Allogeneic Hematopoietic Stem Cell Transplantation With Ixazomib for High Risk Multiple Myeloma (BMT CTN 1302)

Cumulative incidences of grade III-IV acute GVHD were determined using the Aalen-Johansen estimator. Death prior to acute GVHD is treated as the competing risk. Cumulative incidences are compared between treatment arms using Gray's test. Grading of acute GVHD was derived by consensus grading per BMT Clinical Trials Network (CTN) manual of procedures (MOP). The acute GVHD algorithm calculates the grade based on the organ (skin, GI and liver) stage and etiology/biopsy reported on the weekly GVHD form. Grade I aGVHD is defined as Skin stage of 1-2 and stage 0 for both GI and liver organs. Grade II aGVHD is stage 3 of skin, or stage 1 of GI, or stage 1 of liver. Grade III is stage 2-4 for GI, or stage 2-3 of liver. Grade IV is stage 4 of skin, or stage 4 of liver. Grade 4 is the worst outcome.

Cumulative incidences of chronic GVHD were determined using the Aalen-Johansen estimator. Death prior to chronic GVHD is treated as the competing risk. Cumulative incidences are compared between treatment arms using Gray's test. Data of chronic GVHD were collected from providers and chart review according to the recommendations of the 2014 NIH Consensus Criteria. Eight organs are scored on a 0-3 scale to reflect degree of chronic GVHD involvement; 3 indicates the worst symptom. Liver and pulmonary function test results and use of systemic therapy for treatment of chronic GVHD are also recorded.

Response was assessed using the International Uniform Response Criteria. Best response is the best of all the disease response status at each assessment time point after randomization. The order from best to worst is: Stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD). All disease classifications are relative to the patient's disease status prior to allogeneic transplant (i.e. study entry). This outcome was compared between treatment groups using all response data up to 2 years post-transplant. These response data were summarized separately for patients in sCR/CR at the time of randomization vs. those who were not in sCR/CR at the time of randomization. Within each group (in sCR/CR vs not in sCR/CR at randomization), best response to treatment was compared between treatment groups using a Fisher's Exact test instead of a chi-square test because of the small sample size.

Response was assessed using the International Uniform Response Criteria. All disease classifications are relative to the patient's disease status prior to allogeneic transplant (i.e. study entry). Response to treatment after randomization (sCR, CR, VGPR, or PR) is summarized in each arm post-transplant at 18 months and 24 months post-transplant. These response data were summarized separately for patients in sCR/CR at the time of randomization vs. those who were not in sCR/CR at the time of randomization.

Disease progression was evaluated using the International Uniform Response Criteria. Participants in sCR/CR must meet at least one of the criteria for disease progression specified in the protocol for sCR/CR participants; those not in sCR/CR must meet at least one of the disease progression criteria specified in the protocol for those not in sCR/CR. The cumulative incidence of progression from randomization will be estimated for each treatment arm using the Aalen-Johansen estimator, with death in remission treated as a competing risk. Initiation of anti-myeloma therapy will be considered evidence of progression. Participants who were event-free at two years post-transplant are censored at that time.

Overall survival (OS) is defined as freedom from death from any cause. OS post-randomization is estimated for each arm using the Kaplan-Meier estimator and compared between arms using the log rank test. Participants who are alive at two years post-transplant are censored at that time. Confidence intervals for values of 100% were not calculated and are shown as 100%.

Treatment-related mortality is defined as death occurring in a patient from causes other than disease relapse or progression. The cumulative incidence of treatment-related mortality (TRM) post-randomization is estimated for each treatment arm using the Aalen-Johansen estimator, with progression treated as a competing risk. Participants who were event-free at two years post-transplant are censored at that time. Confidence intervals for values of 0% were not calculated.

Toxicities are graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. Higher grades correspond to worse symptoms with the minimum grade being a 0 and the maximum grade being a 5. Toxicities post-randomization are described for each treatment arm by the type of toxicity as well as peak overall grade.

Toxicities are graded using NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. Higher grades correspond to worse symptoms with the minimum grade being a 0 and the maximum grade being a 5. The cumulative incidence of Grade ≥ 3 toxicity was estimated at 6, 12 and 18 months post randomization using Aalen-Johansen estimators for each treatment group. Death from a cause other than toxicity was treated as a competing risk. Comparison of cumulative incidence between the two treatment arms was done using a Z test at fixed time points.

All Grade 2 and 3 infections are reported according to the BMT CTN MOP (Manual of Procedures) where a higher grade corresponds to more severe symptoms. The number of participants with post-randomization infections in each treatment arm is described by severity and type of infection.

All Grade 2 and 3 infections are reported according to the BMT CTN MOP (Manual of Procedures) where a higher grade corresponds to more severe symptoms. The cumulative incidence of severe, life-threatening, or fatal infections (Grade 3), treating death as a competing event, are estimated at 6, 12 and 18 months post randomization using Aalen-Johansen estimators for each treatment group. Comparison of cumulative incidence between the two treatment arms was done using a Z test at fixed time points.

The FACT-BMT version 4.0 instrument is comprised of the Functional Assessment of Cancer Therapy - General (FACT-G), which evaluates the health-related quality of life (HQL) of patients receiving treatment for cancer, and the BMT Concerns module, that addresses disease and treatment-related questions specific to bone marrow transplant. This scale goes from 0 to 196 where higher scores indicate better functioning. The FACT-BMT Total, which has all items in the FACT-G and BMT modules, was used as the outcome measure. This self-reported questionnaire was completed at transplant, randomization, 6 months following the start of maintenance therapy (which corresponds to 6 months post-randomization), and 24 months post-transplant. Comparisons between treatment groups were performed prior to maintenance, 6 months post-randomization and at 24 months after transplant. Only English and Spanish speaking patients were eligible to participate in the quality of life component of this trial.

The MOS SF-36 instrument is a general assessment of health quality of life with eight components: Physical Functioning, Role Physical, Pain Index, General Health Perceptions, Vitality, Social Functioning, Role Emotional, and Mental Health Index. The scale is 0 to 100 where 0 is maximum disability and 100 is no disability, so the higher the score the more positive the outcome. The Physical Component Summary (PCS) and Mental Component Summary (MCS) were used as the outcome measures in summarizing the SF-36 data for this study. This self-reported questionnaire was completed at transplant, randomization, 6 months following the start of maintenance therapy (which corresponds to 6 months post-randomization), and 24 months post-transplant. Comparisons between treatment groups were performed prior to maintenance, 6 months post-randomization and at 24 months after transplant. Only English and Spanish speaking patients were eligible to participate in the quality of life component of this trial.