Ixazomib and Dexamethasone Versus Ixazomib, Dexamethasone and Lenalidomide, Randomized With NFKB2 Rearrangement: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ixazomib and Dexamethasone Versus Ixazomib, Dexamethasone and Lenalidomide, Randomized With NFKB2 Rearrangement (NCT02765854), a randomized phase 2 study. The primary outcome is The Primary Objective of the Study is to Test Whether the NFKB2 Rearrangement Can Guide the Selection of Treatment (Ixazomib Plus Dexamethasone (Id) or Ixazomib Plus Lenalidomide and Dexamethasone (IRd)) by Conducting the 3 Following Comparisons.

2. Clinical Question

3. Trial Design

This is a completed, randomized, open-label, parallel-group phase II trial sponsored by Emory University. The registry record gives an enrollment of 70. The study began on 2016-09-01 and lists primary completion on 2023-05-23. It addresses recurrent or refractory plasma cell myeloma and investigates treatment selection in relation to NFKB2 rearrangement.

The arm descriptions distinguish patients with an unmutated rearrangement from those with a mutated rearrangement. Arm A is ixazomib and dexamethasone for the unmutated group. Arms B and C are described for the mutated group: Arm B uses ixazomib and dexamethasone, while Arm C adds lenalidomide. The record describes the trial as randomized, but does not report the allocation sequence, allocation concealment, or detailed rules for assigning patients to the molecular groups and treatment arms.

Masking is listed as none. This means the registry describes the study as open-label; it does not establish whether any specific outcome assessment was independently blinded. The record’s primary objective includes comparisons with a historical response rate, rather than relying solely on a concurrent randomized control. It does not report how the historical control was selected or whether its assessment methods and patient characteristics were considered comparable.

The registry lists secondary outcomes including time to treatment failure, prevalence of NFKB2 rearrangement among screened patients, response at baseline and at 12 months, and adverse-event incidence. Results for these outcomes are not reported in the registry record. Further details on follow-up, treatment duration, adherence, and the analysis population are also not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as The Primary Objective of the Study is to Test Whether the NFKB2 Rearrangement Can Guide the Selection of Treatment (Ixazomib Plus Dexamethasone (Id) or Ixazomib Plus Lenalidomide and Dexamethasone (IRd)) by Conducting the 3 Following Comparisons, measured over 112 days.

The primary outcome is overall response rate (ORR) at 4 cycles, specified as 112 days. It is a binary clinical outcome: a participant is classified according to whether a response meeting the stated criteria is recorded by that assessment time. The registry describes response using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions, assessed by MRI. Complete response is defined as disappearance of all target lesions. Partial response is defined as a decrease of at least 30% in the sum of the longest diameter of target lesions. Overall response is defined as complete response plus partial response.

Response rate is used to summarize the proportion of participants meeting a response definition within a specified assessment period. In this trial, the planned response-rate comparisons are tied to the proposed treatment-selection role of NFKB2 rearrangement. The registry specifies a historical response rate of 30% as the benchmark. It describes Arms A and C as designed to detect an improved response rate of 60% versus that benchmark, and Arm B as designed to assess equivalence to the historical rate within a tolerance of +/- 20%.

The endpoint description explains the planned measurement, not the observed result. The response counts, response-rate estimates, confidence intervals, and hypothesis-test results are not reported in the registry record. The registry also does not explain how missing or unevaluable MRI assessments were handled.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry gives a phase II randomized parallel-group design and describes three primary comparisons centered on a historical response-rate benchmark. It also identifies an overall response-rate endpoint at 4 cycles (112 days). The exact analysis procedures beyond the stated design objectives are not reported in the registry record.

What does a response-rate comparison test?

In general, a response-rate analysis classifies each participant as meeting or not meeting the endpoint definition at the specified assessment time. A rate summarizes the frequency of response in the analyzed group. A hypothesis test asks whether the observed data are sufficiently inconsistent with a specified benchmark under a statistical model. A confidence interval describes uncertainty around an estimate; it helps distinguish a precise estimate from one compatible with a broad range of response rates.

For Arms A and C, the registry describes a test against a historical response rate of 30%, with a planned improved response rate of 60%. It states use of Simon's 2-stage Optimum design, with power of at least 90% and an alpha error of 5%. The record does not report the stage-specific decision boundaries, the planned number of participants at each stage, or whether any interim stopping rule was applied. Those design details are not reported in the registry record.

What does the equivalence objective mean?

For Arm B, the stated aim is to claim equivalence to the historical response rate of 30%, assuming a true response rate approximately 30% and an equivalence tolerance of +/- 20%. The registry describes power of at least 80% at a significance level of 0.05. In general, an equivalence analysis asks whether uncertainty around the treatment-group estimate is sufficiently contained within prespecified acceptable limits. A non-significant test of difference would not, by itself, demonstrate equivalence. The registry does not report the statistical procedure, interval method, or observed analysis for this objective.

Why does the historical benchmark matter?

General statistical context: a historical benchmark is not a concurrently randomized control group. The validity of the comparison depends on whether the earlier response-rate estimate is relevant to the trial population, endpoint definition, assessment timing, and clinical context. Randomization can balance factors between concurrent groups when allocation is properly implemented, but it does not itself make a historical comparison equivalent to a randomized comparison. The source and comparability assessment for the 30% benchmark are not reported in the registry record.

How should the response definition be understood?

The endpoint uses RECIST v1.0 criteria for target lesions assessed by MRI. Complete response means disappearance of all target lesions. Partial response requires at least a 30% decrease in the sum of the longest diameter of target lesions. The record defines overall response as complete response plus partial response. In general, a prespecified definition supports consistent classification, but interpretation also depends on assessment timing, the handling of unevaluable scans, and the analysis population. Those operational and analytic details are not reported in the registry record.

What is not established by the design description?

Power is a design property calculated under assumptions about the true effect, the analysis, and the planned information. It is not the probability that the treatment is effective, and it is not an observed result. The registry's stated power and alpha describe planning targets for the specified hypotheses. They do not show whether those targets were achieved in the completed trial. The observed response data and corresponding analyses are not reported in the registry record.

General statistical context: multiple endpoints or comparisons can raise multiplicity concerns because repeated testing can increase the chance of at least one false-positive finding if no suitable strategy is used. The record describes several primary comparisons and lists secondary outcomes, but does not report a multiplicity procedure. It also does not report a sample-size justification beyond the objective-specific design statements, an analysis plan, model details, missing-data methods, or the populations included in analyses. These omissions prevent a full appraisal of how the planned methods were implemented.

10. Multiplicity, Missing Data and Analysis Populations

The primary objective is described as involving three comparisons, and the registry also lists secondary outcomes for time to treatment failure, prevalence of NFKB2 rearrangement, response at baseline and at 12 months, and adverse-event incidence. Considering several outcomes or hypotheses can create multiplicity concerns. In general, testing multiple hypotheses without an appropriate strategy can increase the chance of a false-positive result. The registry does not report whether the primary comparisons were treated as a family, whether testing order or error-rate control was prespecified, or how secondary outcomes were interpreted alongside the primary objective.

The record gives objective-specific design targets, including stated power and significance levels, but does not report a complete statistical analysis plan. It does not specify the planned estimand, the precise analysis population, or whether analyses were intention-to-treat, per-protocol, or based on evaluable participants. These details are important because different inclusion rules can lead to different response-rate estimates, particularly for an equivalence objective.

Missing-data handling is not reported in the registry record. The record does not explain how absent or unevaluable MRI assessments, missed visits, withdrawals, or incomplete follow-up were classified for the response endpoint. It also does not report whether sensitivity analyses were planned to assess the consequences of missing outcomes.

Interim analyses and any associated decision rules are not reported in the registry record. Although the description names a Simon two-stage design for Arms A and C, the stage boundaries and actual conduct of interim decisions are not given. The analysis methods for time to treatment failure and other secondary outcomes are also not reported. Accordingly, the available information is insufficient to determine how multiplicity, missingness, or analysis-population choices affected the final conclusions.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: conjunctivtis (18.2%), thrombocytopenia (14.3%), pneumonia (11.1%), colitis (7.4%), diarrhea (7.4%).

The adverse-event summary gives group counts for serious adverse events and for other adverse events. Arm A lists 20 of 27 participants as affected in each category. Arm B lists 10 of 22 as affected in each category. Arm C lists 10 of 21 for serious adverse events and 16 of 21 for other adverse events. These are counts associated with the reported group sizes, not estimates of comparative treatment effect.

The registry also lists serious adverse-event terms with percentages: Conjunctivtis, 18.2%; thrombocytopenia, 14.3%; pneumonia, 11.1%; colitis, 7.4%; diarrhea, 7.4%; and bone pain, 4.8%. The denominator and the method used to select or rank these terms are not reported in the registry record. The term is spelled “Conjunctivtis” in the registry listing.

In general, safety counts describe events recorded under the study’s reporting rules. They do not, on their own, establish that a treatment caused an event or allow a reliable comparison of risk between arms. The registry does not report event severity grades, exposure duration, recurrent-event handling, or a statistical comparison of the groups. These figures should therefore be read as descriptive registry counts, not as evidence of a causal difference.

12. What the Result Does, and Does Not, Mean

The trial is structured to examine a treatment-selection question involving NFKB2 rearrangement in recurrent or refractory plasma cell myeloma. It specifies different response-rate objectives for treatment arms and uses a historical response rate of 30% as the benchmark. The endpoint is overall response at 4 cycles, defined using RECIST v1.0 criteria for target lesions assessed by MRI.

The registry record does not report the observed primary outcome analyses. It gives no response counts, response-rate estimates, confidence intervals, or test results. Therefore, the posted information does not show whether the response rate in any arm exceeded the historical benchmark, whether Arm B met its equivalence objective, or whether NFKB2 rearrangement guided treatment selection as intended. A completed trial status and a stated design objective cannot answer those questions.

The record also does not establish comparative benefit or harm between the treatment strategies. The design description does not provide arm-specific efficacy results, and the adverse-event counts are descriptive without reported comparative analyses. They should not be interpreted as proving that a regimen caused or prevented an event.

In general, a clinical trial result is interpreted by considering the size of the estimated effect, its precision, the prespecified analysis, missing information, and the relevance of the comparison. Here, important elements—including primary outcome estimates, uncertainty, analysis populations, and handling of missing assessments—are not reported in the registry record. The appropriate conclusion is therefore limited: the registry documents the trial’s question, design features, endpoint definition, and some safety counts, but does not provide enough outcome analysis to resolve its treatment-selection question.

13. Why This Trial Matters Statistically

This trial raises a statistical question that goes beyond comparing treatment averages: whether a molecular characteristic can help select between treatment strategies. Such a question requires the marker definition, treatment assignment, response assessment, and analysis to fit together. The registry describes NFKB2 rearrangement-based arm definitions and a response-rate endpoint, making the relationship between molecular subgroup and treatment strategy central to interpretation.

The design also illustrates the distinction between concurrent randomized comparisons and historical-control objectives. A historical rate can serve as a benchmark for a phase II study, but its interpretation depends on the relevance and comparability of the earlier data. The registry names a benchmark and planned response targets, while the source and comparability of that benchmark are not reported in the registry record. This is important when judging how much a response estimate can establish.

The separate equivalence objective is another statistically important feature. Equivalence requires evidence that the estimate is sufficiently close to a benchmark under prespecified limits; lack of evidence for a difference is not enough. The registry states an equivalence tolerance and a design target for Arm B, but does not report the analysis results or the methods used to assess equivalence.

Finally, the record shows why design descriptions and outcome reporting must be read separately. It contains a completed status, an enrollment figure, design objectives, and safety counts, but no primary outcome analysis. Without estimates and measures of uncertainty, readers cannot assess the strength or precision of the trial’s response findings. The distinction between a planned statistical question and a reported answer is essential to responsible interpretation.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

Several trial-specific limitations of interpretation follow from the information not reported in the registry record. The primary response results are absent, including arm-specific response counts, rates, uncertainty intervals, and test results. This prevents evaluation of the planned improvement and equivalence objectives. The record also does not identify the source of the historical response rate of 30% or describe how the benchmark was judged comparable to the enrolled population and endpoint procedures.

The treatment-arm descriptions link Arm A to an unmutated rearrangement and Arms B and C to a mutated rearrangement, but the registry does not fully explain the randomization process or the assignment of participants across arms. It does not report the distribution of enrollment by arm or molecular status. Without that information, the extent of concurrent randomized evidence relevant to each treatment-selection question cannot be assessed from the registry record.

Key analysis details are not reported, including the analysis populations, missing-outcome rules, handling of unevaluable MRI assessments, multiplicity strategy, and the conduct of any stage-based decisions. The record also does not provide follow-up completeness or the operational details for secondary outcome analyses.

The safety listing has limited context: the denominator for the serious-event percentages, event severity, exposure duration, and comparative analysis methods are not reported. These omissions restrict interpretation of both efficacy and safety. The registry’s completed status does not fill these gaps or substitute for outcome analyses.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Ixazomib and Dexamethasone Versus Ixazomib, Dexamethasone and Lenalidomide, Randomized With NFKB2 Rearrangement — NCT02765854.
• Registry record last updated 2025-06-26; status last verified 2025-06.
• Results first posted 2025-06-26.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

NCT02765854 is a completed randomized, open-label, parallel-group phase II trial sponsored by Emory University. It enrolled 70 participants and addresses recurrent or refractory plasma cell myeloma. The study began on 2016-09-01, with primary completion listed as 2023-05-23.

The treatment strategy concerns ixazomib and dexamethasone, with lenalidomide added in one arm, and is described in relation to NFKB2 rearrangement status. The primary endpoint is overall response rate at 4 cycles (112 days), with response defined using RECIST v1.0 criteria for target lesions assessed by MRI. Planned comparisons use a historical response rate of 30%, including improvement objectives for Arms A and C and an equivalence objective for Arm B.

Arm-level primary outcome analyses are not reported in the registry record. The record lists secondary outcomes and descriptive adverse-event counts, but does not provide the analysis details needed to assess the primary treatment-selection question.