Upfront autologous haematopoietic stem-cell transplantation versus carfilzomib–cyclophosphamide–dexamethasone consolidation with carfilzomib maintenance in patients with newly diagnosed multiple myeloma in England and Wales (CARDAMON): a randomised, phase 2, non-inferiority trial

Yong, Kwee; Wilson, William T.; Tute, Ruth M. de; Camilleri, Marquita; Ramasamy, Karthik; Streetly, Matthew; Sive, Jonathan; Bygrave, Ceri; Benjamin, Reuben; Chapman, Michael; Chavda, Selina J; Phillips, E.; Cuadrado, Maria del Mar; Pang, Gavin; Jenner, Richard; Dadaga, Tushhar; Kamora, Sumaiya; Cavenagh, James D.; Clifton‐Hadley, Laura; Owen, Roger G.; Popat, Rakesh

doi:10.1016/s2352-3026(22)00350-7

Cited by 15 publications

(12 citation statements)

References 31 publications

(23 reference statements)

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“…After excluding the studies that did not meet the inclusion criteria, 5 RCTs and 15 observational studies were included in the meta-analysis to compare the treatment outcomes between upfront ASCT and no upfront ASCT (briefly no ASCT) [ 16 – 35 ]. Two latest RCTs were added into the meta-analysis in the revised version after extending the enrolled publication term to 2023/03 [ 36 , 37 ]. Figure 1 and Table 1 showed the research design and the baseline characteristics of the included studies.…”

Section: Resultsmentioning

confidence: 99%

“…In this RCT, 2 of the 3 arms (carfilzomib, lenalidomide, dexamethasone [KRD] + ASCT vs. KRD) were extracted for meta-analysis, while the KCD + ASCT arm (C: cyclophosphamide) was excluded due to a lack of comparative KCD alone group (Supplementary Table S 1 ). The latest PI carfilzomib was used in 4 studies [ 24 , 20 , 34 , 37 ], and the latest IMiD pomalidomide was mentioned in 1 study [ 25 ]. These 2 regimens were not included in the previous reviews [ 7 , 8 ].…”

Section: Resultsmentioning

confidence: 99%

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Treatment benefit of upfront autologous stem cell transplantation for newly diagnosed multiple myeloma: a systematic review and meta-analysis

et al. 2023

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Background Upfront high-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) remains a profitable strategy for newly diagnosed multiple myeloma (MM) patients in the context of novel agents. However, current knowledge demonstrates a discrepancy between progression-free survival (PFS) and overall survival (OS) benefit with HDT/ASCT. Methods We conducted a systematic review and meta-analysis that included both randomized controlled trials (RCTs) and observational studies evaluating the benefit of upfront HDT/ASCT published during 2012 to 2023. Further sensitivity analysis and meta-regression were also performed. Results Among the 22 enrolled studies, 7 RCTs and 9 observational studies had a low or moderate risk of bias, while the remaining 6 observational studies had a serious risk of bias. HDT/ASCT revealed advantages in complete response (CR) with an odds ratio (OR) of 1.24 and 95% confidence interval (CI) 1.02 ~ 1.51, PFS with a hazard ratio (HR) of 0.53 (95% CI 0.46 ~ 0.62), and OS with an HR of 0.58 (95% CI 0.50 ~ 0.69). Sensitivity analysis excluding the studies with serious risk of bias and trim-and-fill imputation fundamentally confirmed these findings. Older age, increased percentage of patients with International Staging System (ISS) stage III or high-risk genetic features, decreased proteasome inhibitor (PI) or combined PI/ immunomodulatory drugs (IMiD) utilization, and decreased follow-up duration or percentage of males were significantly related to a greater survival advantage with HDT/ASCT. Conclusions Upfront ASCT remains a beneficial treatment for newly diagnosed MM patients in the period of novel agents. Its advantage is especially acute in high-risk MM populations, such as elderly individuals, males, those with ISS stage III or high-risk genetic features, but is attenuated with PI or combined PI/IMiD utilization, contributing to divergent survival outcomes.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Treatment benefit of upfront autologous stem cell transplantation for newly diagnosed multiple myeloma: a systematic review and meta-analysis

et al. 2023

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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%

“…Remarkably, after a median follow-up of 51 months among patients who were treated with KRD as induction and consolidation (4 cycles), those who underwent ASCT had a significantly longer PFS compared to those receiving additional 4 cycles without ASCT (KRD12) (4-year PFS = 69% vs. 56%, HR = 0.61, p = 0.0084), whereas no significant PFS difference was found between KCD plus ASCT vs. KRD12. The last recently published randomized phase II CARDAMON study [ 88 ] showed 2-years’ PFS of 75% in the ASCT group vs. 68% in the KCD group, failing to demonstrate a non-inferiority of KCD compared with ASCT. However, of the above-mentioned studies, only EMN02/HO95 trial reported a significant benefit of ASCT over VMP consolidation in term of OS since after an extended median follow-up, 75-month OS was 69% in the ASCT group vs. 63% in the VMP group (HR = 0.81, p = 0.034).…”

Section: Autologous Stem Cell Transplantation In Light Of New Therapiesmentioning

confidence: 99%

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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“…The CARDAMON (Carfilzomib/Cyclophosphamide/Dexamethasone with Maintenance Carfilzomib in Untreated Transplant-eligible Patients with Symptomatic MM to Evaluate the Benefit of Upfront ASCT) trial was a phase II trial exploring upfront carfilzomib/cyclophosphamide/dexamethasone (KCD), followed by randomization to an autologous high-dose stem cell transplant or KCD consolidation, followed by carfilzomib maintenance (Supplementary Fig. 1) 15 . As CARDAMON was a clinical trial employing carfilzomib as the single novel anti-myeloma agent, we reasoned that it could be employed to train a machine learning algorithm to learn carfilzomib responsiveness.…”

Section: Introductionmentioning

confidence: 99%

Machine learning from the CARDAMON trial identifies a carfilzomib-specific mutational response signature

Walker

D'arcy

Khandelwal

et al. 2023

Preprint

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Precision medicine holds great promise to improve outcomes in cancer, including haematological malignancies. However, there are few biomarkers that influence choice of chemotherapy in clinical practice. In particular, multiple myeloma requires an individualized approach as there exist several active therapies, but little agreement on how and when they should be used and combined. We have previously shown that a transcriptomic signature can identify specific bortezomib- and lenalidomide-sensitivity. However, gene expression signatures are challenging to implement clinically. We reasoned that signatures based on the presence or absence of gene mutations would be more tractable in the clinical setting, though examples of such signatures are rare. We performed whole exome sequencing as part of the CARDAMON trial, which employed carfilzomib-based therapy. We applied advanced machine learning approaches to discover mutational patterns predictive of treatment outcome. The resulting model accurately predicted progression-free survival (PFS) both in CARDAMON patients and in an external validation set of patients from the CoMMpass study who had received carfilzomib. The signature was specific for carfilzomib therapy and was strongly driven by genes on chromosome 1p36. Importantly, patients predicted to be carfilzomib-sensitive had a longer PFS when treated with carfilzomib/lenadlidomide/dexamethasone than with bortezomib/carfilzomib/dexamethasone. However, in those predicted to be carfilzomib-insensitive, the latter therapy may have been capable of eradicating carfilzomib-resistant clones. We propose that the signature can be used to make rational therapeutic decisions and could be incorporated into future clinical trials.

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Upfront autologous haematopoietic stem-cell transplantation versus carfilzomib–cyclophosphamide–dexamethasone consolidation with carfilzomib maintenance in patients with newly diagnosed multiple myeloma in England and Wales (CARDAMON): a randomised, phase 2, non-inferiority trial

Cited by 15 publications

References 31 publications

Treatment benefit of upfront autologous stem cell transplantation for newly diagnosed multiple myeloma: a systematic review and meta-analysis

Treatment benefit of upfront autologous stem cell transplantation for newly diagnosed multiple myeloma: a systematic review and meta-analysis

Current Main Topics in Multiple Myeloma

Machine learning from the CARDAMON trial identifies a carfilzomib-specific mutational response signature

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