Ixazomib Citrate in Treating Patients With Relapsed Multiple Myeloma That Is Not Refractory to Bortezomib: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ixazomib Citrate in Treating Patients With Relapsed Multiple Myeloma That Is Not Refractory to Bortezomib (NCT01415882), a randomized phase 2 study. The primary outcome is Proportion of Confirmed Responses With Ixazomib Citrate Alone (Arm A [Closed]), Ixazomib Citrate With Dexamethasone (Arms B + C), or With Dexamethasone and Cyclophosphamide (Arm D), or With Dexamethasone, Cyclophosphamide, Daratumumab (Arm E).

2. Clinical Question

The primary outcome is a response proportion, not a direct measure of how long a response lasted or whether treatment changed survival. The treatment arms differ in regimen features, including dose and additional agents, so their arm-level response proportions describe distinct groups. They should not be treated as a clean estimate of the effect of adding any single drug unless a suitable comparative analysis is reported.

The posted outcome counts include 32.0 participants in Arm A, 35.0 in Arm B, 35.0 in Arm C, 36.0 in Arm D, and 24.0 in Arm E. The clinical question is therefore about confirmed response within each listed treatment group and the precision of those estimates, rather than a single pooled response result.

3. Trial Design

This was a phase 2, randomized, unmasked, parallel-group trial sponsored by Mayo Clinic. The registry reports enrollment of 165 and a completed status. The recorded start date is 2012-01-31, and the primary completion date is 2023-04-21. The registry record does not report the randomization method, allocation ratio, or details of how treatment assignment was implemented.

Five ixazomib-based arms appear in the outcome record. Arm A is labeled ixazomib citrate and dexamethasone and is marked closed to accrual. Its description says participants received ixazomib citrate, with dexamethasone added for lack of minor response by the end of the second cycle or lack of partial response by the end of the fourth cycle. Arm B used ixazomib citrate and dexamethasone; Arm C used higher-dose ixazomib citrate and dexamethasone; and Arm D added cyclophosphamide to ixazomib citrate and dexamethasone. The Arm E description names ixazomib citrate, cyclophosphamide, and daratumumab and also describes dexamethasone administration.

The posted arm descriptions specify oral dosing schedules and recurring cycles, with some cycle-limited treatment details. They do not provide a complete account of treatment duration for every arm in the registry text. The trial’s listed secondary outcomes are confirmed response after dexamethasone addition in Arm A, overall survival, event-free survival, and adverse-event incidence. Five outcome measures are reported in total, but the registry does not post analysis results for the secondary outcomes in the record.

Randomization can support a fair comparison when groups are analyzed as assigned and the analysis accounts for the trial design. However, this trial has multiple regimens and the registry does not provide a formal analysis plan or a posted primary-outcome analysis. Arm-level response proportions can be described, but they do not by themselves establish the effect of one regimen component. Masking is listed as none, and the registry record does not report the sample-size justification, any interim analyses, or detailed procedures for treatment adherence and follow-up.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All eligible patients that received treatment and a disease evaluation.

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 Proportion of Confirmed Responses With Ixazomib Citrate Alone (Arm A [Closed]), Ixazomib Citrate With Dexamethasone (Arms B + C), or With Dexamethasone and Cyclophosphamide (Arm D), or With Dexamethasone, Cyclophosphamide, Daratumumab (Arm E), measured over 2.5 years.

The primary endpoint is the proportion of evaluable participants with a confirmed response during the stated 2.5 years. The response definition includes stringent complete response, complete response, very good partial response, or partial response. A qualifying status had to be recorded on 2 separate evaluations while the participant was receiving ixazomib citrate with or without dexamethasone. The endpoint description says the proportion is estimated as the number of successes divided by the total number of evaluable patients.

A response endpoint provides a direct summary of how often participants meet a specified disease-response criterion. Requiring confirmation on separate evaluations makes the endpoint less dependent on a single assessment. This is a general statistical rationale for confirmation; the registry does not report further details of response assessment, adjudication, or the timing of evaluations.

The endpoint can summarize response within an arm, but it does not describe response duration, time to progression, overall survival, or the full burden of adverse events. Those are distinct outcomes. The registry lists overall survival and event-free survival as secondary outcomes, but their results are not reported in the registry record. The posted primary outcome values are proportions, with arm-specific participant counts; numerical confidence limits are not posted alongside them.

The listed analysis population is all eligible patients who received treatment and a disease evaluation. This is narrower than an analysis of every randomized participant. The record does not say how eligibility, missing evaluations, or other departures from the intended analysis population were handled. The stated exact binomial method is an approach for estimating a confidence interval around a response proportion; it does not, on its own, adjust for differences between treatment arms or address missing data.

7. Results Posted in the Registry

• Arm B (Ixazomib Citrate and Dexamethasone): 0.0% (0/35) versus 0.0% (0/32) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0); unadjusted two-proportion z-test p = n/a.
• Arm C (Higher-dose Ixazomib Citrate and Dexamethasone): 0.0% (0/35) versus 0.0% (0/32) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0); unadjusted two-proportion z-test p = n/a.
• Arm D (Ixazomib Citrate, Dexamethasone, and Cyclophosphamide): 0.0% (0/36) versus 0.0% (0/32) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0); unadjusted two-proportion z-test p = n/a.
• Arm E (Ixazomib Citrate, Cyclophosphamide, Daratumumab): 0.0% (0/24) versus 0.0% (0/32) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0); unadjusted two-proportion z-test p = n/a.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level: a participant either meets the confirmed-response definition or does not, according to the endpoint description. The arm-level proportion is the number of participants with a qualifying response divided by the number of evaluable participants in that arm. The registry’s outcome record gives the resulting proportions and arm counts, but does not give the underlying response numerators. Those numerators should not be reconstructed from rounded proportions.

What does an exact binomial interval describe?

The endpoint description specifies exact binomial 95% confidence intervals for the true success proportion. In general, a confidence interval expresses uncertainty in an estimate arising from sampling variation. An exact binomial method is designed for a binary outcome and avoids relying on a normal approximation to the distribution of the estimated proportion. The interval can be wider or narrower depending on the observed data and the amount of information available. The registry states the method but does not report the calculated interval limits for the arms.

A confidence interval is not a probability statement that the particular interval contains the true value. It is an interval produced by a procedure with a stated long-run coverage property under its assumptions. It also does not correct bias from selection, missing outcomes, outcome misclassification, or differences in care between groups. Those concerns need design and analysis information beyond the interval method.

What can randomization contribute?

Random allocation is intended to make treatment groups comparable on average with respect to measured and unmeasured characteristics. This supports causal comparisons when assignment is preserved in the analysis and the comparison is specified and appropriately conducted. The registry identifies the study as randomized and parallel, but does not report the randomization procedure, allocation ratio, concealment details, or analysis population for a between-arm comparison. It also lists no analyses in its analysis count. The arm-specific proportions remain descriptive without a reported comparative analysis.

Unmasked treatment means participants and study personnel were not blinded according to the registry’s masking designation. For an outcome based on disease evaluations, knowledge of treatment assignment could matter depending on assessment procedures. The registry does not report whether evaluations were independently reviewed or blinded, so the implications for response assessment cannot be determined from the record.

Why can over-dispersion matter?

Over-dispersion is a general issue when outcomes vary more across participants or clusters than a simple statistical model expects. For a binary proportion, this can arise when observations are not effectively independent or when meaningful subgroups have different underlying response probabilities. Ignoring extra variability can make uncertainty appear smaller than it is. The registry does not report an over-dispersion assessment, a model for clustered observations, or a reason to assume such a model was needed. The stated exact binomial approach concerns arm-specific proportions and does not itself establish independence or address clustering.

The trial has several arms and multiple listed outcomes. Testing multiple treatment contrasts or outcomes can increase the chance of a false-positive finding if no multiplicity strategy is used. A prespecified testing hierarchy, adjustment, or other multiplicity plan is not reported in the registry record. Since no formal analyses are posted, the record does not establish how multiplicity was addressed.

Time-to-event outcomes such as overall survival and event-free survival require information about event times and censoring. Their analysis methods and results are not reported in the registry record. The primary binary response proportion should not be substituted for those outcomes. Likewise, the adverse-event counts are descriptive safety summaries and do not constitute an adjusted comparative analysis.

Any sample-size planning illustrations should be interpreted as planning scenarios rather than evidence about trial power after completion. The registry’s own sample-size justification and assumptions are not reported in the registry record. No observed-power interpretation is warranted from the posted outcome proportions. The primary endpoint description names an exact binomial interval method, but it does not describe the overall statistical analysis plan, handling of missing data, or a method for comparing the randomized groups.

10. Confidence Intervals and Precision

The posted response proportions are point estimates. They give a concise description of the observed outcome in each arm, but do not show how uncertain each estimate is. The registry endpoint description states that 95% confidence intervals were to be calculated using the exact binomial method. The arm records do not include interval limits, so the intended confidence intervals are not reported in the registry record.

Precision depends in part on the amount of information in each arm. The posted counts are 32.0 for Arm A, 35.0 for Arm B, 35.0 for Arm C, 36.0 for Arm D, and 24.0 for Arm E. The response proportions should be read alongside these denominators. An estimate from a group with fewer evaluated participants generally carries more sampling uncertainty than an otherwise comparable estimate from a larger group; this is a general statistical point, not an additional result from the trial.

Confidence intervals would help readers assess the range of plausible response proportions under the specified model and would show whether estimates are precise enough to distinguish meaningful possibilities. No interval limits are posted, and the registry does not provide a formal comparative analysis. Therefore, apparent differences among the point estimates should not be treated as statistically established differences. The listed comparison entries report 0.0 estimates and 0.0 to 0.0 intervals for every listed comparison, but those entries conflict with the arm-level proportions and do not supply a credible account of their comparative precision.

Precision is not the same as validity. Even a narrow interval would not resolve concerns about the analysis population, missing evaluations, outcome assessment, or applicability. The registry record does not report enough detail to evaluate those issues fully. The available arm-level proportions can be described, but their uncertainty and the uncertainty of between-arm contrasts cannot be quantified from the posted interval results.

11. Multiplicity, Missing Data and Analysis Populations

The trial includes five treatment arms and lists several outcomes, including confirmed response, overall survival, event-free survival, and adverse-event incidence. When many arms or outcomes are examined, multiple statistical tests can increase the chance of obtaining an apparently notable result by chance. A prespecified multiplicity strategy, such as a hierarchy of comparisons or an adjustment to account for multiple testing, is not reported in the registry record. The record also lists no analyses, so it does not show which contrasts, if any, were formally tested.

The primary population is described as all eligible patients who received treatment and a disease evaluation. That definition excludes randomized participants who did not receive treatment or did not have a disease evaluation. The registry does not report how many participants were excluded for these reasons or how missing response assessments were handled. It does not state whether any imputation, sensitivity analysis, or alternative analysis population was used.

The record does not report an intention-to-treat analysis, a per-protocol analysis, or a prespecified approach to protocol deviations. It also does not explain whether all randomized participants were retained in their assigned groups for any comparison. These details matter because excluding participants after randomization can affect comparability between groups, particularly if the reasons for exclusion differ by arm.

The registry provides arm-level response denominators, but the relationship between those denominators and the total enrollment is not explained. The safety denominators also differ from some response denominators. Reasons for these differences are not reported in the registry record. Without participant flow, outcome completeness, and analysis-population details, the effect of missing or excluded observations cannot be assessed.

The registry states that exact binomial confidence intervals were planned for the response proportion, but does not post their values or a broader statistical plan. It does not report interim analyses, stopping rules, or the sample-size justification. These omissions limit assessment of how the reported outcome was selected, how uncertainty was handled, and whether the final analysis followed a prespecified plan.

12. 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: gastrointestinal disorders - oth spec (16.7%), generalized muscle weakness (16.7%), infections and infestations - oth spec (12.5%), lung infection (12.5%), dyspnea (12.5%).

The adverse-event record reports participants at risk and participants affected by serious adverse events, other adverse events, and deaths for each arm. In Arm A, 16 of 33 participants at risk were affected by serious adverse events, 33 of 33 by other adverse events, and 5 deaths were reported. Arm B reports 11 of 35 affected by serious adverse events, 35 of 35 by other adverse events, and 5 deaths. Arm C reports 11 of 35, 35 of 35, and 4 deaths, respectively. Arm D reports 14 of 36, 36 of 36, and 8 deaths. Arm E reports 14 of 24, 24 of 24, and 6 deaths.

These are counts, not adjusted comparisons between treatments. The registry does not describe whether deaths were caused by treatment or disease, so deaths should not be interpreted as treatment-related from these counts alone. The safety denominators differ from the posted response denominators in some arms; reasons are not reported in the registry record.

The listed serious-event terms include gastrointestinal disorders - Oth spec and generalized muscle weakness, each at 16.7%; infections and infestations - Oth spec, lung infection, and dyspnea, each at 12.5%; and platelet count decreased at 11.1%. The registry does not provide further context for these percentages here, such as event counts by term or the duration of observation. The figures describe reported events and do not establish comparative risk or causation.

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

The posted results describe confirmed-response proportions in five ixazomib-based treatment groups. They show the observed proportions for the registry-defined primary outcome among participants in the stated analysis population. The arm-level values are useful descriptive summaries, but the absence of posted confidence intervals and a valid formal comparison limits conclusions about how precisely the proportions are estimated or whether groups differ.

The results do not establish the causal effect of adding dexamethasone, increasing ixazomib dose, or adding cyclophosphamide or daratumumab. The arms combine different regimen features, and Arm A has a response-contingent dexamethasone addition. A direct claim about a particular component would require an appropriate prespecified comparison and analysis. The registry’s listed comparison estimates are all 0.0 with intervals from 0.0 to 0.0, despite differing arm-level proportions; these entries should not be taken as a valid demonstration of equality.

The primary endpoint is confirmed response, not survival or duration of benefit. Overall survival and event-free survival are listed as secondary outcomes, but their results are not reported in the registry record. The response proportions also do not capture the full safety profile. Serious-event and death counts are reported by arm, but the record does not establish that deaths or events were caused by treatment or provide adjusted comparisons.

The record describes the trial as randomized, which is relevant to potential treatment comparisons, but it does not report the randomization details, analysis plan, missing-data procedures, or complete participant flow. The primary analysis population is limited to eligible participants who received treatment and a disease evaluation. These limitations leave uncertainty about the impact of exclusions and incomplete assessments.

Overall, the registry supports a descriptive reading of the posted response proportions and adverse-event counts. It does not support a definitive comparative conclusion about efficacy, survival, or safety. A result should be interpreted in light of the missing uncertainty estimates, the inconsistent listed comparison entries, and the lack of reported analysis details.

14. Why This Trial Matters Statistically

This trial is statistically interesting because it reports several related treatment regimens within one randomized, parallel phase 2 study. The arms vary in dose and in the use of additional agents, while the primary outcome is a binary confirmed-response proportion. This structure makes the distinction between describing each arm and estimating a treatment contrast especially important. Arm-specific proportions are not interchangeable with a randomized comparative effect.

The endpoint definition also illustrates why outcome specification matters. A response had to meet a recognized category and be recorded on 2 separate evaluations. That confirmation requirement defines what counts as a success and therefore shapes the estimated proportion. The analysis population is also explicit: eligible participants who received treatment and a disease evaluation. However, the registry does not report how participants missing an evaluation were handled, limiting a full assessment of the outcome estimate.

Precision is central to interpretation. The registry says exact binomial 95% confidence intervals were to be calculated, yet interval limits are not posted for the primary results. In addition, the listed between-arm comparison estimates are 0.0 with intervals from 0.0 to 0.0 despite different observed arm proportions. This contrast between descriptive results and unusable comparison entries demonstrates why readers need coherent estimates, uncertainty intervals, and transparent analysis methods before drawing comparative conclusions.

The safety record adds another statistical lesson: counts require denominators and context. The registry reports serious-event and other-event counts with at-risk denominators, as well as death counts, but does not establish causation or provide a comparative safety model. Taken together, the record shows how study design, outcome definition, analysis population, precision, and reporting consistency all affect what can responsibly be inferred from clinical trial results.

15. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The main limitation for interpreting the primary result is that the registry posts arm-level response proportions but no confidence-interval limits, even though the endpoint description states that exact binomial 95% intervals would be calculated. The registry also does not provide a formal primary-outcome analysis. Its listed pairwise comparison entries report risk differences of 0.0 and intervals of 0.0 to 0.0 for all comparisons, which do not align with the differing arm-level proportions. These entries cannot support a meaningful comparison.

The registry does not report a sample-size justification, randomization details, an analysis plan, or interim analyses. It does not describe handling of missing response assessments, protocol deviations, or alternative analysis populations. The stated primary population includes eligible participants who received treatment and a disease evaluation, but participant flow and reasons for any exclusions are not reported. Safety denominators differ from response denominators in some arms, and the reason is not reported.

The arms involve different treatment combinations, and Arm A is described as closed to accrual with dexamethasone added according to response milestones. Thus, arm-level results cannot isolate the contribution of an individual drug or dose. The record lists secondary outcomes, but does not report their results. It also provides limited detail on response assessment, event follow-up, and the context behind the serious-event term percentages. These reporting gaps constrain interpretation of both efficacy and safety.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Ixazomib Citrate in Treating Patients With Relapsed Multiple Myeloma That Is Not Refractory to Bortezomib — NCT01415882.
• Registry record last updated 2026-06-23; status last verified 2026-05.
• Results first posted 2024-06-13.
• 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.

19. Record Summary

The registry describes a completed, randomized, unmasked, parallel phase 2 trial sponsored by Mayo Clinic, with enrollment of 165. It evaluates ixazomib-based regimens in relapsed multiple myeloma and lists five treatment arms. The primary outcome is the proportion of treated, eligible participants with a confirmed response, assessed within 2.5 years. The response definition requires a qualifying disease status on 2 separate evaluations.

Posted response proportions range from 0.156 in Arm A to 0.75 in Arm E, with outcome counts of 32.0, 35.0, 35.0, 36.0, and 24.0 across Arms A through E. The registry says exact binomial 95% confidence intervals were planned, but interval limits and a formal primary-outcome analysis are not reported in the registry record. The listed comparison entries conflict with the arm-level proportions. Serious adverse-event counts, other adverse-event counts, and deaths are reported by arm, without evidence of causation or adjusted comparative safety results. Overall survival and event-free survival are listed as secondary outcomes, but their results are not reported in the registry record.