Bortezomib (Velcade), Thalidomide, Dexamethasone and Panobinostat (VTD-P) Is a Safe, Well Tolerated and Efficacious Regimen for Patients with Relapsed Multiple Myeloma: Preliminary Results of the Muk-Six Trial
Authors: Popat Rakesh , Brown Sarah R , Flanagan Louise M , Hall Andrew , Kishore Bhuvan , Streetly Matthew , Oakervee Heather E , Hallam Simon L. , Smith Matthew , Yong Kwee L , Cook Gordon , Cavenagh James D. 
Published: October 2019

Abstract
Introduction: VTD is an effective regimen for patients with multiple myeloma and forms a backbone for the addition of novel agents. The MUK-six trial aimed to improve the efficacy by adding Panobinostat, a now FDA approved pan-histone deacetylase inhibitor that demonstrated synergy with proteasome inhibition and immunomodulatory agents in pre-clinical models. We have previously reported the phase 1 dose finding part which determined the MTD of panobinostat with VTD to be 20mg. Here we present the efficacy results from the recommended dose (RD) expansion phase (primary end point) and safety, tolerability data for all patients during the induction phase of the study.
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.
Acknowledgments: 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.