Pomalidomide therapy in relapsed/refractory myeloma: A UK multi-centre experience

Neil RabinConsultant Haematologist

on behalf of Dr Nicola MaciociaUniversity 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

San Miguel et al, Lancet Oncology 2013

Medain PFS 4.0 vs 1.9 mo Medain PFS 12.7 vs 8.1 mo

Background• Pomalidomide available in England from December 2013

via National Cancer Drugs Fund:

o Adequate treatment with bortezomib, lenalidomide, alkylatoro Refractory to last line of therapyo Failed treatment with bortezomib OR lenalidomide (different to MM-003

trial)o Performance Status 0-2o No resistance to high dose dexamethasoneo 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

University College London Hospitals NHS Foundation Trust

Guy’s and St.Thomas’ NHS Foundation Trust

King’s College London Foundation NHS Trust

Oxford University Hospitals NHS Foundation 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 o Prior myeloma therapy, and whether refractory to last Rxo Relapsed or refractory to Lenalidomide or Bortezomibo Measurable disease (serum/urine paraprotein, SFLC analysis)o Renal functiono Cytogenetic (FISH) datao International Staging Systemo Response to Pomalidomideo 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)

SexMale 45(57)Female 34(43)

IsotypeIgG 43(54.4)IgA 19(24)Light chain only 14(17.7)Non-secretory 1(1.3)Bence Jones 1(1.3)IgD 1(1.3)

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-003Number (%) 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

RENALFUNCTION

CYTOGENETICRISK

DOUBLE VSTRIPLE 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 1 (1.3)Hyperglycaemia 1 (1.3)ALT rise 1 (1.3)Nausea 1 (1.3)Constipation 1 (1.3)Venous thrombosis 1 (1.3)Strangulated hernia 1 (1.3)Chronic sinusitis 1 (1.3)

Toxicities• Grade 3/4 haematological toxicities

o Neutropenia 28 patients (35%)o Thrombocytopenia in 17 patients (22%)o Anaemia in 8 patients (10%).

• 54 patients came off treatment during study period. o 11/54 (20%) stopped due to toxicitieso 41/54 (76%) stopped due to PDo 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.

AcknowledgementsUniversity College London Hospitals NHS Foundation Trust

o Nicola Maciocia, Andrew Melville, Simon Cheesman, Rakesh Popat, Shirley D’Sa, Ali Rismani, Kwee Yong, Neil Rabin

Guy’s and St.Thomas’ NHS Foundation Trusto Matthew Streetly

King’s College London Foundation NHS Trusto Reuben Benjamin, Steve Schey, Hanna Renshaw

Oxford University Hospitals NHS Foundation Trusto Karthik Ramasamy, Faye Sharpley

University Hospital Southampton NHS Foundation Trusto Matthew Jenner, Edward Belshom

UK Myeloma Forum