The Myeloma XI trial was a phase III, open-label, parallelgroup, 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, characterized 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 undertake was made on an individual patient basis taking into account performance status, clinician judgment, and patient preference.

Transplant-eligible patients were randomized on a 1:1 basis to 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 administered 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 published 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 randomization 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 regulatory authority (Medicines and Healthcare Products Regulatory Agency, London, UK). All patients provided written informed consent. The trial was registered with the EU Clinical Trials Register (EudraCT number, 2009-010956-93) and ISRCTN49407852.

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