Recurrent Plasma Cell Myeloma, Refractory Plasma Cell Myeloma
Conditions
Brief summary
This phase I/II trial studies the best dose and side effects of lenalidomide and thalidomide, and how well they work with dexamethasone in treating participants with multiple myeloma that has come back or does not respond to treatment. Drugs used in chemotherapy, such as lenalidomide, thalidomide and dexamethasone, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.
Detailed description
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of the combination of lenalidomide and thalidomide and dexamethasone (LTD) in patients with relapsed/refractory multiple myeloma (RRMM). (Phase 1) II. To determine the overall (complete remission \[CR)\]+ very good partial response \[VGPR\]+ partial response \[PR)\] response rate of the combination after 4 cycles of therapy. (Phase 2) SECONDARY OBJECTIVES: I. To determine the overall response rate (ORR). (Phase 1) II. To determine the time to progression (TTP). (Phase 1) III. To determine the progression free survival (PFS). (Phase 1) IV. To determine the time to best response. (Phase 1) V. To determine the CR, VGPR. (Phase 2) VI. To determine the time to progression (TTP). (Phase 2) VII. To determine the progression free survival (PFS). (Phase 2) VIII. To determine the time to best response. (Phase 2) IX. To assess the safety of the combination of LTD in patients with RRMM. (Phase 2) X. Time to next therapy. (Phase 2) XI. Symptom measurement - multiple-symptom assessment tool. (Phase 2) OUTLINE: This is a dose-escalation study of lenalidomide and thalidomide. Participants receive lenalidomide orally (PO) on days 1-21 and thalidomide PO once daily (QD) on days 1-28. Participants also receive dexamethasone PO QD on days 1-4, 9-12, and 17-20 of courses 1-2, and days 1, 8, 15, and 22 of subsequent courses. Treatment repeats every 28 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Participants who have stable or responding disease to treatment receive lenalidomide PO on days 1-21 and thalidomide PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Participants may receive dexamethasone at the discretion of the investigator. After completion of study treatment, patients are followed up at 30 days.
Interventions
DRUGDexamethasone
Given PO
DRUGLenalidomide
Given PO
DRUGThalidomide
Given PO
Sponsors
National Cancer Institute (NCI)
M.D. Anderson Cancer Center
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Understand and voluntarily sign an informed consent form * Relapsed/refractory multiple myeloma (MM) with measurable levels of myeloma paraprotein in serum (\>= 0.5 g/dl), urine (\>= 0.2 g excreted in a 24-hour collection sample), or abnormal free light chain (FLC) ratio * Serum creatinine =\< 2.5 mg/dl * Females of childbearing potential (FCBP)\* must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mlU/mL within 10-14 days prior to and again within 24 hours of starting lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. * A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). * Absolute neutrophil count \> 1000 cells/mm\^3 * Platelet count \> 50,000 cells/mm\^3 for patients with \< 50% of bone marrow plasma cells and platelet count \> 25,000 cells/mm\^3 for patients in whom \> 50% of the bone marrow nucleated cells were plasma cells * Total bilirubin =\< 2.0 mg/dL * Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) \< 3 x upper limit of normal (ULN) * Able to take prophylactic anticoagulation, warfarin or equivalent agent * Patient is able to understand and comply with the terms and conditions of the lenalidomide and thalidomide counseling program * All study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist, AND the S.T.E.P.S. program
Exclusion criteria
* Any serious medical condition, or psychiatric illness that would prevent the subject from signing the informed consent form * Pregnant or breast feeding females. (Lactating females must agree not to breast feed while taking lenalidomide) * Use of any cancer therapy within 21 days prior to beginning cycle 1 day 1 of therapy (radiation therapy allowed within 5 days of completion of radiation therapy). * Known hypersensitivity to thalidomide, lenalidomide and dexamethasone. * The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limitations Toxicities of the Combination of Lenalidomide and Thalidomide and Dexamethasone (LTD) in Patients With Relapsed/Refractory Multiple Myeloma (RRMM) | After one 28-day cycle | To determine the dose limitations toxicities of the combination of lenalidomide and thalidomide and dexamethasone (LTD) in patients with relapsed/refractory multiple myeloma (RRMM). |
| Complete Response(CR) and Very Good Partial Response(VGPR) | Evaluated each 28-day cycle and nadir of criteria is considered best overall response (median time to best response for this study was 2 cycles (range for best overall response was 1-21 cycles). | To determine the best overall response (CR+VGPR+PR) of the lenalidomide, thalidomide, dexamethasone combination based on IMWG criteria at nadir. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Best Response | Up to 9 years | Estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups was made using the log-rank test. Cox proportional hazard regression will be employed for multivariate analysis on time-to-event outcomes. |
| Time to Progression | Up to 9 years | Time to Progression was estimated using Kaplan Meier analysis. |
| Time to Next Therapy | Up to 4.5 years | Estimated using the method of Kaplan and Meier. |
| Incidence of Adverse Events | Up to 9 years | Linear regression was utilized to assess the effect of patient prognostic factors on the toxicity rate. |
| Progression Free Survival | Up to 9 years | Estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups was made using the log-rank test. Cox proportional hazard regression will be employed for multivariate analysis on time-to-event outcomes. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| RTD (Cohort 1, Phase 1) Oral Revlimid 15mg, Thalidomide 100mg, Dexamethasone 40mg\*21 days+ 7 days rest and reevaluation=28 day cycle | 3 |
| RTD (Cohort 2, Phase 1) Oral Revlimid 25mg, Thalidomide 100mg, Dexamethasone \*21 days+ 7 days rest and reevaluation=28 day cycle | 3 |
| RTD (Cohort 3, Phase 1) Oral Revlimid 25mg, Thalidomide 200mg, Dexamethasone 40mg\*21 days+ 7 days rest and reevaluation=28 day cycle | 9 |
| RTD (Cohort 2, Phase 2) Oral Revlimid 25mg, Thalidomide 100mg, Dexamethasone \*21 days+ 7 days rest and reevaluation=28 day cycle | 49 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 2 |
| Overall Study | Death | 0 | 0 | 1 | 0 |
| Overall Study | Disease Progression | 0 | 0 | 1 | 16 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 5 |
Baseline characteristics
| Characteristic | RTD (Cohort 1, Phase 1) | RTD (Cohort 3, Phase 1) | RTD (Cohort 2, Phase 2) | RTD (Cohort 2, Phase 1) | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 8 Participants | 23 Participants | 1 Participants | 35 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 1 Participants | 26 Participants | 2 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 9 Participants | 46 Participants | 3 Participants | 61 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 10 Participants | 2 Participants | 18 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 5 Participants | 38 Participants | 1 Participants | 45 Participants |
| Region of Enrollment United States | 3 participants | 9 participants | 49 participants | 3 participants | 64 participants |
| Relapsed/Refractory Multiple Myeloma > = 1 line of previous therapy | 3 Participants | 9 Participants | 49 Participants | 3 Participants | 64 Participants |
| Relapsed/Refractory Multiple Myeloma Abnormal Free Light Chain Ratio | 2 Participants | 9 Participants | 46 Participants | 3 Participants | 60 Participants |
| Relapsed/Refractory Multiple Myeloma Age >= 18 years old | 3 Participants | 9 Participants | 49 Participants | 3 Participants | 64 Participants |
| Relapsed/Refractory Multiple Myeloma Anti-coagulant tolerance (PTT) normal | 2 Participants | 4 Participants | 37 Participants | 3 Participants | 46 Participants |
| Relapsed/Refractory Multiple Myeloma AST or ALT < 3x Upper Limit | 3 Participants | 9 Participants | 49 Participants | 3 Participants | 64 Participants |
| Relapsed/Refractory Multiple Myeloma Cognitively Aware & Physically Able | 2 Participants | 7 Participants | 45 Participants | 2 Participants | 56 Participants |
| Relapsed/Refractory Multiple Myeloma Creatine < 2.5 mg/dL | 3 Participants | 9 Participants | 49 Participants | 3 Participants | 64 Participants |
| Relapsed/Refractory Multiple Myeloma Days off prev treatment >= 25 | 3 Participants | 9 Participants | 44 Participants | 3 Participants | 59 Participants |
| Relapsed/Refractory Multiple Myeloma Females non-procreative sex | 1 Participants | 9 Participants | 19 Participants | 3 Participants | 32 Participants |
| Relapsed/Refractory Multiple Myeloma Measurable levels of myeloma >=.2 Urine-Protein | 0 Participants | 7 Participants | 42 Participants | 1 Participants | 50 Participants |
| Relapsed/Refractory Multiple Myeloma Measurable levels of myeloma >=.5M serum-Protein | 2 Participants | 7 Participants | 44 Participants | 2 Participants | 55 Participants |
| Relapsed/Refractory Multiple Myeloma Men non-procreative sex | 2 Participants | 9 Participants | 30 Participants | 3 Participants | 44 Participants |
| Relapsed/Refractory Multiple Myeloma No Cancer Therapy in 21 days | 3 Participants | 9 Participants | 49 Participants | 3 Participants | 64 Participants |
| Relapsed/Refractory Multiple Myeloma No Desquamating Rash regarding Thalidomide | 3 Participants | 9 Participants | 49 Participants | 3 Participants | 64 Participants |
| Relapsed/Refractory Multiple Myeloma No Known Study Drug Allergies | 3 Participants | 9 Participants | 49 Participants | 3 Participants | 64 Participants |
| Relapsed/Refractory Multiple Myeloma No Pregnant/Breast Feeding Females | 1 Participants | 9 Participants | 19 Participants | 3 Participants | 32 Participants |
| Relapsed/Refractory Multiple Myeloma Platelets > 50,000 | 3 Participants | 9 Participants | 47 Participants | 3 Participants | 62 Participants |
| Relapsed/Refractory Multiple Myeloma Total Bilirubin < 2.0 | 3 Participants | 9 Participants | 49 Participants | 3 Participants | 64 Participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 19 Participants | 0 Participants | 23 Participants |
| Sex: Female, Male Male | 2 Participants | 6 Participants | 30 Participants | 3 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 1 / 9 | 0 / 49 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 9 / 9 | 49 / 49 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 1 / 9 | 7 / 49 |
Outcome results
Primary
Complete Response(CR) and Very Good Partial Response(VGPR)
To determine the best overall response (CR+VGPR+PR) of the lenalidomide, thalidomide, dexamethasone combination based on IMWG criteria at nadir.
Time frame: Evaluated each 28-day cycle and nadir of criteria is considered best overall response (median time to best response for this study was 2 cycles (range for best overall response was 1-21 cycles).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RTD (Cohort 1, Phase 1) | Complete Response(CR) and Very Good Partial Response(VGPR) | Partial Remission | 2 Participants |
| RTD (Cohort 1, Phase 1) | Complete Response(CR) and Very Good Partial Response(VGPR) | Non Evaluable | 1 Participants |
| RTD (Cohort 1, Phase 1) | Complete Response(CR) and Very Good Partial Response(VGPR) | Stringent Complete Remission | 0 Participants |
| RTD (Cohort 1, Phase 1) | Complete Response(CR) and Very Good Partial Response(VGPR) | Progressive Disease | 0 Participants |
| RTD (Cohort 1, Phase 1) | Complete Response(CR) and Very Good Partial Response(VGPR) | Stable Disease | 0 Participants |
| RTD (Cohort 1, Phase 1) | Complete Response(CR) and Very Good Partial Response(VGPR) | Very Good Partial Remission | 0 Participants |
| RTD (Cohort 1, Phase 1) | Complete Response(CR) and Very Good Partial Response(VGPR) | Minimal Residual Disease | 0 Participants |
| RTD (Cohort 2, Phase 1) | Complete Response(CR) and Very Good Partial Response(VGPR) | Non Evaluable | 0 Participants |
| RTD (Cohort 2, Phase 1) | Complete Response(CR) and Very Good Partial Response(VGPR) | Minimal Residual Disease | 0 Participants |
| RTD (Cohort 2, Phase 1) | Complete Response(CR) and Very Good Partial Response(VGPR) | Very Good Partial Remission | 3 Participants |
| RTD (Cohort 2, Phase 1) | Complete Response(CR) and Very Good Partial Response(VGPR) | Stringent Complete Remission | 0 Participants |
| RTD (Cohort 2, Phase 1) | Complete Response(CR) and Very Good Partial Response(VGPR) | Stable Disease | 0 Participants |
| RTD (Cohort 2, Phase 1) | Complete Response(CR) and Very Good Partial Response(VGPR) | Progressive Disease | 2 Participants |
| RTD (Cohort 2, Phase 1) | Complete Response(CR) and Very Good Partial Response(VGPR) | Partial Remission | 0 Participants |
| RTD (Cohort 3, Phase 1) | Complete Response(CR) and Very Good Partial Response(VGPR) | Minimal Residual Disease | 1 Participants |
| RTD (Cohort 3, Phase 1) | Complete Response(CR) and Very Good Partial Response(VGPR) | Partial Remission | 2 Participants |
| RTD (Cohort 3, Phase 1) | Complete Response(CR) and Very Good Partial Response(VGPR) | Progressive Disease | 2 Participants |
| RTD (Cohort 3, Phase 1) | Complete Response(CR) and Very Good Partial Response(VGPR) | Very Good Partial Remission | 1 Participants |
| RTD (Cohort 3, Phase 1) | Complete Response(CR) and Very Good Partial Response(VGPR) | Stringent Complete Remission | 0 Participants |
| RTD (Cohort 3, Phase 1) | Complete Response(CR) and Very Good Partial Response(VGPR) | Non Evaluable | 3 Participants |
| RTD (Cohort 3, Phase 1) | Complete Response(CR) and Very Good Partial Response(VGPR) | Stable Disease | 0 Participants |
| RTD (Cohort 2, Phase 2) | Complete Response(CR) and Very Good Partial Response(VGPR) | Very Good Partial Remission | 8 Participants |
| RTD (Cohort 2, Phase 2) | Complete Response(CR) and Very Good Partial Response(VGPR) | Stable Disease | 7 Participants |
| RTD (Cohort 2, Phase 2) | Complete Response(CR) and Very Good Partial Response(VGPR) | Non Evaluable | 7 Participants |
| RTD (Cohort 2, Phase 2) | Complete Response(CR) and Very Good Partial Response(VGPR) | Progressive Disease | 6 Participants |
| RTD (Cohort 2, Phase 2) | Complete Response(CR) and Very Good Partial Response(VGPR) | Partial Remission | 13 Participants |
| RTD (Cohort 2, Phase 2) | Complete Response(CR) and Very Good Partial Response(VGPR) | Stringent Complete Remission | 3 Participants |
| RTD (Cohort 2, Phase 2) | Complete Response(CR) and Very Good Partial Response(VGPR) | Minimal Residual Disease | 9 Participants |
Primary
Number of Participants With Dose Limitations Toxicities of the Combination of Lenalidomide and Thalidomide and Dexamethasone (LTD) in Patients With Relapsed/Refractory Multiple Myeloma (RRMM)
To determine the dose limitations toxicities of the combination of lenalidomide and thalidomide and dexamethasone (LTD) in patients with relapsed/refractory multiple myeloma (RRMM).
Time frame: After one 28-day cycle
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RTD (Cohort 1, Phase 1) | Number of Participants With Dose Limitations Toxicities of the Combination of Lenalidomide and Thalidomide and Dexamethasone (LTD) in Patients With Relapsed/Refractory Multiple Myeloma (RRMM) | 1 Participants |
| RTD (Cohort 2, Phase 1) | Number of Participants With Dose Limitations Toxicities of the Combination of Lenalidomide and Thalidomide and Dexamethasone (LTD) in Patients With Relapsed/Refractory Multiple Myeloma (RRMM) | 0 Participants |
| RTD (Cohort 3, Phase 1) | Number of Participants With Dose Limitations Toxicities of the Combination of Lenalidomide and Thalidomide and Dexamethasone (LTD) in Patients With Relapsed/Refractory Multiple Myeloma (RRMM) | 3 Participants |
| RTD (Cohort 2, Phase 2) | Number of Participants With Dose Limitations Toxicities of the Combination of Lenalidomide and Thalidomide and Dexamethasone (LTD) in Patients With Relapsed/Refractory Multiple Myeloma (RRMM) | 0 Participants |
Secondary
Incidence of Adverse Events
Linear regression was utilized to assess the effect of patient prognostic factors on the toxicity rate.
Time frame: Up to 9 years
Population: The Number in each of the arms was insufficient to conduct regression analyses, therefore regression analyses was conducted overall. Participants who were Thalidomide incompatible.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RTD (Cohort 1, Phase 1) | Incidence of Adverse Events | 0 Participants |
| RTD (Cohort 2, Phase 1) | Incidence of Adverse Events | 0 Participants |
| RTD (Cohort 3, Phase 1) | Incidence of Adverse Events | 2 Participants |
| RTD (Cohort 2, Phase 2) | Incidence of Adverse Events | 10 Participants |
Secondary
Progression Free Survival
Estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups was made using the log-rank test. Cox proportional hazard regression will be employed for multivariate analysis on time-to-event outcomes.
Time frame: Up to 9 years
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RTD (Cohort 1, Phase 1) | Progression Free Survival | 32.74 Months | Standard Deviation 27 |
| RTD (Cohort 2, Phase 1) | Progression Free Survival | 9.04 Months | Standard Deviation 7.49 |
| RTD (Cohort 3, Phase 1) | Progression Free Survival | 14.61 Months | Standard Deviation 16.41 |
| RTD (Cohort 2, Phase 2) | Progression Free Survival | 10.02 Months | Standard Deviation 17.61 |
Secondary
Time to Best Response
Estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups was made using the log-rank test. Cox proportional hazard regression will be employed for multivariate analysis on time-to-event outcomes.
Time frame: Up to 9 years
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RTD (Cohort 1, Phase 1) | Time to Best Response | 19 months | Standard Deviation 1.41 |
| RTD (Cohort 2, Phase 1) | Time to Best Response | 5 months | Standard Deviation 6.08 |
| RTD (Cohort 3, Phase 1) | Time to Best Response | 5.16 months | Standard Deviation 7.03 |
| RTD (Cohort 2, Phase 2) | Time to Best Response | 3.3 months | Standard Deviation 4.2 |
Secondary
Time to Next Therapy
Estimated using the method of Kaplan and Meier.
Time frame: Up to 4.5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RTD (Cohort 1, Phase 1) | Time to Next Therapy | 52.4 months |
| RTD (Cohort 2, Phase 1) | Time to Next Therapy | 14.3 months |
| RTD (Cohort 3, Phase 1) | Time to Next Therapy | 10.5 months |
| RTD (Cohort 2, Phase 2) | Time to Next Therapy | 6.47 months |
Secondary
Time to Progression
Time to Progression was estimated using Kaplan Meier analysis.
Time frame: Up to 9 years
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RTD (Cohort 1, Phase 1) | Time to Progression | 32.74 Months | Standard Deviation 27 |
| RTD (Cohort 2, Phase 1) | Time to Progression | 9.04 Months | Standard Deviation 7.49 |
| RTD (Cohort 3, Phase 1) | Time to Progression | 14.61 Months | Standard Deviation 16.41 |
| RTD (Cohort 2, Phase 2) | Time to Progression | 10.02 Months | Standard Deviation 17.61 |