Recurrent Plasma Cell Myeloma, Refractory Plasma Cell Myeloma
Conditions
Brief summary
This phase II trial studies how well panobinostat, carfilzomib, and dexamethasone work in treating patients with multiple myeloma that has come back (relapsed) or does not respond to treatment (refractory). Panobinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as carfilzomib and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Using multiple myeloma cells from patients' blood samples, the researchers will do laboratory tests to look at how well each of the drugs, alone and in different combinations, kill multiple myeloma cells. If the laboratory tests work well, they may be used in the future to help plan treatment for future patients.
Detailed description
PRIMARY OBJECTIVE: I. To correlate in vitro drug sensitivity testing with clinical response by determining the rate of in vitro drug sensitivity to panobinostat, carfilzomib, and dexamethasone singly and in combination, doublets and triplets. SECONDARY OBJECTIVE: I. To monitor response rates (partial response \[PR\], very good partial response \[VGPR\], and complete response) using the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma. EXPLORATORY OBJECTIVE: I. Progression free survival and overall survival will be assessed for up to 3 years after last dose. OUTLINE: Patients receive panobinostat orally (PO) on days 1, 3, 5, 15, 17, and 19. Patients also receive carfilzomib intravenously (IV) and dexamethasone PO on days 1, 2, 8, 9, 15, and 16. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and/or bone marrow samples for testing via in vitro chemosensitivity assay. After completion of study treatment, patients are followed up every 3 months for up to 3 years.
Interventions
DRUGCarfilzomib
Given IV
Undergo in vitro chemosensitivity testing
DRUGDexamethasone
Given PO
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGPanobinostat
Given PO
Sponsors
National Cancer Institute (NCI)
SecuraBio
University of Washington
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of multiple myeloma refractory to or relapsed after \>= 1 line of prior therapy (International Myeloma Working Group \[IMWG\] criteria) * Measurable disease, as indicated by one of the following: * Serum monoclonal (M)-protein \>= 1.0 g/dL * Elevated involved free light chain \>= 10 mg/dL as per IMWG criteria, and abnormal ratio * Urine Bence Jones protein \> 200 mg/24 hour (hr) * Absolute neutrophil count (ANC) \>= 750/uL * Platelet count \>= 75,000/uL * Hemoglobin \>= 7 g/dL * Creatinine =\< 2.0 mg/dL or calculated creatinine clearance \>= 30 mL/min * Total bilirubin =\< 1.5 x upper limit of normal (ULN) unless elevation is thought to be due to Gilbert's syndrome * Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) and serum glutamate pyruvate transaminase (SPGT) (alanine aminotransferase \[ALT\]) =\< 2.5 x ULN * Patients must avoid consumption of grapefruit, pomegranates, starfruit, Seville oranges or products containing the juice of each during the entire study and preferably 7 days before the first dose of study medications; orange juice is allowed * Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, should have a pregnancy test prior to the initiation of treatment and use highly effective methods of contraception during and for 3 months post study treatment; highly effective contraception methods include total abstinence, female sterilization, male sterilization, use of oral, injected, or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have comparable efficacy; women using hormonal contraceptives should additionally use a barrier method of contraception; women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural amenorrhea or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks ago * Sexually active males must use a condom during intercourse while taking study drug and for 6 months after stopping treatment; males should not father a child in this period; a condom is required to be used also by vasectomized men as well as during intercourse with a male partner; female partners of sexually active men should also use an effective contraception during treatment and for 6 months after their male partner has stopped taking the drug
Exclusion criteria
* Another bone marrow malignancy * Another cancer with expected survival of \< 2 years * Active viral, bacterial, or fungal infection progressing on current treatment * Clinically significant uncontrolled heart disease and/or recent cardiac event within 6 months prior to enrollment, such as: * History of angina pectoris, symptomatic pericarditis, or myocardial infarction * Left ventricular ejection fraction (LVEF) \< 45% as determined by echocardiogram (ECHO) or multi gated acquisition (MUGA) scan * History or presence of any significant, uncontrolled, or persistent cardiac arrhythmias, e.g. ventricular, supraventricular, nodal arrhythmias or conduction abnormality; stable atrial fibrillation within 6 months prior to randomization is permitted * Presence of unstable atrial fibrillation (ventricular response rate \> 100 beats per minute \[bpm\]); NOTE: patients with stable atrial fibrillation can be enrolled provided they do not meet other cardiac
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response, by Subject | 14 months | Assessed using the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma. Key: 1 = very good partial response (VGPR); 2 = partial response (PR); 3 = minimal response (MR); 4 = stable disease (SD); 5 = progressive disease (PD). Please see IC50 and CI results in the other primary outcome measures. |
| Multiple Myeloma Cells In-vitro Drug Sensitivity to Panobinostat, by Subject | At baseline | Multiple myeloma cells are added to assay with panobinostat. Cell viability and IC50 is determined. IC50 is the inhibitory concentration that kills 50% of cells. Results are reported in concentrations E-9. |
| Multiple Myeloma Cells In-vitro Drug Sensitivity to Carfilzomib, by Subject | At baseline | Multiple myeloma cells are added to assay with carfilzomib. Cell viability and IC50 is determined. IC50 is the inhibitory concentration that kills 50% of cells. |
| Multiple Myeloma Cells In-vitro Drug Sensitivity to Dexamethasone, by Subject | At baseline | Multiple myeloma cells are added to assay with dexamethasone. Cell viability and IC50 is determined. IC50 is the inhibitory concentration that kills 50% of cells. Results are reported in concentrations E-6. |
| Synergy of Panobinostat and Carfilzomib in Combination, Per Subject. | At baseline | Concentration of carfilzomib and panobinostat in combination leading to 90% growth inhibition of multiple myeloma cells in-vitro. The combination index (CI) is calculated using formula: CI = (\[D1\] in the combination / \[D1\] alone) + (\[D2\] in the combination / \[D2\] alone). Key: CI = 1 no synergy; CI\<1 synergy; CI\>1 antagonism. |
| Synergy of Panobinostat and Dexamethasone in Combination, Per Subject | At baseline | Concentration of panobinostat and dexamethasone in combination leading to 90% growth inhibition of multiple myeloma cells in-vitro. The combination index (CI) is calculated using formula: CI = (\[D1\] in the combination / \[D1\] alone) + (\[D2\] in the combination / \[D2\] alone). Key: CI = 1 no synergy; CI\<1 synergy; CI\>1 antagonism. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone Patients undergo collection of blood and/or bone marrow samples for testing via in vitro chemosensitivity assay. Regardless of assay results, patients receive panobinostat PO on days 1, 3, 5, 15, 17, and 19, and carfilzomib IV and dexamethasone PO on days 1, 2, 8, 9, 15, and 16. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. | 9 |
| Total | 9 |
Baseline characteristics
| Characteristic | Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone |
|---|---|
| Age, Customized | 67 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Prior autologous transplant | 88.9 percentage of participants |
| Prior therapy regimes | 5 number of regimens |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Revised ISS Stage | 2.5 ISS Stage |
| Sex/Gender, Customized Female | 3 Participants |
| Sex/Gender, Customized Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 9 |
| other Total, other adverse events | 4 / 9 |
| serious Total, serious adverse events | 3 / 9 |
Outcome results
Primary
Best Overall Response, by Subject
Assessed using the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma. Key: 1 = very good partial response (VGPR); 2 = partial response (PR); 3 = minimal response (MR); 4 = stable disease (SD); 5 = progressive disease (PD). Please see IC50 and CI results in the other primary outcome measures.
Time frame: 14 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Best Overall Response, by Subject | Subject MM-82 | 4 IMWG Uniform Response Grade |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Best Overall Response, by Subject | Subject MM-91 | 2 IMWG Uniform Response Grade |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Best Overall Response, by Subject | Subject MM-92 | 2 IMWG Uniform Response Grade |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Best Overall Response, by Subject | Subject MM-95 | 1 IMWG Uniform Response Grade |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Best Overall Response, by Subject | Subject MM-96 | 1 IMWG Uniform Response Grade |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Best Overall Response, by Subject | Subject MM-98 | 1 IMWG Uniform Response Grade |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Best Overall Response, by Subject | Subject MM-99 | 3 IMWG Uniform Response Grade |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Best Overall Response, by Subject | Subject MM-109 | 4 IMWG Uniform Response Grade |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Best Overall Response, by Subject | Subject M-111 | 1 IMWG Uniform Response Grade |
Primary
Multiple Myeloma Cells In-vitro Drug Sensitivity to Carfilzomib, by Subject
Multiple myeloma cells are added to assay with carfilzomib. Cell viability and IC50 is determined. IC50 is the inhibitory concentration that kills 50% of cells.
Time frame: At baseline
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Carfilzomib, by Subject | Subject MM-82 | 17.5 nM |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Carfilzomib, by Subject | Subject MM-91 | 0.479 nM |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Carfilzomib, by Subject | Subject MM-92 | 0.03 nM |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Carfilzomib, by Subject | Subject MM-95 | 0.269 nM |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Carfilzomib, by Subject | Subject MM-96 | 0.0048 nM |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Carfilzomib, by Subject | Subject MM-98 | 0.159 nM |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Carfilzomib, by Subject | Subject MM-99 | 0.159 nM |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Carfilzomib, by Subject | Subject MM-109 | 0.108 nM |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Carfilzomib, by Subject | Subject MM-111 | 0.0152 nM |
Primary
Multiple Myeloma Cells In-vitro Drug Sensitivity to Dexamethasone, by Subject
Multiple myeloma cells are added to assay with dexamethasone. Cell viability and IC50 is determined. IC50 is the inhibitory concentration that kills 50% of cells. Results are reported in concentrations E-6.
Time frame: At baseline
Population: Results for subject MM-92 were not reported.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Dexamethasone, by Subject | Subject MM-82 | 3.7 uM |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Dexamethasone, by Subject | Subject MM-91 | 10.9 uM |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Dexamethasone, by Subject | Subject MM-95 | 7 uM |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Dexamethasone, by Subject | Subject MM-96 | 1.1 uM |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Dexamethasone, by Subject | Subject MM-98 | 14.8 uM |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Dexamethasone, by Subject | Subject MM-99 | 8.6 uM |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Dexamethasone, by Subject | Subject MM-109 | 80 uM |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Dexamethasone, by Subject | Subject MM-111 | 1.1 uM |
Primary
Multiple Myeloma Cells In-vitro Drug Sensitivity to Panobinostat, by Subject
Multiple myeloma cells are added to assay with panobinostat. Cell viability and IC50 is determined. IC50 is the inhibitory concentration that kills 50% of cells. Results are reported in concentrations E-9.
Time frame: At baseline
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Panobinostat, by Subject | Subject MM-82 | 3.8 nM |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Panobinostat, by Subject | Subject MM-91 | 5.9 nM |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Panobinostat, by Subject | Subject MM-92 | 2.6 nM |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Panobinostat, by Subject | Subject MM-95 | 19.8 nM |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Panobinostat, by Subject | Subject MM-96 | 1.3 nM |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Panobinostat, by Subject | Subject MM-98 | 4.4 nM |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Panobinostat, by Subject | Subject MM-99 | 8.5 nM |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Panobinostat, by Subject | Subject MM-109 | 13.6 nM |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Multiple Myeloma Cells In-vitro Drug Sensitivity to Panobinostat, by Subject | Subject MM-111 | 2.0 nM |
Primary
Synergy of Panobinostat and Carfilzomib in Combination, Per Subject.
Concentration of carfilzomib and panobinostat in combination leading to 90% growth inhibition of multiple myeloma cells in-vitro. The combination index (CI) is calculated using formula: CI = (\[D1\] in the combination / \[D1\] alone) + (\[D2\] in the combination / \[D2\] alone). Key: CI = 1 no synergy; CI\<1 synergy; CI\>1 antagonism.
Time frame: At baseline
Population: CI score was not reported for subject MM-82.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Synergy of Panobinostat and Carfilzomib in Combination, Per Subject. | Subject MM-91 | 2.5 Combination index |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Synergy of Panobinostat and Carfilzomib in Combination, Per Subject. | Subject MM-92 | 2.4 Combination index |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Synergy of Panobinostat and Carfilzomib in Combination, Per Subject. | Subject MM-95 | 0.3 Combination index |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Synergy of Panobinostat and Carfilzomib in Combination, Per Subject. | Subject MM-96 | 2.2 Combination index |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Synergy of Panobinostat and Carfilzomib in Combination, Per Subject. | Subject MM-98 | 2.6 Combination index |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Synergy of Panobinostat and Carfilzomib in Combination, Per Subject. | Subject MM-99 | 1.8 Combination index |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Synergy of Panobinostat and Carfilzomib in Combination, Per Subject. | Subject MM-109 | 1.7 Combination index |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Synergy of Panobinostat and Carfilzomib in Combination, Per Subject. | Subject MM-111 | 62.2 Combination index |
Primary
Synergy of Panobinostat and Dexamethasone in Combination, Per Subject
Concentration of panobinostat and dexamethasone in combination leading to 90% growth inhibition of multiple myeloma cells in-vitro. The combination index (CI) is calculated using formula: CI = (\[D1\] in the combination / \[D1\] alone) + (\[D2\] in the combination / \[D2\] alone). Key: CI = 1 no synergy; CI\<1 synergy; CI\>1 antagonism.
Time frame: At baseline
Population: CI score was not reported for subject MM-82
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Synergy of Panobinostat and Dexamethasone in Combination, Per Subject | Subject MM-91 | 1.3 CI score |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Synergy of Panobinostat and Dexamethasone in Combination, Per Subject | Subject MM-92 | 2.6 CI score |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Synergy of Panobinostat and Dexamethasone in Combination, Per Subject | Subject MM-95 | 1.4 CI score |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Synergy of Panobinostat and Dexamethasone in Combination, Per Subject | Subject MM-96 | 0.6 CI score |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Synergy of Panobinostat and Dexamethasone in Combination, Per Subject | Subject MM-98 | 1.2 CI score |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Synergy of Panobinostat and Dexamethasone in Combination, Per Subject | Subject MM-99 | 0.9 CI score |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Synergy of Panobinostat and Dexamethasone in Combination, Per Subject | Subject MM-109 | 4.6 CI score |
| Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone | Synergy of Panobinostat and Dexamethasone in Combination, Per Subject | Subject MM-111 | 1.2 CI score |