Optimising the value of immunomodulatory drugs during induction and maintenance in transplant ineligible patients with newly diagnosed multiple myeloma: results from Myeloma XI, a multicentre, open‐label, randomised, Phase III trial

Abstract

Summary Second‐generation immunomodulatory agents, such as lenalidomide, have a more favourable side‐effect profile than the first‐generation thalidomide, but their optimum combination and duration for patients with newly diagnosed transplant‐ineligible myeloma (ND‐TNE‐MM) has not been defined. The most appropriate delivery and dosing regimens of these therapies for patients at advanced age and frailty status is also unclear. The Myeloma XI study compared cyclophosphamide, thalidomide and dexamethasone (CTDa) to cyclophosphamide, lenalidomide and dexamethasone (CRDa) as induction therapy, followed by a maintenance randomisation between ongoing therapy with lenalidomide or observation for patients with ND‐TNE‐MM. CRDa deepened response but did not improve progression‐free (PFS) or overall survival (OS) compared to CTDa. However, analysis by age group highlighted significant differences in tolerability in older, frailer patients that may have limited treatment delivery and impacted outcome. Deeper responses and PFS and OS benefits with CRDa over CTDs were seen in patients aged ≤70 years, with an increase in toxicity and discontinuation observed in older patients. Our results highlight the importance of considering age and frailty in the approach to therapy for patients with ND‐TNE‐MM, highlighting the need for prospective validation of frailty adapted therapy approaches, which may improve outcomes by tailoring treatment to the individual.

Geriatric assessments and frailty scores in multiple myeloma patients: a needed tool for individualized treatment?

“…2 ) [ 8 , 9 ]. Nonetheless, aging remains a poor prognostic factor in cancer in general, including in multiple myeloma patients [ 1 ▪ , 8 , 10 ]. As therapy decisions have become more complex and involve multiple choices today, individual management of patients – ranging from fit to frail – should balance efficacy, toxicity and practicability (Fig.…”

“…The choice of the numerous available treatment options for older patients affected by frailty and comorbidities should consequently be individualized [ 1 ▪ ]. Indeed, adjusting for comorbidities induced significant differences in patients’ survival [ 10 , 11 , 14 ▪▪ ]. For example, clinical trials have shown feasibility and benefit of ASCT in older multiple myeloma patients, even with full-dose Melphalan (200 mg/m 2 ) [ 15 ], highlighting that biologically fitter elderly patients can profit from intensive treatment as well as from interventions strengthening their performance and physical capabilities [ 10 , 14 ▪▪ , 16 ].…”

The development and validation of prognostic models for overall survival in the presence of missing data in the training dataset: a strategy with a detailed example

“…Myeloma XI is a phase III trial in which newly diagnosed transplant ineligible patients with multiple myeloma were randomised to receive CTDa (attenuated cyclophosphamide, thalidomide, and dexamethasone) or CRDa (attenuated cyclophosphamide, lenalidomide, and dexamethasone) between 2010 and 2015. Full details of the trial design and results have been reported elsewhere [12,13].…”

“…Despite the training data being taken from a clinical trial, randomised treatment allocation was not included in the imputation model. We made this decision because firstly, as treatment in myeloma is constantly evolving, including treatment as a proposed prognostic factor would limit the model's applicability, and secondly the randomisation treatment for induction in Myeloma XI was not effective [13]. However, this decision might not be justified in a situation where there is a significant treatment effect.…”

Abnormal Ubiquitination of Ubiquitin-Proteasome System in Lung Squamous Cell Carcinomas

“…Considering the importance of ubiquitination in tumorigenesis, different components of ubiquitin-proteasome system could be regarded as targets for discovery of anti-tumor drugs. With the application of first and second therapeutic proteasome inhibitors, such as Bortezomib (FDA has approved it for multiple myeloma and mantle cell lymphoma) [7] and Carfilzomib (FDA has approved it for relapsed and refractory multiple myeloma) [8], more and more anti-tumor drugs targeting UPS have been developed and approved by FDA, such as thalidomide, lenalidomide, and pomalidomide for treatment of multiple myeloma [9,10].…”