Subcutaneous (SC) Bortezomib-Regimens for Patients With RR MM Failing Prior IV Bortezomib-Containing Regimens: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Subcutaneous (SC) Bortezomib-Regimens for Patients With RR MM Failing Prior IV Bortezomib-Containing Regimens (NCT01695330), a na phase 2 study. The primary outcome is The Primary Objective of This Study Will be to Investigate the Incidence and Severity of Peripheral Neuropathy Caused by a Prior Intravenous VELCADE-containing Regimen in Comparison to That Caused by a Subcutaneous VELCADE-containing Regimen..

2. Clinical Question

The clinical question is shaped by a selected treatment history: participants had already received intravenous bortezomib and had relapsed or become refractory to that treatment. Their prior regimen had to differ from the subcutaneous regimen, and other intervening non-bortezomib regimens were permitted if they did not contain thalidomide or vincristine. This eligibility history matters when interpreting any within-participant comparison. The prior intravenous treatment was not assigned as a concurrent control, and the registry does not report adjustment for differences in treatment exposure or timing.

The study also listed secondary objectives involving overall response rate, disease parameters, and injection-site reactions. However, the registry record does not report numerical results for these objectives. The available record therefore supports describing the research question and design, but not estimating whether subcutaneous treatment changed neuropathy, response, or other disease outcomes.

3. Trial Design

This was a phase 2, multicenter, open-label, nonrandomized, single-group study sponsored by Oncotherapeutics. It concerned patients with relapsed or refractory multiple myeloma after prior intravenous bortezomib-containing combination treatment. The record lists a start date of 2012-05, a primary completion date of 2015-10, enrollment of 5, and status as terminated. The reason for termination is not reported in the registry record.

Participants received a subcutaneous bortezomib-containing combination regimen without thalidomide or vincristine, for up to eight 28 day treatment cycles. The specific drug combination is not reported in the registry record. The record describes screening, treatment, and a final assessment, but the available description is truncated and does not give further details of follow-up or assessment timing beyond the endpoint description.

The design does not include a randomized assignment or concurrent control group. As a result, the prior intravenous treatment provides clinical context for the primary objective, but it is not equivalent to a controlled comparison between treatment arms. Treatment history, disease course, and the timing of assessments may differ between the prior regimen and study treatment. The record does not report a statistical method intended to address those differences.

The registry lists 2 outcome measures and no analysis entries. It does not report endpoint results for the primary objective, nor does it report results for the listed secondary objectives. No sample-size justification, statistical analysis plan, or reason for stopping the study is reported in the registry record. The small enrollment and terminated status are important context, but they do not establish why the study ended or what conclusions the investigators intended to draw.

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

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 The Primary Objective of This Study Will be to Investigate the Incidence and Severity of Peripheral Neuropathy Caused by a Prior Intravenous VELCADE-containing Regimen in Comparison to That Caused by a Subcutaneous VELCADE-containing Regimen., measured over Subjects eligible for this study will receive treatment with study drug for a maximum of eight 28 day treatment cycles..

The primary objective concerned the incidence and severity of peripheral neuropathy during treatment with a subcutaneous bortezomib-containing regimen, considered in comparison with neuropathy associated with prior intravenous bortezomib-containing treatment. Incidence was defined as the number of enrolled participants experiencing treatment-emergent peripheral neuropathy. Severity was assessed using neurological examinations and a 0-4 scale based on CTCAE criteria.

Assessments were scheduled on Day 1 and Day 11 of each treatment cycle and at the End of Study visit. The maximum study treatment period was eight 28 day cycles. The registry also describes the primary measure as a count of participants, which is a direct way to report how many participants met the endpoint definition. A count alone, however, does not describe how symptoms changed over time or provide a comparison adjusted for exposure or treatment history.

Peripheral neuropathy is relevant to the study question because the primary objective specifically concerns this safety outcome during prior intravenous and study subcutaneous bortezomib-containing treatment. Repeated neurological assessment and severity grading can characterize whether neuropathy emerged and how severe it was under the stated criteria. The record does not report the observed incidence, severity distribution, participant-level changes, or any formal comparison. Consequently, it establishes how the endpoint was defined, not the endpoint result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a single-group design allow?

In a single-group study, participants receive the study intervention without a concurrent comparison group. The design can describe outcomes observed during treatment, but it cannot by itself separate a treatment effect from other explanations for those outcomes. This is a general limitation of uncontrolled designs. For this trial, the primary objective also refers to participants’ prior intravenous treatment, but that prior treatment is not a randomized control. It occurred earlier in the disease course and may differ in exposure, timing, and circumstances.

What does an incidence count convey?

An incidence count records how many participants meet a defined event criterion during the observation period. It is a direct summary, but it does not show when the event began, how long it lasted, or whether severity changed. The trial defined treatment-emergent peripheral neuropathy using neurological assessments, with severity graded on a 0-4 scale based on CTCAE criteria. The registry does not report the counts or severity results, so the endpoint definition cannot be translated into an observed incidence estimate.

How should severity grading be understood?

A severity scale organizes clinical observations into ordered categories. Such grading can help distinguish less severe from more severe recorded events, but the categories are not necessarily equally spaced: the step between adjacent grades need not represent the same clinical change throughout the scale. A summary of grades should therefore retain the scale’s meaning and should not be treated as though the values were measurements on a continuous ruler. The registry describes the grading method but does not report the distribution of grades or the assessment results.

What would a confidence interval add?

In general, a confidence interval expresses the statistical uncertainty around an estimate under the assumptions of the analysis. A narrow interval indicates greater precision than a wide interval, while neither width nor statistical significance alone establishes clinical importance. For an incidence estimate, the interval would help show how uncertain the observed event frequency is, particularly when the number of participants is limited. The registry record does not report a confidence interval for the primary endpoint or the serious adverse-event information.

Why does the absence of randomization matter?

Randomization is a method for balancing, in expectation, both measured and unmeasured characteristics across treatment groups. This study was nonrandomized and single-group, so there is no randomized between-group contrast. Comparing an outcome during study treatment with an outcome associated with earlier treatment can be affected by changes over time, disease status, treatment exposure, and other care. A statistical adjustment can sometimes address measured differences, but it cannot automatically remove all bias. No adjustment method is reported in the registry record.

What can planning calculations say?

Sample-size calculations are planning illustrations: they describe how many participants might be needed under stated assumptions about the effect, significance level, allocation, and statistical approximation. They are not evidence that a trial had a particular chance of detecting an effect after it was conducted. The stated illustration assumptions use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect expressed as a fraction of the observed effect. The assumptions also distinguish total event counts for time-to-event calculations from participants per arm for other calculations. These are planning conventions, not a description of this trial’s single-group design. No sample-size justification or analysis plan is reported in the registry record, and planning illustrations should not be interpreted as observed power.

How should multiple outcomes be considered?

When a study evaluates multiple outcomes, testing each outcome can increase the chance of at least one apparently notable result arising by chance. Statistical methods may control or describe this multiplicity, depending on the objectives and analysis plan. The record lists a primary objective and secondary outcome topics, but no multiplicity method is reported in the registry record. Without reported analysis results or a stated plan, it is not possible to determine how the investigators intended to handle multiple comparisons.

What is the role of the registry endpoint definition?

An endpoint definition specifies what is counted and how it is assessed. Clear timing and grading criteria help readers understand the intended measurement, but they do not establish that every assessment was completed or that all participants were analyzed under the same rules. The registry describes assessments on Day 1 and Day 11 of each treatment cycle and at the End of Study visit. It does not report adherence to this schedule, the number of evaluable participants, missing assessments, or the analysis population. Those details are needed to judge how the planned measurement translated into the reported results.

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("Subcutaneous Bortezomib")
n      <- c(5)
events <- c(5)
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  Subcutaneous Bortezomib  5  5  100.0  47.8  100.0  56.6  100.0  54.1  99.6

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary objective concerning peripheral neuropathy and secondary objectives concerning overall response rate, disease parameters, and injection-site reactions. It does not report a method for controlling or interpreting multiplicity across these outcomes. When several outcomes are evaluated, the chance of finding a seemingly notable result can increase; statistical plans may address this through prespecified testing strategies or other approaches. Whether any such approach was planned or used is not reported in the registry record.

The registry record contains no analysis entries and does not report numerical results for the primary or secondary outcomes. It also does not report confidence intervals, test results, or an analysis plan. The absence of posted analysis entries does not establish that no analyses were performed; it means the registry record does not provide them.

Missing-data handling is not reported in the registry record. There is no reported account of incomplete neurological assessments, withdrawals, evaluability requirements, or how missing endpoint observations were treated. The analysis population is also not reported: the record does not specify whether the endpoint was analyzed among all enrolled participants, those who started treatment, or another defined group. No imputation or sensitivity-analysis method is reported.

These omissions limit interpretation because outcome counts depend on who was assessed and how incomplete observations were handled. The endpoint schedule and definitions describe intended measurement, but do not show whether the measurements were complete. Without the analysis population and missing-data methods, the precision and representativeness of any unreported endpoint estimate cannot be assessed.

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

Serious events with the highest arm-level rate: gr3 neturopenia (40.0%).

The serious adverse-event group lists 5 participants at risk and 2 affected. The registry also identifies “Gr3 Neturopenia” at 40.0% among the top serious terms. That spelling is retained as recorded. The registry does not explain the denominator used for the term percentage or provide enough context to determine whether it refers to participants, events, or another basis. It should not be treated as an incidence rate without that information.

The posted record does not provide detailed event narratives, timing, duration, outcomes, or participant-level information for these serious events. It also does not report deaths in the serious-event group; the death field is not populated with a count. Separate fields for other adverse events record 0 at risk and 0 affected, but the registry offers no explanation of those entries. They should not be read as a complete account of non-serious adverse events.

Adverse-event descriptions are descriptive safety observations. Their presence does not by itself establish that study treatment caused an event, and the absence of a reported event is not proof that no such event occurred. The study’s single-group design, enrollment of 5, and lack of detailed safety results restrict comparisons and precision. The registry record does not report a formal comparative safety analysis.

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

The record establishes that a phase 2, open-label, nonrandomized, single-group study was conducted for patients with relapsed or refractory multiple myeloma after prior intravenous bortezomib-containing treatment. It reports enrollment of 5 and a terminated status, and describes subcutaneous bortezomib-containing treatment for up to eight 28 day cycles. It also defines the primary neuropathy endpoint and identifies limited serious adverse-event information.

These details do not establish the observed incidence or severity of peripheral neuropathy. The primary endpoint result is not reported in the registry record, and no numerical response or disease-parameter results are reported. The serious adverse-event figures do not establish a causal relationship with treatment, and the registry does not provide a concurrent comparison group that could support a controlled estimate of relative risk or benefit.

The prior intravenous regimen is part of the eligibility history and the primary objective’s framing, not a randomized control arm. A difference between outcomes during earlier and later treatment periods could reflect treatment, disease course, exposure, timing, or other factors. The registry does not report an analysis that separates these explanations.

The study’s enrollment and status should also be interpreted narrowly. The record does not report why the study was terminated, whether the enrollment target was changed, or whether the termination followed any particular safety or operational event. No explanation should be inferred from the status alone.

Overall, the registry supports a description of the research question, study design, and selected reported safety figures. It does not support a treatment-effect estimate, a precise neuropathy risk estimate, or a conclusion about comparative efficacy or safety. Those conclusions would require outcome results, analysis methods, and participant-level or sufficiently detailed summary information that are not reported in the registry record.

14. Why This Trial Matters Statistically

This trial raises a clinically relevant statistical question: how to interpret toxicity observed during a new treatment route when participants have already received a related treatment by another route. A prior-treatment comparison may seem informative because participants have experience with both regimens, but the earlier treatment period is not a concurrent control. Disease status and observation conditions can change over time, so an apparent contrast cannot automatically be attributed to route of administration.

The study also illustrates why endpoint definitions and outcome reporting are both necessary. The registry describes neurological assessments and a severity scale, which clarifies what investigators intended to measure. Yet without the resulting counts, severity distribution, and uncertainty estimates, readers cannot assess the observed frequency or precision. A detailed endpoint description is not a substitute for results.

Small enrollment further underscores the importance of uncertainty. Estimates from a small group can be imprecise, and a limited study may be unable to characterize uncommon outcomes reliably. This general statistical point does not establish what the trial would have found with different enrollment; it emphasizes that interpretation requires the actual estimates and their uncertainty. Those are not reported for the primary endpoint.

Finally, the registry record shows why statistical interpretation depends on more than a headline outcome. The analysis population, missing-data handling, multiplicity approach, and reasons for termination are not reported. Without those details, readers cannot determine how the intended assessments were translated into analyses or how results should be generalized. The study is therefore useful for examining design and reporting limitations, while its posted results do not support a comparative treatment conclusion.

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 primary limitation is that the registry record does not report the primary endpoint result. The incidence and severity of treatment-emergent peripheral neuropathy are not available, and there is no reported comparison with participants’ prior intravenous treatment experience. The secondary objectives are listed, but their results are not reported either.

The study enrolled 5 participants, was nonrandomized and single-group, and is listed as terminated. These features constrain the amount and type of evidence the record can provide. The reason for termination, the planned enrollment target, and any change to the target are not reported in the registry record. The record does not establish whether the trial stopped early or why it stopped.

The prior intravenous regimen cannot serve as a fully comparable control because it occurred before the study treatment and was not assigned concurrently. The registry does not report details needed to evaluate exposure comparability, timing of prior treatment, or adjustment for differences between treatment periods. The specific subcutaneous combination regimen is also not reported.

Further limitations include the absence of reported analysis populations, missing-data methods, multiplicity methods, confidence intervals, and inferential analyses. Safety reporting is limited: the serious adverse-event summary lacks event-level details, and the denominator for the listed 40.0% serious term is not explained. These gaps prevent a full assessment of endpoint completeness, statistical precision, and the context of reported events. No reason for, or interpretation of, these omissions should be inferred.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Subcutaneous (SC) Bortezomib-Regimens for Patients With RR MM Failing Prior IV Bortezomib-Containing Regimens — NCT01695330.
• Registry record last updated 2017-01-16; status last verified 2016-11.
• Results first posted 2017-01-16.
• 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

NCT01695330 is a phase 2, multicenter, open-label, nonrandomized, single-group study sponsored by Oncotherapeutics. It examined subcutaneous bortezomib-containing treatment in patients with relapsed or refractory multiple myeloma after prior intravenous bortezomib-containing treatment. Enrollment was 5; the study is listed as terminated, with a start date of 2012-05 and primary completion date of 2015-10.

The primary objective concerned the incidence and severity of peripheral neuropathy during study treatment, in comparison with neuropathy associated with prior intravenous treatment. The registry describes neurological assessment and CTCAE-based grading but does not report primary endpoint results. Listed secondary objectives concern response rate, disease parameters, and injection-site reactions; their results are not reported. The record contains no analysis entries.

The serious adverse-event information lists 2 affected participants among 5 at risk and identifies “Gr3 Neturopenia” at 40.0% among the top serious terms. The registry does not explain the percentage denominator or report detailed event context. The reason for termination, statistical analysis plan, missing-data methods, and analysis population are not reported in the registry record.