Multiple Myeloma
Conditions
Keywords
Recipients
Brief summary
This is a randomized controlled pilot study designed to evaluate whether the beta-adrenergic antagonist propranolol is effective in decreasing gene expression of stress-mediated beta-adrenergic pathways among a cohort of individuals receiving an autologous hematopoietic stem cell transplant (HCT) for multiple myeloma.
Detailed description
This is a randomized controlled pilot study designed to evaluate whether a drug designed to block the physiologic effects of stress is effective at blocking stress-related gene expression in people receiving autologous stem cell transplants (their own cells) for multiple myeloma. Such stress-related gene expression is one way that the body is programmed to make specific proteins under conditions of stress. These proteins are believed to contribute to worse health outcomes. By using the drug propranolol, we aim to see whether we might block these negative health effects of stress as occur in the cancer setting and during the transplant process. We hypothesize that individuals taking propranolol will have more favorable gene expression. We will enroll 40 individuals, randomizing half to receive propranolol and half to serve as the control group not on the study drug. Study participants will start propranolol three weeks prior to their transplant and continue it until 30 days after the transplant. We will explore the effect of socioeconomic status, depression, and anxiety on individuals' gene expression response to propranolol with the idea that the more impoverished, anxious, or depressed individuals will display an even greater change in their gene expression. Part of the purpose of this study is also be to assess whether it is feasible to give this drug to individuals with cancer. Results of this study may inform larger trials assessing the effects of propranolol on cancer progression.
Interventions
DRUGPropranolol
Sponsors
University of California, Los Angeles
Medical College of Wisconsin
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Patients with multiple myeloma receiving an autologous HCT are eligible when the following criteria are met: 1. 18-75 years of age 2. ≤ 1 year since initiation of systemic anti-myeloma therapy 3. Patient is scheduled for autologous hematopoietic stem cell transplant as the upfront therapy for their multiple myeloma 4. Karnofsky Performance Status of ≥90 %; patients eligible for HCT are eligible for the study 5. All men and women must agree to practice effective contraception during the study period if not otherwise documented to be infertile.
Exclusion criteria
1. Prior autologous HCT 2. Non secretory multiple myeloma 3. Concurrent beta-blocker therapy at or within 3 weeks of study entry. 4. Previous intolerance to beta-blocker therapy 5. Any medical contraindications to beta-blocker therapy including, but not limited to, symptomatic hypotension; drug hypersensitivity; sinus bradycardia, sick sinus syndrome, or 2nd or 3rd degree atrioventricular block without a pacemaker; uncompensated heart failure; or uncontrolled asthma 6. Active, untreated depression screened for by the HCT physician (Patients who screen positive will be offered a referral to the Medical College of Wisconsin Psycho-Oncology program for further evaluation and treatment) 7. Concurrent use of medications as specified in the protocol throughout the study or within one week of study entry. 8. Pregnant or lactating women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Beta-adrenergically Mediated Gene Expression (Change From Baseline) | Baseline (Pre-Transplant); 4 weeks post-transplant | Expression (up or down regulation) of genes involved in the stress response can be modulated through the beta-adrenergic pathway. The log2 RNA abundance is a means to normalize results to determine whether a gene is up regulated (value greater than 1) or down regulated (value less than 1). Differential change in log2 RNA abundance is defined by the fold change (FC) as log2FC=Log2(B)-Log2(A). Logarithmic measures are unitless. The change in the measure between two time points determines whether a gene has up-or down-regulated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Experiencing Engraftment Syndrome as a Function of Beta-blocker Administration | 4 weeks | Number of subjects experiencing any of: fever, diarrhea or rash requiring steroid intervention within 48 hours before or after neutrophil recovery. |
| Time (Days) to Neutrophil Engraftment | 4 weeks after transplant | This measure is the mean time to the beginning of three consecutive days where the neutrophil count (absolute neutrophil count) was 500 cells/mm\^3 (0.5 x 10\^9/L) or greater. |
| Patient-reported Depression and Anxiety Scores | Baseline and 4 weeks | This measure will be assessed using the Hospital Anxiety and Depression Scale (HADS). The HADS scale includes fourteen 4-response Likert-scale questions graded 0 to 3. Seven questions are specific to depression; 7 questions are specific to anxiety. The score is the total of the responses in their respective categories. Lower scores indicated less depression and/or anxiety. Scores 0-7 indicate normal status; scores 8-10 suggest borderline abnormal status; and scores 11-21 indicate abnormal status. Only anxiety scores are presented. |
| Number of Participants Diagnosed With Culture-positive Infection or Neutropenic Fever Greater Than 100.4 Degrees Fahrenheit | Up to 100 days after transplant | This measure is the number of subjects diagnosed with culture-positive infection or neutropenic fever greater than 100.4 degrees Fahrenheit. |
| Number of Participants With Myeloma Response as a Function of Beta-blocker Administration | 100 days after transplant | This measure is the number of participants experiencing a response defined by the International Uniform Response Criteria as: very good partial response (VGPR) or better (near complete response (nCR), complete response (CR), and stringent CR (sCR) according to at day 100 post-Hematopoietic Cell Transplant. |
| Time (Days) to Platelet Engraftment | 4 weeks | This measure is the mean time to the beginning of three consecutive days where the platelet count is at least 20,000/mm\^3 (20 x 10\^9/L) unsupported by a platelet transfusion. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Propranolol Patient's randomized to the Propranolol arm will be starting 7 days prior to transplant and continuing through 28 days post-transplant. Propranolol will start at 20mg twice daily and will be titrated to 40mg twice daily as tolerated. Both groups will come back to the hospital weekly in order to assess items such as patient's level of anxiety, depression, your adherence, and also to monitor for side effects. The patient's will complete questionnaires during your visit. These will take approximately 15 minutes to complete. This will continue for up to 7 total weeks for patient's on the Propranolol arm.
Propranolol | 12 |
| Control Arm Both groups will come back to the hospital weekly in order to assess items such as patient's level of anxiety, depression, your adherence, and also to monitor for side effects. The patient's will complete questionnaires during your visit. These will take approximately 15 minutes to complete. This will continue for 6 total weeks for patient's on the control arm. | 13 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Physician Decision | 0 | 2 |
Baseline characteristics
| Characteristic | Total | Control Arm | Propranolol |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 5 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 8 Participants | 8 Participants |
| Age, Continuous | 61 years STANDARD_DEVIATION 8.6 | 63 years STANDARD_DEVIATION 8.6 | 59 years STANDARD_DEVIATION 9.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 19 Participants | 11 Participants | 8 Participants |
| Region of Enrollment United States | 25 participants | 13 participants | 12 participants |
| Sex: Female, Male Female | 10 Participants | 5 Participants | 5 Participants |
| Sex: Female, Male Male | 15 Participants | 8 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 13 |
| other Total, other adverse events | 12 / 12 | 13 / 13 |
| serious Total, serious adverse events | 2 / 12 | 3 / 13 |
Outcome results
Primary
Beta-adrenergically Mediated Gene Expression (Change From Baseline)
Expression (up or down regulation) of genes involved in the stress response can be modulated through the beta-adrenergic pathway. The log2 RNA abundance is a means to normalize results to determine whether a gene is up regulated (value greater than 1) or down regulated (value less than 1). Differential change in log2 RNA abundance is defined by the fold change (FC) as log2FC=Log2(B)-Log2(A). Logarithmic measures are unitless. The change in the measure between two time points determines whether a gene has up-or down-regulated.
Time frame: Baseline (Pre-Transplant); 4 weeks post-transplant
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Propranolol | Beta-adrenergically Mediated Gene Expression (Change From Baseline) | -0.407 Unitless | Standard Error 0.165 |
| Control Arm | Beta-adrenergically Mediated Gene Expression (Change From Baseline) | 0.0099 Unitless | Standard Error 0.103 |
p-value: 0.337Regression, Logistic
p-value: 0.017Regression, Logistic
Secondary
Number of Participants Diagnosed With Culture-positive Infection or Neutropenic Fever Greater Than 100.4 Degrees Fahrenheit
This measure is the number of subjects diagnosed with culture-positive infection or neutropenic fever greater than 100.4 degrees Fahrenheit.
Time frame: Up to 100 days after transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Propranolol | Number of Participants Diagnosed With Culture-positive Infection or Neutropenic Fever Greater Than 100.4 Degrees Fahrenheit | 1 Participants |
| Control Arm | Number of Participants Diagnosed With Culture-positive Infection or Neutropenic Fever Greater Than 100.4 Degrees Fahrenheit | 6 Participants |
p-value: 0.06Likelihood ration Chi-Square test
Secondary
Number of Participants With Myeloma Response as a Function of Beta-blocker Administration
This measure is the number of participants experiencing a response defined by the International Uniform Response Criteria as: very good partial response (VGPR) or better (near complete response (nCR), complete response (CR), and stringent CR (sCR) according to at day 100 post-Hematopoietic Cell Transplant.
Time frame: 100 days after transplant
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Propranolol | Number of Participants With Myeloma Response as a Function of Beta-blocker Administration | Stable Disease | 1 Participants |
| Propranolol | Number of Participants With Myeloma Response as a Function of Beta-blocker Administration | Partial Response | 5 Participants |
| Propranolol | Number of Participants With Myeloma Response as a Function of Beta-blocker Administration | Very Good Partial Response | 5 Participants |
| Propranolol | Number of Participants With Myeloma Response as a Function of Beta-blocker Administration | Complete Response | 1 Participants |
| Control Arm | Number of Participants With Myeloma Response as a Function of Beta-blocker Administration | Complete Response | 3 Participants |
| Control Arm | Number of Participants With Myeloma Response as a Function of Beta-blocker Administration | Stable Disease | 0 Participants |
| Control Arm | Number of Participants With Myeloma Response as a Function of Beta-blocker Administration | Very Good Partial Response | 5 Participants |
| Control Arm | Number of Participants With Myeloma Response as a Function of Beta-blocker Administration | Partial Response | 5 Participants |
Secondary
Number of Subjects Experiencing Engraftment Syndrome as a Function of Beta-blocker Administration
Number of subjects experiencing any of: fever, diarrhea or rash requiring steroid intervention within 48 hours before or after neutrophil recovery.
Time frame: 4 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Propranolol | Number of Subjects Experiencing Engraftment Syndrome as a Function of Beta-blocker Administration | 6 Participants |
| Control Arm | Number of Subjects Experiencing Engraftment Syndrome as a Function of Beta-blocker Administration | 3 Participants |
Secondary
Patient-reported Depression and Anxiety Scores
This measure will be assessed using the Hospital Anxiety and Depression Scale (HADS). The HADS scale includes fourteen 4-response Likert-scale questions graded 0 to 3. Seven questions are specific to depression; 7 questions are specific to anxiety. The score is the total of the responses in their respective categories. Lower scores indicated less depression and/or anxiety. Scores 0-7 indicate normal status; scores 8-10 suggest borderline abnormal status; and scores 11-21 indicate abnormal status. Only anxiety scores are presented.
Time frame: Baseline and 4 weeks
Population: One propranolol subject was discontinued due to symptomatic hypotension. Two control subjects were discontinued doe to initiation of beta-blocker therapy for cardiac arrhythmia.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Propranolol | Patient-reported Depression and Anxiety Scores | Baseline Anxiety Score | 7.3 units on a scale | Standard Deviation 3.5 |
| Propranolol | Patient-reported Depression and Anxiety Scores | 4-Week Anxiety Score | 4.4 units on a scale | Standard Deviation 2.3 |
| Control Arm | Patient-reported Depression and Anxiety Scores | Baseline Anxiety Score | 7.4 units on a scale | Standard Deviation 3.7 |
| Control Arm | Patient-reported Depression and Anxiety Scores | 4-Week Anxiety Score | 5.2 units on a scale | Standard Deviation 3.7 |
Secondary
Time (Days) to Neutrophil Engraftment
This measure is the mean time to the beginning of three consecutive days where the neutrophil count (absolute neutrophil count) was 500 cells/mm\^3 (0.5 x 10\^9/L) or greater.
Time frame: 4 weeks after transplant
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Propranolol | Time (Days) to Neutrophil Engraftment | 10.5 Days | Standard Deviation 1 |
| Control Arm | Time (Days) to Neutrophil Engraftment | 11.9 Days | Standard Deviation 3.7 |
p-value: 0.14t-test, 2 sided
Secondary
Time (Days) to Platelet Engraftment
This measure is the mean time to the beginning of three consecutive days where the platelet count is at least 20,000/mm\^3 (20 x 10\^9/L) unsupported by a platelet transfusion.
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Propranolol | Time (Days) to Platelet Engraftment | 16.6 Days | Standard Deviation 4.1 |
| Control Arm | Time (Days) to Platelet Engraftment | 19.6 Days | Standard Deviation 5.4 |
p-value: 0.41t-test, 2 sided