Diphosphonates

The Myeloma XI was a phase 3, open-label, randomised, adaptive design trial with three randomisation stages (figure 1). There were three potential randomisations in the study: at trial entry for all patients to allocate induction treatment separately for those considered eligible or ineligible for transplantation; after induction treatment for those patients with a suboptimal response to treatment (minimal or partial response) to allocate induction intensification; and at the completion of induction and intensification or autologous stem-cell transplantation (where applicable) to allocate maintenance treatment. This report is concerned with the results of the randomisation to maintenance treatment. Results of the induction intensification randomisations will be presented elsewhere. The trial was done at 110 National Health Service hospitals in England, Wales, and Scotland (appendix p 2).Figure 1

Trial profile

*Randomisation occurred between May 26, 2010, and April 20, 2016. †Randomisation occurred between Jan 13, 2011, and Aug 11, 2017. ‡Censored for progression-free survival analysis.

The full study protocol including the inclusion criteria for each randomisation is available in the appendix (p 34). Patients aged at least 18 years and who had symptomatic multiple myeloma or non-secretory multiple myeloma based on bone marrow clonal plasma cells, organ or tissue impairment considered by the clinician to be myeloma related, or paraprotein (M-protein) in serum or urine were eligible for the initial randomisation. Exclusion criteria for the initial randomisation included previous or concurrent malignancies, including myelodysplastic syndromes; previous treatment for myeloma (except local radiotherapy, bisphosphonates, and corticosteroids); grade 2 or worse peripheral neuropathy, acute renal failure (unresponsive to up to 72 h of rehydration, characterised by creatinine >500 μmol/L or urine output <400 mL per day, or requiring dialysis); and active or previous hepatitis C infection.
Patients who were young and fit to tolerate autologous stem-cell transplantation (transplantation eligible) entered the intensive treatment pathway. Older and less fit patients (transplantation ineligible) entered the non-intensive treatment pathway. Strict age limits were deliberately avoided so that fit, older patients could receive intensive therapy and undergo autologous stem-cell transplantation. However, generally, patients aged 60 years or younger entered the intensive (younger, fitter) pathway; those aged 70 years or older entered the non-intensive (older, less fit) pathway; and those aged 61–69 years were eligible for either intensive or non-intensive therapy. The decision of treatment pathway was made on an individual patient basis, taking into account Eastern Cooperative Oncology Group performance status, clinician judgment, and patient preference.
For the maintenance therapy randomisation, eligible patients were those who completed their assigned induction therapy according to the protocol (a minimum of four cycles of cyclophosphamide, thalidomide, and dexamethasone [CTD]; cyclophosphamide, lenalidomide, and dexamethasone [CRD]; or carfilzomib, cyclophosphamide, lenalidomide, and dexamethasone [KCRD] in the intensive pathway, or a minimum of six cycles of attenuated CTD or attenuated CRD in the non-intensive pathway), and had achieved at least a minimal response and received at least 100 mg/m² melphalan if assigned to intensive treatment.
The study was approved by the national ethics review board (National Research Ethics Service, London, UK), institutional review boards of the participating centres, and the competent regulatory authority (Medicines and Healthcare Products Regulatory Agency, London, UK), and was undertaken according to the Declaration of Helsinki and the principles of Good Clinical Practice as espoused in the Medicines for Human Use (Clinical Trials) Regulations. All patients provided written informed consent. The study is closed for accrual, but follow-up continues for planned long-term analysis.

Six outcome measures - SF-36 PCS scale, EQ-5D, RMD score, back pain, number of days with restricted activity in last 2 weeks and number of days in bed in last 2 weeks - were analysed using four methods for dealing with missing data: CC analysis, simple imputation with LOCF analysis, MM analysis on all available data and MI analysis.
The CC analysis included only patients with both baseline and all follow-up values for respective outcomes. For the LOCF analysis, only patients with available baseline values were included; missing follow-up values were replaced by the patient's last observed value, based on the assumption that this represented the treatment effect. In contrast with the LOCF method, MI is a stochastic imputation method based on the assumption that missing values can be replaced with values generated by a model incorporating random variation. The generation of such values is performed repeatedly providing a series of complete datasets. These datasets are then analysed using standard methods for complete data, and the results are combined to provide a set of parameter estimates and their standard errors, from which confidence intervals and p-values can be derived. The MI model can be different from the model used for the final data analysis. In this study we imputed data using as-treated models, and analysed them according to ITT [2 (link)].
For the CC, LOCF and MI methods, the analysis was performed using a conventional repeated-measures ANOVA design. The model included treatment group and visit as fixed factors, as well as their interaction, together with covariates representing the randomisation stratification factors (gender, fracture aetiology, use of bisphosphonates at the time of enrolment and use of systemic steroids during the last 12 months before enrolment) and baseline values.
In the MM analysis, all patients with at least one baseline or follow-up value were included. An MM analysis includes both fixed and random factors: in the current analysis, treatment group and visit were included as fixed factors, and patient was included as a random factor. The model included interactions between treatment and visit. Randomisation stratification factors (gender, fracture aetiology, use of bisphosphonates at the time of enrolment and use of systemic steroids during the last 12 months before the time of enrolment) and baseline value were included as covariates. Compound symmetry structure for covariance between measurements was assumed. Maximum restricted likelihood procedure was used to fit the model and denominator degrees of freedom were estimated using Satterthwaite's approximation. This mixed model analysis is, with balanced data, equivalent to the conventional repeated measures ANOVA with sphericity assumption [8 ].

Two commercially available fluorescent imaging probes (PerkinElmer Inc., Hopkinton, MA) were used to evaluate osteoclast functions in the lung. The fluorescent bisphosphonate imaging agent, OsteoSense 750EX (Osteosense) was used to tag microliths in the lung. The cathepsin K cleavage activated fluorescent probe; Cat K 680 FAST probe (Cat K) were used to detect cathepsin K activity in the lung. Npt2b^+/+ and Npt2b^−/− mice were shaved around the chest prior to imaging, and 1 nmol Cat K or 1 nmol Osteosense was administered intratracheally. The fluorescence signal emanating from the chest was monitored using an in vivo imaging system (IVIS Spectrum, PerkinElmer) at 18 h post injection for Cat K, and at days 1, 3, 5, 7, 10 and 12 post-injection for Osteosense. Quantification of fluorescence intensity was performed by evaluating the total radiant efficiency ([photons/sec]/[μW/cm²]) of the signal within a region of interest (ROI). The ROI was defined by an area with a radius of 0.94 cm² that encompassed the lungs of the mice (Fig. 3s) and the total radiant efficiency of Osteosense was normalized to that present at day 3, to limit the mouse-to-mouse variation in delivery of the fluorescent probe.