Pomalidomide, Bortezomib, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma

MC1082: A Phase I/II Trial of Pomalidomide (CC-4047), Bortezomib, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma

RATIONALE: Pomalidomide and bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bortezomib may also stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving pomalidomide and bortezomib together with dexamethasone may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of bortezomib when given together with pomalidomide and dexamethasone and to see how well it works in treating patients with relapsed or refractory multiple myeloma.

Study Overview

• Status: Completed
• Conditions: Refractory Multiple Myeloma
• Intervention / Treatment: Drug: dexamethasone; Other: laboratory biomarker analysis; Drug: bortezomib; Drug: pomalidomide; Other: gene expression analysis

Detailed Description

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) of bortezomib in combination with pomalidomide and dexamethasone.

II. To evaluate the hematologic response rate (PR, VGPR, or CR) of pomalidomide, bortezomib and dexamethasone in patients with relapsed or refractory myeloma.

SECONDARY OBJECTIVES:

I. Time to progression.

II. To assess the toxicity of pomalidomide, bortezomib and dexamethasone in this patient population.

OUTLINE : This is a phase I, dose-escalation study of bortezomib followed by a phase II study. Patients receive oral pomalidomide on days 1-21; bortezomib IV on days 1, 8,15, 22; and oral dexamethasone on days 1, 8, 15, 22 . Treatment repeats every 28 days for 8 courses. Patients then receive maintenance therapy comprising oral pomalidomide on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 months.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States
      • Mayo Clinic in Arizona
  • Florida
    • Jacksonville, Florida, United States
      • Mayo Clinic in Florida
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Serum Creatinine =< 3 mg/dL
• Absolute neutrophil count >= 1000/uL
• Platelet count >= 75,000/uL

• Measurable disease of multiple myeloma as defined by at least ONE of the following:

  • serum monoclonal protein >= 1.0 g/dL
  • > 200 mg of monoclonal protein in the urine on 24 hour electrophoresis
  • serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio
  • monoclonal bone marrow plasmacytosis >= 30% (evaluable disease)
  • measurable plasmacytoma that has not been radiated
• ECOG Performance status (PS) 0, 1, or 2
• Previously treated relapsed or refractory multiple myeloma

• Patients must have received at least one prior therapy but no more than 4 therapies.

  • one or more of the prior regimens must have included lenalidomide and it has been determined the patient is refractory, resistant, or relapsed this therapy
  • prior bortezomib not required but if prior exposure, patients should not be refractory (Refractory means progression on therapy or within 60 days from the last dose of bortezomib.)
• Provide informed written consent
• Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting pomalidomide 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 pomalidomide; FCBP must also agree to ongoing pregnancy testing
• Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a vasectomy
• All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure
• Willing and able to take aspirin or alternate prophylactic anticoagulation
• All previous cancer therapy, including chemotherapy, high dose corticosteroids, immune modulatory drugs or proteosome inhibitors must have been discontinued >= 2 weeks prior to study registration
• Any prior treatment with investigational agents must be discontinued >= 28 days prior to study registration
• Willing to abstain from donating blood during study participation and for 28 days after discontinuation of study drug
• Men must agree to abstain from donating semen or sperm during study participation and for 28 days after discontinuation of study drug
• Willingness to return to enrolling institution for follow-up

Exclusion Criteria:

• Concomitant high dose corticosteroids (concurrent use of corticosteroids); EXCEPTION: Patients may be on chronic steroids (maximum dose 20 mg/day prednisone equivalent) if they are being given for disorders other than myeloma, i.e., adrenal insufficiency, rheumatoid arthritis, etc
• Another malignancy undergoing active treatment with the exception of non melanoma skin cancer or in situ cervical or breast cancer
• Pregnant women or women of reproductive ability who are unwilling to use effective contraception
• Nursing women
• Men who are unwilling to use a condom (even if they have undergone a prior vasectomy) while having intercourse with any woman, while taking the drug and for 4 weeks after stopping treatment
• Other co-morbidity which would interfere with patient's ability to participate in trial, e.g. uncontrolled infection, uncompensated heart or lung disease
• Other concurrent chemotherapy, radiotherapy, or any ancillary therapy considered investigational: NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment
• Active DVT or PE that has not been therapeutically anticoagulated
• Known positive for HIV or active hepatitis infection
• Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
• Known hypersensitivity to thalidomide or lenalidomide including development of erythema nodosum if characterized by a desquamating rash
• > grade 2 peripheral neuropathy
• Any prior use of pomalidomide

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I; Patients receive oral pomalidomide on days 1-21; bortezomib IV on days 1, 8, 15, 22; and oral dexamethasone on days 1, 8, 15, 22. Treatment repeats every 28 days for 8 courses. Patients then receive maintenance therapy comprising oral pomalidomide on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: dexamethasone; Given orally; Other Names: Aeroseb-Dex; Decaderm; Decadron; DM; DXM; Decaspray; Other: laboratory biomarker analysis; Optional correlative studies; Drug: bortezomib; Given IV; Other Names: MLN341; PS-341; LDP 341; VELCADE; Drug: pomalidomide; Given orally; Other Names: CC-4047; Other: gene expression analysis; Optional correlative studies

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Find Maximum Tolerated Dose (MTD) of Bortezomib in Combination With Pomalidomide and Dexamethasone Out to 2.5 Years, by Count of Patients With Dose Limiting Toxicities.	MTD is defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients).	2.5 years
Number of Participants With a Hematologic Response (PR, VGPR, or CR)	The number of participants who achieve PR, VGPR, or CR as defined by The International Myeloma Working Group uniform response criteria(2011). sCR: CR as defined below plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow. VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or > 90% reduction in serum M-protein plus urine M-protein level < 100 mg/24 h. PR: > 50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by >90% or to < 200 mg/24 h. MR: NA. SD: Not meeting criteria for CR, VGPR, PR, or progressive disease. PD: Increase of > 25% from lowest response value in any one or more of the following: Serum M-component and/or (the absolute increase must be > 0.5 g/dL), Urine M-component and/or (the absolute increase must be > 200 mg/24 h)	2.5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival	The progression-free survival (PFS) time is defined as the time from registration to progression or death due to any cause. The distribution of progression-free survival will be estimated using the method of Kaplan-Meier. PD: Increase of > 25% from lowest response value in any one or more of the following: Serum M-component and/or (the absolute increase must be > 0.5 g/dL), Urine M-component and/or (the absolute increase must be > 200 mg/24 h)	2.5 years
Number of Participants With Adverse Events	Reported in Adverse Events section of the results	2.5 years

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Martha Lacy, M.D., Mayo Clinic; Principal Investigator: Joseph R. Mikhael, M.D., Mayo Clinic

Publications and helpful links

General Publications

• Paludo J, Mikhael JR, LaPlant BR, Halvorson AE, Kumar S, Gertz MA, Hayman SR, Buadi FK, Dispenzieri A, Lust JA, Kapoor P, Leung N, Russell SJ, Dingli D, Go RS, Lin Y, Gonsalves WI, Fonseca R, Bergsagel PL, Roy V, Sher T, Chanan-Khan AA, Ailawadhi S, Stewart AK, Reeder CB, Richardson PG, Rajkumar SV, Lacy MQ. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed lenalidomide-refractory multiple myeloma. Blood. 2017 Sep 7;130(10):1198-1204. doi: 10.1182/blood-2017-05-782961. Epub 2017 Jul 6.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2011
• Primary Completion (Actual): August 15, 2017
• Study Completion (Actual): March 22, 2018

Study Registration Dates

• First Submitted: September 29, 2010
• First Submitted That Met QC Criteria: September 29, 2010
• First Posted (Estimate): October 1, 2010

Study Record Updates

• Last Update Posted (Actual): April 17, 2020
• Last Update Submitted That Met QC Criteria: April 7, 2020
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Dexamethasone; Pomalidomide; Bortezomib
• Other Study ID Numbers: MC1082 (Other Identifier: Mayo Clinic Cancer Center); NCI-2010-01967 (Registry Identifier: NCI's CTRO); 10-001545 (Other Identifier: Mayo Clinic IRB); PO-MM-PI-0019 (Other Identifier: Celgene Protocol)