Written by: Kirollos Hanna, PharmD, BCPS, BCOP, University of Minnesota Medical Center & Mayo Clinic
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Description: Ixazomib is an oral proteasome inhibitor indicated in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma after at least one prior therapy. This PQI highlights the management, safety, and efficacy of ixazomib.

Background: Multiple Myeloma (MM) is an incurable disease resulting from malignant plasma cells. MM is rare in younger patients (median age at diagnosis: 72 year). Patients with MM often experience “CRAB” symptoms defined as: hypercalcemia, renal dysfunction, anemia, and bone lesions. Patients generally relapse multiple times and are treated with multi-drug regimens, preferably triplets; common drugs include proteasome inhibitors (PI), immunomodulatory drugs (IMiD), monoclonal antibodies, and steroids. Select patients may be eligible for an autologous stem cell transplant depending on risk factors associated with disease.

Ixazomib is an oral PI that may be used in the relapsed/refractory (r/r) setting in combination with lenalidomide/dexamethasone. Off-label considerations include utilizing ixazomib in the front-line setting regardless of transplant eligibility in combination with lenalidomide and dexamethasone or in the r/r setting with pomalidomide/dexamethasone or with dexamethasone alone. Ixazomib provides an all oral treatment option in patients with MM. In a clinical phase 1/2 trial, front-line ixazomib/lenalidomide/dexamethasone was associated with a very good partial response in 58% of patients. In the r/r setting, ixazomib-containing regimens demonstrated an improvement in response rates and/or progression free survival. The most common side effects associated with ixazomib in ≥20% of patients include:  diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting, and back pain.

PQI Process:

Upon receipt of prescription for ixazomib:

  • Prior to therapy initiation, obtain baseline labs CBC/diff, CMP, and relevant MM labs to assess treatment response
    • Select MM labs: lactate dehydrogenase (LDH), beta-2 microglobulin, protein analyses, bone marrow aspirate, and cytogenetic studies
    • Platelet and neutrophils nadir occurs on days 14-21 of each cycle. Labs should be monitored monthly but may be more frequent with the first three cycles
  • Ixazomib should be dose reduced for severe renal impairment (or ESRD requiring dialysis), or moderate and severe hepatic impairment at baseline. If toxicity occurs during treatment, ixazomib should be withheld and dose reduced to the next lower dose if attributed to therapy
    • Baseline CrCl <30 ml/min or ESRD requiring dialysis: 3 mg PO daily on days 1, 8, 15 every 28 days
    • Baseline total bilirubin >1.5x ULN: 3 mg PO daily on days 1, 8, 15 every 28 days
  • Ixazomib is metabolized by multiple CYP enzymes and non-CYP proteins. Avoid concomitant administration of ixazomib with strong CYP3A inducers
  • Ixazomib is available as 4 mg, 3 mg, and 2.3 mg allowing for 25% incremental dose adjustments
Alternating Dose Reductions with Lenalidomide
ReactionPlateletsNeutrophilsRash
Parameter< 30,000/mm3< 500/mm3Grade 2 or 3
First Occurrence·       Withhold ixazomib and lenalidomide

·       Upon recovery, resume both but reduce lenalidomide at next lower dose and continue ixazomib at most recent dose

Subsequent Occurrence·       Withhold ixazomib and lenalidomide

·       Upon recovery, resume both but reduce ixazomib at next lower dose and continue lenalidomide at most recent dose

      *Continue alternating dose reductions for additional occurrences and review resources for additional information on managing other adverse events

  • Monitor for peripheral neuropathy
  • Ensure patients receiving PI therapies are also receiving antiviral therapy to prevent against herpes zoster reactivation. Patients on IMiDs (lenalidomide or pomalidomide) should be on aspirin for DVT/PE prophylaxis or therapeutic anticoagulation based on clotting history and risk factors
  • Patients receiving ixazomib are likely to receive IMiD therapy. Ensure REMS requirements are met with IMiD therapy for a timely initiation of treatment and to keep cycles on track
  • It is highly recommended that a therapy calendar be utilized for all patients with MM due to complexity of therapies, older age of patients, and the potential lack of a medically-integrated pharmacy (ex. triplet-drug regimens may arrive from different sources). See supplemental index for example

Patient Centered Activities:

  • Provide Oral Chemotherapy Education (OCE) sheet and therapy calendar to all patients
  • Ensure patients understand the dosing schedule. Ixazomib is administered on days 1, 8 and 15 every 28 days. IMiDs and steroids will have a different schedule
  • Advise patients that a missed dose should not be taken with 3 days of the next scheduled dose. If vomiting occurs, do not repeat dose
    • Steroid component of regimen may be taken prior to ixazomib to help with nausea control but steroids should be taken with food. Ixazomib should be taken on an empty stomach (at least 1 hour before or 2 hours after a meal or snack
  • Financial resources are available through Takeda Oncology

Supplemental Information

Example 28-Day Dosing Calendar (ixazomib, lenalidomide, dexamethasone)
 Week 1Week 2Week 3Week 4
 Day 1Days 2-7Day 8Days 9-14Day 15Days 16-21Day 22Days 23-28
Ixazomib     
LenalidomideTake every day on days 1-21  
Dexamethasone    

References:

  1. Ninlaro® (ixazomib) [prescribing information]. Cambridge, MA: Takeda Pharmaceutical Company Limited; February 2020.
  2. SEER Stat Fact Sheets: Myeloma. Available at http://seer.cancer.gov/statfacts/html/mulmy.html.
Important notice: NCODA has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional. This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented. NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.
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Written by: Martina Fraga, PharmD
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Description: The purpose of this PQI is to highlight effective practices to ensure ovarian cancer patients are identified, tested, tracked, and offered a PARP inhibitor when appropriate.

Background: In gynecologic cancer patients, PARP inhibitors (PARP-I), have shown increased progression free survival (PFS) and, in some cases, overall survival. Misconceptions may exist around which patients are eligible for PARP inhibitors and when these therapies should be utilized.  Patients should be educated upfront about the anticipated therapy journey including the role of maintenance treatment. In ovarian cancer, maintenance therapy is rapidly becoming the new standard of care and it is imperative to identify and appropriately offer maintenance therapy to eligible patients.3 Data presented at a 2018 ESMO conference showed that the majority of eligible patients were not on maintenance therapy.4 A real-world data analysis by Garofalo and colleagues found that maintenance therapy was used in 49% of eligible patients; 47% of those on maintenance therapy received a PARP-I as the maintenance agent. A study done by Randall and colleagues found 50% of women with epithelial ovarian cancer underwent BRCA1/2 testing, while Buchanan and colleagues found testing rates in this patient population to be close to around 75%. Use of a PARP-I was higher in those with a BRCA mutation at 61%, vs 45% with wild-type or unknown status.5 This study looked at maintenance after second line or greater therapy; newer data shows progression free survival (PFS) benefit of maintenance after first line therapy, highlighting the need to accurately identify patients up front.6,7

PQI Process:  Upon diagnosis of ovarian cancer stage II, III or IV

  • Identify and track all ovarian cancer patients by utilizing the Electronic Medical Record (EMR)
  • Determine patient’s BRCA mutation status (consider genetic testing if not already completed)
    • Utilize EMR Pathways, Regimens or Patient Management Software when available
  • Work with your EMR vendor to ensure PARP-I are listed as a treatment option
  • Track all current or upcoming first-line platinum therapy patients with estimated completion date:
    • Consider use of a calendar reminder system for dates of treatment milestones
      • The treatment plan should be reviewed with the treating oncologist. A calendar should be maintained to mark the end of systemic therapy
      • Work closely and proactively with provider to determine each unique patient’s anticipated treatment plan (rather than reactive after a prescription is ordered)
    • As completion date approaches, assess treatment plan regarding maintenance therapy
      • Consider re-discussing options with provider
      • Consider monthly follow-up in the EMR during surveillance
      • When appropriate, ensure prescription for a PARP inhibitor is submitted
    • Consider PARP-Inhibitor utilization:
      • For patients in relapsed platinum sensitive ovarian cancer maintenance therapy following partial or complete response to platinum based chemotherapy (niraparib or rucaparib)
      • For first line or relapsed platinum sensitive maintenance therapy in BRCA associated advanced ovarian cancer (olaparib)
    • BRCA1 and BRCA2-positive patients have historically been more responsive to PARP-I therapy than BRCA-negative patients
  • Ensure the entire MIP team is educated about the importance of consistent tracking in the EMR (as described above) to ensure critical appointments and calls are done, accordingly
    • Consider creating a standard treatment plan and inform all potential professionals of the anticipated path and timing (genetic counselors, schedulers, assistants, pharmacists, providers, technicians, financial counselors, administrators, and more)

Patient Centered Activities:

References:

  1. Online Breast Cancer 1 Gene, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 113705. 06/28/2019. https://omim.org/entry/113705#contributors
  2. Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings. Mol Oncol 2011; 5(4):387-93.
  3. Randall LM, Birrer MJ, Herzog TJ. Ovarian cancer maintenance: practice-changing data calls for changing practice. The Oncologist 2019;24:1-4.
  4. Mahner S. Proceedings of ESMO Educational Symposium. Presented October 22, 2018. Available at https://cslide.ctimeetingtech.com/library/esmo/browse/search/262N#2Ea4M. Accessed July 17, 2019.
  5. Garofalo D, Verma-Kurvari S, Aydin E, et al. Real world data analysis of ovarian cancer maintenance utilization among maintenance eligible patients. Presented at the American Society of Clinical Oncology Annual Congress; Chicago, IL: 2019.
  6. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495-2505. doi: 10.1056/NEJMoa1810858.
  7. GSK announces positive headline results in Phase 3 PRIMA study of ZEJULA (niraparib) for patients with ovarian cancer in the first line maintenance setting [press release]. London, UK: GlaxoSmithKline plc; July 15, 2019. https://bit.ly/2YTFO6h. Accessed July 15, 2019.
  8. Childers CP, Childers KK, Maggard-Gibbons M, Macinko J. National estimates of genetic testing in women with a history of breast or ovarian cancer. J Clin Oncol 2017;35(34):3800-3806.
  9. Randall LM, Aydin E, Louie-Gao M, Hazard S, Westin SN. A retrospective analysis of real-world tumor BRCA (tBRCA) testing trends in ovarian cancer before and after PARP inhibitor approvals. Presented at the 17th Biennial Meeting of the International Gynecologic Cancer Society; Kyoto, Japan: 2018.
  10. Buchanan TR, Griffin NE, Leon C, et al. Maintaining adherence rates for genetic testing in an era with fewer in-office counselors. Gynecologic Oncology 2019; 154(1):204.
  11. Daly MB, Pilarski R, Berry M, et al. NCCN guidelines insights: Genetic/familial high-risk assessment: Breast and ovarian, version 3.2019. J Natl Compr Canc Netw 15:1-18-2019.
  12. Zejula® (niraparib) [prescribing information]. Waltham, MA: Tesaro Inc; May 2018.
  13. Lynparza® (olaparib) tablets [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals; December 2018.
  14. Rubraca® (rucaparib) [prescribing information]. Boulder, CO: Clovis Oncology; April 2018.
  15. Talzenna® (talazoparib) [prescribing information]. New York, NY: Pfizer Inc; October 2018.

Supplemental Information:

Current NCCN guidelines for genetic testing describe recommendations for BRCA testing in all ovarian cancer patients and in breast cancer patients that meet specific criteria.11 Please refer to the NCCN guidelines or consulting a genetic counselor for specifics on testing recommendations within that group of patients.

 BRCA Testing Populations in Breast and Ovarian Cancer5
·     Individual from family with known BRCA1/2 variant

·     History of breast cancer + one of the following

o  45 years or younger

o  46-50 years with additional breast cancer primary OR 1 or more close blood relative with either breast cancer or high-grade prostate cancer

o  Unknown or limited family history

·     60 or younger with triple negative breast cancer

·     Any age + one of the following

o  45 years or younger

o  1 or more blood relative with breast cancer diagnosed at 50 years or younger, ovarian carcinoma, male breast cancer, metastatic prostate cancer or pancreatic cancer

o  2 or more diagnoses of breast cancer at any age in patient or close blood relatives

·     Ashkenazi Jewish ancestry

·     History of ovarian cancer

·     History of male breast cancer

·     History of pancreatic cancer

·     History of metastatic prostate cancer

·     Regardless of family history, NCCN guidelines recommend BRCA testing in those that may benefit from targeted therapy

Important notice: NCODA has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional.  This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented.  NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.

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Written by: Jeremiah Moore, PharmD, University of Rochester Medical Center

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This PQI will provide background on the novel medication selinexor for patients with multiple myeloma (MM) who have received at least one prior therapy, relapsed, refractory multiple myeloma (RR-MM), and relapsed, refractory diffuse large b-cell lymphoma (RR-DLBCL) and discuss effective practices to maximize the use of selinexor therapy.
Continue reading Selinexor (Xpovio®) Patient Management

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