Combination Plerixafor (AMD3100)and Bortezomib in Relapsed or Relapsed/Refractory Multiple Myeloma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Combination Plerixafor (AMD3100)and Bortezomib in Relapsed or Relapsed/Refractory Multiple Myeloma (NCT00903968), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Participants With Dose Limiting Toxicity (DLT) [Phase I].

2. Clinical Question

The registry describes a two-phase investigation rather than a trial designed to estimate a comparative treatment effect. Phase I varied doses to assess toxicity, while Phase II used a stated regimen and listed disease-related follow-up outcomes. However, the record does not report results for the primary dose-limiting-toxicity endpoint or the Phase II secondary outcomes. Safety-event summaries are available, but they are not a substitute for those outcome results.

3. Trial Design

The trial is recorded as Phase I/II, nonrandomized, unmasked, and single-group. Enrollment is listed as 58, and the study status is completed. The recorded start was 2009-06-01, with primary completion in 2016-06. Dana-Farber Cancer Institute is listed as sponsor. These record details describe the study’s registration, not the completeness of its posted outcome data.

In Phase I, participants received plerixafor by injection and bortezomib intravenously according to a dose-escalation schedule. The registry lists dose levels that vary the dose of one or both drugs, and one level also changes the listed plerixafor administration days. Treatment was described as continuing until disease progression or unacceptable toxicity. The Phase I primary endpoint is the number of participants with dose-limiting toxicity, with the first 21 days specified as the observation period for maximum-tolerated-dose evaluation.

The Phase II description lists plerixafor 320ug/kg, bortezomib 1.3 mg/m2, and dexamethasone 40mg during induction, with treatment given on specified days of each 21 day cycle. It describes bortezomib as intravenous or subcutaneous in Phase II. The maintenance details are not reported in the registry record.

Because there was no randomized control group, differences between dose levels should not be treated as causal treatment contrasts. The record does not report a randomization procedure, masking, or a separate concurrent comparator. It also does not report the rationale for the planned enrollment or the statistical plan for comparing dose levels.

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.

Only the first 6 of 8 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All Phase I participants who received at least one dose of the study drug were evaluable for MTD.

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 Limiting Toxicity (DLT) [Phase I], measured over Participants were assessed every 3 weeks while on study; The observation period for MTD evaluation was the first 21 days of treatment..

The Phase I primary endpoint is the number of participants with dose-limiting toxicity. The registry says that participants were assessed every 3 weeks while on study and that the observation period for maximum-tolerated-dose evaluation was the first 21 days of treatment. The population defined as evaluable consists of Phase I participants who received at least one dose of study drug.

The registry defines a dose-limiting toxicity using specified severity and treatment-relatedness criteria. These include certain grade 3 or greater non-hematologic toxicities considered related to plerixafor or bortezomib; specified grade 4 hematologic toxicities; and inability to receive the Cycle 2 Day 1 dose because of toxicity. The listed criteria include exceptions for nausea, vomiting, or diarrhea unless maximal medical therapy was being received, and detailed conditions for thrombocytopenia and neutropenia. Adverse events were graded according to CTEP Common Toxicity Criteria (CTCAE v.3.0).

In general, a dose-limiting-toxicity endpoint is used in early dose-finding research to identify toxicity that constrains dose escalation. It is a defined safety outcome over a specified period, not a general count of all adverse events and not an efficacy measure. The registry record names this primary endpoint but does not report its result. The serious adverse-event summaries therefore cannot establish how many participants met the dose-limiting-toxicity definition.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a binary participant-level primary outcome: whether a Phase I participant had a dose-limiting toxicity within the specified evaluation period. Although the endpoint is expressed as a count of participants, its underlying status is event or no event. The record defines who is evaluable and gives toxicity criteria, but it does not report the endpoint count or an associated estimate of uncertainty.

What does a participant count tell the reader?

In general, a count gives the number of people meeting an outcome definition in the population being described. Interpreting a count depends on knowing its denominator, the eligibility or evaluability rules, and the time window for outcome assessment. Here, the primary endpoint description supplies the evaluable-population rule and first-cycle observation period. The primary endpoint result itself is not reported in the registry record, so a count or proportion for that endpoint cannot be stated.

The serious-event summaries are a separate kind of safety information. They report participants with serious adverse events within the registry’s safety groups; they do not say that those participants met the DLT definition. Serious adverse events and dose-limiting toxicities are not interchangeable labels: the primary endpoint uses the trial’s specified severity, attribution, and timing criteria, while the safety summaries are presented as serious adverse-event counts. In general, an event can be important for safety monitoring without satisfying a particular trial’s DLT definition.

Why does the single-group design matter?

In general, random allocation helps make comparison groups similar, on average, with respect to both measured and unmeasured characteristics. This study is recorded as nonrandomized and single-group, so it does not have a randomized control arm. The Phase I dose levels represent the study’s dose-escalation schedule, not interchangeable groups assigned to test a comparative hypothesis. Differences between their recorded counts may reflect group composition, dose assignment, or other factors; the registry record does not provide an analysis that separates these possibilities.

The lack of a comparator also limits interpretation of Phase II outcomes. Time to progression and duration of response are listed as secondary outcomes, but no results are reported. Even if such outcomes were reported, a single-group result would describe the study participants’ observed experience under the regimen; it would not by itself quantify what would have happened under a different treatment.

How should uncertainty be understood?

In general, a confidence interval expresses the range of values compatible with the observed data under a specified statistical model. It communicates precision as well as the point estimate. Small groups can yield substantial uncertainty, even when a point estimate appears high or low. The registry record does not report confidence intervals for the primary endpoint or the adverse-event counts, so precision for those outcomes cannot be assessed from the posted record.

For event-count data, the denominator matters. A count without its group size gives little information about how common the event was in that group. The adverse-event summaries list both affected participants and those at risk for each group. They should be interpreted within those recorded groups, rather than combined across dose levels to create a new estimate. In general, combining groups requires a justified analysis that accounts for their design and the question being asked.

What do the planning illustrations mean?

In general, sample-size planning asks how many participants a future study might need under stated assumptions about an effect, significance level, allocation, and statistical model. The posted planning illustrations are based on the observed effect and specify a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; they also consider a stated fraction of the observed effect. These are planning assumptions, not the design of this nonrandomized single-group study.

Planning figures are not observed power and do not establish that the trial had a particular probability of detecting an effect. The registry record does not report that these assumptions were the trial’s own design assumptions or its sample-size justification. Since no primary endpoint result is reported, the planning illustrations should not be treated as evidence about the trial’s DLT outcome. For time-to-event planning, the stated convention concerns total events; for other outcomes, it concerns participants per arm. Such conventions describe calculations, not observed trial results.

The record lists six outcome measures and zero analyses. It does not report a detailed statistical analysis plan, a method for handling repeated or missing measurements, or an inferential model for the primary endpoint. As a result, the registered definitions and the descriptive safety counts can be explained, but a more detailed account of estimation, adjustment, or hypothesis testing is not possible from 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("Phase I Dose Level 1", "Phase I Dose Level 2", "Phase I Dose Level 3", "Phase I Dose Level 4", "Phase I Dose Level 5", "Phase I Dose Level 5B")
n      <- c(3, 3, 3, 3, 4, 6)
events <- c(0, 0, 0, 0, 0, 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  Phase I Dose Level 1  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Phase I Dose Level 2  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Phase I Dose Level 3  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Phase I Dose Level 4  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Phase I Dose Level 5  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  Phase I Dose Level 5B  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0

11. Multiplicity, Missing Data and Analysis Populations

The record lists six outcome measures, including the Phase I primary endpoint and the Phase II secondary outcomes of time to progression and duration of response. It lists zero analyses. No multiplicity strategy is reported in the registry record. In general, when a study evaluates multiple outcomes or makes multiple statistical comparisons, the chance of at least one apparently unusual result can increase; a prespecified approach can clarify how such results are to be interpreted. The record does not establish whether any adjustment or hierarchy was planned.

The primary endpoint is defined for Phase I participants who received at least one dose of study drug. The record does not report how many participants were evaluable for this endpoint, the number meeting the DLT definition, or how participants with incomplete observation were handled. Missing-data methods and the extent of missing outcome data are not reported in the registry record. Absence of those details should not be interpreted as evidence that there were no missing data.

The safety summaries list group-specific participants at risk and affected, but the record does not describe whether all participants had complete safety follow-up or how missing safety information was handled. It also does not report whether the listed populations were used consistently across all six outcome measures. The endpoint-specific evaluable definition is available for the Phase I DLT measure; other analysis-population definitions are not reported in the registry record.

In general, multiplicity, missingness, and population definitions affect how estimates and tests should be interpreted. Without a reported analysis plan and endpoint results, it is not possible to determine which analyses were prespecified, whether any outcomes were omitted, or how uncertainty from multiple testing or incomplete follow-up was addressed.

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: anemia (33.3%), lymphocytopenia (33.3%), hypophosphatemia (33.3%), thrombocytopenia (25.0%), upper airway infection (9.1%).

The registry’s serious adverse-event summaries list affected participants and participants at risk within each group. The reported figures are 8 of 25 for all Phase I participants and 14 of 33 for all Phase II participants. Across Phase I dose levels, the record lists 1 of 3 at Dose Level 1, 1 of 3 at Dose Level 2, 0 of 3 at Dose Level 3, 2 of 3 at Dose Level 4, 2 of 4 at Dose Level 5, 2 of 6 at Dose Level 5B, and 0 of 3 at Dose Level 6.

The record’s top serious adverse-event terms include anemia, lymphocytopenia, and hypophosphatemia, each listed at 33.3%; thrombocytopenia at 25.0%; upper airway infection at 9.1%; and insomnia at 6.1%. These percentages are registry entries and should be read as reported, not recalculated. The record does not provide additional event-level detail such as the number of recurrent events or their timing in this summary.

Serious adverse events are not the primary endpoint. A serious event does not necessarily satisfy the trial’s DLT definition, which applies specified criteria and a particular observation period. The record does not report death counts. Because the study was nonrandomized and single-group, these safety summaries do not establish comparative risk between treatments.

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

The registry record describes a Phase I/II investigation of plerixafor with bortezomib in relapsed or relapsed/refractory multiple myeloma. Its Phase I primary question concerns dose-limiting toxicity during a defined evaluation period, and the study purpose included safety and identifying the highest dose that could be given safely. The Phase II secondary outcomes listed are time to progression and duration of response.

The posted safety information gives serious adverse-event counts for the Phase I dose groups and for the Phase I and Phase II groups overall, along with selected serious-event terms and percentages. These figures are descriptive. They show what the registry reports for the study groups, but they do not provide a randomized comparison or establish that the treatment caused or prevented a particular event.

The record does not report the primary DLT result or results for the Phase II secondary outcomes. It therefore does not allow a reader to determine from the posted results how many participants met the primary endpoint definition, or what the observed time-to-progression and duration-of-response results were. Serious adverse-event counts cannot fill that gap because they are not the same endpoint.

In general, an outcome recorded in a single-group study describes events observed under the study’s conditions. Without a randomized comparator, there is no direct control-group estimate for distinguishing treatment effects from other explanations. The nonrandomized dose escalation also means dose-level differences should not be interpreted as if participants had been randomly allocated to those doses.

The record is informative about the study’s design, DLT definition, dosing schedule, and reported adverse-event summaries. It does not establish comparative efficacy, comparative safety, or the results of the primary endpoint. These boundaries are important when using registry information to understand what was studied and what the posted outcomes do—and do not—show.

14. Why This Trial Matters Statistically

This trial illustrates why early dose-finding studies and comparative treatment trials answer different statistical questions. The Phase I design varied doses of plerixafor and bortezomib and specified a DLT endpoint for assessing toxicity during the first 21 days. That focus is distinct from estimating a treatment contrast against a randomized control group. The record’s nonrandomized, single-group design is therefore central to interpreting the dose-level safety summaries.

The detailed DLT definition also shows why outcome labels matter. The primary endpoint applies specified event severity, attribution, and timing criteria. A count of serious adverse events is useful safety information, but it is not automatically a count of DLTs. Keeping these endpoints distinct prevents a broad adverse-event summary from being mistaken for the trial’s defined dose-finding outcome.

The registry record also demonstrates the value of distinguishing design information from result information. It includes dosing descriptions, outcome definitions, and safety summaries, while the primary endpoint and listed Phase II secondary outcome results are not reported. A registered endpoint cannot be treated as an observed finding merely because its definition is detailed.

Finally, the single-group design makes it important to avoid causal interpretations of differences between dose groups or phases. In general, descriptive counts can characterize what was recorded in a study, while a causal comparison requires a design and analysis that support the contrast being claimed. The record supports a description of the study and its posted safety figures, but not a randomized estimate of benefit or harm.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

A central limitation of interpretation is that the registry record does not report the primary DLT result, despite giving the endpoint definition and observation period. It also does not report results for the Phase II secondary outcomes of time to progression and duration of response. The available serious adverse-event summaries cannot be used as a replacement for those missing endpoint results.

The study is recorded as nonrandomized, unmasked, and single-group. There is no randomized control group for interpreting differences between dose levels or between phases. The dose levels were part of a dose-escalation schedule, so comparisons across them are not like-for-like randomized comparisons. The record does not report an analysis that adjusts for differences among those groups.

The safety information is limited to the summaries described in the registry. Further details about event timing, recurrence, severity grades, attribution, completeness of follow-up, and missing safety data are not reported in the registry record. Death counts are also not reported. The listed top serious-event terms and percentages should therefore be interpreted only at the level of detail recorded.

The record lists six outcome measures and zero analyses, but does not report a statistical analysis plan, multiplicity handling, or missing-data methods. It does not report a sample-size justification or interim-analysis plan. The maintenance regimen in the Phase II description is not reported in the registry record. These omissions limit evaluation of the intended analysis and completeness of outcome reporting, but do not establish what may or may not have occurred outside the registry entry.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Combination Plerixafor (AMD3100)and Bortezomib in Relapsed or Relapsed/Refractory Multiple Myeloma — NCT00903968.
• Registry record last updated 2020-06-02; status last verified 2020-05.
• Results first posted 2017-09-29.
• 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

NCT00903968 is a completed, nonrandomized, unmasked, single-group Phase I/II trial sponsored by Dana-Farber Cancer Institute. It studied plerixafor with bortezomib in relapsed or relapsed/refractory multiple myeloma; the Phase II regimen description also includes dexamethasone during induction. The record lists enrollment of 58.

The Phase I primary endpoint is the number of participants with dose-limiting toxicity, assessed over the first 21 days for maximum-tolerated-dose evaluation. The registry defines the DLT criteria and the evaluable population, but does not report the primary endpoint result. Phase II secondary outcomes are time to progression and duration of response; their results are not reported in the registry record.

Serious adverse-event summaries are reported by dose level and phase, along with selected event terms and percentages. They are descriptive safety information, not a randomized comparison and not a substitute for the DLT result.