1. NINLARO® (ixazomib) in the real world: UK experience
Dr Rakesh Popat, University College Hospital, London, UK
NINLARO has received a conditional marketing authorisation in Europe
This educational meeting was organised and fully funded by Takeda UK Ltd. Takeda medicines were discussed during this meeting.
Prescribing Information is available on the final slide.
The views expressed during this presentation are those of the speaker
Zinc code: UK/IXA/1711/0061a(1) Date of preparation: April 2019

2. NINLARO (ixazomib) – now recommended by NICE via the CDF1
NINLARO with lenalidomide and dexamethasone is recommended for use within the Cancer Drugs Fund as an option for treating multiple myeloma in adults if they have already had 2 or 3 previous lines of therapy and the conditions of the managed access agreement for NINLARO are followed1 NINLARO is also available to appropriate patients in Wales and Northern Ireland2
CDF, Cancer Drugs Fund; NICE, National Institute for Health and Care Excellence.
1. NICE Final Appraisal Determination – ixazomib for relapsed or refractory multiple myeloma. Issue date: December Available at: (accessed April 2019); 2. New Treatments Fund as found at (accessed April 2019).

3. DIAGNOSIS: IgA lambda myeloma ISS 3
Case 1: presentation
Profession: dentist
Age: 58 years
Presentation: back pain
T12 lesion
Fracture: T6
Multiple other foci
DIAGNOSIS: IgA lambda myeloma ISS 3
IgA, immunoglobulin A; ISS, international staging system.

4. Third treatment decision Second treatment decision
Case 1: treatment
15 months
3 months
Reappearance of bands <3
IgA 25, new rib and back pain
No maintenance CR
Paraprotein: 42 g/L  8g/L (12 cycles)
Third treatment
Rd combination: IRd (patient-driven selection)
2nd ASCT
Clinical trial/bortezomib combination
Rd combinations: DRd/KRd/IRd
Third treatment decision
Second treatment decision
Second treatment: Pulsed dexamethasone
Initial treatment
Restaged: BM 70% PC; FISH; hyperdiploid, 1q+, IgH rearrangement; PET-CT: multiple avid foci
VTD (5 cycles to VGPR)
 ASCT
ASCT, autologous stem cell transplantation; BM, bone marrow; CR, complete response; DRd, daratumumab-lenalidomide-dexamethasone; FISH, fluorescence in situ hybridisation; IgA, immunoglobulin A; IRd, ixazomib-lenalidomide-dexamethasone; KRd, carfilzomib-lenalidomide-dexamethasone; PC, plasma cells; PET-CT, positron emission tomography computed tomography; VGPR, very good partial response; VTD, bortezomib-thalidomide-dexamethasone.

5. Case 1: convenience of IRd treatment
Selection of IRd was patient-driven due to the convenience of administration as he needed to maintain a full-time job
Minimum number of planned hospital visits required for administration/collection of MM treatments over 18 cycles1–5*
*Patients are treated until progression or unacceptable toxicity. Calculation excludes visits for monitoring. Standard carfilzomib (IV) regimen is 18 cycles; number of administrations of carfilzomib (IV) per cycle: cycle 1-12 = 6 doses (2 consecutive doses each week for 3 weeks), cycle = 4 doses (2 consecutive doses during 1st and 3rd week). Treatment with carfilzomib (IV) + Rd for longer than 18 cycles should be based on an individual benefit-risk assessment, as the data on the tolerability and toxicity of carfilzomib (IV) beyond 18 cycles are limited;2–4 Daratumumab is administered (IV) in, weekly for the first 8 weeks, then once every two weeks throughout weeks 9–24, followed by every 4 weeks from week 25 until disease progression or unacceptable toxicity. Calculation: 18 x 4 =72 weeks in 18 cycles. (1 x 8) + (1 x 16/2) + (1 x 64/2) = 28 doses.5
IRd, ixazomib-lenalidomide-dexamethasone; Rd, lenalidomide-dexamethasone.
1. NINLARO® Summary of Product Characteristics; 2. REVLIMID 25 mg Summary of Product Characteristics. 3. Dexamethasone 2 mg Tablets Summary of Product Characteristics; 4. KYPROLIS Summary of Product Characteristics; 5. DARZALEX Summary of Product Characteristics.

6. Case 1: tolerability of IRd
IRd was well-tolerated
The patient’s wife reported increased irritability due to dexamethasone hence patient underwent dose reduction of dexamethasone
Response is deepening with each cycle
Bone pain has been improved
Maintained patient QOL; consistent with EORTC-QLQ-C30 results from the TOURMALINE-MM1 study
EORTC-QLQ-C30, EORTC Quality Of Life Questionnaire - Core Questionnaire; IRd, ixazomib-lenalidomide-dexamethasone; QOL, quality of life.

7. PET-CT taken prior to treatment (baseline)
Case 1: PET-CT results
PET-CT taken prior to treatment (baseline)
PET-CT taken 7 months later
Multiple foci involving: head of right humerus, bilateral clavicles, manubrium sternum, bilateral proximal humeri, multiple bilateral ribs, T2, T7-8, T9, T12, L2-L5; multiple foci within the pelvis.
Complete metabolic remission, residual inflammatory activity compatible with healing fractures.
PET-CT, positron electron tomography computed tomography.

8. Case 1: key learnings
Discrepancy between serological partial response, but complete metabolic response on PET-CT. The role of PET-CT in relapsed MM is still unclear
IRd provides patients with a more flexible treatment schedule to accommodate a full-time job
Carers may identify side-effects or symptoms that the patient has not noticed
Responses deepen with time
Patients’ quality of life is maintained throughout treatment with IRd
IRd, ixazomib-lenalidomide-dexamethasone; MM, multiple myeloma; PET-CT, positron emission tomography computed tomography.

9. Case 2: presentation Biological age: 75 years Smoker
Cytogenetics: 1q21+
Recurrent chest infections due to COPD
Age: 66 years
Presentation: acute renal failure and cast nephropathy
Light chains: 8350 mg/L
Biological age: 75 years
COPD, chronic obstructive pulmonary disease.

10. Recommendations for patients with renal impairment
NINLARO® Summary of Product Characteristics1
Recommendation for treatment of special patient populations
Renal impairment
No dose adjustment of NINLARO 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. NINLARO is not dialysable and, therefore, can be administered without regard to the timing of dialysis. Refer to the lenalidomide SmPC for dosing recommendations in patients with renal impairment.2
1. NINLARO® Summary of Product Characteristics. Available at: 2. Revlimid® Summary of Product Characteristics. Available at:

11. Third treatment decision Second treatment decision
Case 2: treatment
BM: del1p 1q21+, TP53 loss; PET-CT: avid rib lesions
20 months
Rising light chains
VGPR
Light chains:
483 mg/L  61 mg/L (10 cycles)
12 months
Third treatment decision
Third treatment
IRd
Second treatment decision
Second treatment
VTD (6 cycles) and declined 2nd ASCT
Smoker with recurrent chest infections
Dexamethasone reduced to 10 mg due to recurrent infections
Lenalidomide reduced to 15 mg due to fatigue
Initial treatment
CVd (4 cycles)
 ASCT
ASCT, autologous stem cell transplantation; BM, bone marrow; CVd, cyclophosphamide, bortezomib and dexamethasone; IRd, ixazomib-lenalidomide-dexamethasone; PET-CT, positron emission tomography computed tomography; VGPR, very good partial response; VTD, bortezomib, thalidomide and dexamethasone.

12. Case 2: key learnings
Doses should be adjusted due according to frailty rather than age
Ixazomib in combination with lenalidomide and dexamethasone is effective in patients with high-risk cytogenetics
Ixazomib does not need to be dose-reduced in RRMM patients with mild or moderate renal impairment. A reduced dose of 3mg is recommended for patients with severe renal impairment (CrCl <30ml/min) or end stage renal disease requiring dialysis
IRd remains effective despite two prior lines of therapy including bortezomib
IRd, ixazomib-lenalidomide-dexamethasone; RRMM, relapsed/refractory multiple myeloma.
NINLARO® (ixazomib capsules) Summary of Product Characteristics. Available at (accessed October 2017); Moreau P et al. N Engl J Med 2016;374:1621–1634.

13. UCLH real world data: patient demographics
Retrospective review of patients sequentially treated with IRd at a large UK haematology centre
Demographic
N=30
Median age (range)
65 (32–75)
Median prior lines (range)
2 (2–5)
Prior proteasome inhibitor
100%
Prior lenalidomide
10%
Adverse cytogenetics
69%
TP53 loss
23%
Median follow-up
6.8 months
Median time on treatment
5.5 months
IRd, ixazomib-lenalidomide-dexamethasone; RRMM, relapsed/refractory multiple myeloma; UCLH, University College London Hospital.
Ziff M et al. Haematologica 2017;101. Abstract PB1975.

14. UCLH real world data: results
Median PFS: months
Probability of PFS
Time from starting IRd (months)
0 -
20 -
40 -
60 -
80 -
100 - 20 10 30 50
Median PFS: months
Response (N=30)
n (%)
Overall response
70.8% PR
13 (54.1%)
VGPR
3 (12.5%) CR
1 (4.2%)
CR, complete response; IRd, ixazomib-lenalidomide-dexamethasone; PFS, progression-free survival; PR, partial response; UCLH, University College London Hospital; VGPR, very good partial response.
Ziff M et al. Haematologica 2017;101. Abstract PB1975; Unpublished data, personal communication.

15. Abbreviated prescribing information: NINLARO®▼(ixazomib) (Refer to Summary of Product Characteristics (SmPC) before prescribing)
Presentation: Ixazomib 2.3 mg, 3 mg and 4 mg hard capsules. Indication: NINLARO 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. Dosage & Administration: Treatment must be initiated and monitored under the supervision of a physician experienced in the management of multiple myeloma. NINLARO should be used in combination with lenalidomide and dexamethasone. For additional information regarding lenalidomide and dexamethasone, refer to their SmPCs. The recommended starting dose of NINLARO is 4 mg (one capsule) administered orally once a week on Days 1, 8, and 15 of a 28-day treatment cycle 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, absolute neutrophil count should be ≥ 1,000/mm3, platelet count should be ≥ 75,000/mm3, non-haematologic toxicities should, at the physician’s discretion, generally be recovered to patient’s baseline condition or ≤ Grade 1. Treatment should be continued until disease progression or unacceptable toxicity. Treatment with NINLARO 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. Antiviral prophylaxis should be considered in patients being treated with NINLARO to decrease the risk of herpes zoster reactivation. Thromboprophylaxis is recommended in patients being treated with NINLARO in combination with lenalidomide and dexamethasone, and should be based on an assessment of the patient’s underlying risks and clinical status. Elderly: No dose adjustment is necessary in patients over 65 years of age. Renal impairment: Mild or moderate renal impairment, no dose adjustment is necessary. Reduced 3 mg starting dose recommended in severe renal impairment or end-stage renal disease requiring dialysis. Hepatic impairment: Mild hepatic impairment, no dose adjustment is necessary. Reduced 3 mg starting dose recommended in moderate or severe hepatic impairment. Paediatric population: No data are available. Contraindications: Hypersensitivity to the active substance or to its excipients. Warnings & Precautions: Thrombocytopenia: Thrombocytopenia has been reported with NINLARO with platelet nadirs typically occurring between Days of each 28-day cycle and recovery to baseline by the start of the next cycle. Thrombocytopenia did not result in an increase in haemorrhagic events or platelet transfusions. Platelet counts should be monitored at least monthly during NINLARO treatment. Thrombocytopenia can be managed with dose modifications and platelet transfusions as per standard medical guidelines. Gastrointestinal toxicities: Diarrhoea, constipation, nausea and vomiting have been reported with NINLARO, occasionally requiring use of antiemetic and antidiarrhoeal medicinal products and supportive care. The dose should be adjusted for severe (Grade 3–4) symptoms. Peripheral neuropathy: Peripheral neuropathy has been reported with NINLARO. Patients should be monitored for symptoms of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy may require dose modification. Peripheral oedema: Peripheral oedema has been reported with NINLARO. Patients should be evaluated for underlying causes and provide supportive care, as necessary. The dose of dexamethasone should be adjusted per its SmPC or NINLARO for Grade 3 or 4 symptoms. Cutaneous reactions: Rash has been reported with NINLARO. Rash should be managed with supportive care or with dose modification if Grade 2 or higher. Hepatotoxicity: Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have been uncommonly reported with NINLARO. Hepatic enzymes should be monitored regularly and the dose should be adjusted for Grade 3 or 4 symptoms. Pregnancy: Women should avoid becoming pregnant while being treated with NINLARO. Posterior reversible encephalopathy syndrome (PRES): PRES has occurred in patients receiving NINLARO. In patients developing PRES, discontinue NINLARO. Interactions: Strong cytochrome P450 (CYP) 3A inducers: Co-administration of strong CYP3A inducers with NINLARO is not recommended. Strong CYP3A inhibitors: No dose modification is required for NINLARO with co-administration of strong CYP3A inhibitors. Strong CYP1A2 inhibitors: No dose modification is required for NINLARO with co-administration of strong CYP1A2 inhibitors. Fertility, Pregnancy & Lactation: Women should avoid becoming pregnant while being treated with NINLARO. Male and female patients of childbearing potential must use effective contraceptive measures during and for 90 days following treatment. Women using oral hormonal contraceptives should additionally use a barrier method of contraception. No data from use in pregnant women. Avoid use during pregnancy. Unknown whether NINLARO/metabolites are excreted in human milk, a risk to newborns/infants cannot be excluded; therefore breast feeding should be discontinued. The effect of NINLARO on fertility in humans has not been studied. Undesirable Effects: (All grades) Very common (≥1/10): Upper respiratory tract infection, thrombocytopenia, neutropenia, peripheral neuropathies, diarrhoea, nausea, vomiting, constipation, rash, back pain and oedema peripheral. Common (≥1/100, <1/10): Herpes zoster. Outside of the Phase 3 study, the following serious adverse reactions were rarely (≥ 1/10,000 to < 1/1,000) reported: acute febrile neutrophilic dermatosis, Stevens- Johnson syndrome, transverse myelitis, posterior reversible encephalopathy syndrome, tumour lysis syndrome and thrombotic thrombocytopenic purpura. Refer to the SmPC for details on full side effect profile and interactions. Pharmaceutical Precautions: Do not store above 30°C. Do not freeze. Store in the original package in order to protect from moisture. PI Date of Preparation: Dec 2016 PI approval code: UK/IXA/1611/0096 Legal category: POM Basic NHS Price: £6336 for 3 capsules. Marketing Authorisation: EU/1/16/1094/001, EU/1/16/1094/002, EU/1/16/1094/003 Further information is available from: Takeda UK Ltd. Building 3, Glory Park, Glory Park Avenue, Wooburn Green, Buckinghamshire, HP10 0DF. Tel: Fax: NINLARO® is a registered trademark of Takeda Pharmaceutical Company Limited. NINLARO has received a conditional marketing authorisation in Europe. A conditional marketing authorisation is granted to a medicinal product that fulfils an unmet medical need when the benefit to public health of immediate availability outweighs the risk inherent in the fact additional data are still required. The European regulatory agency will review new information on NINLARO at least every year and the summary of product characteristics will be updated as necessary.
Please refer to the Summary of Product Characteristics for details on the full side-effect profile and drug interactions of NINLARO. Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Takeda UK Ltd