A Study of Oprozomib, Pomalidomide, and Dexamethasone in Adults With Primary Refractory or Relapsed and Refractory Multiple Myeloma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Oprozomib, Pomalidomide, and Dexamethasone in Adults With Primary Refractory or Relapsed and Refractory Multiple Myeloma (NCT01999335), a non-randomized phase 1 study. The primary outcome is Number of Participants With Dose-limiting Toxicities (DLTs).

2. Clinical Question

The clinical question is therefore a Phase 1 safety and dose-finding question, rather than a comparative efficacy question. The study description says the Phase 1 part was intended to determine the maximum tolerated dose and assess safety, tolerability, and activity of the combination. The record does not report a maximum tolerated dose or the DLT count, so the stated objective cannot be answered from these registry results.

The record also describes a Phase 3 objective: comparing efficacy for participants randomized to oprozomib or placebo with pomalidomide and dexamethasone. That objective should not be confused with the listed study design and arms. Allocation is recorded as non-randomized, masking as none, and the model as sequential. No randomized placebo arm is listed among the posted arm descriptions. A like-for-like control comparison is therefore not represented by these records.

Several secondary outcomes are named, including overall response rate, clinical benefit rate, and oprozomib pharmacokinetic measures. Their names establish what was planned for assessment, but no corresponding results are reported in the registry record. The available information supports describing the study question and design, not drawing conclusions about efficacy or comparative treatment effects.

3. Trial Design

The registry lists the study as Phase 1, non-randomized, unmasked, and sequential. Enrollment is 33, and the status is terminated. The study start date is 2014-07-30, with primary completion dated 2019-04-25. The reason for termination is not reported in the registry record.

The posted arms are oprozomib combined with pomalidomide and dexamethasone. They include oprozomib 150 mg on a 5/14 schedule with pomalidomide 4 mg or 2 mg; oprozomib 210 mg or 240 mg on a 2/7 schedule with pomalidomide 4 mg; and an expansion phase using oprozomib 210 mg on a 2/7 schedule with pomalidomide 4 mg. Dexamethasone is included in each listed regimen. The arm descriptions specify treatment schedules within 28-day cycles.

Because allocation was non-randomized and the design model was sequential, the listed cohorts should be understood as treatment groups in a dose and schedule exploration, not as randomized arms suitable for a direct causal comparison. Differences between cohorts could reflect their different regimens as well as other differences not described in the registry record. No adjusted comparison or statistical analysis is listed.

The brief summary distinguishes a Phase 1 purpose from a Phase 3 purpose. The Phase 1 part concerns dose, safety, tolerability, and activity. The described Phase 3 part would compare oprozomib with placebo in combination with the other drugs. However, the registry phase is listed as PHASE1, allocation is non-randomized, and the posted arms are oprozomib regimens. The record does not establish that the planned randomized Phase 3 comparison was conducted or reported.

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.

Before assignment: In part 1 participants were enrolled sequentially using a standard 3 + 3 dose escalation schema. Additional participants were to be enrolled in the dose expansion portion once the recommended dose and schedule had been selected; enrollment was halted after 12 participants were enrolled in the expansion cohort.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants who received at least 1 dose of any study drug

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.

Population: The safety population included all participants who received at least 1 dose of any study treatment

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Dose-limiting Toxicities (DLTs), measured over Cycle 1, 28 days.

The primary endpoint is the number of participants with dose-limiting toxicities, measured during Cycle 1, defined as 28 days. The endpoint population is participants who received at least 1 dose of any study drug. A DLT is a defined safety event, not simply any adverse event: the record describes treatment-related toxicities meeting specified severity, duration, or clinical-significance criteria.

As a count endpoint, it communicates how many participants met the DLT definition during the assessment window. In a Phase 1 study, DLTs are relevant because dose and schedule decisions depend on whether treatment-related toxicities cross prespecified limits. The registry description says the Phase 1 purpose included determining the maximum tolerated dose, but the maximum tolerated dose itself is not reported in the registry record.

The definition refers to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. It includes certain nonhematologic toxicities at grade 3 or higher, with listed exceptions, and specified hematologic toxicities such as prolonged grade 4 neutropenia or thrombocytopenia and clinically significant bleeding. The exceptions matter: not every event at a given grade necessarily qualifies as a DLT under this definition.

The endpoint is specified, but its participant count is not reported in the registry record. Without that result, the endpoint cannot show how many participants met the criteria or how DLT experience varied across the listed cohorts.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a count endpoint describe?

General statistical explanation: a count endpoint records the number of participants who meet a defined event criterion. For this study, the event is a dose-limiting toxicity during Cycle 1, defined as 28 days. The count is interpretable only alongside the population assessed and the operational definition of a DLT. Here, the stated population is participants who received at least 1 dose of any study drug, and the definition includes severity and duration rules as well as exceptions.

A count alone does not express the full pattern of events. The number of participants meeting the definition is distinct from the number of individual events, because one participant could experience more than one event. The registry endpoint is explicitly a count of participants. The record does not report that count, and it does not give the participant-level event data needed to examine timing or recurrence.

What does the sequential, non-randomized design imply?

General statistical explanation: in a non-randomized sequential design, treatment groups are not formed by random assignment. A sequential structure can be used to explore regimens in stages, but comparisons across cohorts may be influenced by differences other than the regimen itself. Randomization is one method for balancing measured and unmeasured characteristics on average; it is not recorded for this study. The arm descriptions therefore support a descriptive account of the regimens, not a randomized treatment-effect estimate.

Masking is recorded as none. In general, lack of masking can influence the reporting or assessment of outcomes, particularly outcomes that require clinical judgment. The registry record does not explain how outcome assessment was organized or whether additional procedures were used to reduce assessment bias. Those details are not reported in the registry record.

How should uncertainty be understood?

General statistical explanation: an estimate describes an observed quantity, while a confidence interval describes a range of values compatible with the data under a statistical model. A narrow interval indicates greater statistical precision than a wide interval, though precision does not by itself remove bias or design limitations. No confidence interval for the primary endpoint is reported in the registry record, and no analysis is listed. It is therefore not possible to assess the precision of a DLT estimate.

For a binary event outcome, the observed event count and the number of participants assessed are both important. A percentage can give a scale-free description, but it does not show the underlying count by itself, and its precision depends on the amount of information. No DLT percentage or confidence interval is available for this endpoint. The adverse-event summaries give counts by group, but they should not be substituted for the endpoint's DLT count because the definitions and reporting categories are different.

What do the planning illustrations mean?

General statistical explanation: sample-size planning asks how much information a future study might need to detect a chosen effect under stated assumptions. The registry notes that its planning illustration uses the observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; it also says that the effect to detect is a stated fraction of the observed effect. Time-to-event illustrations use a total event count, while other illustrations use participants per arm. These are planning assumptions, not results from this non-randomized study and not observed power.

The actual illustration values are not included in the registry entries. More fundamentally, the registry record does not report the observed primary endpoint effect needed to interpret planning based on an observed effect. The illustrative assumptions must not be mistaken for the trial's own protocol or design rationale: the sample-size justification and the original statistical plan are not reported in the registry record.

What statistical analyses are documented?

The registry records no analyses. It does not report an inferential model, an adjustment strategy, a hypothesis test, confidence intervals, interim analyses, or a method for handling missing data. These details are not reported in the registry record. The absence of a listed analysis means there is no posted statistical estimate to evaluate for model assumptions or multiplicity. It does not establish which methods may or may not have been used outside the registry record.

General statistical explanation: when event counts are sparse, estimates can be imprecise, and conventional approximations may not behave well. When data are over-dispersed relative to a model, the observed variability exceeds what the model expects; accounting for that can widen uncertainty estimates and prevent overly confident inference. No over-dispersion assessment or model for the DLT endpoint is reported, so this general consideration is not a claim about the study's data.

10. Multiplicity, Missing Data and Analysis Populations

The registry names a primary endpoint and several secondary outcomes. The secondary outcomes include overall response rate, clinical benefit rate, maximum plasma concentration, time to maximum plasma concentration, and area-under-the-curve measures for oprozomib. The record does not report how many hypotheses were tested or whether any multiplicity adjustment was planned or used. A statistical plan is not reported in the registry record.

Multiplicity is a general concern when many outcomes, doses, or comparisons are examined. Testing multiple hypotheses can increase the chance of finding an apparently notable result by chance if no adjustment or other prespecified strategy is used. The registry does not provide results or analysis details that would allow readers to assess this issue for the named outcomes. No claim should be made that adjustment was or was not performed outside the information in the record.

Missing-data methods and analysis populations beyond the primary endpoint population are not reported in the registry record. The primary endpoint specifies participants who received at least 1 dose of any study drug, but the registry does not describe how participants with incomplete Cycle 1 assessments were handled. It also does not report whether analyses used all enrolled participants, treated participants, or another population for the secondary outcomes.

These omissions matter because incomplete follow-up can affect event counts and because different analysis populations can yield different summaries. Without a stated approach, it is not possible to determine how missing assessments were treated, whether sensitivity analyses were conducted, or how robust any result would be to alternative assumptions. Since the primary endpoint result itself is not reported, these uncertainties cannot be evaluated against an observed estimate.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: influenza (100.0%), pneumonia (100.0%), back pain (100.0%), febrile neutropenia (30.0%), gastric haemorrhage (14.3%).

The adverse-event summaries report, for each listed group, the number at risk, the number affected by serious adverse events, the number affected by other adverse events, and deaths. For the oprozomib 150 mg 5/14 plus pomalidomide 4 mg group, the respective counts are 3, 0, 3, and 1. For the 150 mg 5/14 plus pomalidomide 2 mg group, they are 1, 1, 1, and 0. For the 210 mg 2/7 group, they are 7, 3, 7, and 4. For the 240 mg 2/7 group, they are 10, 6, 10, and 3. In the 210 mg 2/7 expansion group, they are 10, 6, 10, and 4.

These are descriptive counts. The groups differ in regimen and size, are non-randomized, and do not form a like-for-like control comparison. The record does not provide exposure-adjusted rates or establish that the events were caused by study treatment. A death count is distinct from a count of serious adverse events, and the registry summary does not state that deaths were treatment-related.

The listed serious-event terms include influenza, pneumonia, and back pain at 100.0%; febrile neutropenia at 30.0%; and gastric haemorrhage and cellulitis at 14.3%. The relevant denominator for these term percentages is not reported in the registry record. They should not be read as percentages of all 33 enrolled participants.

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

The record documents a Phase 1 study of oprozomib with pomalidomide and dexamethasone in adults with primary refractory or relapsed and refractory multiple myeloma. It specifies a DLT endpoint during Cycle 1 and describes several non-randomized regimens. It also contains group-level adverse-event counts. These registry entries describe the study's structure and the safety information posted in the registry.

The record does not report the primary DLT count, the maximum tolerated dose, or results for the named response and pharmacokinetic outcomes. As a result, it cannot establish the observed frequency of DLTs or summarize the efficacy outcomes listed in the study description. A trial objective is not a result, and an endpoint definition does not show what was observed.

The posted adverse-event counts do not establish that a regimen caused an event or that one regimen is safer than another. The cohorts were non-randomized and varied by dose or schedule. The counts also do not provide a fair comparison with a control group: no like-for-like randomized comparator is listed. The planned Phase 3 comparison described in the brief summary should not be treated as a conducted or reported comparison on the basis of this record.

Statistical precision cannot be assessed for the primary outcome because an estimate and its uncertainty are not reported. Nor can the registry entries support a conclusion about whether the study met its objectives, why it was terminated, or what treatment decisions should follow. The termination status is recorded, but its reason is not reported in the registry record.

In short, the registry record is informative about the intended Phase 1 question, regimens, endpoint definition, and some adverse-event counts. It is insufficient to quantify the primary endpoint or draw comparative efficacy conclusions. These limits reflect what is reported in the registry record, not a claim about whether additional information exists elsewhere.

13. Why This Trial Matters Statistically

This study raises several useful statistical issues for interpreting early-phase clinical research. First, the primary endpoint is a safety count tied to a specific assessment period and criteria. Clear definitions are essential: the registry's DLT description distinguishes qualifying toxicities from events that meet exceptions, and the endpoint concerns participants with DLTs rather than a count of all adverse events.

Second, the non-randomized sequential design places limits on comparisons among regimens. Cohort summaries can describe what was recorded in each group, but differences across groups cannot be attributed to dose or schedule alone. The groups are not a randomized control comparison, and the registry does not list an analysis that adjusts for differences between participants or cohorts.

Third, having an endpoint defined is not the same as having an endpoint result. The registry identifies DLTs as the primary outcome but does not report the participant count. Without an estimate, there is no basis for assessing statistical precision, evaluating dose selection, or comparing observed safety with the stated Phase 1 purpose.

Finally, the study description illustrates the importance of distinguishing objectives across phases. The brief summary describes a Phase 3 randomized comparison, while the registry lists Phase 1 and non-randomized allocation, with oprozomib regimens among the posted arms. Keeping those statements separate prevents an intended future comparison from being mistaken for evidence from a completed randomized trial.

The statistical value of the record is therefore mainly in its design and endpoint documentation, alongside descriptive adverse-event summaries. Its missing outcome analyses sharply constrain what can be inferred. This is a useful reminder that interpretation depends not only on the named outcomes but also on whether their results, analysis methods, and uncertainty are reported.

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.

The registry status is terminated, but the reason for termination is not reported in the registry record. Although the study summary describes both Phase 1 and Phase 3 purposes, the phase field lists PHASE1. The record does not explain the relationship between the described Phase 3 objective and the posted Phase 1 study details.

The primary DLT outcome is specified for Cycle 1, but its result is not reported in the registry record. Results for the named secondary outcomes are also not reported. No statistical analyses are listed. Consequently, there is no posted estimate or uncertainty measure for the primary endpoint, and no basis for assessing the stated efficacy or pharmacokinetic outcomes.

The available arms are non-randomized regimens that differ in dose, schedule, or pomalidomide dose. They do not provide a like-for-like control comparison. The record does not describe baseline characteristics, treatment exposure, participant flow, follow-up duration for adverse events, or adjusted comparisons. These omissions limit interpretation of differences in group-level safety counts.

The serious-event term percentages are listed without a denominator in the registry information. The adverse-event summaries also do not establish whether events were attributed to treatment. The record does not report how missing assessments were handled, which analysis populations were used for outcomes other than the stated DLT population, or whether sensitivity analyses were conducted.

Finally, the sample-size assumptions described in the registry are planning illustrations and do not supply trial-specific justification or observed power. The sample-size justification, interim analyses, and full statistical plan are not reported in the registry record. These limitations restrict interpretation to the design and descriptive information that is explicitly recorded.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study of Oprozomib, Pomalidomide, and Dexamethasone in Adults With Primary Refractory or Relapsed and Refractory Multiple Myeloma — NCT01999335.
• Registry record last updated 2021-04-27; status last verified 2021-03.
• Results first posted 2021-04-27.
• 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

The registry record describes NCT01999335, a Phase 1, non-randomized, unmasked, sequential study of oprozomib, pomalidomide, and dexamethasone in adults with primary refractory or relapsed and refractory multiple myeloma. Enrollment is 33; the status is terminated. The study start date is 2014-07-30 and primary completion is 2019-04-25.

The primary outcome is the number of participants with dose-limiting toxicities during Cycle 1, defined as 28 days, among participants who received at least 1 dose of any study drug. The DLT count is not reported in the registry record. The posted adverse-event summaries give group-level counts, but the non-randomized cohorts are not a like-for-like control comparison. Results for the named secondary outcomes and the reason for termination are not reported in the registry record.