Study of the Bruton's Tyrosine Kinase Inhibitor in Subjects With Relapsed or Relapsed and Refractory Multiple Myeloma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of the Bruton's Tyrosine Kinase Inhibitor in Subjects With Relapsed or Relapsed and Refractory Multiple Myeloma (NCT01478581), a non-randomized phase 2 study. The primary outcome is The Clinical Benefit Response (CBR).

2. Clinical Question

3. Trial Design

This was a multicenter phase 2 study with a parallel design and non-randomized allocation. Masking was listed as none. The study is marked completed, with an enrollment of 92. The recorded start is 2012-03 and primary completion is 2018-08. These registry fields describe the study's structure and timing; they do not provide evidence about efficacy or safety beyond the separately posted outcome information.

Four cohorts received different regimens. Cohort 1 received PCI-32765 420 mg per day, and Cohort 3 received PCI-32765 840 mg per day. Cohort 2 received PCI-32765 560 mg per day with 40 mg oral dexamethasone once per week. Cohort 4 received PCI-32765 840 mg per day with 40 mg oral dexamethasone once per week. Random assignment to these cohorts is not reported; the registered allocation is non-randomized.

The primary objective covered PCI-32765 as a single agent and in combination with dexamethasone. Clinical benefit response was the primary endpoint, assessed from first study treatment until disease progression under IMWG criteria, up to 60 months. The record also lists ORR and pharmacokinetic outcomes, including measures of plasma concentration, timing, exposure, elimination, accumulation, and metabolite-to-parent ratios.

Because there was no randomized allocation and no like-for-like control comparison, the design is not a randomized test of one regimen against another. The registry record does not report details of cohort assignment, a protocol-defined statistical analysis plan, or the rationale for choosing the cohort doses.

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: Simon 2-stage design . Stage 1 -13 subjects enrolled in cohort 1. For cohort 2,3, and 4, up to 18 subjects were enrolled in Stage 1. Cohort 4 was selected for expansion for enrollment of 43 subjects in Stage 2.

Overall Study

Analysis population for the primary outcome, as defined in the registry: All treated population

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 Clinical Benefit Response (CBR), measured over From the date of first study treatment until disease progression per IMWG, up to 60 months.

The primary endpoint, clinical benefit response, counts participants who achieved at least one of five specified response categories: stringent complete response, complete response, very good partial response, partial response, or minimal response. The response categories were assessed using modified International Myeloma Working Group criteria. The endpoint was defined as a proportion in the all-treated population, with assessment beginning on the date of first study treatment and continuing until disease progression per IMWG, up to 60 months.

A composite response endpoint can capture several levels of response within one outcome. In general, it is useful when the clinical question concerns whether participants reach any of a defined set of response categories, rather than only the most stringent category. The definition determines which outcomes count: a participant meeting any one of the listed categories qualifies for the clinical benefit response measure.

The registry record does not report how many participants met the endpoint, the denominator used for the reported outcome, or an estimated response proportion. It also does not report confidence intervals or a statistical comparison for this primary endpoint. The endpoint's definition and assessment timeframe therefore describe what was intended to be measured, but do not establish the observed result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is binary at the participant level: each treated participant either meets the clinical benefit response definition or does not. The registered measure is a count of participants, while the endpoint description defines the target quantity as a proportion. The record does not post the response count or denominator, so no response estimate can be stated. The distinction matters: a count depends on the number evaluated, while a proportion expresses the count relative to a defined analysis population.

What does a confidence interval describe?

In general, a confidence interval gives a range of values compatible with an estimate under the statistical method used. A narrower interval indicates greater precision; a wider interval indicates less precision. For a binary response proportion, precision depends on the number of participants contributing data and on the observed response pattern. No confidence interval for clinical benefit response is reported in the registry record, so its precision cannot be evaluated.

What can cohort comparisons establish?

In general, random assignment helps balance measured and unmeasured participant characteristics across treatment groups, supporting a more direct causal comparison. This study is registered as non-randomized, and the cohorts used different regimens. Without randomization and a clearly defined control comparison, an observed difference between cohorts could arise from treatment, participant composition, or other factors. The registry record does not report an analysis that adjusts for such differences. No causal comparison between the four cohorts should be inferred solely from their regimen descriptions.

How should the other outcomes be understood?

The registered secondary efficacy outcome includes ORR. Pharmacokinetic outcomes include mean maximum observed plasma concentration, mean time to maximum observed plasma concentration, mean area under the plasma concentration-time curve from time 0 to 24 hours, mean terminal elimination half-life, mean accumulation ratio for that area, and metabolite-to-parent ratios for maximum concentration and area under the curve. In general, pharmacokinetic measures characterize drug exposure and concentration over time; they are distinct from clinical response outcomes. Their observed values and analysis details are not reported in the registry record.

The record lists 11 outcome measures and 0 analyses. This means the registry material does not present a statistical analysis record from which to identify estimation methods, model specifications, covariate adjustment, or hypothesis tests. The primary endpoint's count-and-proportion definition does not, by itself, specify whether the investigators used a particular interval method, missing-data rule, or model.

What do the planning assumptions mean?

In general, sample-size calculations describe the number of participants needed under specified assumptions; they are not observed evidence about an intervention. The planning assumptions described for the sample-size illustration use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The stated effect to detect is a fraction of the observed effect. These assumptions are described as planning illustrations based on the observed effect, not as the trial's own design. The sample-size illustration is not observed power, and the registry record does not report a trial-specific sample-size justification.

For time-to-event calculations, the stated planning approach concerns total events, while other planning results are expressed as participants per arm. These are general distinctions in the stated planning approach; they do not describe the primary endpoint analysis, which is a participant response count. No numeric planning results are reported in the registry record, and no new sample-size value can be inferred from the posted outcome information.

Over-dispersion is a general concern when count data vary more than a chosen statistical model expects; it can make standard errors too small if ignored. It is not reported as an issue in this study, and the primary endpoint is defined as a binary participant response rather than a rate of repeated events. The registry record does not identify a model for the primary endpoint, so it is not possible to say whether over-dispersion methods were relevant to any analysis.

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("Cohort 1", "Cohort 2", "Cohort 3", "Cohort 4")
n      <- c(13, 18, 18, 43)
events <- c(1, 1, 0, 12)
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  Cohort 1  13  1  7.7  0.2  36.0  1.4  33.3  1.8  33.9
ARM  Cohort 2  18  1  5.6  0.1  27.3  1.0  25.8  1.3  26.0
ARM  Cohort 3  18  0  0.0  0.0  18.5  -0.0  17.6  0.1  17.6
ARM  Cohort 4  43  12  27.9  15.3  43.7  16.7  42.7  16.8  42.8

11. Multiplicity, Missing Data and Analysis Populations

The study lists a primary endpoint and secondary outcomes that include ORR and several pharmacokinetic measures. When a study assesses multiple outcomes, general statistical practice distinguishes the main question from additional or exploratory questions, because repeated testing can increase the chance of at least one apparently notable finding. The registry record does not report a multiplicity strategy, such as an adjustment procedure or a hierarchy for interpreting the secondary outcomes. It is therefore not possible to determine how multiple outcomes were handled.

The registry record does not report how missing outcome data were handled, how many participants were evaluable for each endpoint, or whether the analysis population differed from the all-treated population named for the primary outcome. It does not describe imputation, censoring rules for response assessment, or sensitivity analyses. These omissions matter because the number and pattern of missing assessments can affect a proportion and its precision.

Interim analyses, stopping rules, and an analysis plan are not reported in the registry record. The record lists 0 analyses, so it does not identify statistical tests, confidence-interval procedures, adjustment variables, or planned subgroup analyses. The enrollment of 92 is reported, but the registry record does not provide a trial-specific sample-size justification or describe how enrollment targets were selected.

In general, these details help readers assess whether reported estimates follow prespecified methods and how robust they are to incomplete data or multiple testing. Their absence does not prove that no such procedures were used; it means they are not reported in the registry record.

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: pneumonia (9.3%), clostridium difficile infection (7.7%), plasma cell myeloma (7.7%), syncope (7.7%), aspergillus infection (7.7%).

The safety fields report, for each cohort, the number at risk and the number affected by serious adverse events, as well as corresponding at-risk and affected counts for other adverse events. For serious adverse events, Cohort 1 lists 13 at risk and 6 affected; Cohort 2 lists 18 at risk and 6 affected; Cohort 3 lists 18 at risk and 7 affected; Cohort 4 lists 43 at risk and 12 affected. These are cohort-level counts as recorded, not comparative estimates of treatment effects.

The listed serious adverse event terms include pneumonia at 9.3%, and Clostridium difficile infection, plasma cell myeloma, syncope, Aspergillus Infection, and bone lesion at 7.7% each. The registry record does not provide further context for these percentages, such as the denominator, whether a participant could contribute more than one event term, or the event-specific timing and severity.

In general, adverse events reported during a study do not by themselves establish that treatment caused them. Differences between these non-randomized cohorts should also be interpreted cautiously because the regimens and cohort sizes differ. The record reports deaths by cohort as 2, 1, 1, and 1, respectively, but does not provide a cause-of-death analysis or attribution in the listed fields. The safety information is descriptive and does not support a controlled comparison.

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

The registry record establishes that a phase 2 study evaluated four PCI-32765 regimens, including regimens with dexamethasone, in subjects with relapsed or relapsed and refractory multiple myeloma. It defines clinical benefit response as the primary outcome and specifies response categories, assessment criteria, and a timeframe extending from first treatment until disease progression, up to 60 months.

However, the record does not report the primary response count or proportion. It also does not report confidence intervals, statistical tests, or results for the listed secondary efficacy and pharmacokinetic outcomes. Therefore, the data in this record do not show the magnitude or precision of clinical benefit response, and they do not allow an evaluation of whether response differed across regimens.

The design also does not support a randomized, like-for-like comparison: allocation was non-randomized, there was no masking, and the cohorts received distinct regimens. In general, outcomes across these cohorts could be associated with differences other than regimen. The record does not report enough information to separate those possibilities.

Serious adverse event counts and selected event-term percentages provide descriptive safety information. They are not, on their own, evidence of causation or comparative risk. The registry record does not include the clinical detail or controlled comparison needed to interpret these figures as treatment-attributable effects.

Accordingly, the available record is informative about the planned clinical question and study structure, but not about the result of that question. Completion status and a registered endpoint are not substitutes for observed results. Any conclusion about efficacy, comparative benefit, or causal safety effects would require results and analysis details that are not reported in the registry record.

14. Why This Trial Matters Statistically

This study is statistically instructive because its primary outcome is clinically framed as a composite response but mathematically defined as a participant-level proportion. Understanding that distinction helps readers ask what counts as a response, who is included in the denominator, and how precisely the proportion was estimated. The registry record specifies the response categories and all-treated population, but does not report the response result or its uncertainty.

The four cohorts also illustrate why a list of multiple regimens is not equivalent to a randomized comparison. Dose and dexamethasone use vary between cohorts, while allocation is non-randomized. General statistical interpretation requires separating description of cohort outcomes from evidence that a regimen caused an outcome difference. The registry record does not provide the results or adjustment details needed for such comparisons.

The record further distinguishes efficacy outcomes from pharmacokinetic outcomes. ORR and clinical benefit response concern tumor response criteria, whereas the listed pharmacokinetic measures concern drug concentrations and exposure. These outcomes answer different questions and should not be treated as interchangeable evidence.

Finally, the absence of analysis details has practical consequences for interpretation. Missing-data handling, multiplicity procedures, uncertainty intervals, and the sample-size rationale are not reported in the registry record. Their absence limits assessment of precision and robustness. The posted safety counts add descriptive context, but do not resolve the lack of comparative efficacy results or establish treatment causation.

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.

Several limitations specific to this record constrain interpretation. The study is non-randomized and has no like-for-like control comparison described. Its parallel cohorts differ in PCI-32765 dose and in whether dexamethasone is included, so any between-cohort contrast would be vulnerable to differences in participant composition or other factors. The record does not explain how participants entered each cohort.

The study is listed as unmasked, and the registry record does not report whether response assessments were independently reviewed or blinded. It also does not provide detailed eligibility criteria, baseline disease characteristics, or cohort-level participant accounting for the primary endpoint. These omissions limit assessment of comparability and of the population represented by any outcome estimate.

Most importantly, primary and secondary outcome results are not reported in the registry record. There are no posted analyses, uncertainty estimates, or details of missing-data handling. Actual follow-up duration, assessment completeness, and reasons for withdrawal are also not reported. The planned outcome timeframe of up to 60 months does not establish that each participant was followed for that duration.

The serious adverse event information is limited to at-risk and affected counts by cohort and selected terms with percentages. Event timing, duration, severity grading, attribution, and exposure-adjusted rates are not reported. The record gives deaths by cohort but no cause or attribution details in the listed fields. These limitations mean the safety figures should remain descriptive rather than be interpreted as comparative or causal findings.

The record reports an enrollment of 92 and completion status, but does not report the rationale for the enrollment target, an interim analysis plan, or a detailed statistical analysis plan. Those missing details prevent evaluation of planned precision and analysis choices.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of the Bruton's Tyrosine Kinase Inhibitor in Subjects With Relapsed or Relapsed and Refractory Multiple Myeloma — NCT01478581.
• Registry record last updated 2020-03-10; status last verified 2019-10.
• Results first posted 2018-06-26.
• 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.

19. Record Summary

NCT01478581 is a completed multicenter phase 2 study of PCI-32765 in subjects with relapsed or relapsed and refractory multiple myeloma. The parallel, non-randomized study had no masking and an enrollment of 92. Four cohorts received PCI-32765 at different doses, either alone or with weekly oral dexamethasone.

The primary endpoint was clinical benefit response, defined as the proportion achieving stringent complete response, complete response, very good partial response, partial response, or minimal response under modified IMWG criteria. Its assessment period began at first study treatment and continued until disease progression, up to 60 months. ORR and pharmacokinetic measures were listed as secondary outcomes.

The registry record does not report primary or secondary outcome results or statistical analyses. It lists serious adverse event counts by cohort and selected serious event terms with percentages. Non-randomized allocation, absent analysis details, and missing outcome results limit efficacy and safety interpretation.