, which included 2 VGPR to ncr, 3 VGPR to CR, 1 VGPR to stringent complete response (scr), and 1 CR to scr. At data cut-off, median duration of response was 26.5 mos (range 5.6 26.6+). Among 15 patients achieving VGPR, 5 (33%) had progressed; median duration of VGPR was 23.0 months (range 3.7 26.1+). 7 IRD or RID: Ixazomib citrate/lenalidomide/dexamethasone
Strategies to Reduce Treatment-Associated Side Effects: Antidiarrheal agents (eg, loperamide) are recommended to mitigate diarrhea. Electrolyte monitoring (eg, potassium) to identify and correct electrolyte abnormalities should be performed. Patients should be pre-medicated with antiemetic drugs such as granisetron and ondansetron prior to each dose of ixazomib to prevent nausea and vomiting. Patients should be premedicated with corticosteroids (ie, dexamethasone) and antiemetics prior to each dose of ixazomib. A complete blood count with differential (CBC/diff) should be obtained to monitor neutropenia and thrombocytopenia and intervene (ie, dose reduction, discontinuation of the causative agent) if necessary. Standard aspirin or low-molecular-weight heparin (LMWH) prophylaxis is recommended for patients receiving lenalidomide-containing regimens. Corticosteroids such as dexamethasone can lead to many side effects such as hyperglycemia, mood swings, insomnia, and proximal muscle weakness. Prior to starting a corticosteroid-containing regimen, patients should be screened for a history of diabetes, mood disorders and psychiatric illnesses. Regular physical activity should be encouraged to combat muscle weakness and prevent VTEs. Monitoring Recommendations and Notes: Adverse events (as listed above under Safety ) should be monitored for and addressed at each visit. Regular CBC/diff and chemistry monitoring to assess for myelosuppression and hepatic/renal abnormalities is suggested. Periodic monitoring of blood glucose levels (to assess for hyperglycemia), mood disturbance, and sleep patterns related to corticosteroids is recommended. Patients should be educated regarding additional side effects of medications as listed above (primarily PN, gastrointestinal, signs/symptoms of VTE) and urged to report side effects to the treatment team. Adherence to therapy can be improved by intervening side effects in a timely manner. Objective monitoring of responses to the regimen should be performed on a monthly basis (by International Myeloma Working Group (IMWG) Uniform Response Criteria) and recorded. 8 IRD or RID: Ixazomib citrate/lenalidomide/dexamethasone
References: 1. Ninlaro [prescribing information]. Cambridge, MA: Millennium Pharmaceuticals, Inc.; 2015. 2. Takeda. Newsroom. Press release. Takeda Submits New Drug Application for Ixazomib for Patients with Relapsed/Refractory Multiple Myeloma. July 15, 2015. Accessed at https://www.takeda.com/sp/news/2015/20150715_7060.html on August 24, 2015. 3. Takeda. Newsroom. Press release. January-March 2015. Takeda Announces That the First Interim Analysis of the Phase 3 Study of Oral Ixazomib in Patients with Relapsed or Refractory Multiple Myeloma Met the Primary Endpoint of Improvement in Progression-Free Survival. Release date: February 10, 2015. Accessed at https:// www.takeda.com/news/2015/20150210_6907.html on August 24, 2015. 4. National Comprehensive Cancer Network [NCCN]. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ). Multiple Myeloma. Version 3.2016. 5. Kumar S, Berdeja JG, Niesvizky R, et al. Long-Term Ixazomib Maintenance Is Tolerable and Improves Depth of Response Following Ixazomib-Lenalidomide- Dexamethasone Induction in Patients (Pts) with Previously Untreated Multiple Myeloma (MM): Phase 2 Study Results. Blood [ASH Annual Meeting Abstracts]. 2014;124(21):Abstract 82. 6. Kumar SK, Berdeja JG, Niesvizky R, et al. 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. Lancet Oncol. 2014;15(13):1503-1512. 7. Revlimid [prescribing information]. Summit, NJ: Celgene Corporation; 2015. Primary Author: Beth Faiman, PhD, RN, MSN, APRN-BC, AOCN, Cleveland Clinic, Cleveland, Ohio External Reviewer: Katherine Sanvidge Shah, PharmD, BCOP Internal Reviewer: Eugene R. Tombler, PhD, Medical Director for MediCom Oncology and Managing Myeloma, Patrick Brooks, PharmD, Medical Director for MediCom Oncology and Managing Myeloma History: Version 1.2015: Draft: 4/2015; External Review: 6/2015; Internal and Revisions: 7/2015 8/2015. Version 1.2016: updated to reflect FDA approval for patients who have received at least one previous therapy, inclusion of NCCN recommended uses, NCCN preferred or other designation status, NCCN categories of evidence for recommendations 1/2016.. Version 1.2016 IRD: Ixazomib/Lenalidomide/Dexamethasone 9 IRD or RID: Ixazomib citrate/lenalidomide/dexamethasone