Horizon Scanning Centre November Pomalidomide for multiple myeloma third line SUMMARY NIHR HSC ID: 4436

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1 Horizon Scanning Centre November 2012 Pomalidomide for multiple myeloma third line SUMMARY NIHR HSC ID: 4436 This briefing is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information. Pomalidomide (CC-4047) is intended to be used in combination with dexamethasone as third line treatment for relapsed and/or refractory multiple myeloma (MM) in patients who have received treatment with both lenalidomide- and bortezomib-containing regimens. If licensed, pomalidomide will offer an alternative treatment option for these patients. Pomalidomide is an immunomodulatory drug analogue of thalidomide. It has demonstrated greater activity than thalidomide in vitro and it may also inhibit the destructive effects of MM in the bone microenvironment by inhibiting osteoclast differentiation. In 2009, 4,270 people were diagnosed with MM in England and Wales, giving a crude incidence rate of 8 per 100,000 population. Median survival for MM is approximately 3 to 5 years 1, though this can increase to a median 7 years with use of intensive therapy. Induction therapy followed by high-dose melphalan and autologous stem cell transplantation is primarily offered to MM patients less than 65 years of age, and provides the greatest chance of prolonged survival and complete remission. In older patients combination therapy is usually given, with a treatment regimen which is patient specific, dependent on age, and may include: melphalan, prednisolone and thalidomide; cyclophosphamide, dexamethasone and thalidomide; or bortezomib, melphalan and prednisolone. There are currently no standard third-line therapies for patients with MM, however NICE guidance recommends bortezomib after first relapse and lenalidomide at second or later relapse. Pomalidomide in combination with low-dose dexamethasone is currently in a phase III clinical trial comparing its effect on disease progression with high-dose dexamethasone alone. This trial is expected to complete in May This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health. NIHR Horizon Scanning Centre, University of Birmingham nihrhsc@contacts.bham.ac.uk Web:

2 TARGET GROUP Multiple myeloma (MM): relapsed and/or refractory third or subsequent line; in combination with dexamethasone; patients who have received treatment with both lenalidomide- and bortezomib-containing regimens. TECHNOLOGY DESCRIPTION Pomalidomide (CC-4047) is an immunomodulatory drug analogue of thalidomide (IMiD) 2. It is intended as a treatment for relapsed and/or refractory MM in patients who have received treatment with both lenalidomide- and bortezomib-containing regimens. MM is characterized by accumulation of malignant plasma cells in the bone marrow, bone lesions, and immunodeficiency 3. IMiDs may disrupt stromal support for MM-cells by down regulating the expression of adhesion molecules 4 ; have antineoplastic and apoptotic effects through blockade of nuclear factor-κb and the caspase-8/death receptor pathway signalling 5 ; and overcome conventional drug resistance by down-regulating immunosuppressive cytokines, augmenting the proliferation and activation of T lymphocyte and natural killer cells 2,3. IMiDs also down regulate vascular endothelial growth factor and beta fibroblast growth factor, inhibiting angiogenesis 3. Pomalidomide appears to display equivalent anti-angiogenic activity to thalidomide, however it exhibits increased stimulation of apoptosis via the inhibition of cellular COX-2 production (a predictor of poor outcome) 6, increased anti-inflammatory effects via the inhibition of TNF-alpha production 1, and a much enhanced stimulation and activation of the immune response 2,3. Pomalidomide is administered orally at 4mg once daily on days 1 21 of a 28 day cycle in combination with dexamethasone orally at 40mg once daily on days 1, 8, 15 and 22. Pomalidomide is in phase III clinical trials for the treatment of idiopathic myelofibrosis. INNOVATION and/or ADVANTAGES If licensed, pomalidomide will offer an alternative treatment option for patients with relapsed and/or refractory MM. Pomalidomide has demonstrated greater activity than thalidomide in vitro and it may also inhibit the destructive effects of MM in the bone microenvironment by inhibiting osteoclast differentiation 7. DEVELOPER Celgene. AVAILABILITY, LAUNCH OR MARKETING Pomalidomide is a designated orphan drug in the EU. It is in phase III clinical trials. 2

3 PATIENT GROUP BACKGROUND MM develops from plasma cells in the bone marrow and is the 17 th most common cancer in the UK 8,9. The uncontrolled over-production of abnormal plasma cells in MM results in the production of a large amount of a single type of abnormal antibody, and a reduction in the number of normal white cells, red cells and platelets 8. This leads to anaemia, repeated infections, bone pain, hypercalcaemia, kidney damage, tiredness and weight loss 8,10. NHS or GOVERNMENT PRIORITY AREA This topic is relevant to Improving Outcomes: A Strategy for Cancer (2011). CLINICAL NEED and BURDEN OF DISEASE In 2009, 4,270 people were diagnosed with MM (ICD-10: C90) in England and Wales, giving a crude incidence rate of 8 per 100,000 population 8. This represents around 1% of all cancer diagnoses, however higher incidences are seen in certain ethnic groups, such as those from black ethnic groups 9,11. The risk of developing MM increases with age 12 ; the median age of presentation is 70 years, with only 2% of patients under the age of 40 years 11. In , there were 63,541 hospital admissions with a primary diagnosis of MM (ICD10 C90.0) in England, resulting in 79,298 bed days and 66,495 finished consultant episodes 13. The pattern of disease is typically remission followed by relapse requiring further therapy, often 3 or 4 times before the development of treatment resistance. With each relapse, the following remission is usually shorter than the previous one and more difficult to treat due to the development of bone, renal and haematological problems, which are part of the disease, and the development of drug resistance 14,b. Median survival for MM is approximately 3 to 5 years 15, though this can increase to a median 7 years with use of intensive therapy 16. Patients whose disease has become refractory to bortezomib and immunomodulatory drugs typically have an overall survival (OS) of 9 months, but only 3 months if they receive no therapy following relapse 17. In 2010, 2,298 deaths from MM were registered in England and Wales 18, 82% which were in people aged 65 and over 19. In 2009, it was estimated that 39% of patients with MM had relapsed disease and 65% of patients with relapsed MM had received two or more prior therapies, which equates to 1,082 people 20. However expert opinion suggests that the vast majority (>90%) of myeloma patients will receive a third line treatment 14a. PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance NICE technology appraisal in development. Bortezomib for induction therapy prior to high dose chemotherapy and autologous stem cell transplantation for the treatment of multiple myeloma (ID610). Expected October a Expert personal opinion. 3

4 NICE technology appraisal in development. Lenalidomide for the treatment of newly diagnosed multiple myeloma (ID474). Suspended July NICE technology appraisal in development. Lenalidomide for the maintenance treatment of multiple myeloma after autologous stem cell transplantation (ID475). Suspended July NICE technology appraisal in development. Bortezomib for consolidation therapy after autologous stem cell transplantation for the treatment of multiple myeloma (ID529). Expected May NICE technology appraisal in development. Multiple myeloma (one prior therapy) vorinostat (with bortezomib) (ID501). Suspended May NICE technology appraisal. Bortezomib and thalidomide for the first line treatment of multiple myeloma (TA228) NICE technology appraisal. Lenalidomide for the treatment of multiple myeloma in people who have received at least one prior therapy (TA171) NICE technology appraisal. Bortezomib monotherapy for relapsed multiple myeloma (TA129) NICE Cancer Service guideline. Improving outcomes in haemato-oncology cancer (CSGHO) Other Guidance British Committee for Standards in Haematology. Guidelines on the diagnosis and management of multiple myeloma EXISTING COMPARATORS and TREATMENTS Induction therapy followed by high-dose melphalan and autologous stem cell transplantation (ASCT) provides the greatest chance of prolonged survival and complete remission; however this typically only improves survival by up to a year 13,b. This treatment is also limited to patients who are able to tolerate it; in Europe, ASCT is primarily offered to patients under 65 years of age 30. As the median age at diagnosis is 70 years, more than 50% of newly diagnosed MM patients are likely to be ineligible for this therapy. The aim in such patients is to give effective combination therapy. The treatment regimen will be patient specific and dependent on age and may include melphalan, prednisolone and thalidomide; cyclophosphamide, dexamethasone and thalidomide; or bortezomib, melphalan and prednisolone 31. There are currently no standard third-line therapies for patients with MM, however NICE guidance 27 recommended bortezomib after first relapse and lenalidomide at second or later relapse 13,c. EFFICACY and SAFETY Trial NIMBUS, NCT , CC-4047-MM-003, ; pomalidomide in combination with lowdose dexamethasone vs high-dose dexamethasone; phase III. NCT , CC MM-003/C, ; pomalidomide; phase III extension study. STRATUS, NCT , CC-4047-MM-010, ; pomalidomide in combination with lowdose dexamethasone; phase III. Sponsor Celgene Corporation. Celgene Corporation. Celgene Corporation. Status Ongoing. Ongoing. Ongoing. Source of Trial registry 32, Trial registry 33, Trial registry 34, b Expert personal opinion. 4

5 information manufacturer. manufacturer. manufacturer. Location EU (incl UK), USA, Canada, Russia and EU (incl UK), Canada, Russia and Australia. EU (incl UK), Canada, Russia and Australia. Australia. Design Randomised, activecontrolled. Non-randomised, single arm. Non-randomised, single arm. Participants Schedule Follow-up Primary outcome Secondary outcomes n=426; aged 18 years; MM; refractory or relapsed; 2 consecutive cycles of prior treatment that included lenalidomide, bortezomib and alkylating agent; failed treatment with lenalidomide and bortezomib. Randomised to pomalidomide 4mg, orally on days 1-21 of a 28-day cycle in combination with dexamethasone 20mg (for subjects >75 years of age) or 40mg (for subjects 75 years of age) orally once daily on days 1, 8, 15, and 22 of a 28-day cycle; or dexamethasone 20mg (for subjects >75 years of age) or 40mg (for subjects 75 years of age) orally once daily on days 1-4, 9-12 and of a 28-day cycle. Active treatment until disease progression. Follow-up for up to 5 years. Time to disease progression or death. Adverse events (AEs), survival, response according to IMWG c uniform response criteria, response according to EBMT d criteria, time to progression (TTP), time to IMWG or EBMT response, time from response to disease progression, time to increased haemoglobin (Hb), time to improvement of bone pain, time to improvement of renal function, time to improvement of ECOG e c International Myeloma Working Group. d European Group for Blood and Marrow Transplantation. e Eastern Cooperative Oncology Group. n=85 (planned); aged 18 years; subjects who were enrolled in NCT and discontinued study therapy with dexamethasone alone after disease progression. Pomalidomide 4mg orally on days 1-21 of a 28-day cycle. Active treatment until disease progression or unacceptable toxicity. Follow-up for up to 5 years. Response based on the IMWG uniform response criteria. Response based on EBMT criteria, AEs, survival, time to disease progression based on IMWG or death, time from response to disease progression. n=507 (planned); aged 18 years; MM; refractory or relapsed; 2 consecutive cycles of prior treatment that included lenalidomide and bortezomib either alone or in combination regimens. Pomalidomide 4mg, orally on days 1-21 of a 28-day cycle in combination with dexamethasone 20mg (for subjects >75 years of age) or 40mg (for subjects 75 years of age) orally once daily on days 1, 8, 15, and 22 of a 28-day cycle. Active treatment until disease progression or unacceptable toxicity. Follow-up for up to 5 years. AEs. Overall response rate (ORR), time to response, duration of response (DoR), progression-free survival (PFS), TTP, OS. 5

6 Expected reporting date performance status, EORTC QLQ-MY20 f, EORTC QLQ-C30 g, EQ- 5D h. Study completion date reported as May Study completion date reported as Jun Nov Trial NCT , CDR , P30CA015083, , NCI , MC0789; pomalidomide in combination with dexamethasone; phase II. NCT , IFM , , 2009_28/0924; pomalidomide in combination with dexamethasone; phase II. Sponsor Mayo Clinic. University Hospital, Lille. Status Ongoing. Ongoing. Source of Publication 4,35, abstract 36, trial registry 37, Abstract 38,39, trial registry 40, manufacturer. information manufacturer. Location USA. France. Design Non-randomised. Non-randomised. Participants n=258 (planned); aged 18 years; MM; refractory to lenalidomide and bortezomib. n=84; aged 18 years; MM; symptomatic and progressive following lenalidomide and/or bortezomib treatment. Schedule Follow-up Primary outcomes Secondary outcomes Key results Adverse effects (AEs) Randomised to pomalidomide 2mg or 4mg, both orally on days 1-28, in combination with dexamethasone 40mg orally on days 1, 8, 15, and 22 of a 28- day cycle. Active treatment until disease progression. Follow-up for 6 months. Complete response (CR), partial response (PR), or very good partial response (VGPR). Toxicity, duration of remission. Pomalidomide 2mg (n=35): CR, 0%; VGPR, 14%; PR, 11%; minor response (MR), 23%; overall response (OR), 49%; OS at 6 months, 78% (95% CI, 65-94); PFS at 6 months, 56% (95% CI, 41-75). Pomalidomide 4mg (n=35): CR, 3%; VGPR, 9%; PR, 17%; MR, 14%, OR, 43%; OS at 6 months, 67% (95% CI, 52-86); PFS at 6 months, 34% (95% CI, 21-55). Myelosuppression was the most common toxicity. Grade 3 or 4 haematological toxicity possibly attributable to treatment Randomised to pomalidomide 4mg on days 1-21 or on days 1-28, both orally in combination with dexamethasone 40mg orally on days 1, 8, 15, and 22 of a 28- day cycle. Active treatment until disease progression. Follow-up for 6 months. Response rate. Response, safety, time to response, DoR, TTP, OS, cytogenetic response of the bone marrow tumour plasma cells. Overall median PFS: patients achieving SD, 4.2 months (95% CI ); patients achieving any response, 12.6 months (95% CI ). Pomalidomide on days 1-21 (n=40): VGPR, 7.5%; PR and better, 30%; stable disease (SD), 52%; median DoR, 77 days; PFS at 6.3 months, 57% (95% CI ); 5 deaths. Pomalidomide on days 1-28 (n=36): VGPR, 2.8%; PR and better, 47%; SD, 41%; median DoR, 89 days; PFS at 6.3 months, 61% (95% CI ); 5 deaths. Myelosuppression was the most common toxicity possibly attributable to treatment. f European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients with Multiple Myeloma. g European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients with Cancer. h European Quality of Life-5 Dimensions. 6

7 occurred in 71% of 2mg cohort and 74% of 4mg cohort. Expected reporting date Pomalidomide 2mg (n=35): Grade 3-4 myelosuppression: neutropenia (29%), thrombocytopenia (3%), and anaemia (9.6%). Grade 3-4 non-haematologic toxicities: overall (16%); pneumonitis (3%), hyperglycaemia (3%), renal failure (3%), fatigue (3%), and thrombosis (3%). Primary completion date reported as Sep Study completion date reported as Aug Trial Sponsor Status Source of information Location Design Participants NCT , CC-4047-MM-002; pomalidomide vs pomalidomide in combination with low-dose dexamethasone; phase II. Celgene Corporation. Ongoing. Abstract 41,42,43, presentation 44, trial registry 45, manufacturer. USA and Canada. Randomised, active-controlled. n=221; aged 18 years; relapsed and refractory MM; prior treatment with 2 cycles of lenalidomide and 2 cycles of bortezomib (either in separate regimens or within the same regimen). Schedule Randomised to pomalidomide 4mg on days 1-21; or pomalidomide 4mg on days 1-21 in combination with dexamethasone 40mg on days 1, 8, 15, and 22 of a 28-day cycle. All given orally. Subjects who progress in the pomalidomide only arm crossover to the combination arm. Follow-up Primary outcome Secondary outcomes Key results Active treatment until follow up for survival. PFS. Objective response using EBMT criteria, time to response, DoR, OS, AEs, response using IMWG uniform response criteria, relationship between response and cytogenetic abnormalities. Pomalidomide (n=108) vs pomalidomide with dexamethasone (n=113) At least PR, 9% vs 30%; at least MR, 25% vs 45%; SD, 46% vs 35%; progressive disease, 16% vs 6%; median DoR, not reached (NR) vs 7.4%; median time to response in subjects with at least PR, 2.0 vs 1.9 months; median PFS, 2.5 months vs 3.8 months (p=0.037, hazard ratio (HR) = 0.73); median OS, 13.6 months vs 14.4 months (p=0.449, HR = 0.85). Adverse effects (AEs) Pomalidomide with dexamethasone group only: Lenalidomide and bortezomib refractory subset (n=69): at least PR, 28%; at least MR, 46%; SD, 35%; time to at least PR, 1.8 months; median DoR in subjects with at least PR, 6.2 months; median DoR in subjects with MR, 3.0 months; median PFS, 3.8 months; 1-year survival, 61%; OS, 13.5 months. Lenalidomide and bortezomib refractory with prior BM transplant subset (n=47): at least PR, 34%; at least MR, 53%; SD, 28%; time to at least PR, 1.6 months; median DoR in subjects with at least PR, 5.7 months; median DoR in subjects with MR, 5.7 months; median PFS, 4.6 months; 1-year survival, 67%; OS, NR. Overall grade 3 or 4 AEs Pomalidomide (n=107) vs pomalidomide with dexamethasone (n=112): Neutropenia, 47% vs 38%; thrombocytopenia, 22% vs 19%; anaemia, 22% vs 21%; leukopenia, 6% vs 10%; pneumonia, 14% vs 19%; fatigue, 10% vs 10%; back pain, 12% vs 9%; dyspnoea, 7 vs 13%. 7

8 Expected reporting date Primary completion date reported as Sep ESTIMATED COST and IMPACT COST The cost of pomalidomide is not yet known. IMPACT - SPECULATIVE Impact on Patients and Carers Reduced mortality/increased length of survival Reduced symptoms or disability Other: No impact identified Impact on Services Increased use of existing services Decreased use of existing services Re-organisation of existing services Need for new services Other: None identified Impact on Costs Increased drug treatment costs Reduced drug treatment costs Other increase in costs: Other reduction in costs: Other: uncertain unit cost. None identified Other Issues Clinical uncertainty or other research question identified: REFERENCES None identified 1 British Medical Journal. Clinical Evidence. Myeloma (multiple). Accessed 16 October Cooney MM, Nock C, Bokar J et al. Phase I trial of pomalidomide given for patients with advanced solid tumors. Cancer Chemotherapy and Pharmacology DOI /s Görgün G, Calabrese E, Soydan E et al. Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma. Blood 2010;116(17): Quach H, Kalff A and Spencer A. Lenalidomide in multiple myeloma: Current status and future potential. American Journal of Hematology doi: /ajh Lacy MQ, Hayman SR, Gertz MA et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. Journal of Clinical Oncology 2009;27(30): Ladetto M, Vallet S, Trojan A et al. Cyclooxygenase-2 (COX-2) is frequently expressed in multiple myeloma and is an independent predictor of poor outcome. Blood 2005;105(12): Moreau P. The future of therapy for relapsed/refractory multiple myeloma: emerging agents and novel treatment strategies. Seminars in Hematology 2012;49 Suppl 1:S

9 8 Cancer Research UK. What is myeloma? type/myeloma/about/what-is-myeloma Accessed 16 October Cancer Research UK. Myeloma incidence statistics. Accessed 16 October Macmillan. Symptoms of myeloma. Myeloma/Symptomsdiagnosis/Symptoms.aspx Accessed 2 August Smith A, Wisloff F and Samson D on behalf of the UK Myeloma Forum, Nordic Myeloma Study Group and British Committee for Standards in Haematology. Guidelines for the diagnosis and management of multiple myeloma British Journal of Haematology 2006; 132: British Committee for Standards in Haematology (BCSH) in conjunction with the UK Myeloma Forum. Guidelines on the diagnosis and management of multiple myeloma. London: BCSH; September HESonline. Hospital episode statistics, Inpatient data , primary diagnosis: 4 character table. National Health Service National Institute for Health Research Horizon Scanning Centre. Carfilzomib (Kryprolis) for multiple myeloma third line. September British Medical Journal. Clinical Evidence. Myeloma (multiple). Accessed 16 October Raab MS, Podar K, Breitkreutz I et al. Multiple myeloma. The Lancet 2009;374: Kumar SK, Lee JH, Lahuerta JJ et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia 2012;26(1): Office for National Statistics. Mortality statistics: Deaths registered in Accessed 16 October Cancer Research UK. Myeloma UK mortality statistics. Accessed 16 October National Institute for Health and Clinical Excellence. Costing template for lenalidomide for the treatment of multiple myeloma in people who have received at least one prior therapy. June National Institute for Health and Clinical Excellence. Bortezomib for induction therapy prior to high dose chemotherapy and autologous stem cell transplantation for the treatment of multiple myeloma. Technology appraisal in development ID610. Expected October National Institute for Health and Clinical Excellence. Lenalidomide for the treatment of newly diagnosed multiple myeloma. Technology appraisal in development ID474. London: NICE; Suspended July National Institute for Health and Clinical Excellence. Lenalidomide for the maintence treatment of multiple myeloma after autologous stem cell transplantation. Technology appraisal in development ID475. London: NICE; Suspended July National Institute for Health and Clinical Excellence. Bortezomib for consolidation therapy after autologous stem cell transplantation for the treatment of multiple myeloma. Technology appraisal in development ID529. Expected May National Institute for Health and Clinical Excellence. Multiple myeloma (one prior therapy) vorinostat (with bortezomib). Technology appraisal in development ID501. London: NICE; Suspended May National Institute for Health and Clinical Excellence. Bortezomib and thalidomide for the first line treatment of multiple myeloma. Technology appraisal TA228. London: NICE; July National Institute for Health and Clinical Excellence. Lenalidomide for the treatment of multiple myeloma in people who have received at least one prior therapy. Technology appraisal TA171. London: NICE; June National Institute for Health and Clinical Excellence. Bortezomib monotherapy for relapsed multiple myeloma. Technology appraisal TA129. London: NICE; October National Institute for Health and Clinical Excellence. Improving outcomes in haemato-oncology cancer. Cancer Service Guideline CSGHO. London: NICE; October Morabito F, Gentile M, Mazzone C et al. Therapeutic approaches for newly diagnosed multiple myeloma patients in the era of novel drugs. European Journal of Haematology 2010; 85:

10 31 British Committee for Standards in Haematology (BCSH) in conjunction with the UK myeloma forum. Guidelines on the diagnosis and management of multiple myeloma. London: BCSH; September ClinicalTrials.org. Study to compare efficacy and safety of pomalidomide in combination with lowdose dexamethasone versus high-dose dexamethasone in subjects with refractory or relapsed and refractory multiple myeloma (NIMBUS). Accessed 16 October ClinicalTrials.org. Study to Evaluate the Safety and Efficacy of Pomalidomide Monotherapy in Subjects With Refractory or Relapsed Refractory Multiple Myeloma. Accessed 17 October EU Clinical trials register. A multicenter, single-arm, open-label study with pomalidomide in combination with low dose dexamethasone in subjects with refractory or relapsed and refractory multiple myeloma. Accessed 19 October Lacy MQ, Allred JB, Gertz MA et al. Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dualrefractory disease. Blood 2011;118(11): Lacy M, Gertz M A, Hayman S R et al. Activity of pomalidomide plus dexamethasone (Pom/dex) in dual lenalidomide/bortezomib refractory multiple myeloma. J Clin Oncol 28:15s, 2010 (suppl; abstr 8002). ASCO Annual Meeting. June Chicago, Illinois, USA. Abstract Presentation. confid=74&abstractid= ClinicalTrials.gov. CC-4047 and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma or Amyloidosis. Accessed 18 October Leleu X, Attal M, Arnulf B et al. Phase 2 randomised open label study of 2 modalities of pomalidomide (CC4047) plus low-dose dexamethasone in patients with multiple myeloma, refractory to both lenalidomide and bortezomib. IFM th Congress of the European Hematology Association (EHA). June London, England. Abstract Oral. 39 Leleu X, Attal M, Moreau P et al. Phase 2 Study of 2 Modalities of Pomalidomide (CC4047) Plus Low-Dose Dexamethasone as Therapy for Relapsed Multiple Myeloma. IFM rd American Society of Hematology Annual Meeting and Exposition. December San Diego, California, USA. Abstract 821. Oral ClinicalTrials.gov. IFM Pomalidomide and dexamethasone Phase 2 myeloma. Accessed 18 October Vij R, Richardson PG, Jagannath S et al. Pomalidomide (POM) with or without low-dose dexamethasone (LoDEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Outcomes in pts refractory to lenalidomide (LEN) and/or bortezomib (BORT). ASCO Annual Meeting. June Chicago, Illinois, USA. Abstract Meetings/Abstracts?&vmview=abst_detail_view&confID=114&abstractID= Richardson PG, Siegel D, Baz R et al. Phase 1/2 multi-center, randomized, open label dose escalation study to determine the maximum tolerated dose, safety, and efficacy of pomalidomide alone or in combination with low-dose dexamethasone in patients with relapsed and refractory multiple myeloma who have received prior treatment that includes lenalidomide and bortezomib. 53rd American Society of Hematology Annual Meeting and Exposition. December Atlanta, USA. Abstract 864. Oral Richardson PG, Siegel DS, Vij R et al. Randomized, open label phase 1/2 study of pomalidomide (POM) alone or in combination with low-dose dexamethasone (LoDex) in patients (pts) with relapsed and refractory multiple myeloma who have received prior treatment that includes lenalidomide (LEN) and bortezomib (BORT): phase 2 results. 53rd American Society of Hematology Annual Meeting and Exposition. December San Diego, California, USA. Abstract Vij R, Richardson PG, Jagannath S et al. Pomalidomide with or without low-dose dexamethasone in patients with relapsed/refractory multiple myeloma: outcomes in patients refractory to lenalidomide and bortezomib. ASCO Annual Meeting June Chicago, Illinois, USA. Abstract Oral. %20Pomalidomide.pdf 10

11 45 ClinicalTrials.gov. MTD, Safety, and Efficacy of CC-4047 Alone or With Low-dose Dexamethasone in Patients With Relapsed and Refractory Multiple Myeloma. Accessed 18 October