Chloroquine in Combination With VELCADE and Cyclophosphamide for Relapsed and Refractory Multiple Myeloma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Chloroquine in Combination With VELCADE and Cyclophosphamide for Relapsed and Refractory Multiple Myeloma (NCT01438177), a na phase 2 study. The primary outcome is Response Rate (CR + PR After 2 Cycles).

2. Clinical Question

The clinical question is about the proportion of treated participants meeting a specified response definition, not about the difference between treatment groups. A single-group response proportion can describe outcomes among participants who received the regimen, but without a concurrent comparator it cannot distinguish the regimen’s contribution from other influences on observed outcomes.

The trial is listed as phase II and enrolled 11 participants. Its status is terminated. The registry record does not state why the trial was terminated, so the status alone does not establish whether the reason was related to response, safety, recruitment, or another consideration.

The outcome title refers to response after 2 cycles, while its timeframe is listed as up to 2 years. The registry record also says responses were assessed every two cycles. These descriptions do not establish the exact follow-up period for each participant or whether the primary response assessment was available for everyone enrolled. Those details are not reported in the registry record.

3. Trial Design

This is a phase II, single-group trial sponsored by NYU Langone Health. The registry record describes a combination of Velcade, cyclophosphamide and chloroquine for patients with relapsed or refractory multiple myeloma. Enrollment was 11, and the trial status is terminated. The record lists the start as 2011-10 and primary completion as 2014-02.

The treatment schedule describes Velcade given by intravenous push at 1.3 mg/m^2 on days 1, 4, 8, 11, 22, 25, 29 and 32. Cyclophosphamide is described as 50 mg orally twice per day on days 1-14 and 22-35, and chloroquine as 500 mg orally daily on days 1-14 and 22-35. Each cycle is 42 days in length. These are registry-record descriptions of the regimen; information about dose modifications, treatment discontinuation rules or adherence is not reported in the registry record.

Allocation is listed as not applicable, masking as none, and the model as single group. These features mean that the record describes outcomes in one treatment group, rather than a randomized comparison between groups. No like-for-like control arm is available for estimating a between-group treatment effect.

The primary outcome is the response rate, defined as the percentage of patients who have a complete response or partial response. Responses were assessed every two cycles, using International Myeloma Working Group criteria. The outcome is specified for evaluable patients, but the evaluability criteria and the number evaluated are not reported in the registry record.

The registry record lists three secondary outcomes: participants with adverse events of Grade 3 or higher; the percentage of subjects with complete or partial response and autophagy of 2+ or higher; and median duration of response. It lists four outcome measures in total. Results for the primary and secondary outcomes, analysis methods, and reasons for termination are not reported in the registry record.

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:

Analysis population for the primary outcome, as defined in the registry: Evaluable patients.

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 Response Rate (CR + PR After 2 Cycles), measured over Up to 2 years.

The primary endpoint measures the percentage of evaluable participants who had a complete response or partial response after 2 cycles. It is a binary outcome at the participant level: each evaluated participant either meets the response definition or does not. The reported percentage would describe the share meeting that definition in the assessed population.

The registry record defines complete response using negative immunofixation in serum and urine, disappearance of soft tissue plasmacytomas, and less than 5% plasma cells in bone marrow. Partial response is described using reduction in serum M-protein and urinary M-protein criteria. The record attributes these response criteria to International Myeloma Working Group criteria and cites Durie and colleagues, 2006. The stated definitions include thresholds, which are reproduced in the registry description; they do not establish that any particular participant met either category.

A response proportion is used to summarize how often a defined outcome occurred in a group. It is understandable as a descriptive measure, but its interpretation depends on a clear denominator and consistent outcome assessment. Here the stated denominator is evaluable patients, not necessarily all enrolled participants. Neither the evaluable count nor the observed number with complete or partial response is reported in the registry record.

The outcome title specifies assessment after 2 cycles, while the timeframe is listed as up to 2 years and the description says assessments occurred every two cycles. The registry record does not clarify how these timing descriptions relate to the primary analysis. No estimate, confidence interval or statistical test for the primary endpoint is reported in the registry record, so the response frequency and its precision cannot be assessed from the recorded results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a proportion: the number of evaluated participants meeting the response definition in relation to the number evaluated. In general, this kind of endpoint treats each participant’s response status as a binary outcome. The observed proportion provides a descriptive estimate for the analyzed group. The registry record does not report the numerator, the evaluable denominator or the resulting proportion for this trial.

What does a confidence interval add?

In general, a confidence interval expresses the statistical uncertainty around an estimate. For a response proportion, it helps show how much precision the data support, in addition to stating the estimate itself. A narrow interval indicates greater precision than a wide interval, under the assumptions of the method used. It does not eliminate potential bias from missing participants, outcome measurement, or the absence of a comparator. No confidence interval for the primary response rate is reported in the registry record.

The size and interpretation of an interval depend on the analyzed denominator and the method used to construct it. In a small group, each participant’s outcome can have a substantial influence on the estimated proportion, and uncertainty can remain considerable. This is a general statistical point; the registry record does not provide enough outcome information to quantify the uncertainty for this trial. It also does not report the specific interval method, if one was used.

What can a single-group design estimate?

A single-group study can describe outcomes observed in its participants, such as the proportion meeting a response definition. It does not estimate a randomized between-group contrast when there is no comparator group. Any comparison with outcomes from another population would require assumptions about comparability, treatment, follow-up and outcome assessment. Such a comparison is not reported in the registry record. The listed single-group model and absence of masking should therefore be kept in mind when interpreting any descriptive outcome data.

The outcome definition and assessment schedule also matter. The registry record defines complete and partial response according to stated International Myeloma Working Group criteria and says response was assessed every two cycles. Consistent application of criteria supports comparability of assessments within a study, but the record does not describe assessor procedures or masking. The relationship between the endpoint title’s assessment after 2 cycles and the listed timeframe of up to 2 years is not clarified in the registry record.

What do planning calculations mean?

Planning calculations are not observations from participants. The registry record describes planning illustrations using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a stated fraction of the observed effect. Those assumptions describe an illustration, not the single-group design listed for this trial. They do not establish the trial’s original sample-size justification, and that justification is not reported in the registry record.

When sample-size calculations use an observed effect as a planning reference, the resulting numbers are conditional on the assumed effect and method. They do not say what happened in the trial, and they are not observed power. The record does not report a trial-specific sample-size justification, nor does it provide the outcome estimate needed to independently interpret the planning reference. The illustration should not be mistaken for evidence that the trial was adequately sized to answer the primary question.

In general, power is a design property calculated under specified assumptions about the outcome, effect, variability, sample size and testing approach. It is not a measure of the probability that a particular result is true after observing the data. Retrospective calculations based on the observed effect cannot replace reporting the estimate and its uncertainty. No trial analysis or primary endpoint estimate is reported in the registry record, so such an evaluation is not possible from the record.

Why can over-dispersion matter?

For outcomes measured as counts, over-dispersion means that observed variation is greater than a model assumes. If that extra variation is ignored, statistical uncertainty can be understated. This general issue is relevant to some count outcomes, but the primary endpoint in this trial is a participant-level response percentage, not a reported count-rate analysis. The registry record does not describe an over-dispersion assessment or a statistical model for the primary endpoint. It would not be appropriate to assume one was performed.

For time-to-event outcomes, such as duration of response, analysis generally requires information about event times and censoring, as well as a stated analysis plan. The registry record lists median duration of response as a secondary outcome, but does not report its result, the number of responses available for that analysis, or the method used. No time-to-event estimate can be reconstructed from the recorded information.

Finally, a statistical analysis plan specifies how outcomes and data will be handled, including the analysis population, missing observations and multiplicity. The trial’s statistical analysis plan, interim analyses and details of outcome-analysis methods are not reported in the registry record. The absence of reported analysis information limits assessment of how the endpoint was analyzed and whether the analysis followed a prespecified approach.

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("Velcade+Cyclophosphamide+Chloroquine")
n      <- c(9)
events <- c(3)
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  Velcade+Cyclophosphamide+Chloroquine  9  3  33.3  7.5  70.1  12.1  64.6  12.2  65.2

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists four outcome measures: the primary response rate and three secondary outcomes. When multiple outcomes are examined, multiplicity can arise from testing several hypotheses or making several estimates. In general, the more analyses considered, the greater the chance that some apparently notable findings occur by chance if each is interpreted without accounting for the collection of analyses. Whether adjustment is needed depends on the scientific questions and analysis plan. The registry record does not report a multiplicity strategy, so it is not possible to determine whether any adjustment was planned or used.

The record lists 0 analyses. This means no analysis results are reported in the registry record; it does not establish that no analysis was conducted. The analysis plan, interim analyses, and statistical methods for the outcomes are not reported in the registry record. No conclusion about prespecification or selective reporting can be drawn from the absence of those details alone.

The primary outcome population is described as evaluable patients. The eligibility criteria for that analysis, the number enrolled who were evaluable, and the handling of participants without an assessment are not reported in the registry record. No imputation method or sensitivity analysis for missing response data is reported. These omissions matter because the response proportion’s denominator and the reasons for missing outcome information affect its interpretation.

In general, missing-data methods rely on assumptions about why data are missing and how missing participants’ outcomes relate to observed outcomes. A complete-case proportion, if used, would describe participants with an available assessment, but would not necessarily represent all enrolled participants. The record does not identify the approach used here, so it is not possible to determine how missingness was handled or whether results were robust to alternative assumptions.

The safety summaries give counts at risk and affected for reported adverse-event categories, but the registry record does not describe the completeness of event collection or the treatment exposure used as the observation period. These details limit interpretation of safety frequencies. Further information about populations and analysis methods is not reported in the registry record.

12. 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: pain: pleura (9.1%).

The registry record reports 1 participant with a serious adverse event among 11 participants at risk. It also reports 11 participants with other adverse events among 11 at risk. These are participant counts, not a comparison between treatment groups. The record lists pain: pleura as the serious adverse event term with a reported value of 9.1%.

Serious adverse events and other adverse events are distinct categories in the registry summary. The record does not give the definition used for seriousness or clarify the relationship between the categories. The number of participants affected does not state how many individual events occurred, how long events lasted, or whether participants experienced more than one event. The detailed event-level information is not reported in the registry record.

The serious adverse event count is a descriptive safety observation in a group of 11. It does not establish causation: the record does not attribute the event to a particular drug or distinguish treatment-related from unrelated events. It also cannot show whether the frequency is higher or lower than under another regimen because there is no comparator group.

The registry record does not report deaths in the safety summary, and the death information is not reported in the registry record. It also does not state the duration of exposure or safety follow-up. These limits mean the counts should be read as the events recorded in the available summary, not as a complete account of risk or as evidence about comparative safety.

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

The registry record establishes that a phase II, single-group trial of Velcade, cyclophosphamide and chloroquine was conducted in patients with relapsed or refractory multiple myeloma, with enrollment of 11. It also defines a primary response outcome among evaluable patients and lists adverse-event and other secondary outcomes. These details explain what the trial set out to assess.

The record does not report the observed primary response rate, the number of participants with complete or partial response, or a confidence interval. Consequently, it does not show how often the defined response occurred or how precise an estimate would be. The absence of a reported result is not evidence that no responses occurred, nor does it indicate a particular response level.

The trial has no concurrent comparator group. Even if a response proportion were available, it would be a description of outcomes in the treated group rather than an estimate of the difference between this combination and another treatment. The record does not provide randomized comparative evidence for efficacy or safety.

The recorded adverse-event counts describe participants affected in the trial. They do not determine whether events were caused by the regimen, establish the full range of possible harms, or quantify comparative risk. The listed serious adverse event term is pain: pleura, at 9.1%; detailed event information and attribution are not reported in the registry record.

The terminated status is a trial-status entry, not a clinical finding. The reason for termination is not reported in the registry record, so it should not be interpreted as evidence of benefit, lack of benefit, harm or futility. The record also does not report the statistical analysis plan, the evaluable population size, or how missing outcome information was handled. These omissions prevent a full assessment of the planned and performed analyses.

In general, a treatment conclusion requires appropriate outcome estimates, their precision, and a design that supports the comparison being made. The posted record supplies design and outcome definitions but not the primary outcome result or a control-group comparison. It therefore supports a description of the trial record, not a conclusion about whether the combination is effective or ineffective.

14. Why This Trial Matters Statistically

This trial illustrates the distinction between a clearly named endpoint and a reported endpoint result. The primary outcome is defined as the percentage of evaluable participants with a complete or partial response after 2 cycles, with response criteria described in the registry record. But without the observed numerator, denominator, estimate and uncertainty, readers cannot assess the response frequency or its precision. A detailed definition is important, but it cannot substitute for an outcome analysis.

The single-group structure is also important statistically. A response proportion can characterize outcomes in a treated cohort, while a comparative effect requires a suitable comparison. With allocation listed as not applicable and no comparator group, the record cannot separate treatment-associated outcomes from other explanations. This distinction prevents a descriptive result from being misread as a controlled estimate of treatment effect.

The evaluable-patient population highlights the importance of transparent denominators. Enrollment was 11, but the number deemed evaluable is not reported in the registry record. If the analyzed group differs from the enrolled group, readers need to know which participants were included and why. Without that information, both the endpoint estimate and the possible influence of missing data remain unclear.

The trial also demonstrates why a planning illustration should not be confused with a study’s observed evidence or its original design justification. The registry describes planning assumptions involving two arms, although the recorded model is single group. Those calculations are illustrations and do not report trial outcomes or observed power. The trial-specific sample-size justification is not reported in the registry record.

Finally, trial status, safety counts and response results answer different questions. Termination does not explain why the study stopped, and adverse-event counts do not establish causation or comparative safety. Keeping these distinctions clear is essential when registry information is incomplete. The trial matters statistically as an example of how design, analysis population, missing results and the precision of estimates shape what can responsibly be concluded.

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 enrollment of 11 limits the amount of information available for describing outcomes in this trial. In general, estimates from a small group are sensitive to the outcome of each participant and can have substantial uncertainty. Here, the primary result and its uncertainty are not reported in the registry record, so that uncertainty cannot be quantified.

The single-group design is a central limitation for comparative interpretation. There is no control group, allocation is listed as not applicable, and masking is listed as none. The record therefore does not provide a randomized comparison or a like-for-like control. Any observed outcome, if reported, would describe the treatment group rather than establish a difference attributable to the regimen.

The primary outcome uses an evaluable-patient population, but the evaluability criteria and number assessed are not reported in the registry record. The outcome is titled as response after 2 cycles, while the timeframe is listed as up to 2 years. The record does not explain the relationship between these timing details or give participant-level follow-up information. Missing assessments, exclusions and their handling are also not reported.

The trial is terminated, but the reason is not reported in the registry record. Results for the primary endpoint and secondary outcomes are not reported, despite the listed outcome measures. The statistical analysis plan, outcome-analysis methods, interim analyses, multiplicity approach and original sample-size justification are not reported in the registry record. As a result, readers cannot evaluate whether analyses followed a prespecified plan or how uncertainty and multiple outcomes were addressed.

The safety summary is limited to participant counts and a listed serious adverse event term. Detailed event descriptions, attribution, timing, exposure duration and full death information are not reported in the registry record. These limitations constrain interpretation of the safety profile. Together, the design and reporting gaps mean the record offers a limited account of clinical outcomes and does not support a comparative assessment.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Chloroquine in Combination With VELCADE and Cyclophosphamide for Relapsed and Refractory Multiple Myeloma — NCT01438177.
• Registry record last updated 2020-02-24; status last verified 2020-02.
• Results first posted 2015-06-01.
• 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 phase II, single-group trial of Velcade, cyclophosphamide and chloroquine in relapsed or refractory multiple myeloma. Enrollment was 11, and status is terminated. The primary outcome is the percentage of evaluable participants with complete or partial response after 2 cycles, with response assessment described using International Myeloma Working Group criteria.

The record lists three secondary outcomes concerning adverse events, response with autophagy of 2+ or higher, and duration of response. It reports 1 participant with a serious adverse event among 11 at risk and 11 participants with other adverse events among 11 at risk. Pain: pleura is listed at 9.1% among the serious adverse event terms.

The observed primary response result, evaluable-patient count, analysis methods, reason for termination, and trial-specific sample-size justification are not reported in the registry record. The single-group design does not provide a concurrent comparator, so the record does not establish a comparative treatment effect.