Program: Oral and Poster Abstracts
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster I
Methods: MUK-six was a multi-centre UK Phase I/IIa trial for patients with relapsed and relapsed/ refractory myeloma who had received between 1 and 4 prior lines of therapy. Subjects received VTD-P (bortezomib 1.3mg/2sc days 1 and 8, thalidomide 100mg daily (50mg if pre-existing neuropathy), dexamethasone 20mg days 1, 2, 8, 9 and panobinostat 20mg days 1, 3, 5, 8, 10, 12) every 3 weeks for up to 16 cycles (induction) followed by 1 year of panobinostat maintenance. Those planned for autologous stem cell transplantation (ASCT) received a minimum of 6 cycles of VTD-P. All patients treated with VTD-P received venous thrombosis prophylaxis as per institutional practice. Responses were assessed using modified IWG uniform response criteria and toxicity graded by CTCAE V4.0.
Results: 46 patients were treated at the RD and were of a median age of 60 years (41-76). 80.4% had received one prior line of therapy (range 1-4), 71.7% had prior bortezomib and 39.2% prior thalidomide. Most patients were ISS 1 (60.9%), 45.7% had adverse FISH lesions at baseline, 8.7% had 17p deletion. 6 patients remain on treatment at the time of this abstract. 51.3% of patients came off study to proceed to ASCT.
The overall response rate (≥PR) for patients receiving at least one dose of panobinostat was 91.3%, ≥VGPR 45.7% (CR 6.5%, VGPR 39.1%, PR 45.7%). The ≥VGPR rate for those with standard FISH was 52.1% vs 42.9% for adverse FISH. Those treated at first relapse had higher overall responses to those treated later in their disease course (≥PR 94.6% vs 77.8%). Responses were independent of prior bortezomib exposure (≥PR 90.9%, ≥VGPR 45.5% vs PR≥92.3%, ≥VGPR 46.2%).
Treatment was generally well tolerated, with a mean panobinostat dose of 17.4mg (86.8% of the RD) delivered across all cycles. 32.1% of those starting at 50mg thalidomide stopped the drug due to toxicity, and 52.6% of those starting at 100mg required dose reductions/ stopping. 46 serious adverse events were reported in 27 patients which were mainly infections (17/46, 37.0%). The commonest grade 3-4 toxicities reported for all 57 patients were: neutropenia (14, 24.6%), hypophosphatemia (11, 19.3%), thrombocytopenia (8, 14.1%) and diarrhoea (6, 10.5%). Of note there were no reports of ≥ grade 3 neuropathy. The most frequent grade 1-2 toxicities were fatigue (50, 87.7%), neuropathy (43, 75.5%), constipation (35, 61.4%), diarrhoea (35, 61.4%), bone pain (33, 57.9%), and nausea (27, 47.4%). 2 patients withdrew consent due to toxicity.
Conclusions: This study demonstrated that panobinostat can be safely given in combination with VTD and appears highly effective with a response rate of 91.3%, ≥VGPR 45.6% despite 72% having previous bortezomib. This regimen was well tolerated, in particular the incidence of diarrhoea, neuropathy and asthenia/ fatigue appeared lower than that observed in the PANORAMA 2 trial (San Miguel et al.,2014). It is possible that the incorporation of a low intensity subcutaneous bortezomib schedule (2 doses every 3 weeks) contributed to the lesser toxicity.
Acknowledgements: This trial was part of the Myeloma UK Clinical Trial Network, ISRCTN: 59395590.
Disclosures: Popat: Janssen: Honoraria . Off Label Use: Panobinostat: use outside of FDA licence, not yet EU approved. Kishore: Celgene: Other: Conference Sponsorship ; Jazz pharma: Other: Conference Sponsorship . Oakervee: Janssen: Consultancy , Honoraria ; Celgene: Consultancy , Honoraria ; Novartis: Consultancy , Honoraria . Yong: Janssen: Honoraria ; Autolous: Consultancy ; Amgen: Honoraria ; BMS: Honoraria ; Takeda: Honoraria ; Novartis: Consultancy . Cook: Sanofi: Consultancy , Honoraria , Speakers Bureau ; Jazz Pharma: Consultancy , Honoraria , Speakers Bureau ; Amgen: Consultancy , Honoraria , Speakers Bureau ; Chugai: Consultancy , Honoraria , Speakers Bureau ; Takeda: Consultancy , Honoraria , Speakers Bureau ; Janssen: Consultancy , Honoraria , Speakers Bureau ; Bristol-Myers Squibb: Consultancy , Honoraria , Speakers Bureau ; Celgene: Consultancy , Honoraria , Research Funding , Speakers Bureau . Cavenagh: Novartis: Honoraria , Membership on an entity’s Board of Directors or advisory committees , Speakers Bureau ; Janssen: Honoraria , Membership on an entity’s Board of Directors or advisory committees , Speakers Bureau ; Celgene: Honoraria , Membership on an entity’s Board of Directors or advisory committees , Speakers Bureau ; Amgen: Honoraria , Membership on an entity’s Board of Directors or advisory committees , Speakers Bureau .
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