Lenalidomide, Thalidomide and Dexamethasone in Treating Participants With Relapsed or Refractory Multiple Myeloma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Lenalidomide, Thalidomide and Dexamethasone in Treating Participants With Relapsed or Refractory Multiple Myeloma (NCT00966693), a na phase 1, phase 2 study. The primary outcome is Number of Participants With Dose Limitations Toxicities of the Combination of Lenalidomide and Thalidomide and Dexamethasone (LTD) in Patients With Relapsed/Refractory Multiple Myeloma (RRMM).

2. Clinical Question

The study title and summary place the question in the setting of multiple myeloma that has returned or does not respond to treatment. The primary endpoint focuses on toxicity during the initial cycle, while the listed secondary outcomes include time to progression, progression-free survival, time to best response, adverse-event incidence, and time to next therapy. These outcomes address different aspects of treatment experience and follow-up; their results are not reported in the registry record.

Because the study has no listed randomized comparator, it cannot answer a controlled comparative question from the design information alone. Its primary question is whether dose-limiting toxicities were observed during the specified cycle in participants receiving the combination. The registry record gives the endpoint definition and timeframe but not the observed count, so the magnitude of toxicity for this endpoint cannot be assessed from the primary result.

3. Trial Design

This is a phase I/II study of lenalidomide, thalidomide, and dexamethasone in participants with relapsed or refractory multiple myeloma. The registry record lists M.D. Anderson Cancer Center as sponsor, an enrollment of 77, a start date of 2009-08-25, and a primary completion date of 2018-07-20. The study status is completed.

The design is recorded as sequential, with allocation listed as NA and masking as none. No randomized allocation is described, and the record explicitly warns that the arms are not a like-for-like control comparison. Phase I cohorts and a phase II cohort are listed in the safety results. The cohorts represent parts of a sequential study structure; they should not be interpreted as concurrent randomized arms with comparable baseline risk.

The listed treatment schedule has participants receive lenalidomide by mouth on days 1-21 and thalidomide by mouth once daily on days 1-28. Dexamethasone is scheduled by mouth on days 1-4, 9-12, and 17-20 of courses 1-2, then on days 1, 8, 15, and 22 of subsequent courses. Treatment is described as repeating every 28 days for up to 8 courses, subject to a condition whose wording is truncated in the registry record. Dose amounts, dose-escalation details, and cohort-transition rules are not reported in the registry record.

The primary endpoint is a count of participants with dose-limiting toxicities after one 28-day cycle. The record lists 7 outcome measures, including the primary endpoint and secondary outcomes addressing progression, response timing, adverse events, and time to next therapy. It lists 0 analyses. That means no statistical analysis results are listed in the registry record; it does not establish what analyses may have been conducted outside the record.

The sequential design and the early-cycle toxicity endpoint fit a dose-finding purpose, as described in the study summary. However, the precise dose-selection strategy, stopping rules, sample-size justification, and statistical analysis plan are not reported in the registry record. The reported enrollment should therefore be understood as the study enrollment, not as evidence that a particular target precision or power was achieved.

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:

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 Participants With Dose Limitations Toxicities of the Combination of Lenalidomide and Thalidomide and Dexamethasone (LTD) in Patients With Relapsed/Refractory Multiple Myeloma (RRMM), measured over After one 28-day cycle.

The primary endpoint is the number of participants with dose-limiting toxicities from the combination of lenalidomide, thalidomide, and dexamethasone after one 28-day cycle. It is a participant count: it asks how many people met the study's definition of a dose-limiting toxicity within the stated timeframe. The registry record does not provide the operational criteria used to classify a toxicity as dose-limiting, nor does it report the observed count.

In general, an early-cycle toxicity endpoint can inform dose-finding because it focuses on harms that arise during an initial treatment period, when tolerability may influence whether a dose or combination is suitable for further study. A count is readily interpretable as the number of participants meeting the endpoint, but the count alone is most informative when its denominator, endpoint rules, and ascertainment procedures are clear. Those additional details are not reported in the registry record.

The endpoint is not the same as the broader adverse-event outcome or the serious adverse-event figures. The primary outcome is specifically described as dose-limiting toxicity after one cycle. Serious adverse events are separately reported by cohort, and the registry record does not state that every serious event met the dose-limiting definition. The primary endpoint result is not reported in the registry record, so no conclusion about its observed frequency can be drawn from the endpoint description alone.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count represent?

The primary measure is a count of participants with a defined event, rather than a continuous measurement such as a laboratory value. In general, a count answers how many participants met the endpoint rule during the specified observation period. To interpret it fully, readers need both the number meeting the rule and the number assessed, as well as a clear definition of the event and how missing or incomplete observations were handled. The registry record states the endpoint timeframe as after one 28-day cycle, but it does not report the primary count, its denominator, the dose-limiting toxicity criteria, or the missing-data approach.

A count is not automatically a rate. A rate usually incorporates time at risk, while this endpoint is defined within a cycle. Nor can a count alone show how precisely the underlying event frequency has been estimated. In general, an interval estimate can communicate uncertainty around an event frequency, but no confidence interval for the primary endpoint is reported in the registry record.

Why does the sequential structure matter?

General explanation: a sequential study can assign participants to cohorts over the course of investigation rather than allocating them at random between concurrent treatment and control groups. The record identifies this study as sequential, with allocation NA and no masking. It lists Phase 1 cohorts and a Phase 2 cohort in the safety results. This organization can support a study that develops from dose assessment toward further evaluation, but the specific sequence rules and dose-selection algorithm are not reported in the registry record.

Because assignment is not described as randomized, cohort differences may reflect when participants entered, which cohort they joined, or other differences not captured in the posted information. This is why cohort counts should be read descriptively. A numerical contrast between cohorts would not, by itself, isolate the effect of dose or phase. The record also says the arms are not a like-for-like control comparison.

What can the safety summaries tell readers?

The safety results give the number at risk and the number affected for serious and other adverse events, along with deaths, for each listed cohort. These figures describe recorded participants and events, not the probability that an event was caused by the treatment. General explanation: an adverse event is an event observed during a study; causal attribution requires additional assessment and cannot be inferred from the event count alone. The registry record does not give event-level timing, severity grading beyond the serious-event grouping, duration, recurrence, or attribution details for these summaries.

The serious-event terms are accompanied by percentages, but the registry record does not state the denominator or calculation basis for those percentages. Terms may also represent events rather than unique participants; the record does not clarify this point. Consequently, those percentages should be read as registry-reported descriptions, not as directly comparable participant risks unless their denominator and counting rules are established.

What statistical analysis is documented?

The record lists 0 analyses. No inferential test, regression model, confidence interval, adjustment method, or analysis population is reported for the primary endpoint in the registry record. The primary endpoint is a participant count, but that endpoint type does not reveal which statistical method was planned or used. The sample-size assumptions described for planning illustrations state a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect set as a stated fraction of the observed effect. Those assumptions are for planning illustrations, not a description of the trial's own design or an observed-power calculation. The record does not provide the trial's sample-size justification.

General explanation: a confidence interval expresses a range of values compatible with the data under a specified statistical method and assumptions. A p-value addresses how unusual data at least as extreme as those observed would be under a specified null model. Neither is reported for the primary endpoint in the registry record. Without the endpoint result and analysis method, statistical significance or estimation precision cannot be assessed.

How should secondary outcomes be distinguished?

The listed secondary outcomes include time to progression, progression-free survival, time to best response, incidence of adverse events, and time to next therapy. These outcomes do not all have the same statistical structure. General explanation: time-to-event outcomes account for the timing of an event and can involve participants whose event has not occurred by the end of observation. Binary outcomes classify whether an event occurred within a defined period, while counts record the number of participants meeting a rule. The registry record does not report analyses or results for the listed secondary outcomes.

General explanation: over-dispersion matters when the variability of count data exceeds what a chosen statistical model expects; failing to account for it can make uncertainty estimates too narrow. The record does not identify a count model or provide a count distribution for the primary endpoint, so there is no basis for asserting that over-dispersion was assessed or was present. The appropriate emphasis is on the endpoint definition, observed count, denominator, and uncertainty method—details that are not reported for the primary endpoint 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("RTD (Cohort 1, Phase 1)", "RTD (Cohort 2, Phase 1)", "RTD (Cohort 3, Phase 1)", "RTD (Cohort 2, Phase 2)")
n      <- c(3, 3, 9, 49)
events <- c(1, 0, 3, 0)
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  RTD (Cohort 1, Phase 1)  3  1  33.3  0.8  90.6  6.1  79.2  6.8  80.6
ARM  RTD (Cohort 2, Phase 1)  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  RTD (Cohort 3, Phase 1)  9  3  33.3  7.5  70.1  12.1  64.6  12.2  65.2
ARM  RTD (Cohort 2, Phase 2)  49  0  0.0  0.0  7.3  0.0  7.3  0.1  7.1

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists several outcomes: the primary dose-limiting toxicity count and secondary outcomes covering progression, response timing, adverse events, and time to next therapy. It does not report a multiplicity strategy, such as a hierarchy of confirmatory outcomes or an adjustment for testing several hypotheses. It also lists 0 analyses. Therefore, the record does not establish which outcomes were formally tested, whether any results were designated confirmatory, or how multiple comparisons were handled.

General explanation: when several outcomes are tested, the chance of at least one apparently unusual result can increase if each test is interpreted independently. A prespecified testing order or adjustment can address that issue, but the registry record does not report such a plan. This absence does not show that no plan existed outside the record; it means the plan is not reported in the registry record.

Missing-data handling and analysis populations are also not reported in the registry record. The overall enrollment is 77, but the number enrolled is not necessarily the number assessed for every endpoint. The record does not state how many participants began treatment, completed the first cycle, were included in the primary endpoint denominator, or had incomplete follow-up. It also does not describe exclusions from analysis or the treatment of participants with missing outcome information.

General explanation: incomplete outcome data can affect a result when the chance of missingness is related to a participant's outcome or treatment experience. Clear reporting of the analysis population, missingness, and handling assumptions is therefore important. Since those details and the primary endpoint result are not reported, the completeness and representativeness of the primary endpoint estimate cannot be judged from 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: death (11.1%), pneumonia (6.1%), altered mental status (4.1%), fatigue (2.0%), urinary tract infection (2.0%).

The safety figures are presented separately for four cohorts: RTD (Cohort 1, Phase 1), RTD (Cohort 2, Phase 1), RTD (Cohort 3, Phase 1), and RTD (Cohort 2, Phase 2). The registry reports serious adverse events in 0 of 3, 0 of 3, 1 of 9, and 7 of 49 participants at risk, respectively. Other adverse events are reported in 3 of 3, 3 of 3, 9 of 9, and 49 of 49 participants at risk, respectively. Deaths are reported as 0, 0, 1, and 0 across those cohorts, respectively.

These are cohort-specific descriptive figures. They should not be combined into a comparative treatment estimate: the study is sequential, allocation is NA, and the record cautions that the arms are not a like-for-like control comparison. The registry does not explain how the at-risk populations were defined for each safety summary or provide event timing and attribution details.

The record also lists serious-event terms and percentages, including Death at 11.1%, Pneumonia at 6.1%, Altered Mental Status at 4.1%, Fatigue at 2.0%, Urinary Tract Infection at 2.0%, and Diarrhea at 2.0%. The denominator and counting basis for those percentages are not reported in the registry record. They should not be treated as percentages of all enrolled participants without that information. These safety summaries do not substitute for the missing primary endpoint result, which is specifically the count with dose-limiting toxicity after one 28-day cycle.

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

The record establishes that a phase I/II study examined lenalidomide, thalidomide, and dexamethasone in relapsed or refractory multiple myeloma, using a sequential design. Its primary endpoint was a participant count for dose-limiting toxicities after one 28-day cycle. The study enrolled 77 participants and is recorded as completed. The safety results provide cohort-level counts for serious and other adverse events and deaths.

Those details do not reveal the observed primary endpoint count. Without that result, it is not possible to state how many participants met the dose-limiting toxicity definition or how precisely the corresponding frequency was estimated. The record also does not report the endpoint denominator, toxicity criteria, or analysis method. The safety summaries provide related information, but serious adverse events and other adverse events are not interchangeable with the primary endpoint unless the endpoint definition explicitly makes them so; that relationship is not reported.

The study design does not support a randomized comparison. Allocation is NA, masking is none, and the record warns that the arms are not a like-for-like control comparison. Therefore, the cohort descriptions should not be taken as evidence that one cohort or phase performed better or worse than another, or that the combination caused each recorded event. The record contains no analyses and no reported results for the listed secondary outcomes.

General statistical interpretation: an observed count describes what was recorded in a study population under its endpoint rules. It does not, by itself, establish a causal effect, a treatment advantage, or what would happen in a different population. Here, even the primary count is absent, so the conclusions are limited to the study's stated question, design, and posted safety counts. The record does not support a claim that the treatment works or does not work.

14. Why This Trial Matters Statistically

This study illustrates why the design and the endpoint need to be read together. Its primary question is a dose-limiting toxicity count after one 28-day cycle, and its sequential structure includes Phase 1 and Phase 2 cohorts. That context is different from a randomized comparison intended to estimate differences between treatment and control. A cohort count can describe what was observed, but it does not provide a controlled estimate of comparative effect.

The record also demonstrates the difference between naming an endpoint and reporting its result. The primary endpoint is defined in recognizable terms, but the observed count, denominator, and toxicity criteria are not reported in the registry record. Without those elements, readers cannot determine the endpoint frequency or its precision. The existence of an overall enrollment figure does not resolve that gap because endpoint-specific participation is not stated.

The safety summaries make another statistical point: event figures need their population and counting rules. Cohort denominators are listed for serious and other adverse events, while the denominator basis for the listed serious-event percentages is not stated. Percentages without clear denominators are harder to interpret and should not be silently assigned to the overall study population.

Finally, the record lists multiple outcomes but no analyses. That distinction matters because outcome names alone do not reveal the analysis method, multiplicity approach, missing-data handling, or analysis populations. General lesson: transparent reporting of endpoint results and statistical procedures is necessary for readers to distinguish a descriptive safety account from an inferential comparison. The record supports a careful description of design and posted safety observations, while leaving the central primary endpoint result and its uncertainty unreported.

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 most direct limitation is the absence of the primary endpoint result. Although the registry defines the endpoint as the number of participants with dose-limiting toxicities after one 28-day cycle, it does not report the count or the endpoint-specific denominator. The criteria for a dose-limiting toxicity and the method used to assess it are also not reported in the registry record. This prevents interpretation of the central dose-finding outcome.

The design information limits comparative interpretation. The study is sequential, allocation is NA, and masking is none. The registry explicitly cautions that the arms are not a like-for-like control comparison. Cohort-specific safety counts should therefore remain descriptive, rather than being read as evidence of relative effects between cohorts or phases.

The treatment schedule is described, but dose amounts, dose escalation rules, and cohort-transition criteria are not reported in the registry record. The treatment description ends with a truncated condition after the statement that courses repeat for up to 8 courses, so the stopping condition cannot be fully interpreted from that text. The sample-size justification and statistical analysis plan are not reported.

The record lists 0 analyses and does not report results for the secondary outcomes. It also does not report missing-data handling, analysis populations, endpoint-specific denominators, or the basis for the percentages attached to serious-event terms. Details such as adverse-event attribution and timing are not given. These omissions limit assessment of completeness, precision, and the relationship between safety summaries and the primary endpoint. They do not establish that the information was never collected; they mean it is not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Lenalidomide, Thalidomide and Dexamethasone in Treating Participants With Relapsed or Refractory Multiple Myeloma — NCT00966693.
• Registry record last updated 2020-11-04; status last verified 2020-10.
• Results first posted 2020-11-04.
• 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

NCT00966693 is a completed, sequential phase I/II study sponsored by M.D. Anderson Cancer Center. It enrolled 77 participants with relapsed or refractory multiple myeloma and examined lenalidomide, thalidomide, and dexamethasone. The listed dates are 2009-08-25 for study start and 2018-07-20 for primary completion. Allocation is recorded as NA and masking as none.

The primary endpoint is the number of participants with dose-limiting toxicities after one 28-day cycle. Its observed result is not reported in the registry record. Four cohorts have descriptive safety counts for serious and other adverse events and deaths. The registry lists secondary outcomes related to progression, response timing, adverse events, and time to next therapy, but does not report analyses or results for them. The missing primary endpoint result, unspecified analysis details, and lack of a randomized comparator constrain statistical interpretation.