Efficacy and safety of oral panobinostat plus subcutaneous bortezomib and oral dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma (PANORAMA 3): an open-label, randomised, phase 2 study

Laubach, Jacob P.; Schjesvold, Fredrik; Mariz, Mário; Dimopoulos, Meletios A.; Lech-Maranda, Ewa; Špıčka, Ivan; Hungria, Vânia; Shelekhova, Tatiana; Abdo, André; Jacobasch, Lutz; Polprasert, Chantana; Hájek, Roman; Illés, Árpád; Wróbel, Tomasz; Sureda, Anna; Beksaç, Meral; Gonçalves, Iara; Bladé, Joan; Rajkumar, S. Vincent; Chari, Ajai; Lonial, Sagar; Spencer, Andrew; Maison‐Blanche, Pierre; Moreau, Philippe; Miguel, Jesús F. San; Richardson, Paul G.

doi:10.1016/s1470-2045(20)30680-x

Cited by 50 publications

(49 citation statements)

References 25 publications

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“…The class I specific HDACi, romidepsin, along with the pan-HDACi dacinostat (LAQ824), belinostat, vorinostat, and panobinostat showed clearly anti-myeloma cells in Ivyspring International Publisher vitro and in vivo [7,8]. Moreover, HDACi panobinostat, in combination with bortezomib and dexamethasone, has been approved as the first HDAC inhibitor to treat MM [9,10].…”

Section: Introductionmentioning

confidence: 99%

Chidamide, a subtype-selective histone deacetylase inhibitor, enhances Bortezomib effects in multiple myeloma therapy

He¹,

Jiang²,

Zhang³

et al. 2021

J. Cancer

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Drug resistance is the major cause for disease relapse and patient death in multiple myeloma (MM). It is an urgent need to develop new therapies to overcome drug resistance in MM. Chidamide (CHI), a novel oral HDAC inhibitor targeting HDAC1, 2, 3 and 10, has shown potential therapeutic effect in MM. In this study, we determined that CHI exhibited significant anti-tumor effect on MM cells both in vitro and in vivo, which was positively correlated with the expression of HDAC1. Meanwhile, CHI enhanced Bortezomib (BTZ) effects synergistically in MM cells and a combination of CHI with BTZ induced myeloma cell apoptosis and G0/G1 arrest in vitro and in vivo. Mechanistically, the synergistic anti-tumor effect of CHI and BTZ was related with the increased production of reactive oxygen species (ROS) dependent DNA damage and the changes of cell apoptosis and cycle pathways. Our data indicate that CHI may be a suitable drug to sensitize BTZ in MM cells, which provides novel insight into the therapy for MM patients.

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Section: Introductionmentioning

confidence: 99%

Chidamide, a subtype-selective histone deacetylase inhibitor, enhances Bortezomib effects in multiple myeloma therapy

He¹,

Jiang²,

Zhang³

et al. 2021

J. Cancer

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“…The optimal dose and schedule of pano-Vd was confirmed in the randomized phase 3 PANORAMA 3 trial as 20 mg thrice weekly; DOR with this regimen was 22.6 months and tolerability was improved with subcutaneous administration of bortezomib with only 11.5% of patients in the 20 mg TIW dosing group reporting grade 3/4 diarrhea compared with intravenous delivery of bortezomib, as was standard practice at the time of previous clinical trials. 16 Broad-spectrum HDACis also enhance the anti-MM activity of IMiDs, such as lenalidomide, by suppressing diverse oncogenic transcriptional programs 10 , including the interferon regulatory factor-4/MYC axis 17 . In a phase 2 study of patients with RRMM, panobinostat plus lenalidomide and dexamethasone (pano-Rd) demonstrated an encouraging ORR (41%) and median PFS (7.1 months) in patients with high-risk, lenalidomide-refractory (81%), and/or bortezomib-refractory (52%) MM, suggesting that panobinostat is also able to overcome resistance to IMiDs.…”

Section: Introductionmentioning

confidence: 99%

Phase 1 open-label study of panobinostat, lenalidomide, bortezomib + dexamethasone in relapsed and relapsed/refractory multiple myeloma

et al. 2021

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Additional therapeutic options are needed for relapsed and refractory multiple myeloma (RRMM). We present data from a phase 1b, open-label, dose-escalation study (NCT01965353) of 20 patients with RRMM (median age: 63 years [range: 50–77]) and a median of four prior regimens (range: 2–14); 85% had refractory disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib [50%]). Patients received a median of six cycles (range: 1–74) of panobinostat (10 or 15 mg), lenalidomide 15 mg, bortezomib 1 mg/m2, and dexamethasone 20 mg (pano-RVd). Median follow-up was ~14 months. Six dose-limiting toxicities were reported (mostly hematological); maximum tolerated dose of panobinostat (primary endpoint) was 10 mg. Most common adverse events (AEs) were diarrhea (60%) and peripheral neuropathy (60%); all grade 1/2. Grade 3/4 AEs occurred in 80% of patients and included decreased neutrophil (45%), platelet (25%) and white blood cell (25%) counts, anemia (25%) and hypophosphatemia (25%). No treatment-related discontinuations or mortality occurred. In evaluable patients (n = 18), overall response rate was 44%, and clinical benefit rate was 61%. Median duration of response was 9.2 months; progression-free survival was 7.4 months; overall survival was not reached. Pano-RVd proved generally well-tolerated and demonstrated potential to overcome lenalidomide and/or bortezomib resistance.

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“…However, serious adverse events were reported in 60% of patients in the panobinostat group compared to 42% in the placebo group. PANORAMA-3, a phase II study examining three different dosing regimens of panobinostat with subcutaneous (SC) bortezomib and dexamethasone, has demonstrated a more favourable safety profile, suggesting that SC bortezomib improves the tolerability of the regimen [ 129 ]. The greatest ORR was observed in the three-time weekly group (62.2%), at the expense of increased adverse events.…”

Section: Novel Therapiesmentioning

confidence: 99%

Targeted Therapies for Multiple Myeloma

Leow

Löw

2021

JPM

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Multiple myeloma continues to be a challenging disorder to treat despite improved therapies and the widespread use of proteasome inhibitors and immunomodulatory drugs. Although patient outcomes have improved, the disease continues to invariably relapse, and in the majority of cases, a cure remains elusive. In the last decade, there has been an explosion of novel drugs targeting cellular proteins essential for malignant plasma cell proliferation and survival. In this review, we focus on novel druggable targets leading to the development of monoclonal antibodies and cellular therapies against surface antigens (CD38, CD47, CD138, BCMA, SLAMF7, GPRC5D, FcRH5), inhibitors of epigenetic regulators such as histone deacetylase (HDAC), and agents targeting anti-apoptotic (BCL-2), ribosomal (eEF1A2) and nuclear export (XPO1) proteins.

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Efficacy and safety of oral panobinostat plus subcutaneous bortezomib and oral dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma (PANORAMA 3): an open-label, randomised, phase 2 study

Cited by 50 publications

References 25 publications

Chidamide, a subtype-selective histone deacetylase inhibitor, enhances Bortezomib effects in multiple myeloma therapy

Chidamide, a subtype-selective histone deacetylase inhibitor, enhances Bortezomib effects in multiple myeloma therapy

Phase 1 open-label study of panobinostat, lenalidomide, bortezomib + dexamethasone in relapsed and relapsed/refractory multiple myeloma

Targeted Therapies for Multiple Myeloma

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