Carfilzomib, lenalidomide, and dexamethasone or lenalidomide alone as maintenance therapy after autologous stem-cell transplantation in patients with multiple myeloma (ATLAS): interim analysis of a randomised, open-label, phase 3 trial

Dytfeld, Dominik; Wróbel, Tomasz; Jamroziak, Krzysztof; Kubicki, Tadeusz; Robak, Paweł; Walter‐Croneck, Adam; Czyż, Jarosław; Tyczyńska, Agata; Druzd‐Sitek, Agnieszka; Giannopoulos, Krzysztof; Nowicki, Adam; Szczepaniak, Tomasz; Łojko‐Dankowska, Anna; Matuszak, Magdalena; Gil, Lidia; Puła, Bartosz; Rybka, Justyna; Majcherek, Maciej; Usnarska−Zubkiewicz, Lidia; Szukalski, Łukasz; Końska, Agnieszka; Zaucha, Jan Maciej; Walewski, Jan; Mikulski, Damian; Czabak, Olga; Robak, Tadeusz; Lahoud, Oscar; Zonder, Jeffrey A.; Griffith, Kent A.; Stefka, Andrew; Major, Ajay; Derman, Benjamin A.; Jakubowiak, Andrzej

doi:10.1016/s1470-2045(22)00738-0

Cited by 24 publications

(24 citation statements)

References 24 publications

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“…However, based on the significant MRD negativity rates obtained with continuous therapies or through the different phases of treatment, sequential MRD evaluation could better assess the efficacy of each treatment phases, allowing therapy escalation or de-escalation with the aim to minimize toxicity and costs. Ongoing phase III trials [ 88 , 105 , 117 , 129 , 130 ] will enable us to understand if MRD-driven approach will be the right tool to personalize therapy. Early results on the comparison between bone marrow data and peripheral blood MRD assessment by mass spectrometry (MS) seem to be promising—and this and other similar techniques may represent a turning point in the clinical practice.…”

Section: Discussion and Expert Opinionmentioning

confidence: 99%

“…In the phase III FORTE trial [ 87 ], carfilzomib plus lenalidomide (K-R) significantly improved PFS compared with lenalidomide alone (3-year PFS 75% vs. 65%, respectively) whereas the addition of ixazomib to Rd did not translate in a PFS benefit vs. Rd in the Spanish GEM2014MAIN trial [ 104 ]. In contrast, preliminary data from phase III ATLAS trial [ 105 ] suggested that a maintenance with a triplet including lenalidomide (KRd) can improve PFS if compared with lenalidomide alone (HR = 0.51, p = 0.012). Furthermore, in the maintenance setting, some studies will evaluate novel immunotherapies and the phase III MajesTEC-4 trial will compare the efficacy of teclistamab plus lenalidomide vs. lenalidomide in patients who have completed induction therapy followed by ASCT.…”

Section: Pros and Cons Of Continuous Vs Fixed-duration Therapymentioning

confidence: 99%

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Current Main Topics in Multiple Myeloma

Morè¹,

Corvatta²,

Manieri³

et al. 2023

Cancers

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Multiple Myeloma (MM) remains a difficult to treat disease mainly due to its biological heterogeneity, of which we are more and more knowledgeable thanks to the development of increasingly sensitive molecular methods that allow us to build better prognostication models. The biological diversity translates into a wide range of clinical outcomes from long-lasting remission in some patients to very early relapse in others. In NDMM transplant eligible (TE) patients, the incorporation of mAb as daratumumab in the induction regimens, followed by autologous stem cell transplantation (ASCT) and consolidation/maintenance therapy, has led to a significant improvement of PFS and OS.; however, this outcome remains poor in ultra-high risk MM or in those who did not achieve a minimal residual disease (MRD) negativity. Several trials are exploring cytogenetic risk-adapted and MRD-driven therapies in these patients. Similarly, quadruplets-containing daratumumab, particularly when administered as continuous therapies, have improved outcome of patients not eligible for autologous transplant (NTE). Patients who become refractory to conventional therapies have noticeably poor outcomes, making their treatment a difficult challenge in need of novel strategies. In this review, we will focus on the main points regarding risk stratification, treatment and monitoring of MM, highlighting the most recent evidence that could modify the management of this still incurable disease.

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Section: Discussion and Expert Opinionmentioning

confidence: 99%

Section: Pros and Cons Of Continuous Vs Fixed-duration Therapymentioning

confidence: 99%

Current Main Topics in Multiple Myeloma

Morè¹,

Corvatta²,

Manieri³

et al. 2023

Cancers

View full text Add to dashboard Cite

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“…The detailed design of the ATLAS trial has been previously described 21 . Briefly, patients with MM that completed any induction therapy followed by single ASCT were eligible for enrolment up to 100 days after the ASCT.…”

Section: Methodsmentioning

confidence: 99%

“…All survival analyses were conducted using the previously published results from the unplanned interim report 21 …”

Section: Methodsmentioning

confidence: 99%

“…[17][18][19][20] Recently, two studies investigating carfilzomib-based maintenance regimens demonstrated superior PFS compared to lenalidomide alone, suggesting a potential role for even more intensive maintenance therapy following ASCT. 21,22 Considering the impact that extended treatment may have not only on malignant plasma cells but also on normal plasma cells, 23,24 we evaluated polyclonal immunoglobulin recovery after ASCT and its prognostic significance in the setting of extended post-transplant maintenance therapy. Towards this goal we have performed a subanalysis of the prospective, randomized, phase 3 ATLAS trial where patients with MM after ASCT were continuously treated either with single agent lenalidomide (R) or minimal residual disease (MRD)-directed, risk-adapted therapy with carfilzomib, lenalidomide and dexamethasone (KRd).…”

Section: Introductionmentioning

confidence: 99%

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Polyclonal immunoglobulin recovery in patients with newly diagnosed myeloma receiving maintenance therapy after autologous haematopoietic stem cell transplantation with either carfilzomib, lenalidomide and dexamethasone or lenalidomide alone: Subanalysis of the randomized phase 3 ATLAS trial

Kubicki,

Dytfeld,

Wróbel

et al. 2023

Br J Haematol

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SummaryPrevious studies suggest that postautologous stem cell transplant (ASCT) recovery of polyclonal immunoglobulin from immunoparesis in patients with multiple myeloma is a positive prognostic marker. We performed a longitudinal analysis of polyclonal immunoglobulin concentrations and unique B‐cell sequences in patients enrolled in the phase 3 ATLAS trial that randomized 180 subjects to either carfilzomib, lenalidomide, dexamethasone (KRd) or lenalidomide (R) maintenance. In the KRd arm, standard‐risk patients with minimal residual disease negativity after six cycles de‐escalated to R alone after cycle 8. One year from the initiation of maintenance at least partial recovery of polyclonal immunoglobulin was observed in more patients on the R arm (58/66, p < 0.001) and in those who de‐escalated from KRd to R (27/38, p < 0.001) compared to the KRd arm (9/36). In patients who switched from KRd to R, the concentrations of uninvolved immunoglobulin and the number of B‐cell unique sequences increased over time, approaching values observed in the R arm. There were no differences in progression‐free survival between the patients with at least partial immunoglobulin recovery and the remaining population. Our analysis indicates that patients receiving continuous therapy after ASCT experience prolonged immunoparesis, limiting prognostic significance of polyclonal immunoglobulin recovery in this setting.

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Randomized comparison between KTd and KRd induction therapy followed by maintenance therapy with K or observation in transplant‐ineligible patients with newly diagnosed multiple myeloma

Ludwig,

Melchardt,

Sormann

et al. 2024

American J Hematol

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Carfilzomib (K) is highly effective in newly diagnosed and relapsed/ refractory patients with multiple myeloma and is not associated with dose-limiting neurotoxicity, 1 allowing therapy over longer periods of time, for example, as maintenance therapy. K is often combined with lenalidomide as IMiD, but prospective comparisons between lenalidomide and thalidomide as combination partners for K-based regimens are not available. Recent data have shown that K-based maintenance therapy provides a significant PFS benefit in transplant-eligible patients. 2,3 We present here a study comparing induction therapy with KTd and KRd for nine cycles, followed by a second randomization to maintenance therapy with K for 1 year or observation in 123 patients who were ineligible for transplantation. All patients gave

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Carfilzomib, lenalidomide, and dexamethasone or lenalidomide alone as maintenance therapy after autologous stem-cell transplantation in patients with multiple myeloma (ATLAS): interim analysis of a randomised, open-label, phase 3 trial

Cited by 24 publications

References 24 publications

Current Main Topics in Multiple Myeloma

Current Main Topics in Multiple Myeloma

Polyclonal immunoglobulin recovery in patients with newly diagnosed myeloma receiving maintenance therapy after autologous haematopoietic stem cell transplantation with either carfilzomib, lenalidomide and dexamethasone or lenalidomide alone: Subanalysis of the randomized phase 3 ATLAS trial

Randomized comparison between KTd and KRd induction therapy followed by maintenance therapy with K or observation in transplant‐ineligible patients with newly diagnosed multiple myeloma

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