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This phase 2 trial investigated reinduction with carfilzomib, pomalidomide, and dexamethasone (KPd) and continuous pomalidomide/dexamethasone in patients at first progression during lenalidomide maintenance. The second objective was to evaluate high-dose melphalan with autologous stem cell transplantation (HDM/ASCT) at first progression. Patients were eligible who had progressive disease according to International Myeloma Working Group (IMWG) criteria. Treatment consisted of 8 cycles carfilzomib (20/36 mg/m2), pomalidomide (4 mg) and dexamethasone. Patients without prior transplant received HDM/ASCT. Pomalidomide 4 mg w/o dexamethasone was given until progression. One hundred twelve patients were registered of whom 86 (77%) completed 8 cycles of KPd. Thirty-five (85%) eligible patients received HDM/ASCT. The median time to discontinuation of pomalidomide w/o dexamethasone was 17 months. Best response was 37% ≥ complete response, 75% ≥ very good partial response, 92% ≥ partial response, respectively. At a follow-up of 40 months median PFS was 26 and 32 months for patients who received KPd plus HDM/ASCT and 17 months for patients on KPd (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.37-1.00, P = 0.051). PFS was better after longer duration of prior lenalidomide (HR 3.56, 95% CI 1.42-8.96, P = 0.035). Median overall survival (OS) was 67 months. KPd-emerging grade 3 and 4 adverse events included hematologic (41%), cardiovascular (6%), respiratory (3%), infections (17%), and neuropathy (2%). KPd followed by continuous pomalidomide is an effective and safe triple drug regimen in second-line for patients previously exposed to bortezomib and/or refractory to lenalidomide.

Introduction and background Treatment of newly diagnosed Multiple Myeloma (MM) with Bortezomib, Imid and Dexamethasone followed by high-dose therapy and Lenalidomide maintenance has become standard with an estimated progression-free survival (PFS) of 5 years. In the EMN02 collaborative trial VCD induction (Bortezomib, Cyclophosphamide, Dexamethasone) followed by HDM/ASCT or VMP (Bortezomib, Melphalan, Prednisone), followed by VRD consolidation and Lenalidomide maintenance until progression resulted in a median PFS of 57.5 months from start of maintenance at a median follow-up of 73 months (Cavo et al, Lancet Haematol 2020; Sonneveld et al, J Clin Oncol 2021). Patients with progressive disease during Lenalidomide maintenance are defined as double refractory and have limited options for treatment. The present Phase 2 trial was designed to evaluate a salvage treatment of next generation proteasome inhibition and IMId, i.e., Carfilzomib, continuous Pomalidomide and Dexamethasone (KPd) for patients who developed a first progression after treatment in EMN02 The primary endpoint was progression-free survival (PFS). This trial is registered as NTR5349 and EudraCT 2013-003265-34. Methods Patients were eligible if they had PD according to IMWG criteria during treatment in EMN02. Treatment consisted of 8 cycles of KPd, i.e. Carfilzomib (20/36mg/m 2, days 1,2,8,9,15,16) with Pomalidomide (4 mg days 1-21) and Dexamethasone (20mg days 1,2,8,9,15,16). In patients who had not previously received HDM/ASCT, HDM(200 mg/m 2) was administered followed by autologous transplantation with stem cells previously harvested.. Patients who achieved stable disease or better were randomized to receive Pomalidomide 4mg (21/28 days) with or without Dexamethasone 40mg (days 1, 8, 15, 22) in 28 days cycles until progression. Results At the time of the final analysis 112 patients were registered of whom 1 was ineligible. 59% had received prior HDM/ASCT and 41% VMP. Prior best responses in the EMN02 trial were 39% ³CR , 81% ≥VGPR, 96% ≥PR. The median duration of maintenance in EMN02 had been 33 months and median PFS from start of maintenance 59 months. At inclusion adverse risk factors were available in 92/111 patients, ie R-ISS II or III 62%, del17p 14%, t(14;16) 1%, t(4;14) 20%, amp1q 40%. One hundred (90%) of patients had progressed during or within 6 months after discontinuation of Lenalidomide maintenance. 86 (77%) patients completed 8 cycles of KPd, of whom 69(62%) without dose reduction and received continuous Pomalidomide with Dexamethasone (38%) or without (40%). The median time to discontinuation of Pomalidomide w/o Dexamethasone was 17 months (18 vs 15 months, n.s.). In addition, thirty-three of 42 (79%) eligible patients received their first HDM plus ASCT. Time to first response was 2 months. Best response on protocol was 37% ≥CR, 75% ≥VGPR, 92% ≥PR, respectively. At a median follow-up of 40 months (range 9-66 months) median PFS from registration was 26 months. PFS from randomization was 27 months (Pom/Dex) and 18 months (Pom) respectively (HR 0.68, 95%CI 0.41-1.13, p=0.14). 70 (63%) of patients are alive and in follow-up. With Cox regression analysis predefined risk factors including high-risk cytogenetics (HR 1.36, 95%CI 0.80-2.41), prior HDM/ASCT (HR 1.25, 95%CI 0.78-2.01) and duration of prior maintenance >36 months (HR 3.56, 95%CI 1.42-8.96) were not significant. Median overall survival (OS) was 67 months. KPd-emerging grade 3 and 4 adverse events included hematologic (41%), cardiovascular (6%), respiratory (3%), infections (17%) and neuropathy (2%). There were 6 fatal SAEs not related to progression (1 patient cardiovascular). Discussion This Phase 2 trial demonstrates that KPd followed by Pomalidomide until progression is an effective and safe triple drug regimen in second-line for patients who are refractory to Lenalidomide. The benefit is observed across subgroups of risk factors. A 92% overall response and 26 months PFS is clinically relevant in this population and compares favourably to Pom/Vd. Using this regimen HDM/ASCT could be performed in the majority of patients. Acknowledgements This trial was conducted as an investigator sponsored trial by HOVON and the European Myeloma Network EMN and supported by a grant from the Dutch Cancer Foundation and by independent grants and drug supply from Amgen and BMS/Celgene. Disclosures Sonneveld: Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Zweegman: Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cavo: Novartis: Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Broyl: Sanofi: Honoraria; Janssen Pharmaceuticals: Honoraria; Celgene: Honoraria; Bristol-Meyer Squibb: Honoraria; Amgen: Honoraria. Corradini: Amgen; Takeda; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations; KiowaKirin; Incyte; Daiichi Sankyo; Janssen; F. Hoffman-La Roche; Kite; Servier: Consultancy; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Honoraria; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Consultancy; Novartis; Gilead; Celgene: Consultancy, Other: Travel and accommodations; BMS: Other: Travel and accommodation; Sanofi: Consultancy, Honoraria; Incyte: Consultancy; Novartis, Janssen, Celgene, BMS, Takeda, Gilead/Kite, Amgen, AbbVie: Other: travel and accomodations. Minnema: BMS: Consultancy; Janssen: Consultancy; Cilag: Consultancy; Celgene: Other: Travel expenses; Alnylam: Consultancy; Kite/Gilead: Consultancy. Boccadoro: Janssen and GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and AbbVie: Honoraria; Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and Mundipharma: Research Funding.

Introduction and background The treatment of patients with Multiple Myeloma (MM) with relapse or progressive disease after bortezomib, lenalidomide and high-dose therapy represents an important challenge. In the EMN02 collaborative trial newly diagnosed patients with symptomatic MM were randomized to receive VCD induction followed by HDM/ASCT or VMP, followed by a second randomization for VRD consolidation or no consolidation, followed by lenalidomide maintenance until progression (Cavo et al, ASH2017, abstract #397; Sonneveld et al, EHA2018, abstract #108). The present Phase 2 trial was designed for patients with refractory disease or first progression after inclusion in EMN02 in order to evaluate a salvage treatment with next generation proteasome inhibition and IMId, i.e., Carfilzomib, Pomalidomide and Dexamethasone. The primary endpoints were response and progression-free survival (PFS). This trial is registered at www.trialregister.nl as NTR5349 and EudraCT 2013-003265-34. Methods Patients who were included received four 28-days re-induction cycles of KPd, i.e. Carfilzomib (20/36mg/m2, days 1,2,8,9,15,16) with Pomalidomide (4 mg days 1-21) and Dexamethasone (20mg days 1,2,8,9,15,16). In patients who had not previously received HDM/ASCT, HDM(200 mg/m2) was administered followed by autologous stem cell transplantation with stem cells harvested during after induction therapy in the EMN02 trial. Consolidation consisted of 4 additional cycles of KPd, identical to the induction cycles. Patients with stable disease or better received Pomalidomide 4mg w/o Dexamethasone in 28 days cycles until progression. Results At the time of this first planned interim analysis 82 patients were registered and this analysis was performed in the first 60 patients. 48% were randomized prior HDM/ASCT and 42% VMP, and 10% were not randomized. Prior best responses in the EMN02 trial were 35% CR/sCR , 75% ≥VGPR, 97% ≥PR. The median follow-up from inclusion in EMN02 was 43 months (range 21 - 62 months). In 44 patients cytogenetic risk were known, 15 (34%) of them had high-risk FISH (del17p, t(14;16) or t(4;14)). 57 fifty-seven (95%) of patients had progressed during lenalidomide maintenance, 3 patient's data are not yet available. In the present trial 38 (63%) of patients achieved normal completion of treatment according to of the protocol. Twenty patients received their first HDM plus ASCT. Median time on therapy was 14 months. Full dose re-induction treatment according to protocol could be administered in 68% (for Carfilzomib) and 64% (for Pomalidomide) of patients respectively, while for consolidation this was 62% for both Carfilzomib and Best response on protocol was 31% CR/sCR, 65% ≥VGPR, 87% ≥PR, respectively, with no difference according to response on initial treatments. Median time to response (≥PR) was 2 months. At a median follow-up of 16.3 months (range 3 - 32 months) median PFS was 18 months with better outcome in standard risk cytogenetics (HR=0.27 (0.09, 0.83) 95% CIs vs NR) and in patients with prior VMP treatment (HR=0.49 (0.21, 1.16) 95% CIs vs NR). 48 (80%) of patients are alive and in follow-up. KPd-emerging non-hematologic grade 3 and 4 adverse events included cardiovascular (5%), respiratory (5%), infections (20%) and neuropathy (3%). There were 3 fatal SAEs not related to progression (1 patient cardiac failure, 2 patients pneumonia). KPd-emerging hematological toxicity grade 3 and 4 occurred in 30% of patients. Discussion This Phase 2 clinical trial demonstrates that KPd is a feasible, effective and safe triple drug regimen in RRMM patients who have been previously treated and/or are refractory to bortezomib and refractory to lenalidomide. A 87% overall response rate including 31% CR/sCR is clinically relevant in this population. Since median OS has not been reached, longer follow-up is needed. Acknowledgments This trial was conducted as an investigator sponsored trial in EMN and supported by independent grants and drug supply from Amgen and Celgene. Disclosures Sonneveld: BMS: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cavo:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Corradini:Roche: Honoraria, Other: Advisory Board & Lecturer; Gilead: Honoraria, Other: Advisory Board & Lecturer; Takeda: Honoraria, Other: Advisory Board & Lecturer; Novartis: Honoraria, Other: Advisory Board & Lecturer; Sandoz: Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board & Lecturer; Abbvie: Honoraria, Other: Advisory Board & Lecturer; Janssen: Honoraria, Other: Lecturer; Sanofi: Honoraria, Other: Advisory Board & Lecturer; Celgene: Honoraria, Other: Advisory Board & Lecturer. Patriarca:Janssen: Other: Advisory role; Celgene: Other: Advisory Role; Travel, accommodations, expenses; Jazz: Other: Travel, accommodations, expenses; MSD Italy: Other: Advisory Role; Medac: Other: Travel, accommodations, expenses. Minnema:Celgene: Consultancy, Research Funding; Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Servier: Consultancy. Costa:celgene: Employment. Iskander:amgen: Employment. Boccadoro:Mundipharma: Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding.