Continuous Versus Intermittent Dosing Regimens for Pomalidomide in Relapsed/Refractory Multiple Myeloma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Continuous Versus Intermittent Dosing Regimens for Pomalidomide in Relapsed/Refractory Multiple Myeloma (NCT01319422), a randomized phase 2 study. The primary outcome is Percentage of Participants With Response, Analyzed Per International Myeloma Working Group Response Criteria.

2. Clinical Question

3. Trial Design

This was a randomized, open-label, parallel-group phase 2 trial sponsored by Yale University. The registry record lists the condition as multiple myeloma and the intervention as pomalidomide. Participants were assigned to one of two dosing regimens: 2 mg/d on 28 days of a 28-day cycle, or 4 mg/d on 21 days of a 28-day cycle. Masking is recorded as none, so the study was not described as blinded.

The record lists enrollment of 40. The arm-level primary outcome results use denominators of 19 in the 2 mg/d group and 20 in the 4 mg/d group. The registry does not explain the relationship between the enrollment figure and these outcome denominators, so no reason for the difference should be inferred. The record lists a start date of 2011-06, primary completion in 2014-11, and status as completed.

The primary outcome was the percentage of participants with a response according to International Myeloma Working Group response criteria. Efficacy assessments were planned after the first two cycles, approximately 56 days, with each cycle lasting 28 days. Partial and complete responses were required to be confirmed with another efficacy assessment no less than 4 weeks apart. The record does not report further details about allocation procedures, eligibility criteria, the original sample-size justification, or the trial’s statistical analysis plan.

The secondary objectives concern cellular and immune measures, including F Actin polymerization, tumor antigen-specific T cells, innate lymphocytes, cytokine profiles, adverse effects, and clinical responses. These objectives describe questions the trial intended to examine; they are not additional numerical findings in the posted primary outcome data.

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: Four screened subjects did not meet eligibility criteria. Forty subjects were enrolled, but one withdrew after randomization without receiving treatment, and is listed as a "non-completer". Thus, data are presented for 39 participants.

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 Percentage of Participants With Response, Analyzed Per International Myeloma Working Group Response Criteria, measured over Efficacy assessments will be made after the first two cycles of therapy (approximately 56 days--each cycle is 28 days).

The primary endpoint is the percentage of participants with a response, assessed according to International Myeloma Working Group response criteria. It is a binary outcome at the participant level: each participant is classified as having a response or not having a response for this measure. The registry specifies that partial and complete responses must be confirmed with another efficacy assessment no less than 4 weeks apart.

The assessment was scheduled after the first two cycles of therapy, approximately 56 days, with each cycle lasting 28 days. Thus, the reported measure concerns response at this early efficacy assessment, not response over an unspecified longer period or a time-to-event outcome. The 2 mg/d regimen had a posted response percentage of 15.8%, based on 3 responses among 19 participants; the 4 mg/d regimen had a posted percentage of 20.0%, based on 4 responses among 20 participants.

As a general statistical concept, a response percentage is easy to interpret as the proportion of participants meeting a defined outcome. It also reduces a complex clinical course to a yes-or-no classification at the specified assessment. That simplicity does not describe response duration, changes in the underlying measurements, or other benefits and harms. Those questions require separate outcomes and analyses. The registry record does not report the detailed rules used to handle participants without an evaluable assessment.

7. Results Posted in the Registry

• Pomalidomide 4 mg/d on 21 Days/28 Day Cycle: 20.0% (4/20) versus 15.8% (3/19) on control; risk difference 4.2 percentage points (95% CI -19.8 to 28.2), risk ratio 1.27 (0.33–4.93); unadjusted two-proportion z-test p = 0.732.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary measure is binary: each participant either met the response definition or did not. The registry states that response was evaluated using International Myeloma Working Group response criteria and that partial and complete responses needed confirmation at least 4 weeks apart. For a binary outcome, the response proportion is the number classified as responders divided by the relevant outcome denominator. The posted values are 3 of 19 for the 2 mg/d regimen and 4 of 20 for the 4 mg/d regimen, reported as 15.8% and 20.0%.

What does the risk difference represent?

As a general statistical concept, the risk difference subtracts one group’s response probability from the other group’s response probability, using a specified ordering of the arms. It is expressed on the probability scale. The posted risk difference is 0.042, with a 95% confidence interval from -0.198 to 0.282. The interval reflects the uncertainty in estimating the difference from the observed groups. Because the interval spans zero, it is compatible with no difference as well as differences in either direction. This is not the same as demonstrating that the true difference is zero.

How do risk ratios and odds ratios differ?

In general, a risk ratio compares the response probabilities between groups. An odds ratio compares the odds of response between groups, where odds are the probability of response relative to the probability of no response. These measures express relative rather than absolute contrasts. In this trial, the posted risk ratio is 1.267, with an interval from 0.326 to 4.93; the posted odds ratio is 1.333, with an interval from 0.256 to 6.94. Both intervals are broad. The numerical estimates alone should not be interpreted without their uncertainty, and a relative measure does not replace the absolute response proportions.

What does a confidence interval communicate?

In general, a confidence interval is a range of values compatible with the observed data under the method used to calculate it. Its width reflects statistical precision: a wider interval allows a wider range of possible effects and indicates less precision. The confidence interval is not a guarantee that the true effect lies within its endpoints, and it does not describe the probability that a particular effect is true. The registry record does not state the confidence-interval method used for the posted comparison.

How should the p-value be read?

The posted p-value is unadjusted and equals 0.732. As a general concept, a p-value measures how unusual data at least as inconsistent with a specified null hypothesis would be if that hypothesis and the test’s assumptions held. It is not the probability that the null hypothesis is true, nor a measure of clinical importance. A p-value alone does not show equivalence or establish that the groups have the same response probability. The registry record does not report a more detailed testing plan or any multiplicity adjustment.

Why can small counts make estimates uncertain?

In general, estimates based on fewer outcome observations can vary substantially with the classification of a small number of participants. Here, the posted response counts are 3 and 4. That limited event information is consistent with the broad confidence intervals for the risk difference, risk ratio, and odds ratio. The numerical response percentages should therefore be interpreted as estimates with substantial uncertainty rather than as precise descriptions of a stable difference.

What is and is not documented about the analysis?

The record describes a randomized parallel-group trial and posts the primary outcome percentages and an unadjusted comparison. It does not report the original sample-size justification, a full statistical analysis plan, the analysis population definition, or how missing primary outcome assessments were handled. It also lists three secondary objectives but no posted analyses. These absences limit evaluation of whether the displayed comparison followed a prespecified plan and how participants were handled across outcomes. They do not, on their own, establish that a particular analysis choice or missing-data problem occurred.

10. Confidence Intervals and Precision

The confidence interval for the risk difference is -0.198 to 0.282 around an estimate of 0.042. Its width is important: the data are compatible with a negative difference, a value near zero, and a positive difference. Thus, the point estimate should not be treated as a precise estimate of the contrast between schedules. The interval crosses zero, so the posted data do not pin down the direction of the risk difference.

The relative-effect intervals are also broad. The risk ratio estimate is 1.267, with a 95% confidence interval from 0.326 to 4.93. The odds ratio estimate is 1.333, with a 95% confidence interval from 0.256 to 6.94. These ranges permit substantially different relative effects. The unadjusted p-value of 0.732 is consistent with the lack of a precise separation in the posted comparison, but it does not demonstrate equivalence.

As a general concept, precision depends on the amount and variability of information available for an estimate, not just on the displayed point estimate. The observed response counts are 3 and 4, and the outcome denominators are 19 and 20. With limited event information, estimates can be sensitive to individual outcome classifications. The registry record does not state the interval-calculation method, so the method cannot be assessed from the posted results alone.

These intervals concern the primary response comparison and do not quantify uncertainty for unreported secondary outcomes or safety terms. They also do not address potential limitations from missing data or analysis-population choices, which are not described 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 events. They are illustrations based on the observed effect, rather than a report of the original trial’s design calculation. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect.

For planning at 100% of the observed effect, the displayed values are 1,300 participants per arm for 80% power and 1,740 participants per arm for 90% power. For planning at 75% of the observed effect, the values are 2,258 participants per arm for 80% power and 3,023 participants per arm for 90% power. For planning at 50% of the observed effect, the values are 4,960 participants per arm for 80% power and 6,639 participants per arm for 90% power.

In general, 80% power means that a study designed under the stated assumptions would have an 80% chance of detecting the specified effect at the stated significance level if that effect were the true one. The 90% column uses a higher target chance of detection, and therefore calls for a larger planned sample in these illustrations. Smaller effects are harder to distinguish from random variation, so the displayed planning figures increase as the assumed fraction of the observed effect gets smaller.

These values are not observed power and should not be read as a retrospective assessment of the completed trial. The original trial’s own sample-size assumptions and justification are not reported in the registry record. The posted planning figures are sensitive to the estimated observed effect, which is imprecise in this comparison, and are not a guarantee that a future study using those sample sizes would reproduce the same result.

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 = 0.158; treatment proportion p₁ = 0.200; average p̄ = 0.179.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5421 = 1.0625.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5413 = 0.4555.
4. n = (1.0625 + 0.4555)² / (0.0421)² = 1,299.8, rounded up to 1,300 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 <- 0.157894736842105                          # control proportion
p1 <- 0.2                          # 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(1319422)
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 = 1,300 (80% power), 1,740 (90% power)
 75% of observed effect: n per arm = 2,258 (80% power), 3,023 (90% power)
 50% of observed effect: n per arm = 4,960 (80% power), 6,639 (90% power)
power.prop.test: 1299.8 
Simulated power at n = 1,300 per arm: 0.802 (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 trial lists a primary response outcome and three secondary objectives. The secondary objectives concern the effects of the dosing regimens on F Actin polymerization, activation of tumor antigen-specific T cells and innate lymphocytes, correlations between drug-induced changes in F Actin and adverse effects or clinical responses, and correlations between F Actin and cytokine profile. The registry record does not report numerical analyses for these secondary objectives.

Multiplicity arises when a study tests several outcomes or comparisons: even if each test is considered separately, the chance of at least one apparently unusual result can increase across a set of tests. As a general statistical approach, investigators may prespecify a hierarchy or use an adjustment, depending on the aims. The registry record does not report whether multiplicity was addressed, whether secondary analyses were prespecified in detail, or which secondary outcomes were intended to be confirmatory rather than exploratory. No adjustment should be assumed.

The primary comparison is posted with an unadjusted p-value of 0.732. The record does not describe whether other tests were part of a larger analysis family, so that value cannot be interpreted as a multiplicity-adjusted result. The record also does not report interim analyses or stopping rules.

Details about missing data and analysis populations are not reported in the registry record. The primary outcome denominator is 19 in the 2 mg/d group and 20 in the 4 mg/d group, while enrollment is listed as 40. The record does not explain this difference or state whether the analysis used an intention-to-treat, per-protocol, or other population. It does not explain how unevaluable or missing response assessments were handled. These gaps limit assessment of possible bias from exclusions or missing outcomes; they are not evidence that such bias occurred.

The registry’s primary outcome description requires confirmation of partial and complete responses, but it does not give further information about adjudication, assessment timing variations, or the handling of confirmation assessments that were unavailable. Those details are not reported in the registry record.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: febrile neutropenia (15.8%), lung infection (15.0%), dyspnea (15.0%), thrombocytopenia (10.5%), fever (10.5%).

The registry records serious adverse events in 11 of 20 participants in the 4 mg/d on 21 days of a 28-day cycle group and in 7 of 19 participants in the 2 mg/d on 28 days of a 28-day cycle group. Other adverse events are recorded for 20 of 20 and 19 of 19 participants, respectively. These are group-level counts in the safety record. The registry does not report death counts for either group.

The listed serious adverse event terms and percentages are febrile neutropenia, 15.8%; lung infection, 15.0%; dyspnea, 15.0%; thrombocytopenia, 10.5%; fever, 10.5%; and anemia, 5.3%. The record does not provide event counts alongside these percentages in this listing, and they should not be treated as a complete account of every event or as direct measures of comparative risk between regimens.

As a general interpretation point, a serious adverse event is a safety classification, not a statement that the study drug caused the event. The registry figures describe reported events and affected participants; they do not establish causality. The record does not give enough detail to assess event timing, duration, severity categories beyond seriousness, or exposure-adjusted rates. These figures should be read separately from the primary response comparison.

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

The primary results show response percentages of 15.8% for the 2 mg/d schedule and 20.0% for the 4 mg/d schedule at the assessment after the first two cycles. The comparison estimate is 0.042 for the risk difference, with a 95% confidence interval from -0.198 to 0.282. The interval is broad and spans both negative and positive values. The posted result therefore does not precisely determine the direction or size of the difference in response proportions.

The finding does not establish that the regimens are equivalent. Equivalence is a specific question that requires a prespecified equivalence margin and appropriate analysis, neither of which is reported in the registry record. The result also does not establish that one schedule is superior. A numerical difference in the observed percentages is not, by itself, sufficient to establish a reliable difference.

The primary endpoint is an early response measure, with efficacy assessment after the first two cycles, approximately 56 days. It does not directly answer questions about how long a response lasted, later disease outcomes, or other aspects of participants’ experience. The secondary objectives include pharmacodynamic and immune measures, but numerical results for those measures are not reported in the registry record. Safety information is recorded separately and should not be collapsed into the response percentage.

As a general statistical point, uncertainty is part of the result, not a reason to ignore it. The confidence interval makes clear that the observed group comparison is compatible with a range of effects. The unadjusted p-value of 0.732 does not prove the absence of a difference, and it does not indicate the probability that either schedule is effective. The comparison should be interpreted as an imprecise estimate from this randomized phase 2 trial.

The record does not report sufficient information about missing data, analysis-population definitions, or the original analysis plan to resolve all design and analysis questions. No conclusion about broader populations or settings follows from the posted primary endpoint alone. The results describe the comparison recorded for these dosing schedules and this specified response assessment.

16. Why This Trial Matters Statistically

This trial raises a useful statistical question about how to compare two schedules of the same drug when the primary outcome is a participant-level response. A randomized parallel-group design provides a framework for comparing the response proportions between assigned groups. Reporting both the arm-level percentages and an absolute risk difference makes the contrast interpretable in terms of response probability, while relative measures such as the risk ratio and odds ratio describe the comparison on different scales.

The posted estimates also illustrate why effect estimates should be read with their uncertainty. The risk difference is 0.042, but its 95% confidence interval ranges from -0.198 to 0.282. The relative-effect intervals are broad as well. The small posted response counts—3 and 4—help explain why the estimated contrast is not precise. A point estimate alone can give a misleading impression of certainty when the underlying information is limited.

The record’s focus on pharmacodynamic outcomes alongside clinical response also illustrates a distinction between biological measures and clinical endpoints. The secondary objectives ask about cellular changes and their relationships with adverse effects and clinical responses. Those relationships require their own analyses; the existence of an objective does not establish that the association was found. Numerical secondary results are not reported in the registry record.

Finally, the trial highlights the value of documenting the analysis population, missing-data approach, multiplicity handling, and original sample-size rationale. Those details help readers assess how results were generated and what conclusions are warranted. Their absence from the registry record leaves important questions unresolved, without proving that any particular methodological problem occurred.

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.

The primary response comparison has limited precision: the risk-difference interval extends from -0.198 to 0.282, and the intervals for the risk ratio and odds ratio are also broad. The posted response counts are 3 and 4. These features mean the observed percentages should not be treated as a precise estimate of the difference between schedules.

The registry record does not report the original sample-size justification or the statistical analysis plan. It also does not state the analysis population, how missing or unevaluable response assessments were handled, or why the primary outcome denominators differ from the enrollment figure. The record therefore does not allow a full assessment of the consequences of exclusions or missing outcome data.

The primary outcome is assessed after the first two cycles, approximately 56 days. It does not by itself describe later outcomes or response duration. The registry lists three secondary objectives, but numerical analyses for those objectives are not reported in the registry record. Multiplicity procedures and interim analyses are also not reported.

The trial is recorded as open-label, with masking listed as none. This describes the design but does not establish that assessments were biased. The record does not explain any safeguards for response assessment or provide further information about allocation procedures. Safety counts and listed adverse event terms are descriptive; the record does not establish that the events were caused by pomalidomide or provide enough detail to compare event rates by exposure time.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Continuous Versus Intermittent Dosing Regimens for Pomalidomide in Relapsed/Refractory Multiple Myeloma — NCT01319422.
• Registry record last updated 2016-08-11; status last verified 2016-06.
• Results first posted 2016-08-11.
• 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

NCT01319422 is a completed randomized, open-label, parallel-group phase 2 trial sponsored by Yale University. It compared pomalidomide 2 mg/d on 28 days of a 28-day cycle with pomalidomide 4 mg/d on 21 days of a 28-day cycle in multiple myeloma. Enrollment is listed as 40, with the primary outcome denominators recorded as 19 and 20.

The primary endpoint was the percentage of participants with a response by International Myeloma Working Group response criteria after the first two cycles, approximately 56 days. The posted response percentages were 15.8% and 20.0%. The unadjusted risk difference was 0.042, with a 95% confidence interval from -0.198 to 0.282 and an unadjusted p-value of 0.732. The interval indicates substantial uncertainty about the size and direction of the comparison.

The registry record lists cellular and immune secondary objectives and safety information, but does not report numerical secondary analyses, the original sample-size rationale, or detailed missing-data and analysis-population methods.