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G.H. Jackson et al.
Introduction
The introduction of novel agents, such as immunomod- ulatory drugs and proteasome inhibitors, has contributed to the recent dramatic improvements in outcomes observed for patients with multiple myeloma.1-3 Following induction, high-dose melphalan-based chemotherapy with autologous stem cell transplantation (ASCT) remains the standard of care for eligible patients.4-9 The optimal approach to induction therapy prior to ASCT and consol- idation or maintenance after ASCT in this new era has not yet been defined. However, several principles have been established, including the value of using at least triplet combinations of agents that can induce deeper, longer remissions by targeting different clonal populations.10,11
The efficacy of immunomodulatory drugs in multiple myeloma has been linked to their mode of action. These drugs target the cereblon ubiquitin ligase complex, which leads to both tumoricidal effects early on and immunomodulatory effects beneficial for long-term tumor control.12-15 The immunomodulatory drugs thalidomide and lenalidomide are recognized as effective treatment options in both the induction7,9,10,16-18 and maintenance set- tings.6,19-21 Lenalidomide has fewer side effects than thalidomide, enabling long-term treatment and disease control.19-21 We have addressed how to optimize the use of these agents between induction and maintenance for patients receiving ASCT in a large, randomized trial (UK National Cancer Research Institute [NCRI] Myeloma XI).
Methods
The Myeloma XI study had a multifactorial design enabling the investigation of a number of pertinent clinical questions with ade- quate statistical control and power. Importantly, the influence of one phase of treatment or question on another could be separated and controlled for. This was achieved by stratifying the consolida- tion and maintenance randomizations for earlier treatment alloca- tions. This report concentrates on induction and its interaction with maintenance therapy in the transplant-eligible population of patients within the trial. The other questions posed by the study are addressed in separate manuscripts.
Study design and eligibility criteria
The Myeloma XI trial was a phase III, open-label, parallel- group, multi-arm, adaptive design trial with three randomization stages conducted at 110 National Health Service hospitals in England, Wales, and Scotland (see Online Supplementary Data for a list of study sites with principal investigators and number of patients recruited). Eligible patients were aged ≥18 years and newly diagnosed with multiple myeloma. Exclusion criteria included previous or concurrent malignancies (including myelodysplastic syndromes), grade ≥2 peripheral neuropathy, acute renal failure (unresponsive to up to 72 h of rehydration, char- acterized by creatinine >500 mmol/L or urine output <400 mL/day or requiring dialysis), and active or prior hepatitis C infection.
The trial design included an intensive treatment pathway for transplant-eligible patients and a less intensive treatment pathway for transplant-ineligible patients. Strict age limits were deliberately avoided so that fit, older patients could receive intensive therapy and ASCT. The decision of which treatment pathway to under- take was made on an individual patient basis taking into account performance status, clinician judgment, and patient preference.
cyclophosphamide, lenalidomide, and dexamethasone (CRD) or cyclophosphamide, thalidomide, and dexamethasone (CTD) (induction randomization), stratified according to certain factors (Online Supplementary Methods). Patients received a minimum of four cycles in the absence of progressive disease, and treatment continued until maximum response was achieved.
Additional intensification therapy before ASCT was adminis- tered to patients with a suboptimal response to induction therapy using a response-adapted approach: patients with stable disease after induction therapy or those with progressive disease at any time during induction therapy received a maximum of eight cycles of cyclophosphamide, bortezomib, and dexamethasone (CVD); patients with a minimal or partial response were randomized (1:1) to CVD or no CVD. Patients with a very good partial response or complete response received no additional therapy before ASCT. The results of the intensification randomization have been pub- lished elsewhere.22
Three months after ASCT, eligible patients were randomized to observation or to maintenance therapy with lenalidomide alone, or in combination with vorinostat until unacceptable toxicity or progressive disease. Patients were excluded from maintenance randomization if they did not respond to CRD induction, had no response to any prior study treatment, had progressive disease, or relapsed after achieving a complete response. Randomized patients were stratified according to treatment center and previous randomization group(s). The results of the maintenance random- ization have been published elsewhere.23
Further details on the dose and schedule of all study treatments are provided in Online Supplementary Table S1, and a flow diagram of the CRD and CTD groups of patients is shown in Online Supplementary Figure S1.
The study was approved by the national ethics review board (National Research Ethics Service, London, UK), institutional review boards of the participating centers, and the competent reg- ulatory authority (Medicines and Healthcare Products Regulatory Agency, London, UK). All patients provided written informed con- sent. The trial was registered with the EU Clinical Trials Register (EudraCT number, 2009-010956-93) and ISRCTN49407852.
Study endpoints and statistical analysis
The co-primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints included PFS-Two (PFS2), response, and safety. Further details regarding the statistical analysis are provided in the Online Supplementary Material.
Results
Patients
Between May 26, 2010 and April 20, 2016, 2,042 trans- plant-eligible patients underwent induction randomiza- tion (Online Supplementary Figure S1). Baseline characteris- tics were well balanced between the two treatment groups (Table 1). The median age of all the patients was 61 years (range, 28-75 years), 60% of the patients were male, and 24% had International Staging System (ISS) stage III disease. Of the 836 (40.9%) patients for whom genetic risk could be calculated, 266 (31.8%) had high-risk and 111 (13.3%) had ultra-high-risk cytogenetics. The median duration of follow-up since study entry was 36.3 months (interquartile range [IQR], 23.0-48.5 months).
Induction randomization results
Progression-free survival and overall survival
Transplant-eligible patients were randomized on a 1:1 basis to
Disease progression or death occurred in 456 patients in
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haematologica | 2021; 106(7)