Pomalidomide therapy in relapsed/refractory myeloma: A UK multi-centre experience Neil Rabin Consultant Haematologist on behalf of Dr Nicola Maciocia University College London Hospitals, UK 4th November 2015 Maciocia N, Sharpley F, Belsham E, Schey S, Benjamin R, Streetly M, Jenner M, Ramasamy K, Yong KL, Rabin N. IMW 2015

Poor outcome for patients with Relapsed Refractory Myeloma Kumar et al, Leukemia 2011

Background Pomalidomide + Dexamethasone licensed in Europe August 2013 for patients with relapsed/refractory myeloma, who have received at least two prior therapies (lenalidomide/bortezomib) and have progressed on their last therapy. San Miguel J, et al. Lancet Oncol. 2013.

Pomalidomide treatment for patients with RRMM Medain PFS 4.0 vs 1.9 mo Medain PFS 12.7 vs 8.1 mo San Miguel et al, Lancet Oncology 2013

Background Pomalidomide available in England from December 2013 via National Cancer Drugs Fund: Adequate treatment with bortezomib, lenalidomide, alkylator Refractory to last line of therapy Failed treatment with bortezomib OR lenalidomide (different to MM-003 trial) Performance Status 0-2 No resistance to high dose dexamethasone No peripheral neuropathy of grade 2 or more

Aim To assess the real-world clinical efficacy of POMA-DEX within its licensed indication in a retrospective analysis of patients treated at 5 UK centres

Oxford University Hospitals NHS Foundation Trust University College London Hospitals NHS Foundation Trust Guy’s and St.Thomas’ NHS Foundation Trust King’s College London Foundation NHS Trust University Hospital Southampton NHS Foundation Trust

Methods All patients who received Pomalidomide + Dexamethasone (until Feb 2015, data updated for this meeting) Data collected retrospectively using a pre-defined proforma Prior myeloma therapy, and whether refractory to last Rx Relapsed or refractory to Lenalidomide or Bortezomib Measurable disease (serum/urine paraprotein, SFLC analysis) Renal function Cytogenetic (FISH) data International Staging System Response to Pomalidomide Toxicities – non haematological / haematological to Pomalidomide

Methods To be included in response analyses patients had to have IMWG measurable disease, and have received at least one cycle of Pomalidomide and Dexamethasone Response assessed using IMWG criteria High risk disease defined as per IMWG (ISS II/III and t(4;14) or 17p13del).

Results 79 patients identified from August 2013 onwards. Followed until Feb 2015 (IMW abstract, updated for this meeting) 62 (78.5%) suitable to be included in response analyses. All patients received Pomalidomide (2-4mg D1-21) plus Dexamethasone. 30/79 (38%) received another agent(s): clarithromycin (23); cyclophosphamide (9); carfilzomib (1); bortezomib(1). In 15 (50%) the third agent was added from start of therapy. In 15 (50%) it was added midway through treatment.

Characteristic Number (%) n = 79 Median age (years) 67 (40-89) Sex Male 45(57) Female 34(43) Isotype IgG 43(54.4) IgA 19(24) Light chain only 14(17.7) Non-secretory 1(1.3) Bence Jones IgD Time from diagnosis (yrs) 4.86 (0.52-18.03) CrCl < 45ml/min 14/71 (20) IMWG high risk 11/40 (27.5) No. of prior lines therapy 4 (1-8)

Previous treatments Thalidomide 66 (83.5) Lenalidomide 79 (100) Bortezomib 78 (98.7) ASCT 48 (60.8) Refractory to bortezomib 19/76 (25) Relapsed and refractory to bortezomib 39/76 (51.3) Intolerant of bortezomib 7/78 (8.9) Refractory to lenalidomide/thalidomide 76 (96.2) Double refractory 58 (73.4) Refractory to last therapy 73 (92.4)

Results Median FU was 13.7 months (0.9-42.8). Median no of cycles was 4 (range 1-32). Median dose Pomalidomide 4 mg (range 2-4). In those with starting GFR <45ml/min, 50% (7/14) received < 4mg Pomalidomide.

Response Rates ORR (≥ PR) was 53%, VGPR 5%, and >/= SD 94%. UK retrospective data MM-003 Number (%) n = 62 No (%) n=302 Overall response rate 33(53) 95 (31) Complete response or stringent Complete response 0 (0) 3 (1) Very good partial response 3 (4.7) 14 (5) Partial response 30 (48.4) 78 (26) Stable disease 25 (40) 129 (43) Progressive disease 4(6.25) 29 (10)

Survival

Results PFS 4.8 mo, OS 16.3 mo. Median duration of response (DoR) 3.9 mo. 25/79 (32%) patients received further therapy Median time to next treatment (TNT) 6.2 mo (0.3 – 18.5 mo.).

PFS OS RENAL FUNCTION CYTOGENETIC RISK DOUBLE VS TRIPLE THERAPY

Toxicities Grade 3/4 non-haem toxicities occurred in 27/79 (34%) patients: Non haem toxicities (grade 3/4) No of episodes (%) n = 79 Lower respiratory tract infection 15 (19) Neutropenic sepsis 9 (11.4) Acute kidney injury 3 (3.8) Epistaxis 1( 1.3) CVA 1 (1.3) Fatigue Hyperglycaemia ALT rise Nausea Constipation Venous thrombosis Strangulated hernia Chronic sinusitis

Toxicities Grade 3/4 haematological toxicities Neutropenia 28 patients (35%) Thrombocytopenia in 17 patients (22%) Anaemia in 8 patients (10%). 54 patients came off treatment during study period. 11/54 (20%) stopped due to toxicities 41/54 (76%) stopped due to PD One patient developed lung ca, one death of unknown cause

Conclusion POMA-DEX is effective in relapsed/refractory myeloma, with outcomes comparable to results from the phase 3 NIMBUS study (MM-003). Improved OS compared to published data (16.3 mo vs 12.7 mo), equivalent PFS (4.8 mo vs 4.0 mo) Reduced renal function and adverse genetics do not appear to influence outcomes. The addition of a third agent should be explored prospectively in ongoing clinical trials. Our rates of infection slightly higher than published data but toxicity still acceptable in this heavily pre-treated population.

Acknowledgements UK Myeloma Forum University College London Hospitals NHS Foundation Trust Nicola Maciocia, Andrew Melville, Simon Cheesman, Rakesh Popat, Shirley D’Sa, Ali Rismani, Kwee Yong, Neil Rabin Guy’s and St.Thomas’ NHS Foundation Trust Matthew Streetly King’s College London Foundation NHS Trust Reuben Benjamin, Steve Schey, Hanna Renshaw Oxford University Hospitals NHS Foundation Trust Karthik Ramasamy, Faye Sharpley University Hospital Southampton NHS Foundation Trust Matthew Jenner, Edward Belshom UK Myeloma Forum