Ixazomib Plus Pomalidomide and Dexamethasone in Treating Patients With Relapsed or Relapsed/Refractory Multiple Myeloma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ixazomib Plus Pomalidomide and Dexamethasone in Treating Patients With Relapsed or Relapsed/Refractory Multiple Myeloma (NCT02119468), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Patients With Dose-Limiting Toxicities (Phase I).

2. Clinical Question

3. Trial Design

This was a phase I/II trial with non-randomized allocation, no masking, and a parallel model. The registry record lists enrollment of 32 and identifies City of Hope Medical Center as the sponsor. The study status is completed. Its recorded start date is 2014-07-22, and its primary completion date is 2016-05-18.

The intervention combined ixazomib citrate, pomalidomide, and dexamethasone. The two treatment descriptions differ in the ixazomib dose: one is labeled 3mg MLN9708 and the other 4mg MLN9708. In both descriptions, ixazomib is taken orally on days 1, 8, and 15; dexamethasone orally on days 1, 8, 15, and 22; and pomalidomide orally on days 1-21. Courses repeat every 28 days unless disease progression or unacceptable toxicity occurs.

The primary outcome is a phase I count of patients with dose-limiting toxicities during cycle 1. The record defines a dose-limiting toxicity as a qualifying toxicity at least possibly related to pomalidomide or MLN9708, occurring during cycle 1 and graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. The described dose-finding rule identifies the maximum tolerated dose using a threshold of 1/6 dose-limiting toxicities in course 1. The recommended phase II dose would generally be the maximum tolerated dose, but could be lower after review of available data and cumulative toxicities.

Non-randomized dose groups cannot be treated as randomized alternatives. Differences between them may reflect group composition, treatment exposure, or other factors in addition to dose. The registry record does not report a randomized comparator, a masking procedure, or an adjusted comparison between the groups.

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

Analysis population for the primary outcome, as defined in the registry: Patients were considered evaluable for DLT if receiving at least 75% of both Pomalidomide and MLN9708 and followed for the full 28 days during cycle 1 or experience a DLT. All patients who are not evaluable for DLT were replaced.

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 Number of Patients With Dose-Limiting Toxicities (Phase I), measured over From the initial treatment to Day 28 (Cycle #1).

The primary endpoint counts patients with dose-limiting toxicities during the first 28-day treatment cycle. It is a safety and dose-finding measure, rather than a measure of tumor response or survival. The endpoint is intended to identify toxicities that may help determine a tolerable dose for further study.

The registry defines a dose-limiting toxicity as a toxicity listed in Section 7.3 that is at least possibly related to pomalidomide or MLN9708 and occurs during cycle 1. Toxicity grading follows National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. The endpoint timeframe runs from initial treatment to Day 28 of cycle 1.

Eligibility for this assessment is also specified. A patient is evaluable if they received at least 75% of both pomalidomide and MLN9708 and completed the full 28-day follow-up during cycle 1, or experienced a dose-limiting toxicity. Patients who were not evaluable were replaced. This definition affects which patients contribute to the dose-finding assessment; the registry record does not report the observed number evaluable or the dose-limiting toxicity count.

The protocol description says the highest dose level producing 1/6 dose-limiting toxicities in course 1 would be the maximum tolerated dose. The registry record does not report the observed dose-finding result or the dose selected for phase II. It therefore describes the endpoint and its intended role, but not what the endpoint showed in this trial.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record describes a phase I/II, non-randomized, parallel-group study. These design labels help define what statistical conclusions are possible. A parallel structure means participants were assigned to one of the described dose groups rather than receiving both dose schedules in sequence. Non-randomized allocation means the groups were not formed by random assignment. Differences across them may therefore reflect more than the dose level itself.

What does the primary count represent?

The primary endpoint is a count of patients with dose-limiting toxicities during cycle 1. A count records how many patients met the endpoint definition; it is not itself a rate or a time-to-event estimate. In general, a count is easier to interpret when its assessment population and event definition are clear. The registry specifies both an eligibility rule for DLT evaluation and a toxicity definition based on possible relation to pomalidomide or MLN9708 and occurrence during cycle 1. It also states that patients who were not evaluable were replaced.

The dose-finding rule uses the observed DLT count to guide selection of a maximum tolerated dose. The record says the highest dose level producing 1/6 DLTs in course 1 would be the maximum tolerated dose, with the recommended phase II dose generally set at that dose or potentially lower after review of available data and cumulative toxicities. This is a protocol description, not a reported finding. The registry record does not report the observed count or the selected dose.

How should the two dose groups be compared?

Randomization is a design method used to make treatment groups comparable, on average, with respect to measured and unmeasured factors. This study is explicitly non-randomized, so that protection does not apply. The 3mg and 4mg groups can be described separately, but a difference between them cannot be attributed to ixazomib dose alone on the basis of this design. The registry record does not report an adjusted comparison, covariate model, or other statistical method for separating dose effects from group differences.

No masking was used. In general, masking can reduce the influence of knowledge about assigned treatment on some aspects of care, event assessment, or reporting. Its absence does not by itself determine the direction or size of bias, but it is relevant context when interpreting outcomes that involve judgment. The record does not describe a blinded endpoint review.

What do estimates and confidence intervals usually add?

In general, an estimate describes the observed outcome in the study, while a confidence interval expresses uncertainty around that estimate under the statistical model used. A narrow interval indicates greater precision than a wide interval, but neither an estimate nor its interval establishes causality when the design does not support a causal comparison. The registry record does not report a primary DLT estimate with a confidence interval, or confidence intervals for the secondary outcomes. It is therefore not possible to assess the precision of those outcome estimates from the registry record.

Likewise, a p-value is a measure used in a statistical test under specified assumptions; it is not a measure of clinical importance or the probability that a treatment works. The registry record reports no analyses, p-values, or test results. It also does not report the statistical analysis plan, so the intended models, testing procedures, and handling of covariates are not reported in the registry record.

What do the planning calculations mean?

The sample-size assumptions describe planning illustrations based on a stated fraction of the observed effect, with a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. For non-time-to-event outcomes, the illustrations are expressed as participants per arm; for time-to-event outcomes, they use a total event count. These calculations are planning illustrations, not observed power and not a description of the trial's own design. The record does not report the underlying observed effect estimate or the planning values needed to interpret individual illustrations.

In general, planning calculations depend on assumptions about the effect to detect, variability or event frequency, significance level, allocation, and analysis method. If those assumptions do not match the eventual study or target question, the resulting planning figures may not apply. Such calculations do not establish that a study was adequately powered, and they do not replace reporting of the observed outcome estimate and its uncertainty.

What remains unknown statistically?

The record does not report an analysis population for efficacy outcomes, methods for missing outcome data, a multiplicity adjustment, interim analyses, or a statistical analysis plan. It also does not report the observed primary endpoint or secondary outcome estimates. Those omissions limit evaluation of the analysis and its precision. They do not imply that a particular method was or was not used outside the registry record; the relevant information is not reported in the registry record.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Dose Level #1: 3mg MLN9708", "Dose Level #2: 4mg MLN9708")
n      <- c(6, 6)
events <- c(1, 1)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Dose Level #1: 3mg MLN9708  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Dose Level #2: 4mg MLN9708  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists seven outcome measures and names secondary outcomes for duration of response, clinical benefit response rate, one-year overall survival, and one-year progression-free survival at the recommended phase II dose. The primary endpoint is the cycle-one count of patients with dose-limiting toxicities. Considering multiple outcomes can raise a multiplicity issue: when several hypotheses are tested, the chance of at least one apparently notable result can increase. Statistical plans may address this through a prespecified hierarchy or adjustment, but no multiplicity method is reported in the registry record. No outcome analyses are reported either.

The phase I DLT-evaluable population has a stated definition: patients had to receive at least 75% of both pomalidomide and MLN9708 and be followed for the full 28 days during cycle 1, unless they experienced a DLT. Patients not evaluable for DLT were replaced. The record does not provide the number evaluable or the observed DLT count. This endpoint-specific rule should not be assumed to describe the analysis population for response or survival outcomes.

Methods for missing data on secondary outcomes, the handling of incomplete follow-up, and the definition of analysis populations for those outcomes are not reported in the registry record. The statistical analysis plan, including any interim analyses or prespecified hypothesis-testing strategy, is also not reported. Without those details and the outcome estimates, it is not possible to assess how missing observations or multiple outcome assessments influenced the reported evidence.

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: lung infection (28.6%), anemia (14.3%), sinus tachycardia (14.3%), skin infection (14.3%), back pain (14.3%).

The adverse-event record separates the two dose groups and reports participants at risk, participants affected by serious adverse events, participants affected by other adverse events, and deaths. At the 3mg MLN9708 dose level, serious adverse events affected 4 of 7 participants, other adverse events affected 7 of 7, and 4 deaths were reported. At the 4mg MLN9708 dose level, serious adverse events affected 11 of 25 participants, other adverse events affected 25 of 25, and 6 deaths were reported.

These are descriptive counts. The record does not state that the events or deaths were caused by the study drugs, and it does not report causes of death. Because treatment allocation was non-randomized, the counts should not be interpreted as a causal comparison of dose-related risk. The registry also lists serious-event terms, including lung infection at 28.6%, and anemia, sinus tachycardia, skin infection, back pain, and muscle weakness lower limb at 14.3% each. These term-level percentages are reported as recorded; the registry entry does not provide further context for attributing them to treatment.

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

The registry record establishes that a phase I/II trial was conducted to study ixazomib with pomalidomide and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma. It defines a first-cycle dose-limiting toxicity endpoint, describes two ixazomib dose levels, and provides some adverse-event counts. These details help readers understand the trial's purpose and the structure of its safety reporting.

The record does not report the primary endpoint result. It therefore does not show how many evaluable patients experienced a dose-limiting toxicity, whether the stated dose-finding criterion was met, or which dose was selected as the maximum tolerated or recommended phase II dose. It also does not report estimates for the listed response or survival outcomes. No confidence intervals or hypothesis-test results are reported, so the precision of any efficacy estimate cannot be assessed from the registry record.

The non-randomized dose groups do not provide a like-for-like control comparison. Even if outcome counts differed between groups, the design would not by itself establish that dose caused the difference. The posted safety counts are descriptive, and the record does not identify whether events or deaths were attributed to study treatment.

Accordingly, the registry record supports a description of the study design, regimen, endpoint rules, and reported safety counts. It does not support a conclusion about the size or precision of a treatment effect, a comparative benefit between dose levels, or the overall efficacy of the combination. Those questions require outcome results and analysis details that are not reported in the registry record.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of early-phase dose-finding in a non-randomized, parallel-group setting. Its primary endpoint is not a general measure of treatment benefit: it is a defined count of dose-limiting toxicities within cycle 1, intended to inform dose selection. Understanding that distinction prevents a safety and dose-finding endpoint from being mistaken for evidence about response or survival.

The registry record also illustrates why the analysis population matters. DLT evaluability depends on receiving a specified proportion of both study drugs and completing the stated cycle-one follow-up, unless a DLT occurs. Patients who are not evaluable are replaced. Those rules determine who contributes to the dose-finding assessment, but the record does not provide the resulting evaluable count or event count. Without these results, the dose-finding rule cannot be connected to an observed conclusion.

The non-randomized structure is equally important. Two dose groups may look like a direct comparison, but they are not randomized control and treatment arms. Statistical interpretation must therefore distinguish descriptive group summaries from causal effects. This matters when reading both adverse-event counts and any potential dose-related outcome differences.

Finally, the record names several secondary outcomes but does not report their estimates or the analysis strategy. The absence of reported analyses limits assessment of precision, missing-data handling, and multiplicity. These are not minor details when a study considers several outcomes; they define how much confidence readers can place in any apparent pattern. Here, the available registry information is useful for understanding the intended design, but it does not provide the results needed to judge the trial's efficacy findings.

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.

The main limitation for statistical interpretation is that the registry record does not report the observed primary endpoint count, the dose-finding outcome, or estimates for the listed secondary outcomes. Without those results, neither the magnitude nor precision of the trial outcomes can be evaluated. Completion status and enrollment information do not replace endpoint reporting.

Allocation was non-randomized, and the two groups differed by intended ixazomib dose. The registry record does not report a control group or an adjusted analysis that would support a causal comparison between dose levels. Differences in descriptive counts could reflect group composition or other factors, not solely dose.

The primary endpoint uses a defined DLT-evaluable population, with patients who are not evaluable replaced. The registry record does not report how many patients met the evaluability definition or how replacement affected the analysis. It also does not describe analysis populations or missing-data methods for response and survival outcomes. These features limit assessment of how fully the available observations represent the study population for each endpoint.

Statistical analysis details are also limited: the analysis plan, multiplicity strategy, interim analyses, and outcome-level uncertainty estimates are not reported in the registry record. The adverse-event counts do not include attribution or causes of death. Taken together, the record permits a design-level and descriptive safety reading, but not a comprehensive statistical assessment of efficacy, dose differences, or treatment-related risk.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Ixazomib Plus Pomalidomide and Dexamethasone in Treating Patients With Relapsed or Relapsed/Refractory Multiple Myeloma — NCT02119468.
• Registry record last updated 2026-10-26; status last verified 2026-10.
• Results first posted 2021-09-16.
• 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

NCT02119468 is a completed, non-randomized phase I/II parallel-group trial sponsored by City of Hope Medical Center. It studied ixazomib, also called MLN9708, with pomalidomide and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma. The registry lists enrollment of 32, a start date of 2014-07-22, and a primary completion date of 2016-05-18.

The primary endpoint was the number of patients with dose-limiting toxicities from initial treatment through Day 28 of cycle 1. The registry describes 3mg and 4mg ixazomib dose levels and a dose-finding rule, but does not report the observed primary endpoint result or selected dose. It lists secondary response and survival outcomes but reports no analyses. Adverse-event counts are reported by dose group; attribution of events and deaths is not stated.