TMI With HD Mel in ASCT for R/R Multiple Myeloma (BMT-03): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for TMI With HD Mel in ASCT for R/R Multiple Myeloma (BMT-03) (NCT02043847), a non-randomized phase 1 study. The primary outcome is Maximum Tolerated Dose (MTD) of Gy.

2. Clinical Question

The clinical question is about dose escalation in a transplant-conditioning setting, not a randomized estimate of TMI’s effect compared with melphalan conditioning alone. All described cohorts received TMI with standard high-dose melphalan before autologous stem cell rescue. The registry’s brief summary describes the trial as a conventional 3+3 phase I trial with increasing TMI doses from minimum 3Gy to maximum 9Gy; the listed cohort counts are 3 participants at 3Gy, 3 participants at 6Gy, and 6 participants at 9Gy.

In a phase I study, the central objective is generally to assess dose-related safety and identify a dose suitable for further study. That is a general description of the phase I purpose, not a claim about a particular dose decision in this trial. The registry names maximum tolerated dose as the primary outcome, but does not report the criteria used to define dose-limiting toxicity or the decision rule for selecting a maximum tolerated dose. Those details, and whether the stated primary objective was met, are not reported in the registry record.

The record also lists progression-free survival as a secondary outcome. It does not provide a result for that outcome. Thus, the registry information describes the population and planned dose question, but does not establish a comparative effect on disease control or provide a reported maximum tolerated dose.

3. Trial Design

This was a completed phase I trial with non-randomized allocation, no masking, and a sequential model. The registry lists enrollment of 12 and describes patients with relapsed or refractory multiple myeloma receiving high-dose melphalan conditioning before autologous transplant, with TMI added to the conditioning regimen. Its brief summary characterizes the trial as a conventional 3+3 phase I trial with increasing TMI doses from minimum 3Gy to maximum 9Gy.

The listed cohorts received TMI doses of 3Gy, 6Gy, and 9Gy alongside standard high-dose melphalan before autologous stem cell rescue. The primary outcome description states that 3 participants received 3Gy, 3 participants received 6Gy, and 6 participants received 9Gy. These are observed cohort counts in the registry. Because allocation was not randomized and the cohorts correspond to different dose levels, they are not treatment groups in a randomized comparative trial. Differences between their outcomes, if reported, could not be interpreted as unbiased treatment contrasts on the basis of this design alone.

The registry lists the study start as 2014-01-14, primary completion as 2016-09-14, and status as completed. The primary outcome timeframe is up to 60 days post-transplant. The record lists total marrow irradiation, melphalan, filgrastim (G-CSF), and autologous transplant among the interventions. It repeats these intervention entries in the record, but does not describe additional treatment contrasts.

The record does not report details of the dose-escalation decisions, the toxicity criteria used, or the statistical analysis plan. The registry’s 3+3 description conveys the stated design, but is not enough to reconstruct how decisions were made during conduct of the trial. Any protocol-specific rules beyond the listed description 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

Analysis population for the primary outcome, as defined in the registry: 3 participants received 3Gy, 3 participants received 6Gy and 6 participants received 9Gy

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 Maximum Tolerated Dose (MTD) of Gy, measured over Up to 60 days post-transplant..

The primary endpoint is named “Maximum Tolerated Dose (MTD) of Gy,” with the unit recorded as participants. Its stated purpose is assessing the MTD of TMI at 3Gy, 6Gy, and 9Gy, with assessment up to 60 days post-transplant. The registry gives the number of participants who received each dose: 3 participants at 3Gy, 3 participants at 6Gy, and 6 participants at 9Gy.

In general, a maximum tolerated dose endpoint is used in early-phase dose-finding research to identify a dose level judged acceptable under prespecified safety criteria. It is not, by itself, an estimate of comparative efficacy. The interpretation depends on how dose-limiting toxicity is defined, the observation window, and the dose-escalation rules. Those specific criteria and rules are not reported in the registry record. The registry does specify the timeframe as up to 60 days post-transplant, but does not state which events counted toward the MTD decision.

The outcome title identifies the endpoint, but the posted primary result is a count by dose cohort rather than a stated MTD conclusion. The record does not say whether a maximum tolerated dose was identified, whether the highest listed dose was considered tolerable, or whether any dose was selected for subsequent research. These conclusions should not be inferred from cohort enrollment alone. The endpoint’s clinical and statistical meaning is therefore only partly recoverable from the registry entry: the goal and timeframe are given, while the operational definition and final dose decision are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a sequential dose-escalation design mean?

In general, a sequential dose-escalation design evaluates dose levels in sequence, using observed safety information to guide decisions about subsequent dosing. This differs from randomization: participants are not assigned by chance to concurrent treatment groups for a balanced comparison. In this trial, the registry describes a conventional 3+3 phase I design and lists TMI cohorts at 3Gy, 6Gy, and 9Gy. The record does not report the detailed dose-escalation rules or the specific observations that informed movement between cohorts. The listed cohort sizes alone do not reveal those decisions.

General dose-finding interpretation depends on a prespecified definition of dose-limiting toxicity, an observation period, and a rule for how toxicity observations affect escalation or stopping. Here, the primary outcome timeframe is given as up to 60 days post-transplant, but the toxicity definition and decision rules are not reported in the registry record. Without those details, readers cannot independently reconstruct the MTD determination from the cohort counts.

What does a count endpoint communicate?

The primary endpoint is recorded as a count of participants, and the registry lists the number treated at each dose. A count answers how many participants were recorded in a category; it does not automatically express the probability of an event or identify a dose as acceptable. To interpret an MTD outcome, one would also need to know which participants experienced qualifying toxicities and how those observations were used in the dose-selection rule. Those details are not reported in the registry record.

In general, a confidence interval describes the range of values compatible with an estimate under a specified statistical model and its assumptions. It communicates uncertainty rather than guaranteeing that the true value lies in a particular interval. No confidence interval or statistical analysis for the primary endpoint is reported in the registry record, so there is no precision estimate for an MTD decision to interpret.

Why does the lack of randomization matter?

In general, randomization helps make treatment groups comparable, on average, with respect to measured and unmeasured characteristics. This study is identified as non-randomized and sequential, and it has no masking. The dose cohorts therefore are not concurrent randomized controls. If outcomes differ across cohorts, those differences could reflect dose, cohort composition, timing, or other factors; the registry does not permit those possibilities to be separated. Cohort-to-cohort differences should not be treated as causal dose effects.

Masking is also listed as none. In general, lack of masking can affect outcome assessment when judgments involve discretion, though the extent depends on the outcome and assessment process. The registry does not describe outcome adjudication procedures, so the implications for this trial cannot be determined from the record.

How should adverse-event counts be read?

General adverse-event reporting distinguishes the number of participants who experienced an event from the number of events, because a participant may experience more than one event. The registry’s safety fields are described in terms of participants affected and at risk for serious and other events. The cohort-level counts report one serious event in each cohort, and other-event counts of 2, 2, and 3 for the 3Gy, 6Gy, and 9Gy cohorts, respectively. The record does not specify whether affected participants overlap across serious and other-event categories, so these counts should not be added together or treated as mutually exclusive groups.

Over-dispersion is a general statistical issue that arises when variation in count data exceeds what a simple model assumes. It can make standard errors too small if ignored. No count-model analysis or related model assumptions are reported in the registry record, so over-dispersion cannot be evaluated as a feature of the posted analysis.

What do planning calculations represent?

In general, a sample-size calculation is a planning exercise based on an assumed effect, allocation, significance level, and statistical model. It does not describe the number of participants actually observed, and it is not observed power. The registry’s stated planning assumptions describe 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. For time-to-event outcomes, the stated planning quantity is the total number of events; for other outcomes, it is participants per arm. These are general planning conventions, not the trial’s own design justification. A sample-size justification for this trial is not reported in the registry record.

The registry reports no analyses. It therefore does not provide an analysis model, adjustment strategy, inferential test, or uncertainty estimate for the listed outcomes. The 3+3 design description and the recorded counts should not be mistaken for a complete statistical analysis plan.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome for maximum tolerated dose and a secondary outcome for progression-free survival. It reports two outcome measures and no analyses. The record does not describe a multiplicity strategy, such as whether or how statistical error across multiple outcomes or analyses was addressed. A multiplicity adjustment should not be assumed, and a lack of a reported adjustment does not establish that one was or was not used outside the registry entry.

The registry does not report a statistical analysis plan, analysis populations, or the handling of missing outcome data. It does not state how participants with incomplete follow-up were treated, whether any endpoint data were unavailable, or how censored observations were handled for progression-free survival. These details are not reported in the registry record. The listed cohort counts describe participants who received the specified doses; they do not establish the completeness of endpoint follow-up.

In general, missing data can affect interpretation when the chance that a measurement is unavailable is related to participant characteristics or outcomes. Methods for addressing missing data depend on the endpoint and the reason for missingness. Without information on completeness, follow-up, and the analysis population, it is not possible to assess whether missingness affected the posted results.

The registry record also does not provide an analysis of progression-free survival, despite listing it as a secondary outcome. There is no reported estimate or uncertainty measure to assess. The absence of an analysis in the registry record should be distinguished from evidence that the outcome was not measured; its measurement and analysis status are not reported in the registry record.

11. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: death (33.3%).

The registry reports serious adverse events for the three TMI cohorts. The numbers at risk were 3 for 3Gy, 3 for 6Gy, and 6 for 9Gy; the numbers affected by a serious event were 1 in each cohort. For other adverse events, the numbers at risk were 3, 3, and 6, and the numbers affected were 2, 2, and 3, respectively. These are counts of participants, not a complete description of event type, severity, timing, or duration.

Death is listed as the top serious term at 33.3%. The registry does not explain the denominator or provide enough context to reconcile that percentage with the cohort-specific counts. It also does not report whether deaths were considered related to the study treatment, their causes, or when they occurred. The cohort fields list one death for each dose cohort, but that information alone does not establish causation.

In general, adverse-event counts are descriptive. They do not by themselves show that an intervention caused an event, and small cohort counts provide limited precision for comparing event frequencies. Because this was not a randomized comparison, the safety counts should not be treated as a controlled estimate of the effect of one dose relative to another. The registry does not report a formal comparative safety analysis.

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

The registry record establishes that this completed phase I trial evaluated TMI added to high-dose melphalan conditioning before autologous transplant for relapsed or refractory multiple myeloma. It describes a non-randomized, sequential design and lists cohorts at 3Gy, 6Gy, and 9Gy. It reports cohort counts of 3, 3, and 6 participants, respectively, and specifies that the primary endpoint was maximum tolerated dose assessed up to 60 days post-transplant.

Those details do not establish which dose was selected as the maximum tolerated dose. The primary result lists the numbers treated at each dose, but the MTD conclusion, toxicity criteria, and dose-escalation decision rules are not reported in the registry record. Enrollment at 9Gy does not by itself mean that this dose met a prespecified tolerability standard, and the listed cohort sizes do not show how the investigators interpreted safety observations.

The record also does not establish a comparative benefit. It lists progression-free survival as a secondary outcome but provides no outcome result or statistical analysis. There is no randomized control group receiving melphalan conditioning without TMI, and the cohorts are not like-for-like randomized comparisons. Therefore, the registry information cannot support a causal estimate of TMI’s effect on disease control or a comparison of the three dose levels.

Safety information is limited to the recorded counts: one serious adverse event in each cohort, other adverse events affecting 2 participants in each of the 3Gy and 6Gy cohorts and 3 in the 9Gy cohort, and a listed serious term of Death at 33.3%. The record does not provide the context required to attribute these events to treatment or to interpret the reported percentage fully.

In general, a small phase I dose-escalation study can provide early information about dose administration and observed safety, but findings require the endpoint definitions, follow-up, and decision rules to be interpretable. The registry entry gives some of that framework but leaves key details and the MTD conclusion unreported. It neither demonstrates that a treatment works nor establishes that it does not work.

13. Why This Trial Matters Statistically

This trial is statistically notable because it addresses a dose-finding question in a complex conditioning regimen rather than testing a treatment against a randomized control. The registry describes TMI added to high-dose melphalan before autologous transplant, with sequential dose cohorts at 3Gy, 6Gy, and 9Gy. That structure is relevant to how the evidence should be read: the core goal is a dose decision under safety criteria, not an unbiased efficacy contrast between independent groups.

For dose-finding studies, transparent reporting of the toxicity definition, observation window, escalation rules, and final dose decision is essential. The record provides the timeframe of up to 60 days post-transplant and names the MTD endpoint, but does not report the detailed criteria or the resulting MTD. Without those elements, readers cannot reproduce or assess the dose-selection reasoning from the registry information.

The design also illustrates why treatment cohorts should not automatically be compared as if randomized. Participants entered sequential dose levels, so any differences in observed events can be influenced by factors beyond dose. The reported cohort sizes are limited, and the safety summaries are descriptive rather than comparative. General statistical reasoning therefore supports caution about interpreting apparent differences across these cohorts.

Finally, the registry lists progression-free survival but provides no result or analysis for it. This separates the early-phase safety and dose question from later questions about disease outcomes. The record’s statistical value lies in documenting the design, cohorts, endpoint timeframe, and selected event counts; its limitations arise from unreported endpoint definitions, analyses, and conclusions. These reporting gaps matter because they determine whether a reader can evaluate the precision and meaning of the primary dose-finding result.

14. 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 registry identifies a non-randomized, sequential design with no masking and no like-for-like control group. This limits causal interpretation of any apparent differences between dose cohorts. The record provides no randomized comparison of TMI-containing conditioning against conditioning without TMI, and the cohorts receive different dose levels rather than serving as concurrent randomized treatment arms.

The primary outcome is named as maximum tolerated dose, but the record does not report the operational definition of dose-limiting toxicity, the dose-escalation decision rules, or the final MTD conclusion. Although the timeframe is stated as up to 60 days post-transplant, the record does not explain which events within that period counted toward the primary endpoint. The listed participant counts by dose cannot substitute for these details.

The safety information is limited to participant counts and a top serious term. The registry does not report event descriptions beyond the listed term, timing, causes, treatment relatedness, or the context needed to interpret the 33.3% entry for Death. It does not clarify overlap between participants affected by serious and other adverse events. No formal safety comparison is reported.

Progression-free survival is listed as a secondary outcome, but no result or analysis is reported. The record does not describe analysis populations, completeness of follow-up, missing-data handling, censoring, or statistical methods. It also does not report a multiplicity strategy or a sample-size justification. These limitations are specific to what is documented in the registry record; further protocol or study-report details are not reported in the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: TMI With HD Mel in ASCT for R/R Multiple Myeloma (BMT-03) — NCT02043847.
• Registry record last updated 2024-11-13; status last verified 2024-10.
• Results first posted 2024-10-21.
• 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.

18. Record Summary

NCT02043847 is a completed phase I trial sponsored by the University of Illinois Chicago. The registry lists a start date of 2014-01-14, primary completion date of 2016-09-14, and enrollment of 12. The study concerned TMI added to high-dose melphalan conditioning before autologous transplant for relapsed or refractory multiple myeloma.

The design is listed as non-randomized, unmasked, and sequential. The described TMI cohorts were 3Gy, 6Gy, and 9Gy, with 3 participants, 3 participants, and 6 participants, respectively. The primary outcome was maximum tolerated dose, assessed up to 60 days post-transplant. The record lists progression-free survival as a secondary outcome but reports no analyses.

Safety entries report one serious adverse event in each cohort, other adverse events affecting 2, 2, and 3 participants, and Death as the top serious term at 33.3%. The registry does not report the MTD conclusion, detailed toxicity criteria, progression-free survival results, or a statistical analysis plan.