A Study of Weekly Carfilzomib in Combination With Dexamethasone for Progressive Multiple Myeloma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Weekly Carfilzomib in Combination With Dexamethasone for Progressive Multiple Myeloma (NCT01677858), a na phase 1, phase 2 study. The primary outcome is Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs).

2. Clinical Question

The two phases address related but distinct questions. Dose escalation in Phase 1 evaluates tolerability across carfilzomib dose levels when combined with dexamethasone. Phase 2 then has a response-estimation objective at the dose selected from Phase 1. A response estimate and a toxicity count describe different aspects of the study; neither can be inferred from the other.

The record lists multiple myeloma as the condition and describes the intended population as people with relapsed or refractory disease after 1 to 3 prior therapies. It does not report the actual primary-outcome counts or the Phase 2 overall response rate. Consequently, the clinical question can be described from the objectives, but the posted information does not establish the observed answer to either objective.

3. Trial Design

This was a Phase 1/2 study sponsored by Amgen, with a sequential model and no masking. The registry lists allocation as NA, and the study is marked completed. Enrollment is recorded as 116. The study started on 2012-07-04, and primary completion is recorded as 2016-07-22.

Phase 1 evaluated four sequential carfilzomib dose cohorts: 45, 56, 70 and 88 mg/m². Participants also received dexamethasone. The Phase 1 objective was to determine the maximum tolerated dose using treatment-related dose-limiting toxicities during the first 28-day cycle. The registry defines the MTD as the highest carfilzomib dose at which < 33% of participants had a treatment-related DLT during that cycle.

Phase 2 was intended to estimate the overall response rate for participants treated with the MTD established in Phase 1. The record also lists secondary outcomes including clinical benefit response rate, progression-free survival, time to progression, duration of response, adverse events and several carfilzomib pharmacokinetic measures. Listing an outcome does not by itself establish that its result or analysis is available in the registry record.

Because the design is sequential and allocation is listed as NA, the dose groups do not constitute randomized treatment arms. Participants in different cohorts may have entered at different stages of dose escalation, and the record does not describe a concurrent randomized comparator. Differences between cohort results, if available, would therefore not have the straightforward interpretation of a randomized between-group treatment effect.

The record does not report further details of the dose-escalation decision process, the planned Phase 2 sample size, or the statistical analysis plan. Those details should not be inferred from the sequential design or from the enrollment total.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: In phase 1 participants were enrolled into 1 of 4 sequential dose-escalating cohorts to establish the maximum tolerated dose (MTD) of carfilzomib plus dexamethasone. In phase 2 participants were enrolled to evaluate the efficacy and safety of carfilzomib plus dexamethasone at the MTD established in phase 1.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants in phase 1 who received at least 1 dose of any investigational product (carfilzomib or dexamethasone).

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 Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs), measured over 28 days.

The Phase 1 primary endpoint is the number of participants with dose-limiting toxicities during the first 28-day cycle. A DLT is a prespecified safety event, not simply any symptom or laboratory abnormality. The registry separates qualifying events into nonhematologic and hematologic categories, with criteria based on severity, duration, clinical consequences or failure to control symptoms. Examples in the definition include severe nonhematologic toxicity, specified kidney injury, prolonged severe neutropenia, febrile neutropenia and severe thrombocytopenia.

Counting participants with at least one qualifying DLT gives a direct way to assess whether the tested dose is associated with early treatment-limiting toxicity under the protocol’s definition. The MTD rule uses the proportion of participants with a treatment-related DLT during that cycle and defines the MTD as the highest dose at which < 33% experience one. This makes the endpoint relevant to the Phase 1 dose-selection objective.

The endpoint is not a complete account of safety over the entire study. Its stated timeframe is 28 days, and its definition covers specific events and thresholds. Other adverse events and later toxicities are distinct safety information. The registry record does not report the observed number of participants with DLTs for this primary outcome, so the endpoint definition alone does not show which dose met the MTD rule.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a sequential dose study do?

In general, a sequential dose-escalation study examines dose levels in an ordered process rather than assigning participants randomly among all dose levels at once. In this study, the registry lists four Phase 1 carfilzomib cohorts: 45, 56, 70 and 88 mg/m². The stated purpose was to identify the MTD with dexamethasone. The registry record does not report the detailed escalation algorithm, decision rules beyond the MTD definition, or the timing of decisions. Those aspects should not be reconstructed from the cohort list.

Sequential cohorts are useful for describing tolerability as doses are explored, but they do not have the same comparative properties as randomized groups. Allocation is listed as NA, and the registry notes that the arms are not a like-for-like control comparison. Comparisons among dose cohorts can be descriptive, while causal claims about differences require more than a contrast of their observed counts.

What is a dose-limiting toxicity?

In general, a DLT is a protocol-defined event used to inform dose selection. Its definition determines which events count and the timeframe in which they are assessed. Here, the primary endpoint concerns participants with treatment-related DLTs in the first 28-day cycle. The registry specifies nonhematologic and hematologic criteria, including severity grades and duration thresholds. Some symptoms or laboratory findings are excluded unless they meet specified conditions. These rules make the endpoint narrower than a count of every adverse event.

The MTD definition uses a threshold for the proportion experiencing a treatment-related DLT and selects the highest dose below that threshold. This is a decision rule, not a reported result. To apply it, the observed DLT counts and the relevant numbers of participants at each dose are needed. The registry record does not report the primary endpoint results, so it is not possible to verify the selected dose from the posted primary-outcome information.

What does a count communicate?

For a binary event outcome, each participant is classified according to whether the event occurred under the endpoint definition. A count is easy to understand, but it should be interpreted alongside the number of participants assessed and the endpoint’s timeframe. The primary endpoint is reported as a number of participants, not as a continuous measurement. No estimate of uncertainty for the DLT outcome is reported in the registry record.

In general, a confidence interval describes a range of values compatible with the observed data under a statistical model and its assumptions. It conveys precision, not certainty that the true value lies within a particular interval. The record does not report a confidence interval for the primary endpoint or Phase 2 response objective. Without such an interval and the underlying result, the precision of those estimates cannot be evaluated from the posted information.

How should the safety summaries be read?

In general, serious adverse events and other adverse events are separate categories. A participant may be counted in the serious-event category if at least one event meets the serious-event definition; the count does not necessarily represent the number of individual events. The registry lists, for each cohort, the number at risk and the number affected by serious adverse events, and it separately lists numbers affected by other adverse events. These counts are descriptive and do not establish that an event was caused by treatment.

The size of a cohort affects how much information its count contains. A count from a small cohort is less stable as a description of the experience of a broader population than a count from a larger cohort. In general, uncertainty measures help communicate that imprecision, but corresponding intervals are not reported in the registry record. The serious adverse event term percentages listed by the registry also should be read as reported descriptive figures; the record excerpt does not identify their denominators or provide a comparative analysis for those terms.

What is over-dispersion, and does it apply?

In general, over-dispersion describes variability greater than a statistical model expects. It can matter for count outcomes when a simple model assumes more regular variation than the data exhibit, and ignoring it can make uncertainty appear too small. The posted primary endpoint is a participant count, but the registry record does not report a fitted count model or an analysis addressing over-dispersion. There is therefore no basis to claim that over-dispersion was assessed or that a particular model was used.

How should planning illustrations be understood?

In general, a sample-size calculation estimates how many observations might be needed under specified assumptions to detect a chosen effect with a chosen statistical error rate and power. Such a calculation is a planning illustration, not an observed result and not evidence that a study achieved a particular power. The stated illustration assumptions use a two-sided significance level of 0.05, equal allocation, a normal approximation and an effect expressed as a fraction of the observed effect. For time-to-event outcomes, the illustration concerns total events; for other outcomes, it concerns participants per arm.

Those illustrations do not describe the trial’s original design justification. The registry record does not report that justification or the Phase 1/2 analysis plan. The posted study is sequential and is not a randomized two-arm comparison, so equal-allocation illustrations should not be mistaken for the design actually used. Any planning estimate also depends on its effect assumption; it is not observed power.

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 1 Carfilzomib 45 mg/m²", "Phase 1: Carfilzomib 56 mg/m²", "Phase 1: Carfilzomib 70 mg/m²", "Phase 1: Carfilzomib 88 mg/m²")
n      <- c(3, 3, 15, 6)
events <- c(0, 0, 1, 2)
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 1 Carfilzomib 45 mg/m²  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Phase 1: Carfilzomib 56 mg/m²  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Phase 1: Carfilzomib 70 mg/m²  15  1  6.7  0.2  31.9  1.2  29.8  1.6  30.2
ARM  Phase 1: Carfilzomib 88 mg/m²  6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a Phase 1 primary objective based on DLTs and a Phase 2 primary objective to estimate overall response rate. It also lists 16 outcome measures, including clinical benefit response, progression-free survival, time to progression, duration of response, adverse events and pharmacokinetic outcomes. Multiple outcomes create several opportunities to examine results. In general, multiplicity procedures can control the chance of false-positive findings when multiple hypotheses are tested, but the registry record does not report a multiplicity adjustment or a hierarchy for interpreting the listed outcomes.

The registry identifies one analysis, but does not report enough detail to establish which analysis populations, models, covariates, missing-data rules or uncertainty measures were used for the outcomes. The Phase 1 primary-endpoint population is defined as participants who received at least 1 dose of any investigational product. That definition should not automatically be assumed to apply to every other outcome. The analysis populations for Phase 2 response and the secondary outcomes are not reported in the registry record.

In general, missing outcome data can affect estimates when participants without observed results differ from those with results. Methods may include explicit assumptions or sensitivity analyses, but no missing-data method is reported in the registry record. The handling of participants with incomplete follow-up, early discontinuation or unassessed outcomes is also not reported. Consequently, the completeness and potential missing-data sensitivity of the outcome analyses cannot be assessed from the posted information.

The sample-size illustrations are planning calculations under stated assumptions, not the trial’s own sample-size justification and not observed power. The registry record does not report the original sample-size rationale, interim-analysis plan or statistical analysis plan. These omissions limit appraisal of how the planned objectives were translated into analysis procedures.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: blood creatinine increased (33.3%), hyponatraemia (33.3%), cardiac failure congestive (16.7%), chronic obstructive pulmonary disease (13.3%), acute kidney injury (6.7%).

The serious adverse event figures are cohort-level counts: the number at risk and the number affected. In Phase 1, the listed at-risk and affected counts are 3 and 1 at 45 mg/m², 3 and 0 at 56 mg/m², 15 and 4 at 70 mg/m², and 6 and 1 at 88 mg/m². In Phase 2, the listed counts are 89 at risk and 35 affected at 70 mg/m². These figures describe participants recorded as affected, not the total number of individual serious events.

The registry separately lists other adverse events. Those figures should not be added to the serious adverse event counts because the categories are distinct in the record. The serious adverse event terms include Blood creatinine increased at 33.3%, Hyponatraemia at 33.3%, Cardiac failure congestive at 16.7%, Chronic obstructive pulmonary disease at 13.3%, Acute kidney injury at 6.7%, and Pneumonia at 6.7%. The registry excerpt does not identify the denominators for these term percentages, so they should be read as reported rather than used to derive additional comparisons.

These are descriptive safety summaries from a sequential, nonrandomized study. They do not establish treatment causation or support a like-for-like comparison among cohorts. The registry record does not report deaths for these groups, and it does not provide uncertainty intervals for the serious adverse event counts.

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

The study’s design and endpoints clarify what its investigators sought to learn. Phase 1 aimed to determine the maximum tolerated carfilzomib dose in combination with dexamethasone using treatment-related DLTs during the first 28-day cycle. Phase 2 aimed to estimate overall response rate at the dose established in Phase 1. These objectives address dose selection and response estimation, respectively.

The primary-outcome result is not reported in the registry record. The Phase 2 response estimate is also not reported. As a result, the posted record does not show whether the stated MTD criterion was met at any particular dose, which dose was selected, or what response rate was observed. The endpoint definitions and planned objectives cannot substitute for those results.

Adverse-event counts provide some descriptive information about the listed cohorts. They should not be interpreted as proof that a particular event was caused by treatment. Nor should contrasts across the cohorts be treated as randomized comparisons: the design is sequential, allocation is listed as NA, and the registry cautions that the arms are not like-for-like controls. Different cohort sizes also affect how much information each count contains.

In general, statistical estimates are most informative when reported with their denominators, uncertainty measures and analysis methods. The record does not report these details for the primary DLT result or the Phase 2 response objective. Therefore, neither the magnitude nor the precision of those central outcomes can be judged from the registry information. The completed status and enrollment total do not resolve these gaps.

The appropriate reading is limited: the registry describes a Phase 1/2 sequential study, its dose cohorts, safety summaries and intended endpoints. It does not provide the primary efficacy and dose-selection results needed to determine what the study observed on its central questions.

14. Why This Trial Matters Statistically

This trial is statistically notable for combining a dose-escalation question with a later response-estimation objective. Those objectives require different interpretations. The Phase 1 DLT count supports a dose-selection rule, while the Phase 2 overall response rate is an estimate of a binary clinical outcome. Treating them as one generic measure of benefit or risk would obscure the distinct questions they address.

The sequential structure is also important. The Phase 1 cohorts were not randomized arms, and the registry explicitly cautions that they are not like-for-like control comparisons. This illustrates why dose-cohort counts should be interpreted as descriptive evidence in the context of a dose-escalation design, rather than as direct treatment-effect estimates from a randomized comparison.

The MTD definition demonstrates how an endpoint can be tied to a decision threshold: the selected dose is defined by the DLT proportion during the first 28-day cycle. Yet a clear rule does not reveal the outcome. Without the observed DLT counts, the registry reader cannot evaluate the rule’s application or identify the dose selected from the posted information.

The record also illustrates the difference between listing an outcome and reporting its result. It names numerous secondary outcomes and includes adverse-event summaries, but the central Phase 1 and Phase 2 results are not reported in the registry record. Statistical interpretation depends not only on the planned endpoint but also on the estimate, denominator, uncertainty and analysis population. When those elements are absent, the conclusions that can be drawn must remain correspondingly narrow.

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 main limitation for statistical interpretation is that the registry record does not report the primary DLT result or the Phase 2 overall response rate. It therefore does not permit assessment of the MTD decision, the response estimate or the precision of either central outcome. The record’s completion status and enrollment total do not fill in these outcome details.

The study is sequential, with allocation listed as NA and no masking. The registry cautions that the arms are not a like-for-like control comparison. Accordingly, between-cohort contrasts cannot be interpreted as if participants had been randomized to comparable groups. The record does not report adjustment methods or analyses that would address differences among cohorts.

The registry record does not report the sample-size justification, detailed dose-escalation algorithm, interim-analysis plan, full statistical analysis plan, multiplicity procedures or missing-data methods. It also does not report analysis populations for the Phase 2 response and secondary outcomes. These gaps limit assessment of how the objectives were translated into statistical procedures and how incomplete observations were handled.

Safety summaries are descriptive counts, and uncertainty intervals are not reported. The serious adverse event term percentages are listed without denominators in the record excerpt. The primary DLT outcome covers the first 28-day cycle and has a specific event definition; it should not be read as a complete summary of all safety experience over the study. Together, these limitations mean that the posted information supports an account of design and selected safety counts, but not a full evaluation of outcome estimates or their uncertainty.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of Weekly Carfilzomib in Combination With Dexamethasone for Progressive Multiple Myeloma — NCT01677858.
• Registry record last updated 2022-09-23; status last verified 2022-09.
• Results first posted 2017-08-09.
• 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 describes a completed Phase 1/2 sequential study of carfilzomib with dexamethasone for progressive multiple myeloma. Enrollment is 116. Phase 1 evaluated carfilzomib dose cohorts of 45, 56, 70 and 88 mg/m², with the objective of determining the MTD from treatment-related DLTs in the first 28-day cycle. Phase 2 aimed to estimate overall response rate at the MTD established in Phase 1.

The primary DLT outcome result and the Phase 2 response estimate are not reported in the registry record. Safety counts are listed by cohort, but the study is not a randomized comparison and the record cautions against treating its arms as like-for-like controls. The record also does not report the full analysis plan, multiplicity procedures or missing-data methods.