You are using an outdated browser. We suggest you update your browser for a better experience. Click here for update.
Close this notification.
Skip to main content Skip to search
A - Regimen Name

DEXAIXAZLENA Regimen
Dexamethasone-Ixazomib-Lenalidomide (oral)


Disease Site
Hematologic - Multiple Myeloma

Intent
Palliative

Regimen Category
Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR).  Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.


Rationale and Uses

In combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.

Note:  Approval was based on the initial results of a randomized, double-blind, placebo-controlled, multicentre Phase III study in patients with relapsed and/or refractory multiple myeloma who had received at least one prior line of therapy; patients who were refractory to lenalidomide or proteasome inhibitors (any line) were excluded from the study.  There was a statistically significant improvement in median progression free survival of approximately 6 months compared to the placebo regimen (20.6 months vs 14.7 months).


Supplementary Public Funding

dexamethasone
ODB - General Benefit (dexamethasone) (ODB Formulary )

 
B - Drug Regimen

ixazomib
4 mg PO once a week on Days 1, 8, and 15
(This drug is not currently publicly funded for this regimen and intent)

(available as 2.3 mg, 3 mg, and 4 mg capsules)

lenalidomide

1

25 mg PO once daily on Days 1 to 21
(This drug is not currently publicly funded for this regimen and intent)

(available as 5 mg, 10 mg, 15 mg, and 25 mg capsules)

dexamethasone
40 mg PO once a week on Days 1, 8, 15, and 22

 

1 Lenalidomide may only be prescribed and dispensed by physicians and pharmacists registered with RevAid®.  Patients must also be registered and meet all conditions of the RevAid® program.

back to top
 
C - Cycle Frequency

REPEAT EVERY 28 DAYS

Until disease progression or unacceptable toxicity.

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Low – No routine prophylaxis; PRN recommended

Other Supportive Care:

Consider the use of antiviral prophylaxis during ixazomib therapy to decrease the risk of herpes zoster reactivation.

Also refer to CCO Antiemetic Recommendations.

 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. The following recommendations have been adapted from clinical trials or product monographs and may be considered.

Prior to initiating a new cycle of therapy:

  • Absolute neutrophil count should be ≥ 1.0 x 109/L

  • Platelet count should be ≥75 x 109/L

  • Non-hematologic toxicities should, at the physician’s discretion, generally be recovered to patient’s baseline condition or ≤ Grade 1

Dosage with toxicity

Dexamethasone doses may be reduced for dexamethasone-related adverse events (i.e. hypertension, hyperglycemia, fluid retention) to improve tolerability.

 

Table 1:  Dose Reduction Levels 

Dose Level

Ixazomib Dose

Lenalidomide Dose

Starting Dose*

4 mg

25 mg

-1

3 mg

15 mg

-2

2.3 mg

10 mg

-3

discontinue

5 mg**

 * Recommended starting dose of 3 mg in patients with moderate or severe hepatic impairment, severe renal impairment or end-stage renal disease requiring dialysis. 

** Do not dose below 5 mg daily

 

Table 2:  Dose Modification for Toxicities

An alternating dose modification approach is recommended for ixazomib and lenalidomide for overlapping toxicities (thrombocytopenia, neutropenia, rash). 

Toxicity

Action

Ixazomib Dose when restart

Lenalidomide dose when restart

First Occurrence

Platelet count < 30 x 109/L

OR

ANC < 0.5 x 109/L

 

Hold until platelets ≥ 30  AND ANC ≥ 0.5; consider adding G-CSF

No change

1 dose level ↓

Second Occurrence

Platelet count < 30 x 109/L

 

OR

 

ANC < 0.5 x 109/L

Hold until platelets ≥ 30  AND ANC ≥ 0.5; consider adding G-CSF

1 dose level ↓

No change

Rash

Grade 2 or 3

Hold both until  ≤ Grade 1

Continue at same dose. If recurs, hold until recovery and then resume with 1 dose level ↓

Resume with 1 dose level ↓

Discontinue if ≥ Grade 2 exfoliative skin toxicity or SJS/TEN

Grade 4

Discontinue

Discontinue

Discontinue

Toxicity Action Ixazomib Dose when restart Lenalidomide Dose when restart

Peripheral Neuropathy

Grade 1 with Pain or Grade 2

Hold ixazomib until ≤ Grade 1 without pain or patient’s baseline

Resume at same dose

Continue at same dose

Grade 2 with pain or Grade 3

Hold both until ≤ Grade 1 without pain or patient’s baseline

 1 dose level ↓

Consider 1 dose level ↓ if grade 3

Grade 4

Discontinue

Discontinue

Discontinue

≥ Grade 2 VTE

Hold lenalidomide and start anticoagulants

No change

Resume when recovered at same dose

 

 

Other Grade 3 or 4 Non-Hematological Toxicities

 

Hold both until recovery to baseline or ≤ Grade 1

 

If toxicity due to ixazomib, resume at 1 dose level ↓ once recovered or discontinue

 

If toxicity due to lenalidomide, resume at 1 dose level ↓ once recovered or discontinue.  If pneumonitis investigate and discontinue if confirmed

Increased LFTS

 

See table below for dosage with hepatic dysfunction

Hold until recovery then consider dose reduction

*For additional occurrences, alternate dose modification of lenalidomide and ixazomib
**Do not dose below 5 mg daily 



Hepatic Impairment

Hepatic impairment

Ixazomib dose

 Lenalidomide dose

mild (total bilirubin ≤ ULN and AST > ULN OR total bilirubin 1-1.5 x ULN and any AST)

no dosage adjustment required

No dose adjustment required

moderate or severe (total bilirubin > 1.5 x ULN)

3 mg

No data


Renal Impairment

Creatinine Clearance (mL/min)

Ixazomib dose

Lenalidomide dose

≥ 60

No dose adjustment

No dose adjustment

   30 – <60

No dose adjustment

10 mg daily*

< 30 (not requiring dialysis)

3 mg

15 mg every other day

< 30 (requiring dialysis)

3 mg**

5 mg once daily. On dialysis days, the dose should be administered following dialysis

* may be escalated to 15 mg q24h after 2 cycles if patient is not responding to treatment and is tolerating the drug.

***Ixazomib is not dialyzable and can be administered without regard to the timing of dialysis. 


Dosage in the Elderly

No dosage adjustment of ixazomib is required for patients over 65 years of age.  No clinically significant differences in safety and efficacy have been demonstrated.
 

The incidences of serious and non-serious adverse events with lenalidomide are significantly higher in patients > 65 years (constipation, confusion, dyspnea, atrial fibrillation, diarrhea, fatigue, pulmonary embolism, syncope).  This may be related to renal impairment. Monitor geriatric patients closely, especially cardiac and renal function. Consider dose modification based on degree of renal impairment.

 

Dosage based on ethnicity:

No clinically significant effect demonstrated during PK analysis of ixazomib; mean AUC was 35% higher in Asian patients than White patients.

Children:

Safety and efficacy of both ixazomib and lenalidomide has not been established.


 
F - Adverse Effects

Refer to ixazomib, lenalidomide, dexamethasone drug monograph(s) for additional details of adverse effects


Very common (≥ 50%)

Common (25-49%)

Less common (10-24%)

Uncommon (< 10%), but may be severe or life-threatening

 

  • Fatigue
  • Constipation
  • Diarrhea
  • Myelosuppression ± infection, bleeding (May be severe)
  • Musculoskeletal pain
  • Peripheral neuropathy
  • Edema
  • Headache
  • Cough, dyspnea
  • Eye disorders
  • Nausea, vomiting (generally mild)
  • Dizziness
  • Rash, pruritus (may be severe)
  • Tremor
  • Infection
  • Anorexia
  • Dyspepsia
  • Hyperglycemia
  • Abnormal electrolytes
  • Dysguesia
  • Depression
  • Insomnia
  • Abdominal pain
  • Venous and arterial thromboembolism
  • Cholecystitis
  • Pneumonitis
  • Renal failure
  • ↑ LFTs
  • Adrenal insufficiency
  • Cardiotoxicity
  • Arrhythmia
  • Hypersensitivity
  • GI ulcer
  • Hemolysis
  • Muscle weakness
  • Myelitis
  • Pancreatitis
  • PRES
  • Thrombotic thrombocytopenic purpura
  • Tumor lysis syndrome
  • Wound dehiscence
 
G - Interactions

Refer to ixazomib, lenalidomide, dexamethasone drug monograph(s) for additional details


  • Avoid strong CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc.) as they reduce ixazomib concentrations
  • Avoid taking ixaxomib with high-fat meals due to decreased abosorption
  • Digoxin levels may increase if taken together with lenalidomide; caution and monitor levels
  • Additive risks of thromboembolic events with lenalidomide and hormonal therapies, erythropoietic agents, corticosteroids; monitor carefully and consider anticoagulant prophylaxis

 

 
H - Drug Administration and Special Precautions

Refer to ixazomib, lenalidomide, dexamethasone drug monograph(s) for additional details


Administration 

Ixazomib:

  • Ixazomib should be taken once a week on the same day and at approximately the same time for the first 3 weeks of a four week cycle. 
  • The capsule should be swallowed whole with water, on an empty stomach (at least one hour before or at least two hours after food).
  • The capsule should not be crushed, chewed, or opened.  Direct contact with capsule contents should be avoided as inhalation, ingestion, or skin absorption may be harmful.
  • If a dose is missed, it should be taken only if the next scheduled dose is ≥ 72 hours away.  A double dose should not be taken to make up for a missed dose.
  • If a patient vomits after taking a dose, the patient should not repeat the dose; resume dosing at the time of the next scheduled dose.
  • Store capsules at room temperature (15-30oC) in original packaging.  Do not freeze.

Lenalidomide:

  • Oral self-administration; swallow capsules whole; they should not be broken, chewed, or opened. Do not extensively handle the capsules.
  • Give capsules preferably with water, either with or without food. Do not remove from blister packs until ready to take the dose. 
  • Note:  Females who could become pregnant, or who plan to become pregnant can handle lenalidomide capsules if they are using latex gloves.
  • If a dose is missed, it may be taken up to 12 hours after the time it is normally taken.  Otherwise, skip this and take the next dose on the following day at its usual scheduled time.
  • Store capsules at room temperature (15 to 30°C) 

Dexamethasone:

  • oral self-administration
  • give tablets with food, preferably in the morning

 Contraindications:

  • patients who have a hypersensitivity to these drugs or any of their components
  • women at risk of being pregnant and male patients who do not comply with contraception requirements

Other Warnings/Precautions:

  • Avoid direct contact with capsule contents; ixazomib may be harmful by inhalation, ingestion, or skin absorption.
  • Lenalidomide contains lactose; carefully consider use in patients with hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption
  • Use with caution and consider venous thromboembolism prophylaxis when lenalidomide is used in combination with corticosteroids or thrombogenic agents, such as hormones and erythropoietin (see adverse effects section)
  • Exercise caution in patients with risk factors for arterial thromboembolism (e.g. hypertension and hyperlipidemia), or risk factors for atrial fibrillation (e.g. electrolyte abnormalities, pre-existing heart disease, hypertension, infection).
  • Use with caution in patients with high tumour burden; monitor closely and use appropriate precautions for tumour lysis syndrome.

Pregnancy and Lactation:

Lenalidomide is contraindicated in pregnancy and in females and males of childbearing potential who do not comply with the contraception conditions of the RevAid® program.  Females of childbearing potential (all women who are not  ≥ 2 years menopausal OR have not had hysterectomy or bilateral oophorectomy) must be capable of understanding and complying with the patient registration, education, and safety requirements of the RevAid® program, regular pregnancy testing and the use of two simultaneous contraception methods (must be started at least one month prior to starting treatment, continued during dose interruptions, during treatment and for at least 1 month following the cessation of lenalidomide). SEE FULL DETAILS ON THE REVAID® PROGRAM. Hormonal contraceptives are not recommended due to the increased risk of thromboembolism.  If pregnancy occurs during treatment, lenalidomide must be discontinued and patient referred to a gynecologist/obstetrician for evaluation and counselling.

Lenalidomide is present in semen, and there is a potential risk of birth defects, stillbirths and spontaneous abortions in the exposed fetus, Male patients must be capable of understanding and complying with the patient registration, education, and safety requirements of the RevAid®, including mandatory contraceptive measures for men (condoms should be used even with vasectomized males) and must inform their female sexual partners of the risk.  Male patients should not donate semen while taking lenalidomide and for 4 weeks after cessation.

Patients should not donate blood while taking lenalidomide and for 4 weeks after stopping therapy to prevent fetal exposure via transfusion of pregnant women.

Breastfeeding is contraindicated.

 

 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph

Recommended Clinical Monitoring

  • CBC; Baseline and every 2 weeks for the first 12 weeks, then before each cycle
  • Clinical assessments and grading of cardiac and respiratory symptoms, rash, fatigue, infection, bleeding, tumour lysis syndrome, neuropathy, GI effects, edema, pain, eye problems, arterial and venous thromboembolism; At each visit
  • Liver function tests; Baseline and before each cycle
  • Renal function tests; Baseline and before each cycle
  • RevAid requirements regarding pregnancy tests for women of child-bearing potential; Before starting and as indicated per RevAid
  • Thyroid function tests; Baseline and as clinically indicated
  • Cancer screening for occurrence of second primary malignancy; Assess risk prior to starting treatment; then at each visit or as clinically indicated
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

 

  • ECG; Baseline and as clinically indicated
  • INR in patients receiving warfarin; Baseline and as clinically indicated 

 


back to top
 
J - Administrative Information

Outpatient prescription for home administration


 
K - References

Ixazomib and lenalidomide drug monographs, Cancer Care Ontario.

Ninlaro (ixazomib) product monograph.  Takeda Canada Inc.  August 3, 2016.

Moreau P, Masszi T, Grzasko N, et al.  Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma.  N Engl J Med 2016;  374:1621-1634.


May 2019 Updated emetic risk category; added PEBC guideline link


back to top
 
M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.