Clinical trial NCT02128230: UARK 2012-02 Trial For High-Risk Myeloma Evaluating Accelerating and Sustaining Complete Remission
Official title: A Phase II Trial For High-Risk Myeloma Evaluating Accelerating and Sustaining Complete Remission (AS-CR) by Applying Non-Host-Exhausting and Timely Dose-Reduced Mel-80-CFZ-TD-Pace Transplant(s) With Interspersed Mel-20-CFZ-TD-Pace With CFZ-RD and CFZ-D Maintenance
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: High-Risk
Carfilzomib
Lead sponsor: University of Arkansas
Sponsor class: OTHER
Collaborators: name: Amgen
First posted: 2014-05-01
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to improve the clinical outcomes of research subjects with high-risk multiple myeloma in the context of the immediately preceding Total therapy 5 trial 2008-02 and Total therapy 3 trials 2003-33 and 2006-66.

Detailed description: Total therapy 5B will attempt to accelerate and sustain, at 2 years from starting therapy, the proportion of subjects in complete remission by reducing host-imposed toxicity and facilitating timely completion of highly synergistic 8-drug combination therapy, including the next generation proteasome inhibitor, Carfilzomib. This will result in avoiding multiple myeloma re-growth that, we postulate, ensued in Total therapy 3 during recovery phases from severe de-conditioning. It is speculated that the incidence of positive minimal residual disease will be reduced with the addition of one cycle of consolidation therapy. The following approach will be implemented:

* apply a 4-day fractionated lower dose melphalan (80 mg/m2) together with CFZ-TD-PACE regimen in MEL80-CFZ-TD (carfilzomib, thalidomide, dexamethasone) PACE as a hopefully less toxic and more effective transplant regimen
* interspersed with 1 cycle of non-transplant supported MEL-20-CFZ-TD (carfilzomib, thalidomide, dexamethasone) PACE (in lower doses than with transplant) inter-therapy (reduced from two cycles due to prolonged thrombocytopenia)
* followed by CFZ-TD (carfilzomib, thalidomide, dexamethasone) PACE consolidation therapy post transplant #2
* CFZ-RD (carfilzomib, lenalidomide and dexamethasone) maintenance for 1 year followed by CFZ-D for an additional year

Eligibility criteria: Inclusion Criteria:

* Patients must have newly diagnosed active MM requiring treatment. Patients with a previous history of smoldering myeloma will be eligible if there is evidence of progressive disease requiring chemotherapy.
* Patients must be either untreated or have not had more than one cycle of systemic MM therapy, excluding bisphosphonates and localized radiation.
* Participants must have high-risk disease, as defined by GEP70 risk score of ≥ 0.66
* Zubrod ≤ 2, unless solely due to symptoms of MM-related bone disease.
* Patients must have a platelet count of ≥ 50,000/μL, unless lower levels are explained by extensive bone marrow plasmacytosis.
* Patients must be at least 18 years of age and not older than 75 years of age at the time of registration.
* Participants must have preserved renal function as defined by a serum creatinine level of \< 3 mg/dL.
* Participants must have an ejection fraction by ECHO or MUGA scan ≥ 45%
* Patients must have adequate pulmonary function studies \> 50% of predicted on mechanical aspects (FEV1, FVC, etc) and diffusion capacity (DLCO) \> 50% of predicted. If the patient is unable to complete pulmonary function tests due to MM related pain or condition, exception may be granted if the principal investigator documents that the patient is a candidate for high dose therapy.
* Patients must have signed an IRB-approved informed consent indicating their understanding of the proposed treatment and understanding that the protocol has been approved by the IRB.

Exclusion Criteria:

* Does not have high-risk disease
* Poorly controlled hypertension, diabetes mellitus, or other serious medical illness or psychiatric illness that could potentially interfere with the completion of treatment according to this protocol.
* Patients must not have prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has not received treatment for one year prior to enrollment. Other cancers will only be acceptable if the patient's life expectancy exceeds five years.
* Pregnant or nursing women may not participate. Women of childbearing potential must have a negative pregnancy documented within one week of registration. Subjects of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.

Primary outcomes:
measure: The Remission Rate for Participants With High-risk Myeloma
timeFrame: from baseline to either death or study completion for each subject (up to approximately 48 months)
Secondary outcomes:
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
Study officials:
affiliation: University of Arkansas
name: Frits Van Rhee, MD, Ph.D
role: PRINCIPAL_INVESTIGATOR
References:
citation: Pawlyn C. High-risk myeloma: a challenge to define and to determine the optimal treatment. Lancet Haematol. 2021 Jan;8(1):e4-e6. doi: 10.1016/S2352-3026(20)30361-6. Epub 2020 Dec 22. No abstract available.
citation: Davies FE, Rosenthal A, Rasche L, Petty NM, McDonald JE, Ntambi JA, Steward DM, Panozzo SB, van Rhee F, Zangari M, Schinke CD, Thanendrarajan S, Walker B, Weinhold N, Barlogie B, Hoering A, Morgan GJ. Treatment to suppression of focal lesions on positron emission tomography-computed tomography is a therapeutic goal in newly diagnosed multiple myeloma. Haematologica. 2018 Jun;103(6):1047-1053. doi: 10.3324/haematol.2017.177139. Epub 2018 Mar 22.