Study of Vorinostat (MK0683), an Histone Deacetylase (HDAC) Inhibitor in Combination With Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma (MK-0683-095): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Vorinostat (MK0683), an Histone Deacetylase (HDAC) Inhibitor in Combination With Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma (MK-0683-095) (NCT00773838), a non-randomized phase 2 study. The primary outcome is Objective Response Rate (RR).

2. Clinical Question

Statistically, the main question is descriptive: what proportion of the specified treated population met the response definition during the study? The question is not whether the combination produced a larger response rate than a concurrent alternative, because no such group was included. The design can describe observed responses under the study conditions, but it cannot isolate a treatment effect from other explanations for outcomes.

3. Trial Design

This was an international, multicenter, open-label Phase 2 study with non-randomized allocation and a single-group model. The registry record lists a total enrollment of 143 and describes participants with relapsed or refractory multiple myeloma after at least 2 prior treatment regimens. The study is marked completed. Its listed start date is 2008-12-01, and its primary completion date is 2011-05-16.

Participants received vorinostat with bortezomib. The described schedule was vorinostat 400 mg orally once daily on Days 1-14 of each 21-day cycle and bortezomib 1.3mg/m^2 by intravenous injection on Days 1, 4, 8 and 11 of each cycle, for up to 26 cycles. Dexamethasone appears in the intervention list, but the available arm description ends in a sentence about participants with progressive disease after 2 cycles. The remainder of that sentence and any corresponding treatment details are not reported in the registry record.

Open-label means that masking was absent; the registry record lists masking as none. The primary outcome was assessed by an Independent Adjudication Committee, which is a distinct feature of the outcome assessment, but the record does not explain the committee's procedures or whether assessors were blinded to treatment information. The outcome timeframe was up to approximately 30 months, through the final analysis data cut-off of 16-May-2011.

Secondary outcomes included adverse events, discontinuations due to adverse events, time to disease progression, progression-free survival, and overall survival. Time-to-event outcomes were listed both for Independent Adjudication Committee assessment and investigator assessment where applicable. Their estimates and detailed analysis results are not reported in the registry record. The single-group design means none of these outcomes has a randomized concurrent control comparison in this study.

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: Of 143 participants enrolled, 142 participants were allocated to treatment. Five participants received additional treatment for about 1 year during an extension as per investigator's discretion based on clinical benefit of the treatment received. All 5 participants discontinued extension treatment and were followed for survival up to 2 years post last dose of treatment.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants who received at least one dose of study treatment

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: All allocated participants

6. Primary Endpoint

The registry lists the primary outcome as Objective Response Rate (RR), measured over Up to approximately 30 months (through Final Analysis data cut-off of 16-May-2011).

The primary endpoint was objective response rate, defined as the percentage of participants with a complete response or partial response according to European Blood and Marrow Transplant criteria. Response was assessed by an Independent Adjudication Committee. The primary analysis population was all participants who received at least one dose of study treatment.

The criteria require changes in disease measures, not simply a participant's subjective impression. Complete response required disappearance of the original monoclonal paraprotein from blood and urine on at least 2 determinations for at least 6 weeks by immunofixation studies, <5% plasma cells in bone marrow on at least 1 determination, no increase in the size or number of lytic bone lesions, and disappearance of soft tissue plasmacytomas for at least 6 weeks on skeletal survey if available. Partial response required specified reductions in serum M protein, urinary light chain excretion when present, and soft tissue plasmacytoma size, with no increase in lytic bone lesions on skeletal survey if available.

General: a response rate is a proportion defined by an outcome rule. It gives a clinically interpretable summary of how many participants met that rule in the analyzed population, while a confidence interval communicates uncertainty about the underlying response proportion. The registry record states that an exact binomial method was used for the response rate and its 95% confidence interval. The actual response estimate and interval are not reported in the registry record, so the magnitude and precision of the observed response cannot be described from the listed details.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a binary outcome at the participant level: each participant either met the response definition or did not, based on the committee assessment. The reported summary would be the percentage of participants meeting the definition in the analysis population. The registry record states that the response rate and 95% confidence interval were calculated using an exact test of the binomial parameter. It does not report the response count, denominator, estimate, or interval.

What does an exact binomial interval represent?

General: a binomial model describes the number of participants meeting a yes-or-no outcome rule among an analyzed group, under assumptions that make the participant outcomes suitable for this model. An exact interval uses the binomial distribution directly rather than relying only on a large-sample normal approximation. The interval gives a range of values compatible with the observed data and the procedure's coverage properties. It is not a range containing a fixed proportion of individual participant outcomes, and it does not mean that there is a probability that the already-observed study rate lies within the interval.

The interval's width is related to the amount of information in the data and to the observed proportion. However, the registry record does not give the endpoint's count or denominator, so the interval cannot be reconstructed or assessed for width. The stated enrollment is not a substitute for the primary analysis denominator: the endpoint population is defined as participants who received at least one dose, and the record does not state the number in that population.

Why use a committee assessment?

The endpoint was assessed by an Independent Adjudication Committee under European Blood and Marrow Transplant criteria. Standardized criteria can reduce reliance on unstructured judgments by defining which combinations of laboratory, marrow, imaging, and disease findings qualify as response. In this study, complete and partial response had separate definitions, and either category contributed to the objective response endpoint. The registry record does not describe the committee charter, adjudication workflow, disagreement resolution, or blinding. Those details are relevant to evaluating measurement reliability and possible assessment bias.

How should the analysis be read with one group?

General: an estimate within a single group is not the same quantity as a difference between treatment groups. A randomized comparison can support an estimate of the contrast between assigned groups, subject to its assumptions and conduct. A single-group response rate instead reports the proportion observed under the study's treatment and assessment conditions. Without a concurrent control group, the design does not provide a randomized estimate of what would have happened to a comparable group without the study combination.

The registry lists non-randomized allocation, no masking, and a single-group model. These features do not by themselves determine the direction or size of bias, but they define the context for interpretation. Open-label conduct can matter particularly when assessment depends on judgment; the independent committee is relevant to that concern, while its procedures are not reported in the registry record.

What do the planning illustrations mean?

General: a sample-size calculation asks how many participants a hypothetical future study might need under specified assumptions. The planning assumptions listed for this study's illustration are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. These are planning assumptions, not a report of the trial's own design justification, which is not reported in the registry record.

The illustrations are not observed power. Observed power is not a substitute for reporting an estimate and its uncertainty; planning calculations are conditional on assumed effects and analysis choices. The two-arm equal-allocation assumption is also distinct from this study's actual single-group design. The registry record does not give the numerical planning outputs in the registry record listed, and no calculated sample-size values can be inferred from the assumptions alone.

Why do time-to-event methods need separate detail?

General: time-to-event outcomes measure time until an event, while accounting for participants whose event has not been observed by the end of available follow-up. Such analyses depend on event definitions, follow-up, and censoring rules. The registry lists time to disease progression, progression-free survival, and overall survival, but does not report their estimates, analytic methods, censoring details, or event counts. Methods for the binary response endpoint should not be assumed to describe those outcomes.

For time-to-event planning illustrations, the stated convention is that the total number of events is used; for other illustrations, the stated convention is participants per arm. That distinction describes the planning outputs, not observed outcome results. No numerical illustrations are available in the registry record details listed for interpretation.

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("Vorinostat + Bortezomib")
n      <- c(142)
events <- c(16)
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  Vorinostat + Bortezomib  142  16  11.3  6.6  17.7  7.1  17.5  7.1  17.5

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists objective response rate as the primary endpoint and names several secondary outcomes. It does not report a multiplicity strategy for controlling the chance of false-positive findings across multiple outcomes or analyses. It also does not report a prespecified hierarchy, adjustment method, or decision rule for interpreting secondary endpoints. Without those details and without the outcome estimates, it is not possible to characterize how inferential claims across outcomes were intended to be handled.

Missing-data methods are not reported in the registry record. The response definition requires specified assessments, but the record does not state how missing, incomplete, or unevaluable response assessments were handled, whether participants without an evaluable assessment were counted as nonresponders, or whether any imputation was used. The response analysis denominator and missing assessment count are also not reported.

The primary analysis population is defined as all participants who received at least one dose of study treatment. This is a treated-population definition rather than an assignment-based intention-to-treat definition, which generally relies on randomized assignment; this trial was not randomized. The record does not describe additional analysis populations or sensitivity analyses. The safety group lists 142 participants at risk for serious and other adverse events, but the record does not establish that this group is identical to the primary response population.

Interim analyses, stopping rules, and sample-size justification are not reported in the registry record. The study's completion status and the listed final analysis cut-off do not establish whether interim looks were conducted. These absences limit assessment of the analysis plan and how missing information or repeated testing may have affected interpretation.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: neoplasm malignant (21.1%), pneumonia (9.2%), accidental overdose (8.5%), renal failure acute (7.0%), diarrhoea (5.6%).

The registry record lists one treatment group, Vorinostat + Bortezomib, with 142 participants at risk for serious adverse events and 92 recorded as affected. For other adverse events, 142 were at risk and 140 were affected. The record also lists 85 deaths. These are posted counts, not an estimate of comparative risk: the study had no concurrent control group. The record does not explain the relationship between the deaths and adverse events, causes of death, or attribution to study treatment.

The listed serious adverse event terms and percentages are Neoplasm malignant, 21.1%; Pneumonia, 9.2%; Accidental overdose, 8.5%; Renal failure acute, 7.0%; Diarrhoea, 5.6%; and Pyrexia, 4.9%. They are presented as terms with reported percentages. The registry record does not state the denominator or additional calculation details for these term-level percentages, so they should not be used to infer counts. Nor should the term percentages be added: a participant may have more than one event, and the record does not describe overlap.

General: adverse-event counts describe events recorded under the study's reporting rules. They do not, by themselves, establish that treatment caused an event. Interpretation also depends on definitions, collection procedures, follow-up, severity grading, and attribution; those details are not reported in the registry record details listed. The recorded figures should therefore be read as safety observations in the study group, not as a comparison with another treatment.

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

The study was designed to evaluate the clinical activity of vorinostat in combination with bortezomib in participants with relapsed or refractory multiple myeloma after at least 2 prior treatment regimens. Its primary endpoint was a response proportion based on complete or partial response under European Blood and Marrow Transplant criteria. This describes what the study set out to measure, but the observed response result is not reported in the registry record. The result's magnitude and precision therefore cannot be characterized.

The record does show the design context: a completed Phase 2, open-label study with one non-randomized treatment group. This permits a description of outcomes observed among participants treated under the study conditions. It does not provide a randomized comparison, and it cannot determine how outcomes would have differed under another treatment or no study treatment. No causal conclusion follows from the single-group design alone.

The registry also lists secondary outcomes and safety counts. Their presence identifies outcomes of interest, but the listed details do not supply numerical results for time to disease progression, progression-free survival, overall survival, or treatment discontinuations due to adverse events. The serious and other adverse-event group counts and selected serious event terms provide safety observations, not a controlled estimate of excess risk or treatment-attributable harm.

General: statistical uncertainty and design limitations answer different questions. A confidence interval can express uncertainty around an estimate under the analysis model, while randomization and a suitable comparison group address whether differences can be attributed to treatment. This record states that an exact binomial confidence interval was used for response, but the interval and estimate are not reported. Even if an interval were available, it would not create a missing control comparison.

The registry information can therefore establish the study question, endpoint definition, treatment schedule as far as described, and broad design and safety context. It cannot establish the size or precision of the primary response finding, a comparative benefit, the causal relationship of adverse events to treatment, or the results of unreported secondary analyses. Those distinctions keep the interpretation aligned with what the record actually reports.

14. Why This Trial Matters Statistically

This trial illustrates why a clearly defined endpoint and a study design must be considered together. Objective response rate provides a direct summary of the proportion meeting specified disease-response criteria. The criteria combine laboratory, marrow, and disease findings, and the registry states that an Independent Adjudication Committee assessed response. The endpoint's definition is therefore important to understanding what a reported rate would represent.

At the same time, the single-group, non-randomized design makes the estimand descriptive rather than comparative. A response proportion can characterize the treated group, but there is no randomized control group against which to estimate a treatment contrast. This distinction is central in clinical biostatistics: the precision of a within-group estimate and the strength of a causal comparison are separate properties.

The record also demonstrates why outcome populations and denominators should be explicit. Enrollment is listed as 143, the primary response population includes participants receiving at least one dose, and 142 participants are listed as at risk for adverse events. Those figures should be read in their stated contexts, rather than assumed to represent one common analysis population. The response denominator is not reported in the registry record.

Finally, an analysis method cannot replace the result it is meant to quantify. The record states that an exact binomial method was used to report the response rate and 95% confidence interval, but does not give the estimate or interval. Methodological detail helps readers understand how a result would be calculated; it does not permit the missing result to be reconstructed. This is a useful reminder to separate endpoint definition, statistical procedure, observed findings, and the claims a design can support.

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.

A central limitation of the available record is that it does not report the primary response estimate, response denominator, or 95% confidence interval. Although the endpoint and its analysis method are described, the observed response magnitude and precision cannot be assessed. The listed enrollment does not establish the number included in the treated analysis population.

The single-group, non-randomized design has no concurrent control group. As a result, it does not support a randomized comparison of outcomes and cannot separate treatment effects from differences in participant characteristics, disease course, prior care, or other influences. Open-label conduct may also be relevant to assessment. Independent committee review is specified, but the procedures and blinding status of that assessment are not reported in the registry record.

The arm description is incomplete: it ends after a statement beginning “Participants with progressive disease (PD) after 2 cycles of”. The remaining treatment description is not reported in the registry record. Dexamethasone is listed as an intervention, but its role and schedule are not specified in the registry entries. These gaps limit a full description of the treatment regimen.

Handling of missing or unevaluable response data, additional analysis populations, interim analyses, multiplicity, and the statistical analysis plan are not reported in the registry record. Secondary outcome results and time-to-event analysis details are also absent in the registry record listed. Finally, the safety figures are not a controlled comparison, and term-level percentage denominators and event attribution details are not reported.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of Vorinostat (MK0683), an Histone Deacetylase (HDAC) Inhibitor in Combination With Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma (MK-0683-095) — NCT00773838.
• Registry record last updated 2021-04-01; status last verified 2021-03.
• Results first posted 2021-04-01.
• 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 record describes a completed, international, multicenter, open-label Phase 2 study of vorinostat with bortezomib in relapsed or refractory multiple myeloma. Allocation was non-randomized, the model was single-group, and enrollment was 143. The listed start date is 2008-12-01, with primary completion on 2011-05-16.

The primary endpoint was objective response rate, assessed by an Independent Adjudication Committee using European Blood and Marrow Transplant criteria. The stated analysis used an exact binomial method for the rate and its 95% confidence interval. The primary analysis population was participants who received at least one dose of study treatment. The response estimate, confidence interval, and response denominator are not reported in the registry record.

The registry lists secondary disease and safety outcomes. The safety group records 142 at risk for serious adverse events, 92 affected, 142 at risk for other adverse events, 140 affected, and 85 deaths. These figures describe the single study group and do not provide a comparative safety estimate.