Identifying patients suitable for Ixazomib
Ixazomib is indicated in combination with lenalidomide (R) and dexamethasone (d) (IRd) for the treatment of adult patients with multiple myeloma (MM) who have received at least one prior therapy.1
Despite the increasing use of lenalidomide in the 1L treatment of MM, a proportion of patients remain eligible for re-treatment with a lenalidomide-based regimen, such as IRd, in the relapsed setting.2-5
Lenalidomide is typically continued until disease progression or intolerance4, but this is not always the case. It is therefore important to differentiate between lenalidomide exposure and lenalidomide refractoriness.3,4 Patients who have been exposed to, but are not refractory to, lenalidomide can still achieve a meaningful response to re-treatment with a lenalidomide-based regimen such as IRd, at a later line of therapy (LoT).5
Defining the lenalidomide status of patients can help guide treatment decisions at later lines of therapy6
When patients reach ≥2L, it’s important to look at their lenalidomide status to help guide and optimise MM treatment recommendations. Recent guidelines propose tailoring therapeutic approaches according to lenalidomide exposure/sensitivity:6

Patients with the following lenalidomide status are typically eligible for IRd:
- Lenalidomide naive: Not previously treated with lenalidomide5
- Lenalidomide sensitive/exposed: Previously treated with lenalidomide but do not fulfill the criteria of refractoriness5*
- Non-refractory progression: Do not meet the criteria for primary refractory or relapsed refractory to lenalidomide7

Patients with the following lenalidomide status are generally not eligible for IRd:
- Lenalidomide intolerant: Adverse events (AEs) requiring dose reduction as per clinical judgement or treatment cessation

Patients with the following lenalidomide status are not eligible for IRd:
- Lenalidomide refractory: Primary refractory patients have disease that is not responsive to a lenalidomide-based therapy, whereas relapsed refractory patients demonstrate an initial response followed by disease progression while on treatment with lenalidomide or within 60 days of the last dose of lenalidomide2,5
*Treatment with lenalidomide stopped for reasons other than disease progression.5
In routine clinical practice, prior lenalidomide exposure appeared to have minimal impact on the effectiveness of IRd in lenalidomide-non-refractory patients with relapsed/refractory multiple myeloma (RRMM).5,8 Prior exposure, to lenalidomide should not preclude use of IRd in subsequent LoTs for patients with RRMM whose disease is not refractory to lenalidomide.5
The INSURE study was a pooled analysis of patients with RRMM who received ≥2L IRd in clinical practice5,8
INSURE pooled analysis: Summary of studies included8
The INSURE study analysed patients with RRMM who received ≥2L IRd in clinical practice.5,8
INSURE study design

Figure adapted from Lee HC, et al. 20228
The INSURE study assessed whether patients with RRMM with prior lenalidomide or proteasome inhibitor (PI) exposure achieved clinical benefit when re-treated with these agents as part of the IRd regimen.5,8 The study pooled data from the INSIGHT-MM, UVEA-IXA and REMIX studies. Analyses of outcomes by prior lenalidomide use (lenalidomide naïve, lenalidomide exposed or lenalidomide refractory) are presented here.5,8*
*Refractory was defined as having progressed on treatment or within 60 days of discontinuing treatment, or a treatment-free interval between discontinuation and next index regimen of ≤60 days.5
INSURE primary outcome measure: Progression-free survival (PFS)5
- There was little difference in PFS between lenalidomide naïve and lenalidomide exposed patients taking IRd for RRMM management (median PFS was 21.6 and 25.8 months, respectively)5
- These outcomes were similar to those reported in the TOURMALINE-MM1 pivotal Phase 3 study (20.6 months)9
- By contrast, median PFS for lenalidomide refractory patients was significantly shorter than for lenalidomide naïve or lenalidomide exposed patients at 5.6 months5
- This suggests that prior exposure, to lenalidomide should not preclude the use of IRd in subsequent LoTs for patients with RRMM whose disease is not refractory to lenalidomide5
Kaplan-Meier analysis of PFS with IRd by prior lenalidomide exposure5*

Figure adapted from Lee HC, et al. 20245
*Median duration of follow-up from start of IRd was 19.4/18.8/10.4 months for patients in lenalidomide -naïve/-exposed/ -refractory cohorts, respectively.5
Multivariate Cox model analysis of PFS10

Figure adapted from Lee HC, et al. 2024 (Suppl).10
Multivariable analysis of PFS was conducted to adjust for potential confounders. 9,10
INSURE primary outcome measure: Time to next treatment (TTNT)5,8
TTNT was not significantly different between lenalidomide naïve and lenalidomide exposed patients in the INSURE study.5,8 TTNT was significantly shorter in patients who were refractory to lenalidomide.5,8
Kaplan-Meier analysis of TTNT with IRd by prior lenalidomide exposure5*

Figure adapted from Lee HC, et al. 2024.5
*Median duration of follow-up from start of IRd was 19.4/18.8/10.4 months for patients in lenalidomide-naïve/-exposed/-refractory cohorts, respectively.5
Multivariate Cox model analysis of TTNT10

Figure adapted from Lee HC, et al. 2024 (Suppl).10
Multivariable analysis of TTNT was conducted to adjust for potential confounders.9,10
Safety and tolerability
Adverse events (AEs) and discontinuations/dose reductions due to AEs were reported separately for each of the studies included in the pooled INSURE analysis.5 Overall, the safety profile of IRd was manageable with no new, additional safety concerns identified.5
Dose reductions and discontinuations due to AEs in INSIGHT MM and UVEA-IXA by prior lenalidomide exposure5**

REMIX safety summary by prior lenalidomide exposure5

*Occurring in >15% of patients for AEs and >10% for serious AEs in at least one subgroup.
** AE discontinuation rates were unavailable for the REMIX study.
Ixazomib FAQs
Ixazomib is an oral, highly selective and reversible proteasome inhibitor. Each capsule of Ixazomib contains Ixazomib citrate, a prodrug that rapidly hydrolyses under physiological conditions to its biologically active form, Ixazomib.1
1. Ixazomib. Summary of Product Characteristics.
Ixazomib in combination with lenalidomide and dexamethasone is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.1
1. Ixazomib. Summary of Product Characteristics.
In England, IRd is recommended by NICE as an option for treating multiple myeloma in adults if they have already had two or three previous lines of therapy and the company provides Ixazomib according to the commercial arrangement.1 Ixazomib is also available to appropriate patients in Wales and Northern Ireland.2
1. NICE. Ixazomib with lenalidomide and dexamethasone for treating relapsed or refractory multiple myeloma. Available from www.nice.org.uk/guidance/TA870. Accessed March 2026
2. All Wales Therapeutics and Toxicology Centre. Ixazomib citrate. Available at: https://awttc.nhs.wales/accessing-medicines/medicine-recommendations/Ixazomib-citrate-ninlaro.
Ixazomib preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome.1 Ixazomib induced apoptosis of several tumour cell types in vitro. Ixazomib demonstrated in vitro cytotoxicity against myeloma cells from patients who had relapsed after multiple prior therapies, including bortezomib, lenalidomide, and dexamethasone.1 The combination of Ixazomib and lenalidomide demonstrated synergistic cytotoxic effects in multiple myeloma cell lines. In vivo, Ixazomib demonstrated antitumour activity in various tumour xenograft models, including models of multiple myeloma. In vitro, Ixazomib affected cell types found in the bone marrow microenvironment including vascular endothelial cells, osteoclasts and osteoblasts.1
1. Ixazomib. Summary of Product Characteristics.
Ixazomib should be taken in combination with lenalidomide and dexamethasone.1
- The recommended starting dose of Ixazomib is 4 mg administered orally on Days 1, 8, and 15 of a 28-day treatment cycle. Ixazomib should be swallowed whole with water at least 1 hour before or at least 2 hours after food
- The recommended starting dose of lenalidomide is 25 mg administered daily on Days 1 to 21 of a 28-day treatment cycle
- The recommended starting dose of dexamethasone is 40 mg administered on Days 1, 8, 15, and 22 of a 28-day treatment cycle
Prior to initiating a new cycle of therapy:1
- Absolute neutrophil count should be ≥1000/mm3
- Platelet count should be ≥75000/mm3
- Non‑haematologic toxicities should, at the physician’s discretion, generally be recovered to patient’s baseline condition or ≤Grade 1
Antiviral prophylaxis should be considered in patients being treated with Ixazomib to decrease the risk of herpes zoster reactivation. Patients included in studies with Ixazomib who received antiviral prophylaxis had a lower incidence of herpes zoster infection compared to patients who did not receive prophylaxis.1
Thromboprophylaxis is recommended in patients being treated with Ixazomib in combination with lenalidomide and dexamethasone, and should be based on an assessment of the patient's underlying risks and clinical status.1
Ixazomib should be taken at approximately the same time on Days 1, 8, and 15 of each treatment cycle at least 1 hour before or at least 2 hours after food.1 The capsule should be swallowed whole with water. It should not be crushed, chewed, or opened.1
Treatment should be continued until disease progression or unacceptable toxicity.1 Treatment with Ixazomib in combination with lenalidomide and dexamethasone for longer than 24 cycles should be based on an individual benefit risk assessment, as the data on the tolerability and toxicity beyond 24 cycles are limited.1
Refer to the Ixazomib SmPC for full dosing guidelines.
1. Ixazomib. Summary of Product Characteristics.
Elderly1
- No dose adjustment of Ixazomib is required for patients over 65 years of age
Hepatic impairment1
- No dose adjustment of Ixazomib is required for patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or total bilirubin > 1-1.5 x ULN and any AST). The reduced dose of 3 mg is recommended in patients with moderate (total bilirubin > 1.5-3 x ULN) or severe (total bilirubin > 3 x ULN) hepatic impairment
Renal impairment1
- No dose adjustment of Ixazomib is required for patients with mild or moderate renal impairment (creatinine clearance ≥ 30 mL/min). The reduced dose of 3 mg is recommended in patients with severe renal impairment (creatinine clearance < 30 mL/min) or end-stage renal disease (ESRD) requiring dialysis. Ixazomib is not dialyzable and, therefore, can be administered without regard to the timing of dialysis
Paediatric population1
- The safety and efficacy of Ixazomib in children below 18 years of age have not been established. No data are available
Refer to the Ixazomib SmPC for the full dose modification guidelines. Refer to the Ixazomib SmPC for an overview of all Ixazomib side effects. For additional information regarding lenalidomide or dexamethasone, please refer to each respective SmPC.
1. Ixazomib. Summary of Product Characteristics.
Clinical studies have shown the most frequently reported adverse reactions (≥ 20%) in 418 patients treated with IRd to be diarrhoea (47%), thrombocytopenia (41%), neutropenia (37%), constipation (31%), upper respiratory tract infection (28%), peripheral neuropathy (28%), nausea (28%), back pain (25%), rash (25%), peripheral oedema (24%), vomiting (23%) and bronchitis (20%). Serious adverse reactions reported in ≥ 2% of patients included diarrhoea (3%), thrombocytopenia (2%) and bronchitis (2%).1
Please refer to the SmPC for further information on the Ixazomib tolerability profile.
1. Ixazomib. Summary of Product Characteristics.

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1L, first line; 2L, second line; AE, adverse event; CI, confidence interval; d, dexamethasone; HR, hazard ratio; IRd, Ixazomib + lenalidomide + dexamethasone; LoT, line of therapy; MM, multiple myeloma; PFS, progression-free survival; PI, proteasome inhibitor; R, lenalidomide; Rd, lenalidomide + dexamethasone; RRMM, relapsed/refractory multiple myeloma; TTNT, time to next treatment; UVEA, used via early access.
1. Ixazomib. Summary of Product Characteristics. 2. Kastritis E, et al. Clin Lymphoma Myeloma Leuk. 2024;24:468–477. 3. Goel U, et al. Blood Cancer J. 2024;14:55. 4. Lecat CSY, et al. Front Oncol. 2021;11:703233. 5. Lee HC, et al. Eur J Haematol. 2024;113:190–200. 6. Dimopoulos MA, et al. Ann Oncol. 2021;32:309–322. 7. Lee JH and Kim SH. Blood Res. 2020;55:S43–553. 8. Lee HC, et al. Poster number 925. Presented at the European Haematology Hybrid Congress, 9–12 June 6 2022, Vienna, Austria. 9. Moreau P, et al. N Engl J Med. 2016;374:1621–1634. 10. Lee HC, et al. Eur J Haematol. 2024;113(Suppl):190–200.
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