Expert perspectives real-world clinical experiences in relapsed myeloma

Takeda Oncology-sponsored satellite symposium at the British Society for Haematology (BSH) 57 th Annual Scientific Meeting Expert perspectives real-world clinical experiences in relapsed myeloma This satellite symposium 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/1612/0107e. Date of preparation: May 2017.

Statement on NINLARO (ixazomib) availability NINLARO has received approval for the following indication: NINLARO in combination with lenalidomide and dexamethasone is indicated for the of adult patients with multiple myeloma who have received at least one prior therapy NINLARO is currently not commercially available NINLARO is awaiting relevant Health Technology Appraisals (HTAs) and commercial stock will become available upon confirmed availability of NHS funding

Objectives To provide insights on the real-world use of ixazomib using experiences from the UK and the US, citing clinician and patient experiences and perspectives from the introduction of ixazomib To facilitate discussions surrounding the practicalities and learnings from ixazomib use in clinical practice, drawing on these experiences utilising short case studies To explore how the introduction of ixazomib will impact on the paradigm in the UK

Disclosures Dr Popat has received advisory board and speaker fees from: Janssen Novartis Takeda Dr Jenner has received advisory board and speaker fees from: Amgen Novartis Celgene Takeda Janssen Dr Ramasamy has received advisory board and speaker fees from: Amgen Janssen Celgene Takeda

Case study 1: (Dr Rakesh Popat) Age Occupation 58 years Dentist Presentation Presentation with back pain. Diagnosis: IgA lambda myeloma; ISS 3; BM: 70% plasma cells; FISH: 1q+ (95% cells), del 13 (81%) Fracture T6, large T12 lesion, multiple other foci ASCT, autologous stem cell transplant; BM, bone marrow; CR, complete response; FDG, fluorodeoxyglucose; FISH, fluorescence in situ hybridisation; Ig, immunoglobulin; ISS, International Staging System; PET-CT, positron emission tomography - computed tomography; QoL, quality of life; Rd, lenalidomide-dexamethasone; VGPR, very good partial response; VTD, bortezomib-thalidomide-dexamethasone.

Case study 1: (Dr Rakesh Popat) Age Occupation 58 years Dentist Presentation Presentation with back pain. Diagnosis: IgA lambda myeloma; ISS 3; BM: 70% plasma cells; FISH: 1q+ (95% cells), del 13 (81%) Fracture T6, large T12 lesion, multiple other foci Initial VTD x 5; VGPR; ASCT: response CR; no maintenance Decision point 15 months later: Reappearance of bands <3; 18 months later: IgA 25, new rib & back pain Second Decision point Pulsed dexamethasone. Restaged: BM 70% plasma cells; cytogenetics: Hyperdiploid, 1q+, IgH rearrangement unknown partner; PET-CT: Multiple FDG avid foci Treatment options discussed: 2nd ASCT; clinical trial/bortezomib combination; Rd combinations: daratumumab-rd; carfilzomib-rd; ixazomib-rd ASCT, autologous stem cell transplant; BM, bone marrow; CR, complete response; FDG, fluorodeoxyglucose; FISH, fluorescence in situ hybridisation; Ig, immunoglobulin; ISS, International Staging System; PET-CT, positron emission tomography - computed tomography; QoL, quality of life; Rd, lenalidomide-dexamethasone; VGPR, very good partial response; VTD, bortezomib-thalidomide-dexamethasone.

Case study 1: (Dr Rakesh Popat) Age Occupation 58 years Dentist Presentation Presentation with back pain. Diagnosis: IgA lambda myeloma; ISS 3; BM: 70% plasma cells; FISH: 1q+ (95% cells), del 13 (81%) Fracture T6, large T12 lesion, multiple other foci Initial VTD x 5; VGPR; ASCT: response CR; no maintenance Decision point 15 months later: Reappearance of bands <3; 18 months later: IgA 25, new rib & back pain Second Decision point Third Pulsed dexamethasone. Restaged: BM 70% plasma cells; cytogenetics: Hyperdiploid, 1q+, IgH rearrangement unknown partner; PET-CT: Multiple FDG avid foci Treatment options discussed: 2nd ASCT; clinical trial/bortezomib combination; Rd combinations: daratumumab-rd; carfilzomib-rd; ixazomib-rd Ixazomib-Rd cycle 1: IgA 30; currently cycle 6: IgA 9.45 ASCT, autologous stem cell transplant; BM, bone marrow; CR, complete response; FDG, fluorodeoxyglucose; FISH, fluorescence in situ hybridisation; Ig, immunoglobulin; ISS, International Staging System; PET-CT, positron emission tomography - computed tomography; QoL, quality of life; Rd, lenalidomide-dexamethasone; VGPR, very good partial response; VTD, bortezomib-thalidomide-dexamethasone.

Case study 1: (Dr Rakesh Popat) Age Occupation 58 years Dentist Presentation Presentation with back pain. Diagnosis: IgA lambda myeloma; ISS 3; BM: 70% plasma cells; FISH: 1q+ (95% cells), del 13 (81%) Fracture T6, large T12 lesion, multiple other foci Initial VTD x 5; VGPR; ASCT: response CR; no maintenance Decision point 15 months later: Reappearance of bands <3; 18 months later: IgA 25, new rib & back pain Second Decision point Third Pulsed dexamethasone. Restaged: BM 70% plasma cells; cytogenetics: Hyperdiploid, 1q+, IgH rearrangement unknown partner; PET-CT: Multiple FDG avid foci Treatment options discussed: 2nd ASCT; clinical trial/bortezomib combination; Rd combinations: daratumumab-rd; carfilzomib-rd; ixazomib-rd Ixazomib-Rd cycle 1: IgA 30; currently cycle 6: IgA 9.45 Learnings Continues to work full time; minimal disruption and good QoL ASCT, autologous stem cell transplant; BM, bone marrow; CR, complete response; FDG, fluorodeoxyglucose; FISH, fluorescence in situ hybridisation; Ig, immunoglobulin; ISS, International Staging System; PET-CT, positron emission tomography - computed tomography; QoL, quality of life; Rd, lenalidomide-dexamethasone; VGPR, very good partial response; VTD, bortezomib-thalidomide-dexamethasone.

First interim analysis: median follow-up of ~15 months Ixazomib-Rd extends PFS across a broad group of patients vs. placebo-rd n Median PFS (months) Variable Subgroup Ixazomib-Rd Placebo-Rd Ixazomib-Rd Placebo-Rd HR All patients ALL 360 362 20.6 14.7 0.74 Age (years) ISS stage Cytogenetic risk 65 >65-75 >75 I or II III Standard-risk High-risk 168 145 47 314 46 199 75 176 125 61 318 44 216 62 20.6 17.5 18.5 21.4 18.4 20.6 21.4 14.1 17.6 13.1 15.7 10.1 15.6 9.7 0.68 0.83 0.87 0.75 0.72 0.64 0.54 Number of prior therapies 1 2 or 3 224 148 213 149 20.6 NE 16.6 12.9 0.88 0.58 Proteasome inhibitor Exposed Naive 250 110 253 109 18.4 NE 13.6 15.7 0.74 0.75 Prior IMiD therapy Exposed Naive 193 167 204 158 NE 20.6 17.5 13.6 0.74 0.70 Relapsed or refractory Relapsed Refractory* Relapsed & Refractory 276 42 41 280 40 42 18.7 NE NE 15.6 13.0 13.1 0.77 0.78 0.51 Baseline CrCl group <50 ml/min 50 ml/min 36 324 56 305 16.8 21.4 12.2 15.6 0.83 0.72 TOURMALINE-MM1 was not powered to assess efficacy in any specific subgroups, and as multiple myeloma is a heterogeneous disease, benefit may vary across subgroups 0.250 0.500 1.000 2.000 Favours ixazomib-rd Favours placebo-rd Figure adapted from NINLARO Summary of Product Characteristics NINLARO (ixazomib capsules) Summary of Product Characteristics March 2017. *Includes primary refractory patients. CrCL, creatinine clearance; HR, hazard ratio; IMiD, immunomodulatory drug; ISS, International Staging System; NE, not estimable; PFS, progression-free survival; Rd, lenalidomide-dexamethasone.

Peripheral neuropathy Peripheral neuropathy (PN) in TOURMALINE-MM1 1 Grade 3 PN was reported in 2% of patients in both groups in TOURMALINE-MM1 No grade 4 PN events were reported in either group Management of PN 2 Patients on ixazomib should be monitored for symptoms of neuropathy For grade 1 PN with pain or grade 2 PN, withhold ixazomib until PN recovers to grade 1 without pain or patient s baseline and then resume ixazomib at its most recent dose For grade 2 PN with pain or grade 3 PN, withhold ixazomib. Toxicities should, at the physician s discretion, generally recover to patient s baseline condition or grade 1 prior to resuming ixazomib at the next lower dose Discontinue regimen for grade 4 PN 1. Moreau P et al. N Engl J Med 2016;374:1621 1634; 2. NINLARO (ixazomib capsules) Summary of Product Characteristics March 2017. PN, peripheral neuropathy.

No difference in response by prior PI exposure 1,2 In TOURMALINE-MM1, 70% of patients had prior PI exposure (69% to bortezomib; 1% to carfilzomib) No difference was seen in response stratified by prior PI exposure Median PFS (months) Variable Subgroup Ixazomib-Rd Placebo-Rd HR All patients ALL 20.6 14.7 0.74 Proteasome inhibitor Exposed Naive 18.4 NE 13.6 15.7 0.74 0.75 0.250 0.500 1.000 2.000 Favours ixazomib-rd Favours placebo-rd Figure adapted from NINLARO Summary of Product Characteristics 1. Moreau P et al. N Engl J Med 2016;374:1621 1634; 2. NINLARO (ixazomib capsules) Summary of Product Characteristics March 2017. HR, hazard ratio; NE, not estimable; PI, proteasome inhibitor; PFS, progression-free survival; Rd, lenalidomide-dexamethasone.

Case study 2 (Dr Matthew Jenner) Age 58 years Diagnosis February 2010 Presentation Physical condition: Fatigue; back pain; Investigations: IgG lambda paraprotein 31 g/l; Hb 125 g/l; renal function and calcium normal; ISS 2; skeletal survey vertebral collapse T11; BMA: 70% plasma cells; no FISH available Second Serological progression October 2011: Paraprotein 14 g/l; Clinical progression January 2012: Paraprotein 21 g/l; Hb 120 g/l; BMA 46% plasma cells; FISH: t(4;14) in 100%; del (17p) in 30%; Chromosome 1 failed; Myeloma X trial: PAD x4, paraprotein fell to 4.3 g/l; 2nd high dose melphalan (200 mg/m 2 ) ASCT; post ASCT nadir 1.4 g/l; Serological progression 10 months post 2nd ASCT ASCT, autologous stem cell transplant; BMA, bone marrow aspirate; CTD, cyclophosphamide-thalidomide-dexamethasone; FISH, fluorescence in situ hybridisation; Hb, haemoglobin; Ig, immunoglobulin; ISS, International Staging System; PAD, bortezomib-doxorubicin-dexamethasone; PR, partial response; VGPR, very good partial response.

Case study 2 (Dr Matthew Jenner) Age 58 years Diagnosis February 2010 Presentation Physical condition: Fatigue; back pain; Investigations: IgG lambda paraprotein 31 g/l; Hb 125 g/l; renal function and calcium normal; ISS 2; skeletal survey vertebral collapse T11; BMA: 70% plasma cells; no FISH available DOR: 24 months DOR: 18 months DOR: 26 months Third September 2013: Paraprotein peak 29 g/l, total IgG 71.6 g/l; Hb 113; BMA: heavy PC infiltration; FISH: t(4;14) in 100%; del (17p) in 87%; gain of 1q21 in 80%; consistent with clonal evolution; Treatment: TOURMALINE-MM1 trial: ixazomib-rd/placebo-rd; 26 cycles; nadir 9 g/l; symptomatic progression after 26 cycles Learnings Rationale for continuous, especially in high-risk myeloma; role of FISH in newly diagnosed and relapsed myeloma ASCT, autologous stem cell transplant; BMA, bone marrow aspirate; CTD, cyclophosphamide-thalidomide-dexamethasone; DOR, duration of response; FISH, fluorescence in situ hybridisation; Hb, haemoglobin; Ig, immunoglobulin; IRd, ixazomib-lenalidomide-dexamethasone; ISS, International Staging System; PAD, bortezomib-doxorubicin-dexamethasone; PC, plasma cell; PR, partial response; Rd, lenalidomide-dexamethasone; VGPR, very good partial response.

Case study 2 (Dr Matthew Jenner) Thrombocytopenia Platelets x 10 9/ litre

Ixazomib-Rd was generally well tolerated with manageable side effects AEs after median follow-up of 23 months Moreau P et al. N Engl J Med 2016;374:1621 1634. Ixazomib-Rd (n=361), % Placebo-Rd (n=359), % Preferred terms All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 AEs overlapping with lenalidomide Diarrhoea 45 6 0 39 3 0 Constipation 35 <1 0 26 <1 0 Nausea 29 2 0 22 0 0 Fatigue 29 4 0 28 3 0 Vomiting 23 1 0 12 <1 0 Rash* 36 5 0 23 2 0 Back pain 24 <1 0 17 3 0 Upper respiratory tract infection 23 <1 0 19 <1 0 Thrombocytopenia 31 12 7 16 5 4 AEs with proteasome inhibitors Peripheral neuropathies* 27 2 0 22 2 0 Peripheral oedema 28 2 0 20 1 0 AEs with lenalidomide Thromboembolism* 8 2 <1 11 3 <1 Neutropenia* 33 18 5 31 18 6 *Represents multiple MedDRA preferred terms. AE, adverse event; Rd, lenalidomide-dexamethasone.

Special warnings and precautions for use: myelosuppression 1,2 For overlapping toxicities (thrombocytopenia, neutropenia and rash), the first dose reduction step is to reduce lenalidomide Platelet counts should be monitored at least monthly during ixazomib. More frequent monitoring should be considered during the first three cycles as per the lenalidomide SmPC An alternating dose modification approach is recommended for ixazomib and lenalidomide for overlapping toxicities of thrombocytopenia and neutropenia Withhold ixazomib and lenalidomide for platelet or neutrophil counts <30,000/mm 3 or <500/mm 3, respectively. Following recovery, resume lenalidomide at the next lower dose according to its SmPC and resume ixazomib at its most recent dose If platelet or neutrophil counts drop again to <30,000/mm 3 or <500/mm 3, withhold ixazomib and lenalidomide until recovery and resume ixazomib at the next lower dose and lenalidomide at its most recent dose 1. NINLARO (ixazomib capsules) Summary of Product Characteristics March 2017; 2.REVLIMID (lenalidomide) Summary of Product Characteristics March 2017. SmPC, summary of product characteristics.

Special warnings and precautions for use: gastrointestinal toxicities 1-3 Gastrointestinal (GI) toxicities have been observed to occur both with ixazomib and with the use of lenalidomide-dexamethasone, occasionally requiring use of antiemetics, antidiarrhoeals and supportive care The medical management of diarrhoea included the use of antidiarrhoeal agents and dose adjustment of lenalidomide or ixazomib For grade 3 or 4 GI toxicities, withhold the ixazomib dose. At the physician s discretion, generally recover to patient s baseline condition or at most grade 1 prior to resuming ixazomib. If attributable to ixazomib, resume ixazomib at the next lower dose following recovery. For lenalidomide-related toxicity, refer to its SmPC for dose adjustments In case of severe GI events, monitoring of serum potassium level is recommended 1. NINLARO (ixazomib capsules) Summary of Product Characteristics March 2017; 2. Moreau P et al. N Engl J Med 2016;374:1621 1634; 3. REVLIMID (lenalidomide) Summary of Product Characteristics March 2017. GI, gastrointestinal; SmPC, summary of product characteristics.

Special warnings and precautions for use: rash 1,2 For overlapping toxicities (thrombocytopenia, neutropenia and rash), the first dose reduction step is to reduce lenalidomide The medical management of rash included the use of antihistamines or topical glucocorticoids and dose adjustment to manage symptoms An alternating dose modification approach is recommended for ixazomib and lenalidomide for the overlapping toxicity of rash For grade 2 or 3 rash, withhold lenalidomide until rash recovers to grade 1 and resume lenalidomide at the next lower dose according to its SmPC If grade 2 or 3 rash occurs again, withhold ixazomib and lenalidomide until rash recovers to grade 1 then resume ixazomib at the next lower dose and lenalidomide at its most recent dose. For additional occurrences, alternate the dose modification of lenalidomide and ixazomib 1. NINLARO (ixazomib capsules) Summary of Product Characteristics March 2017; 2. Moreau P et al. N Engl J Med 2016;374:1621 1634. SmPC, summary of product characteristics.

Available for download at www.ninlaro.co.uk Patient support materials

A late response to therapy is not detrimental to overall outcomes Outcomes for patients in the TOURMALINE-MM1 study who achieved an early (0 4 month) or late (>4 month) response to therapy* ( PR) were compared. Outcomes Median number cycles Ixazomib-Rd Early (0 4 mos) n=174 Late (>4 mos) n=109 Early (0 4 mos) n=159 Placebo-Rd Late (>4 mos) n=106 16 23 15 23 Median PFS, mos 18.5 NE 14.9 NE Median DOR in PR pts, mos n=173 n=108 n=156 n=105 16.6 23.1 12.6 NE Premature discontinuation of therapy due to slow response should be avoided and patients should stay on therapy until progressive disease. Reprinted with permission from Laurent Garderet. Garderet L et al. Blood 2016;128(22): Abstract 2134. *Response was assessed every cycle based on central laboratory results and by IRC evaluation using IMWG criteria; Analysed to address the possibility of guarantee-time bias. DOR, duration of response; mos, months; IMWG, International Myeloma Working Group; IRC, independent review committee; NE, not estimable; PFS, progression-free survival; PR, partial response; Rd, lenalidomide-dexamethasone.

Case study 3 (Dr Karthik Ramasamy) Age 68 years Diagnosis June 2013 Presentation Anaemia leading to fatigue and hypercalcemia, Raised paraprotein levels. Right nephrectomy for previous renal cell carcinoma. Initial CTD x 5 followed by ASCT Decision point Decision made to treat because of symptoms and laboratory findings Second Decision point VCD x 6 Developed hemianopia during cycle one due to posterior circulation stroke put down to history of diabetes mellitus. Grade 2 neuropathy. Did not progress on VCD Hypercalcaemia, rising paraprotein ASCT, autologous stem cell transplant; CTD, cyclophosphamide-thalidomide-dexamethasone; VCD, bortezomib-cyclophosphamide-dexamethasone.

Case study 3 (Dr Karthik Ramasamy) Age 68 years Diagnosis June 2013 Presentation Anaemia leading to fatigue and hypercalcemia, Raised paraprotein levels. Right nephrectomy for previous renal cell carcinoma. Initial CTD x 5 followed by ASCT Decision point Decision made to treat because of symptoms and laboratory findings Second Decision point Third VCD x 6 Developed hemianopia during cycle one due to posterior circulation stroke put down to history of diabetes mellitus. Grade 2 neuropathy. Did not progress on VCD Hypercalcaemia, rising paraprotein Ixazomib-Rd (time on ixazomib-rd: 7 8 months with best paraprotein response to date) ASCT, autologous stem cell transplant; CTD, cyclophosphamide-thalidomide-dexamethasone; Rd, lenalidomide-dexamethasone; VCD, bortezomib-cyclophosphamide-dexamethasone.

Case study 3 (Dr Karthik Ramasamy) Age 68 years Diagnosis June 2013 Presentation Anaemia leading to fatigue and hypercalcemia, Raised paraprotein levels. Right nephrectomy for previous renal cell carcinoma. Initial CTD x 5 followed by ASCT Decision point Decision made to treat because of symptoms and laboratory findings Second Decision point Third VCD x 6 Developed hemianopia during cycle one due to posterior circulation stroke put down to history of diabetes mellitus. Grade 2 neuropathy. Did not progress on VCD Hypercalcaemia, rising paraprotein Ixazomib-Rd (time on ixazomib-rd: 7 8 months with best paraprotein response to date) Learnings Good partial response with third-line ASCT, autologous stem cell transplant; CTD, cyclophosphamide-thalidomide-dexamethasone; Rd, lenalidomide-dexamethasone; VCD, bortezomib-cyclophosphamide-dexamethasone.

Ixazomib exposure in renal impairment Phase 1/1b study Note that this Phase 1/1b study was not part of the registrational trial. 2016 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd. Gupta N et al. Br J Haematol 2016;174:748 759. ESRD, end-stage renal disease; MM, multiple myeloma; PK, pharmacokinetics; RI, renal impairment.

Ixazomib exposure in renal impairment Phase 1/1b study Similar absorption Higher unbound AUC in patients with severe RI/ESRD, standard dosing for ESRD patients: 3 mg Not dialysable 2016 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd. Gupta N et al. Br J Haematol 2016;174:748 759. AUC, area under the curve; ESRD, end-stage renal disease; RI, renal impairment.

Special populations: renal impairment 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 requiring dialysis Ixazomib 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 NINLARO (ixazomib capsules) Summary of Product Characteristics March 2017. SmPC, summary of product characteristics.

Quality of life maintained with ixazomib-rd vs. placebo-rd: EORTC-QLQ-C30 Quality of life was maintained with the addition of ixazomib to a standard Rd regimen Reprinted with permission from Philippe Moreau. Moreau P et al. Oral presentation 727, presented at ASH 2015 CI, confidence interval; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 module; EOT, end of ; QoL, quality of life; Rd, lenalidomide-dexamethasone.

Ixazomib-Rd regimen Ixazomib NINLARO (ixazomib capsules) Summary of Product Characteristics March 2017. *The recommended starting dose of dexamethasone is 40 mg; each tablet contain 2 mg dexamethasone.

Comparison in the number of planned hospital visits associated with adding PIs to the Rd backbone Route of administration Lenalidomide Dexamethasone PI Minimum number of clinic visits (18 cycles)* Rd 1 Ixazomib-Rd 2 Carfilzomib-Rd 3 PO PO Dosing schedule of PI PO PO PO PO PO/IV IV 18 18 96 Once weekly on days 1, 8, and 15 of 28-day cycles Twice weekly on days 1, 2, 8, 9, 15, and 16 of 28-day cycles for 12 cycles then days 1, 2, 15, and 16 1. REVLIMID (lenalidomide) Summary of Product Characteristics March 2017; 2. NINLARO (ixazomib capsules) Summary of Product Characteristics accessed March 2017; 3. KYPROLIS (carfilzomib) Summary of Product Characteristics March 2017. *Patients are treated until progression or unacceptable toxicity. Calculation excludes visits for monitoring. Standard carfilzomib regimen is 18 cycles; number of administrations of carfilzomib per cycle: cycle 1 12 = 6 doses (2 consecutive doses each week for 3 weeks), cycle 13 18 = 4 doses (2 consecutive doses during 1st and 3rd week). Treatment with carfilzomib-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 beyond 18 cycles are limited. HRQoL, health-related quality of life; IV, intravenous; PI, proteasome inhibitor; PO, per os (oral); Rd, lenalidomide-dexamethasone.

Abbreviated prescribing information: NINLARO (ixazomib) 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 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 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 cycle. The recommended starting dose of dexamethasone is 40 mg administered on Days 1, 8, 15, and 22 of a 28-day cycle. Prior to initiating a new cycle of therapy, absolute neutrophil count should be 1,000/mm 3, platelet count should be 75,000/mm 3, 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 14-21 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. 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: Coadministration 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. 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: 01628 537900 Fax: 01628 526617. 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 https://yellowcard.mhra.gov.uk/. Adverse events should also be reported to Takeda UK Ltd 01628 537900