Is sustained triplet therapy the new standard of care in relapsed/refractory multiple myeloma?

Transcription

1 Takeda Oncology-sponsored satellite symposium at the British Society for Haematology (BSH) 57 th Annual Scientific Meeting Is sustained triplet therapy the new standard of care in relapsed/refractory multiple myeloma? Professor Kwee Yong University College Hospital, London, UK 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/1612/0107c. Date of preparation: May 2017.

2 Statement on NINLARO (ixazomib) availability NINLARO has received approval for the following 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 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

3 Disclosures Professor Kwee Yong has received advisory board and speaker fees from: AbbVie Amgen Janssen Novartis Takeda

4 Aims of myeloma treatment There are three main objectives in myeloma treatment: Efficacy PFS and OS improvements Efficacious in a variety of atrisk groups Tolerability Well tolerated safety profile Manageable adverse events Limited toxicity Simplicity Easy-toadminister and convenient regimens Maintained HRQoL Speaker personal opinion. HRQoL, health-related quality of life; OS, overall survival; PFS, progression-free survival.

5 Multiple myeloma is a progressive, relapsing disease Non-malignant accumulation Malignant transformation M protein MM clone Clonal evolution Aggressive and stromal independent 10 ASYMPTOMATIC SYMPTOMATIC Active myeloma Relapse 5 Relapse 2 MGUS or smouldering myeloma Remission Time Figure adapted from Durie BGM. 2017, International Myeloma Foundation, adapted with permission Durie BGM. Concise review of the disease and treatment options. Multiple myeloma, cancer of the bone marrow. International Myeloma Foundation, Available at: (accessed March 2017). Relapsed refractory Variable timeline dependent on individual risk factors, including genetic and phenotypic changes, depth and duration of response to therapy, persistence of malignant MM stem cells, and evolution of competing MM clones. MGUS, monoclonal gammopathy of unknown significance; MM, multiple myeloma.

6 Disease activity (M-protein level) Relapse is usually associated with diminishing duration and depth of response over time 1 4 Multiple myeloma disease course Active disease Remission Median TTP 18 months; 74% CR/VGPR Median TTP 13 months; 58% CR/VGPR Median TTP 7 months; 43% CR/VGPR Time Diagnosis Relapse 1 Relapse 2 Relapse 3 Proportion of patients receiving treatment at each line of therapy First line: 95% Second line: 61% Third line: 38% CR/VGPR, complete response/very good partial response; TTP, time to progression. Figure adapted from Durie BGM. 2017, International Myeloma Foundation, adapted with permission. 1 Values for duration and response data from Yong K et al Durie BGM. Concise review of the disease and treatment options. Multiple myeloma, cancer of the bone marrow. International Myeloma Foundation, Available at: (accessed March 2017); 2. Kumar SK et al. Mayo Clin Proc 2004;79: ; 3. Moreau P & Touzeau C. Am Soc Clin Oncol Educ Book 2015:e504 e511; 4. Yong K et al. Br J Haematol 2016;175: Fourth line: 15%

7 New mechanisms of action have markedly expanded the treatment options for RRMM 1-9 Evolution of treatments in RRMM Bortezomib APEX Lenalidomide MM-009 MM-010 +d Pomalidomide MM-003 +d Carfilzomib ASPIRE +Rd ENDEAVOR +d Daratumumab SIRIUS, GEN 501 monotherapy CASTOR +Vd POLLUX +Rd Ixazomib TOURMALINE-MM1 +Rd IMiD PI mab HDACi PANORAMA-1 +Vd Panobinostat ELOQUENT-2 +Rd Elotuzumab A variety of drug classes have demonstrated clinical benefits in the treatment of RRMM, and gaining access to these triplet combination therapies in the UK setting is a key next step 1. European Medicines Agency. [Myeloma keyword search of public assessment reports]; 2. Dimopoulos MA et al. N Engl J Med 2016;375: ; 3. Usmani SZ et al. Blood 2016;128:37 44; 4. Moreau P et al. N Engl J Med 2016;374: ; 5. Stewart AK et al. N Engl J Med 2015;372: ; 6. Lonial S et al. N Engl J Med 2015;373: ; 7. Richardson PG et al. Blood 2016;127: ; 8. Palumbo A et al. N Engl J Med 2016;375: Lonial S et al. Lancet 2016;387: d, dexamethasone; HDACi, histone deacetylase inhibitor; IMiD, immunomodulatory drug; mab, monoclonal antibody; MM, multiple myeloma; NDMM, newly diagnosed multiple myeloma; NICE, National Institute for Health and Care Excellence; PI, proteasome inhibitor; Rd, lenalidomide-dexamethasone; RRMM, relapsed/refractory multiple myeloma; Vd, bortezomib-dexamethasone.

8 Not one, but many myelomas Disease progression may not evolve in a linear manner Tumour-initiating cell Ancestral clones Diagnosis Dominant clone Subclones with unique non-linear branching mutations Minor clone Treatment Subclones with linearly derived mutations Relapse Genetically distinct Stable Linear Figure 2012 by The American Society of Hematology 1 1. Bahlis NJ. Blood 2012;120:

9 Heterogeneity in multiple myeloma supports the need for combination therapy Rationale for combining agents with different MoAs Lohr JG et al. Cancer Cell. 2014;1325: IMiD, immunomodulatory drug; MoA, mechanism of action; PI, proteasome inhibitor.

10 Superiority of triplet vs. doublet therapy The superiority of triplet vs. doublet regimens in RRMM have been demonstrated by the addition of a novel agent to the standard Rd regimen in recent Phase 3 trials: TOURMALINE-MM1 1 Ixazomib-Rd significantly improved PFS vs. placebo-rd (median PFS 20.6 vs months, respectively) HR: 0.74 (95% CI: ; p=0.01) ASPIRE 2 Carfilzomib-Rd significantly improved PFS vs. Rd (median PFS 26.3 vs months, respectively) HR: 0.69 (95% CI: ; p=0.0001) ELOQUENT-2 3 Elotuzumab-Rd significantly improved PFS vs. Rd (median PFS 19.4 vs months, respectively) HR: 0.70 (95% CI: ; p<0.001) POLLUX 4 Daratumumab-Rd: median PFS not reached vs. Rd (18.4 months) HR: 0.37 (95% CI: ; p<0.001) Bortezomib-based triplet regimens have also demonstrated treatment benefits vs. doublet regimens (e.g. PANORAMA-1 and CASTOR) 5,6 1. Moreau P et al. N Engl J Med 2016;374: ; 2. Stewart AK et al. N Engl J Med 2015;372:142 15; 3. Lonial S et al. N Engl J Med 2015;373: ; 4. Dimopoulos MA et al. N Engl J Med 2016;375: ; 5. Richardson PG et al. Blood 2016;127: ; 6. Palumbo A et al. N Engl J Med 2016;375: CI, confidence interval; HR, hazard ratio; PFS, progression-free survival; Rd, lenalidomide-dexamethasone; RRMM, relapsed/refractory multiple myeloma.

11 Triplet therapies need to have minimal cumulative toxicity Tolerability is important for keeping patients on long-term, sustained therapy Regimen Study arm AEs (grade 3) Comparator arm Study arm SAEs Comparator arm Ixazomib-Rd vs. placebo-rd 1 74% 69% 47% 49% Carfilzomib-Rd vs. Rd % 80.7% 59.7% 53.7% Elotuzumab-Rd vs. Rd 3 Not reported Not reported 65% 57% Daratumumab-Rd vs. Rd 4,5 Not reported Not reported 48.8% 42.0% 1. Moreau P et al. N Engl J Med 2016;374: ; 2. Stewart AK et al. N Engl J Med 2015;372: ; 3. Lonial S et al. N Engl J Med 2015;373: ; 4. Dimopoulos MA et al. N Engl J Med 2016;375: ; 5. Dimopoulos MA et al. Haematologica 2016;101(S1): Abstract LB2238. AE, adverse event; Rd, lenalidomide-dexamethasone; SAE, serious adverse event.

12 Probability of survival Longer duration of treatment at second line is associated with improved 1-year survival The odds of 1-year OS increased along with each additional month of second-line therapy OR: 1.17 (95% CI: ; p<0.001) Duration of second-line therapy (months) 1. Parameswaran H et al. J Clin Oncol 2016;34(S): Abstract E1323. CI, confidence interval; OR, odds ratio; OS, overall survival.

13 Considerations for overall treatment burden What factors influence patients ability to stay on long-term treatment? Inconvenient and complicated administration schedule 1 Inconvenient route of administration (IV, SC) 2 Hospital and clinic visits (driving distance, number of visits, visit duration) 3,4 1. Baz R et al. Support Care Cancer 2015;23: ; 2. Borner M et al. Oncologist 2001;6:12 16; 3. Huntington SF et al. Lancet Hematol 2015;2:e408 e416; 4. Goodwin JA et al. Cancer Nurs 2013;36: IV, intravenous; SC, subcutaneous.

14 Considerations for overall treatment burden (cont.) Poor tolerability can affect duration of treatment Infusion-site reactions Cardiac events Renal events Gastrointestinal-related events Venous thrombosis Peripheral neuropathy Myelosuppression Second primary malignancy Fatigue Hypertension Infection Rash Colson K. Support Care Cancer 2015;23:

15 Conclusions Myeloma is characterised by considerable heterogeneity, within and between tumours, and is characterised by repeated relapses 1,2 Combination therapy employing agents with different mechanisms of action increases chances of disease control 3 11 Triplet therapies have demonstrated superiority over doublet regimens in RRMM 4,6 10 Longer time on treatment has been shown to be associated with improved 1-year survival 12 New triplet regimens will need a tolerability profile that allows sustained therapy OS, overall survival; RRMM, relapsed/refractory multiple myeloma. 1. Bahlis NJ. Blood 2012;120: ; 2. Durie BGM. Concise review of the disease and treatment options. Multiple myeloma, cancer of the bone marrow. International Myeloma Foundation, Available at: (accessed March 2017); 3. European Medicines Agency. [Myeloma keyword search of public assessment reports]; 4. Dimopoulos MA et al. N Engl J Med 2016;375: ; 5. Usmani SZ et al. Blood 2016;128:37 44; 6. Moreau P et al. N Engl J Med 2016;374: ; 7. Stewart AK et al. N Engl J Med 2015;372: ; 8. Lonial S et al. N Engl J Med 2015;373: ; 9. Richardson PG et al. Blood 2016;127: ; 10. Palumbo A et al. N Engl J Med 2016;375: ; 11. Lonial S et al. Lancet 2016;387: ; 12. Parameswaran H et al. J Clin Oncol 2016;34(S): Abstract E1323

16 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 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/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 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: 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 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