Subgroup Analysis: Efficacy and Safety of Panobinostat in Combination with SC Bortezomib and Oral Dexamethasone in Multiple Myeloma Patients with Lenalidomide-Refractory Disease
Authors: Richter Joshua , Laubach Jacob P. , Stricker Steve , Schjesvold Fredrik H. , Cohan David , Sureda Anna , Lech-Marańda Ewa , Beksac Meral , Hungria Vania , Dimopoulos Meletios A. , Chari Ajai , Richardson Paul G. , Moreau Philippe 
Published: November 2021

Abstract

Background: Panobinostat (Pano), a pan-histone deacetylase inhibitor, is approved for the treatment of relapsed or relapsed/refractory multiple myeloma (RRMM) in combination with bortezomib (BTZ) and dexamethasone (d) (FVd) in patients who received ≥2 prior lines of therapy, including BTZ and an IMiD. The randomized phase 2 PANORAMA 3 study was conducted to optimize FVd dosing by comparing three different regimens and by incorporating subcutaneous (SC) BTZ. This study demonstrated favorable outcomes, more durable responses, and a favorable AE profile compared to those seen in the earlier PANORAMA 1. Over the past decade as lenalidomide (LEN) has become a standard of care in the up-front and early relapse setting, it is highly likely that patients will become LEN-refractory within their first few lines of treatment. Here we present data indicating that response outcomes and AEs in the subset of PANORAMA 3 patients refractory to lenalidomide (LEN) were equivalent to or perhaps slightly improved over those of the general PANORAMA 3 trial population.
Aims: To evaluate the overall response rate (ORR; IMWG 2011 criteria) after up to 8 treatment cycles by Independent Review Committee assessment. Secondary endpoints included in this abstract are duration of response (DOR) and safety.
Methods: PANORAMA 3 (NCT02654990) was a randomized, open-label, international multicenter phase 2 study. Eligible patients were ≥18 years old with 1-4 prior lines of therapy, including an IMiD. Patients primarily refractory to BTZ were excluded. Patients were randomized 1:1:1 to Pano 20 mg TIW (d 1, 3, 5, 8, 10, 12), Pano 20 mg BIW (d 1, 4, 8, 11) or Pano 10 mg TIW (d 1, 3, 5, 8, 10, 12), all administered in 21-day cycles. For cycles 1-4, patients ≤75 years received BTZ 1.3 mg/m2 BIW and then decreased frequency to weekly (QW) from cycle 5 onwards; patients &gt;75 years received BTZ 1.3 mg/m2 QW throughout the course of treatment. Dexamethasone was given day of and day after BTZ at a dose of 20 mg with an option to reduce to 10 mg for patients &gt;75 years.
Results: In total, 248 patients were randomized, and 241 patients received treatment. Of those, 43 patients were refractory to LEN at the time of initiation of study treatment. For all study patients across the 3 arms, the ORR after 8 cycles was 59.3%. Across the 3 arms, the ORR for LEN-refractory patients was 53.5%. This decrease in ORR relative to the general population was driven primarily by an inferior ORR in the Pano 10 mg TIW arm, as LEN-refractory patients in the Pano 20 mg TIW and 20 mg BIW arms had numerically higher ORRs (64.7% and 70% respectively; table 1) than corresponding patients in the general study population. Duration of response could not be estimated for patients in the Pano 20 mg TIW arm, but for those in the 20 mg BIW arm it was 5 months, as compared to 12 months for the overall 20mg BIW cohort -- a difference likely explained by a higher degree of pre-treatment in the LEN-refractory subset. Across the general study population, treatment-related Grade ≥3 AEs (table 2) were reported in 78%, 72%, and 54% of patients in the 20 TIW, 20 BIW and 10 TIW arms respectively; and discontinuations due to AEs occurred in 29.5%, 28%, and 15% of patients respectively. By contrast, in LEN-refractory patients, Grade ≥3 AEs were reported in 94%, 80%, and 73% of patients in the 20 TIW, 20 BIW, and 10 TIW arms respectively; but discontinuations due to AEs occurred in only 11.8%, 20%, and 20% of patients respectively.
Summary/Conclusion: In PANORAMA 3, SC BTZ improved the tolerability of FVd relative to that seen with IV BTZ in PANORAMA 1. Across the entire patient population, the most durable and deepest responses were observed in the 20 mg TIW arm, which yielded a median DOR of 22 months. Patients who were LEN-refractory had similar overall response rates to patients in the general study population. Response rates by arm were also similar between the LEN-refractory and general population patients, except in the 10 mg TIW arm, wherein the LEN-refractory patients appeared to have a lower overall response rate, perhaps due to biologically more virulent disease (in the context of suboptimal dosing). The small number of LEN-refractory patients makes interpretation of AE data challenging, but Grade ≥3 diarrhea, an AE of special interest from PANORAMA 1, was notably lower in LEN-refractory patients at the 20 mg TIW dose. In summary, FVd appears to be an efficacious and tolerable treatment option for patients with LEN-refractory multiple myeloma.
Figure 1 Figure 1.

Disclosures
Richter: X4 Pharmaceuticals: Consultancy; Sanofi: Consultancy; Antengene: Consultancy; Karyopharm: Consultancy; BMS: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Adaptive Biotechnologies: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau; Oncopeptides: Consultancy; Adaptive Biotechnologies: Consultancy; Secura Bio: Consultancy; Astra Zeneca: Consultancy. Stricker: Secura Bio: Current Employment. Schjesvold: Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Nordics Nanovector: Current holder of individual stocks in a privately-held company; GSK: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyliteDX: Honoraria; Bayer: Consultancy; AbbVie: Honoraria; Adaptive Biotechnologies: Consultancy; Schain: Honoraria. Cohan: Secura Bio: Current Employment. Sureda: MSD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: 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, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Bluebird: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau. Lech-Marańda: AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees. Beksac: Amgen,Celgene,Janssen,Takeda,Oncopeptides,Sanofi: Consultancy, Speakers Bureau. Hungria: Takeda: Honoraria; Sanofi: Honoraria, Other: Support for attending meetings/travel ; Amgen, BMS, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings/travel ; Abbvie: Honoraria. Dimopoulos: Janssen: Honoraria; Beigene: Honoraria; Takeda: Honoraria; BMS: Honoraria; Amgen: Honoraria. Chari: Oncopeptides: Consultancy; Sanofi Genzyme: Consultancy; Karyopharm: Consultancy; Takeda Pharmaceutical Company: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy, Research Funding; Antegene: Consultancy; Glaxosmithkline: Consultancy; Secura Bio: Consultancy. Richardson: Karyopharm: Consultancy, Research Funding; AstraZeneca: Consultancy; Protocol Intelligence: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Secura Bio: Consultancy; Sanofi: Consultancy; Regeneron: Consultancy; Takeda: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Moreau: Celgene BMS: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria.