Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial

Miguel, Jesús F. San; Hungria, Vânia; Yoon, Sung‐Soo; Beksaç, Meral; Dimopoulos, Meletios Α.; Elghandour, Ashraf; Jędrzejczak, Wiesław Wiktor; Günther, Andreas; Nakorn, Thanyaphong Na; Siritanaratkul, Noppadol; Schlossman, Robert; Hou, Jian; Moreau, Philippe; Lonial, Sagar; Lee, Jae H; Einsele, Hermann; Sopala, Monika; Bengoudifa, Bourras-Rezki; Binlich, Florence; Richardson, Paul G.

doi:10.1016/s2352-3026(16)30147-8

Cited by 124 publications

(80 citation statements)

References 26 publications

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“…New therapies, including proteasome inhibitors (PIs; bortezomib [BORT], carfilzomib [CAR], and ixazomib), immunomodulatory drugs (IMiDs; thalidomide, lenalidomide [LEN], and pomalidomide [POM]), and histone deacetylase inhibitors (panobinostat and vorinostat), have been used in various combinations as both first-and later-line treatments, resulting in improved response rates and longer progression-free survival (PFS) compared with traditional therapies. [1][2][3][4][5][6][7][8] More recently, 2 first-inclass monoclonal antibodies (mAbs) with novel mechanisms of action (daratumumab [DARA] 9,10 and elotuzumab [ELO] 11,12 ) have been approved for use in the treatment of patients with relapsed/refractory multiple myeloma (RRMM) and have generated considerable enthusiasm for the use of immunotherapies for this malignancy.…”

Section: Introductionmentioning

confidence: 99%

A phase 1b study of isatuximab plus lenalidomide and dexamethasone for relapsed/refractory multiple myeloma

Martin

Baz

Benson

et al. 2017

Blood

152

138

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Key Points• Isatuximab (anti-CD38 monoclonal antibody) given with lenalidomide/ dexamethasone is active in heavily pretreated relapsed/ refractory myeloma • Overall, the safety profile of this combination is similar to the characteristic safety profiles of the individual agents. remained on treatment at data cutoff. Isatuximab-lenalidomide-dexamethasone was generally well tolerated with only 1 dose-limiting toxicity reported (grade 3 pneumonia at 20 mg/kg QW/ Q2W); the MTD was not reached. The most common isatuximab-related adverse events were infusion-associated reactions (IARs) (56%), which were grade 1/2 in 84% of patients who had an IAR and predominantly occurred during the first infusion. In the efficacy-evaluable population, the overall response rate (ORR) was 56% (29/52) and was similar between the 10 mg/kg Q2W and 10 and 20 mg/kg QW/Q2W cohorts. The ORR was 52% in 42 evaluable lenalidomide-refractory patients. Overall median progression-free survival was 8.5 months. Isatuximab exposure increased in a greater than dose-proportional manner; isatuximab and lenalidomide pharmacokinetic parameters appeared independent. These data suggest that isatuximab combined with lenalidomide and dexamethasone is active and tolerated in heavily pretreated patients with RRMM. This trial was registered at www.clinicaltrials.gov as #NCT01749969. (Blood. 2017;129(25):3294-3303)

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Section: Introductionmentioning

confidence: 99%

A phase 1b study of isatuximab plus lenalidomide and dexamethasone for relapsed/refractory multiple myeloma

Martin

Baz

Benson

et al. 2017

Blood

152

138

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“…The first of these trials showed that, in first relapse after HDT/ASCT, bortezomibthalidomide-dexamethasone (VTD) was superior to TD in terms of response rate, PFS, and OS. 56 More recently, 7 large randomized trials compared triplets with the addition of 1 new agent to 1 of the backbone combinations, either RD [57][58][59][60] or VD [61][62][63][64] ; these trials are summarized in Table 4. The triplet was always superior to the standard doublet in terms of response rate and PFS.…”

Section: General Considerations Available Therapiesmentioning

confidence: 99%

“…Pomalidomide has been developed mostly in heavily pretreated patients 40 and panobinostat is more active in patients with 2 prior lines or more. 62 Carfilzomib, ixazomib, and daratumumab combinations are superior whatever the number of lines (1-3). 59,68,69 c The prior use and results of IMIDs and PIs are becoming important issues.…”

Section: 55mentioning

confidence: 99%

How I treat first relapse of myeloma

Harousseau

Attal

2017

Blood

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The standard treatment of relapsed multiple myeloma has been either lenalidomide-dexamethasone (RD) or bortezomib-dexamethasone (VD) but it is changing rapidly for 2 reasons. First, lenalidomide and bortezomib are currently used in frontline treatment and many patients become resistant to these agents early in the course of their disease. Second, 6 second-line new agents have been recently developed and offer new possibilities (pomalidomide, carfilzomib and ixazomib, panobinostat, elotuzumab, and daratumumab). Recent randomized studies have shown that triple combinations adding 1 of these new agents (except pomalidomide) to the RD or VD regimens were superior to the double combinations in terms of response rate and progression-free survival (PFS). Their place in the treatment of first relapse is discussed here. Among these agents, daratumumab is clearly a breakthrough and daratumumab-based combinations might become the preferred option in the near future. However, all of these drugs are expensive and are not available or affordable in all countries. We propose a decision algorithm for first relapse in fit patients with the objective of achieving the best PFS. The choice of salvage regimen is based on lenalidomide/bortezomib resistance, daratumumab availability, and cost. Autologous transplantation should be considered in younger patients if not used upfront.

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“…OS in the PANO arm was 40.3 months and 35.8 months in the control arm, but this difference was not statistically significant (HR 0.94; 95% CI, 0.78–1.14). Of note, a higher percentage of patients in the placebo arm received post-study therapy, which may have confounded the OS results [49]. PANO cohort was almost twice as likely to have G3–4 thrombocytopenia, neutropenia, diarrhea, fatigue.…”

Section: Clinical Development Of Histone Deacetylase Inhibitorsmentioning

confidence: 99%

“…Sub-analyses also indicated that those who were able to tolerate and receive a longer duration of treatment with PANO-BTZ-DEX also had a longer PFS. Those who completed the first phase treatment had a mPFS of 14.6 months, compared to 17.6 months for those who completed the second phase as well [49]. Based on the strength of PANORAMA 1 results, particularly the subgroup analysis, FDA, in 2015, approved PANO-BTZ-DEX regimen for the treatment of RRMM patients who have received ≥2 prior regimens including BTZ and IMiD [116].…”

Section: Clinical Development Of Histone Deacetylase Inhibitorsmentioning

confidence: 99%

Novel Proteasome Inhibitors and Histone Deacetylase Inhibitors: Progress in Myeloma Therapeutics

Chhabra

2017

Pharmaceuticals

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The unfolded protein response is responsible for the detection of misfolded proteins and the coordination of their disposal and is necessary to maintain the cellular homoeostasis. Multiple myeloma cells secrete large amounts of immunoglobulins, proteins that need to be correctly folded by the chaperone system. If this process fails, the misfolded proteins have to be eliminated by the two main garbage-disposal systems of the cell: proteasome and aggresome. The blockade of either of these systems will result in accumulation of immunoglobulins and other toxic proteins in the cytoplasm and cell death. The simultaneous inhibition of the proteasome, by proteasome inhibitors (PIs) and the aggresome, by histone deacetylase inhibitors (HDACi) results in a synergistic increase in cytotoxicity in myeloma cell lines. This review provides an overview of mechanisms of action of second-generation PIs and HDACi in multiple myeloma (MM), the clinical results currently observed with these agents and assesses the potential therapeutic impact of the different agents in the two classes. The second-generation PIs offer benefits in terms of increased efficacy, reduced neurotoxicity as off-target effect and may overcome resistance to bortezomib because of their different chemical structure, mechanism of action and biological properties. HDACi with anti-myeloma activity in clinical development discussed in this review include vorinostat, panobinostat and selective HDAC6 inhibitor, ricolinostat.

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Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial

Cited by 124 publications

References 26 publications

A phase 1b study of isatuximab plus lenalidomide and dexamethasone for relapsed/refractory multiple myeloma

A phase 1b study of isatuximab plus lenalidomide and dexamethasone for relapsed/refractory multiple myeloma

How I treat first relapse of myeloma

Novel Proteasome Inhibitors and Histone Deacetylase Inhibitors: Progress in Myeloma Therapeutics

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