S0232 Dexamethasone With or Without Lenalidomide in Treating Patients With Previously Untreated Stage I, Stage II, or Stage III Multiple Myeloma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for S0232 Dexamethasone With or Without Lenalidomide in Treating Patients With Previously Untreated Stage I, Stage II, or Stage III Multiple Myeloma (NCT00064038), a randomized phase 3 study. The primary outcome is Progression-Free Survival.

2. Clinical Question

The central question is whether the registry-recorded progression-free survival percentage differed between participants assigned to lenalidomide plus dexamethasone and those assigned to dexamethasone alone. The trial enrolled people with previously untreated stage I, stage II, or stage III multiple myeloma. It was a randomized, parallel-group phase III trial with triple masking.

The primary outcome is stated as a percentage of participants rather than as a hazard ratio or a median time. The registry reports 78% for the lenalidomide-plus-dexamethasone arm and 52% for dexamethasone. These values describe the recorded outcome in this trial; they do not, by themselves, identify the analysis method or explain how participants with incomplete follow-up were handled.

3. Trial Design

This was a phase III, randomized, parallel-group trial sponsored by SWOG Cancer Research Network. The registry lists triple masking, but does not identify which people or study roles were masked. Enrollment was 198. The trial began in 2004-11, had primary completion in 2008-10, and is listed as completed.

The two arms compared lenalidomide plus dexamethasone with dexamethasone alone. The intervention descriptions refer to oral drugs, induction treatment, and possible maintenance treatment. The registry description for each arm is truncated, however, so the complete schedule, duration, dose details, and rules for moving from induction to maintenance are not reported in the registry record. The comparator description refers to placebo, consistent with the listed triple masking, but the masking procedures are not described.

The primary outcome was progression-free survival, expressed as a percentage of participants. The stated timeframe runs from initial registration until progression or relapse, or death from any cause, up to 5 years. Toxicity is listed as a secondary outcome. The registry reports 97 participants in the lenalidomide-plus-dexamethasone outcome group and 95 in the dexamethasone group. These outcome denominators do not account for all 198 enrolled participants, and the reasons for the difference are not reported in the registry record.

The record does not describe the original sample-size justification, planned analysis, interim analyses, allocation procedures, or the definitions of the analysis populations. It lists no analysis entries. Those gaps limit what can be concluded about how the reported percentages were estimated and how the trial was intended to address uncertainty before results were observed.

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.

Initial Randomization

Crossover to Lenalidomide+Dexamethasone

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 Progression-Free Survival, measured over From date of initial registration to date of progression/relapse of disease or death from any cause, whichever came first, up to 5 years.

Progression-free survival is the time from initial registration until disease progression or relapse, or death from any cause, whichever comes first. The registry reports the primary outcome as the percentage of participants and gives a timeframe of up to 5 years. Its progression definition includes a more than 25% increase from baseline in myeloma protein production or other signs of disease progression. For participants with a confirmed partial remission, remission, or complete remission, relapse is based on specified changes in myeloma protein, the reappearance of a myeloma peak that had disappeared, or changes in lytic bone lesions.

As a general statistical concept, a progression-free survival endpoint combines disease worsening and death into one outcome. It can therefore describe how long participants remain alive without the defined progression event, rather than addressing either component alone. The event definition matters: changes in assessment criteria or follow-up can affect when an event is recorded.

The registry gives percentages and confidence intervals but does not report the estimation method, the precise assessment schedule, censoring rules, or a specific evaluation time within the stated follow-up timeframe. It is therefore not possible to infer from the entry whether the percentages are Kaplan-Meier estimates or another summary, or how incomplete follow-up contributed to them.

7. Results Posted in the Registry

• Dexamethasone: 51.6% (49/95) versus 78.4% (76/97) on control; risk difference -26.8 percentage points (95% CI -39.7 to -13.8), risk ratio 0.66 (0.53–0.82); unadjusted two-proportion z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

What does the outcome scale represent?

The primary measure is reported as a percentage of participants. For a binary outcome, each participant is classified according to whether the event or event-free status meets the outcome definition, and the percentage summarizes the group. Here, the outcome is called progression-free survival, with progression, relapse, or death treated as the event and follow-up extending up to 5 years. The registry does not describe the calculation used to produce the percentages, so the exact statistical estimator cannot be identified from the entry.

What is a risk difference?

A risk difference subtracts one arm's outcome probability from the other arm's probability. It is expressed on the probability scale and can be positive or negative depending on the arm order and outcome coding. The recalculated estimate is -0.268 for dexamethasone compared with lenalidomide plus dexamethasone. The negative sign reflects that ordering: the dexamethasone arm's recorded percentage is lower. The confidence interval, -0.397 to -0.138, describes uncertainty around that unadjusted contrast.

How do risk ratios and odds ratios differ?

A risk ratio divides one arm's probability by the other arm's probability. An odds ratio compares the odds in one arm with the odds in the other. The registry comparison gives a risk ratio of 0.658 (95% confidence interval 0.528 to 0.821) and an odds ratio of 0.294 (95% confidence interval 0.157 to 0.552). Both comparisons are oriented to dexamethasone relative to the combination arm. Because odds and probabilities are different quantities, the odds ratio should not be read as a risk ratio, particularly when an outcome is not rare.

What does a confidence interval convey?

As a general statistical explanation, a confidence interval gives a range of values compatible with the observed data under a particular estimation procedure and its assumptions. It reflects uncertainty in the estimate; it is not a range containing every participant's outcome, nor is it a probability statement about the true value after the interval has been calculated. The intervals in the registry are labeled 95% confidence intervals. The record does not state the interval construction method.

What does the p-value address?

The unadjusted p-value is <0.001. In general, a p-value measures how unusual data at least as discrepant as those observed would be under a specified null hypothesis and statistical model. It does not measure the probability that the null hypothesis is true, the size or importance of an effect, or the probability that the result will recur. The registry does not report a complete prespecified testing plan, so the p-value should not be assumed to reflect adjustment for multiple testing or a protocol-defined analysis.

Why can over-dispersion matter?

As a general concept, over-dispersion occurs when observed variability exceeds what a model assumes. If a model assumes that individual outcomes vary independently with a particular degree of spread, extra variation can make standard errors too small and intervals too narrow unless the analysis accounts for it. This trial's registry record does not report a model for over-dispersion or indicate that this issue arose. It is a general consideration, not a claim about the trial's actual analysis.

What remains unknown about the analysis?

The registry does not report whether the primary comparison was adjusted, how censoring or missing outcome data were handled, the precise time point used for each percentage, or whether any interim analyses were planned. It also does not identify the exact analysis population. These are important details for interpreting a progression-free survival outcome: participants may have different follow-up durations, and the treatment of incomplete observation can affect the estimate. No specific method should be attributed to the trial without a registry description.

The two arm-level percentages and the unadjusted contrast offer complementary summaries, but they do not answer every methodological question. The arm values describe the outcome in each group, while the contrast puts the between-group comparison on a single scale. The confidence intervals communicate statistical precision under the relevant calculation; they cannot correct for missing design or analysis information.

10. Confidence Intervals and Precision

The arm-level estimates are 78% with a 95% confidence interval from 70% to 78% for lenalidomide plus dexamethasone, and 52% with a 95% confidence interval from 41% to 62% for dexamethasone. The interval widths differ, indicating different reported degrees of precision for the two arm estimates. The registry does not explain the method behind these intervals or why the first interval's upper limit equals its estimate.

For the unadjusted risk difference, the estimate is -0.268, with a 95% confidence interval from -0.397 to -0.138. Because the interval does not include zero, it is consistent with a difference in the direction indicated by the arm ordering. The interval still allows a range of possible contrast values; it does not pinpoint a single known effect. The unadjusted p-value is <0.001, which is related to but not a replacement for the interval's information about magnitude and precision.

As a general explanation, confidence intervals are affected by both the amount of information in the data and the variability assumed by the calculation. More information can often improve precision, but the outcome definition, follow-up, and analytic method also matter. The available outcome denominators are 97 and 95, and the registry lists 198 enrolled participants. It does not explain why the outcome denominators are smaller than enrollment, or how any unavailable outcomes were handled.

The follow-up timeframe is described as up to 5 years, rather than as one specified assessment time. Without the estimator, censoring rules, or participant-level follow-up information, the intervals cannot be independently assessed for their treatment of time-to-event data. They should be read as the registry's reported uncertainty around its posted summaries, with the unadjusted contrast understood separately from any analysis not documented in the registry record.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total event counts. This outcome is not identified as a time-to-event planning calculation in the assumptions; the stated rule is that non-time-to-event planning figures are participants per arm. The illustration uses the observed effect as its reference and considers planning for 100% of that effect, 75% of the observed effect, and 50% of the observed effect.

The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Under those assumptions, planning for 100% of the observed effect gives 49 participants per arm for 80% power and 65 participants per arm for 90% power. Planning for 75% of the observed effect gives 84 participants per arm for 80% power and 111 participants per arm for 90% power. Planning for 50% of the observed effect gives 177 participants per arm for 80% power and 237 participants per arm for 90% power.

In plain language, the 80% power column gives the estimated number per arm for a design with an 80% chance of detecting the stated effect under the planning assumptions; the 90% column gives the number for a 90% chance under those assumptions. Smaller effects need more participants to detect, which is why the figures increase as the planning effect becomes a smaller fraction of the observed effect. These are planning illustrations, not observed power. The original trial's own sample-size assumptions and justification are not reported in the registry record, so these figures should not be treated as its protocol design targets.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.784; treatment proportion p₁ = 0.516; average p̄ = 0.650.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6747 = 1.3224.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6476 = 0.5450.
4. n = (1.3224 + 0.5450)² / (-0.2677)² = 48.7, rounded up to 49 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.783505154639175                          # control proportion
p1 <- 0.515789473684211                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(64038)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 49 (80% power), 65 (90% power)
 75% of observed effect: n per arm = 84 (80% power), 111 (90% power)
 50% of observed effect: n per arm = 177 (80% power), 237 (90% power)
power.prop.test: 48.7 
Simulated power at n = 49 per arm: 0.801 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists toxicity as a secondary outcome and reports one secondary outcome. It lists no analysis entries. The record does not describe a prespecified hierarchy of outcomes, a family of hypothesis tests, or an adjustment for multiple comparisons. It is therefore not possible to determine whether or how multiplicity was addressed in the trial's statistical plan. As a general principle, testing several outcomes or subgroups can increase the chance of obtaining at least one apparently notable result by chance; methods to control that issue depend on the planned testing structure.

Missing data and analysis populations are also not described in sufficient detail. The trial enrollment is 198, while the primary outcome denominators are 97 for lenalidomide plus dexamethasone and 95 for dexamethasone. The registry does not explain the remaining participants' disposition, whether all randomized participants were included in an intention-to-treat analysis, or whether exclusions occurred. It also does not report how participants with incomplete follow-up were treated.

For a progression-free survival outcome, incomplete follow-up can involve participants whose event status is unknown after their last recorded observation. General methods may account for that through censoring, but the specific method, censoring rules, and assumptions are not reported in the registry record. The exact time point underlying each percentage is also unspecified beyond follow-up up to 5 years.

The registry record does not report interim analyses, stopping rules, subgroup analyses, covariate adjustment, or a missing-data sensitivity analysis. These absences do not establish that such procedures were or were not used outside the registry entry; they mean the methods cannot be verified from the record. The unadjusted recalculation should consequently be distinguished from a fully documented protocol analysis.

14. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

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: thrombosis/thrombus/embolism (13.5%), pneumonitis/pulmonary infiltrates (5.2%), albumin, serum-low (hypoalbuminemia) (5.0%), sodium, serum-low (hyponatremia) (5.0%), central nervous system (cns) cerebrovascular ischemia (5.0%).

The registry records serious adverse events affecting 41 of 96 participants in the lenalidomide-and-dexamethasone safety group, 21 of 94 in the dexamethasone group, and 14 of 40 in the crossover-to-Rev+Dex group. Other adverse events are recorded for 91 of 96, 90 of 94, and 39 of 40 participants, respectively. These are counts of participants affected and the corresponding groups at risk, not measures of event severity for an individual participant.

The most frequently listed serious event terms include thrombosis/thrombus/embolism at 13.5%, pneumonitis/pulmonary infiltrates at 5.2%, and albumin, serum-low (hypoalbuminemia), sodium, serum-low (hyponatremia), central nervous system cerebrovascular ischemia, and renal failure at 5.0% each. The registry does not give further detail in this record about event definitions, observation periods, or whether these terms refer to participants or event episodes. Death counts are not reported in the registry record.

The crossover group is listed separately and should not be treated as another randomized comparison arm. Safety counts alone do not establish that an intervention caused an event or support a direct causal comparison, particularly when exposure and follow-up details are not reported.

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

The posted results show different recorded progression-free survival percentages between the randomized arms: 78% for lenalidomide plus dexamethasone and 52% for dexamethasone. The unadjusted recalculated risk difference is -0.268 when expressed as dexamethasone compared with the combination, with a 95% confidence interval from -0.397 to -0.138 and an unadjusted p-value of <0.001. These statistics describe the observed contrast and its uncertainty under the unadjusted calculation.

They do not, on their own, establish the trial's prespecified treatment-effect estimate or analysis method. The registry does not report the precise time point, estimator, censoring rules, missing-data approach, or complete participant accounting. It also does not provide details of the original statistical plan. The arm-level percentages are therefore best understood as the results as recorded, not as fully specified time-to-event estimates whose methods can be reconstructed from this entry.

The outcome is a composite: progression or relapse and death from any cause are treated as events. The result does not separately describe each component, and the registry does not report component-specific estimates. The safety counts provide additional descriptive information, but do not establish causation. The record also does not report death counts in the adverse-event listing.

As a general statistical distinction, a small p-value does not measure the size, clinical importance, or certainty of a finding, and a confidence interval does not resolve potential bias or missing-method concerns. No medical advice follows from these data alone. The registry provides a record of a completed randomized comparison, while important details needed to evaluate its analysis and generalizability are not reported in the registry record.

16. Why This Trial Matters Statistically

This trial raises several useful statistical issues for clinical researchers. First, a progression-free survival endpoint is a time-to-event concept, but the registry presents the primary result as a percentage of participants. The timeframe extends up to 5 years, yet the precise time point and estimation method are not stated. That distinction matters because a percentage and a time-to-event estimate can rely on different treatment of follow-up and incomplete observation.

Second, the arm-level percentages and the comparative estimate answer related but distinct questions. The percentages describe each arm, while the risk difference, risk ratio, and odds ratio express the contrast on different scales. The direction of a contrast depends on arm ordering, so the negative risk difference is meaningful only when read as dexamethasone compared with lenalidomide plus dexamethasone.

Third, statistical precision and design information should be read separately. Confidence intervals communicate uncertainty around reported estimates, while the sample-size illustrations use the observed effect and stated planning assumptions. They do not reveal the original trial's design target; that justification is not reported in the registry record. Treating post-result planning illustrations as the trial's prospective calculation would confuse distinct purposes.

Finally, participant accounting and analysis transparency matter. Enrollment was 198, whereas the outcome denominators are 97 and 95. Without an accounting of those denominators, outcome availability, and analysis populations, readers cannot determine how all randomized participants contributed. These considerations do not erase the posted result, but they define the limits of what can be inferred from the registry entry alone.

17. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

Several limitations are specific to the registry record. The intervention descriptions are incomplete, including the maintenance details, so the full treatment schedules cannot be reconstructed. Although masking is listed as triple, the masked roles and procedures are not stated. The registry also does not give the randomization procedure or allocation details.

The outcome is described as a percentage over follow-up up to 5 years, but the specific assessment time and estimator are not reported. No censoring rules, follow-up distribution, or handling of incomplete outcome data are given. The outcome denominators, 97 and 95, do not sum to the total enrollment of 198, and the record does not explain the participant disposition or analysis population.

The registry does not report the original sample-size justification, a prespecified statistical analysis plan, interim analyses, multiplicity procedures, covariate adjustment, or missing-data sensitivity analyses. The unadjusted recalculation is based on posted summary statistics and should not be mistaken for a documented adjusted or protocol-defined analysis. The registry lists toxicity as a secondary outcome but does not provide detail on safety observation periods or event ascertainment in this record.

These gaps limit assessment of the precision and robustness of the endpoint estimates, and the safety groups include a separately listed crossover group whose relationship to the randomized comparison is not detailed. The limitations concern what the registry record documents; they do not establish what procedures may have been described elsewhere.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: S0232 Dexamethasone With or Without Lenalidomide in Treating Patients With Previously Untreated Stage I, Stage II, or Stage III Multiple Myeloma — NCT00064038.
• Registry record last updated 2015-03-25; status last verified 2015-03.
• Results first posted 2013-07-17.
• 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.

21. Record Summary

NCT00064038 is a completed, randomized, triple-masked, parallel-group phase III trial sponsored by SWOG Cancer Research Network. It enrolled 198 participants with previously untreated stage I, stage II, or stage III multiple myeloma. The two principal arms compared lenalidomide plus dexamethasone with dexamethasone alone.

The primary outcome was progression-free survival, reported as a percentage of participants over follow-up up to 5 years. The registry reports 78% in the combination arm and 52% in the dexamethasone arm. An unadjusted recalculated contrast is a risk difference of -0.268 for dexamethasone compared with the combination, with a 95% confidence interval from -0.397 to -0.138 and p < 0.001.

Toxicity is listed as a secondary outcome. Important details of the analysis plan, outcome estimation, participant accounting, and original sample-size justification are not reported in the registry record.