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Trial represents ‘bold move’ for treatment of newly diagnosed myeloma
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Researchers at The University of Alabama at Birmingham are recruiting for a phase 2 clinical trial designed to offer an innovative treatment approach for patients with newly diagnosed multiple myeloma.
“I believe for the first time that we have treatments that are effective enough to make it possible to eradicate multiple myeloma definitively in a substantial proportion of patients, along with having the technology to detect that the disease has been targeted and treatment can be stopped,” Luciano Costa, MD, PhD, medical oncologist at The UAB Comprehensive Cancer Center and lead of the Hematologic-Malignancy Working Group, said in a press release. “That is what patients want, after all — a treatment that gives them the possibility of eliminating any trace of the myeloma without having to be on therapy for the rest of their lives. It is a bold move, but bold moves are what our patients deserve.”
HemOnc Today spoke with Costa about the rationale behind this trial, how it will be conducted, a timeline for completion and data availability, and the potential importance of the findings if the trial approach is proven successful.
Question: Can you explain the rationale behind this trial?
Answer: We hope this trial will be a pilot approach that challenges some of the key paradigms in the treatment of multiple myeloma. Treatment essentially has been based on induction therapy for a fixed duration, followed by an autologous transplant among fit, younger patients. There is a controversial role of consolidation after transplant but, in the end, patients go on maintenance therapy indefinitely until progression or intolerance. Most patients will have a recurrence and need salvage therapy. This has been the treatment paradigm. Although it is much improved from what we had 10 to 15 years ago, there is a lot of room for improvement. Although most patients do have remission, many of those remissions are not complete remissions. Also, among patients who meet traditional criteria for complete remission, there still is significant burden of disease, which is partially the reason why they relapse down the road.
Q: How can the paradigm change?
A: We have a few new tools that allow us to challenge these paradigms. One of these tools is new drugs. Carfilzomib (Kyprolis, Amgen) is a proteasome inhibitor, like bortezomib (Velcade, Takeda), that is used for upfront therapy. Carfilzomib in the relapsed setting has been shown to be more active than bortezomib, and studies that used carfilzomib upfront showed very impressive response rates. A second new drug is daratumumab (Darzalex, Janssen), a CD38-binding monoclonal antibody approved for treatment of relapsed multiple myeloma. We know daratumumab enhances the activity of proteasome inhibitors in the relapsed setting, greatly improving the quality and duration of responses. Another tool I would like to highlight is the availability of disease assessment at a much deeper level than what can be obtained with traditional methods — specifically assessment of minimal residual disease by next-generation sequencing. Even among patients with complete remission, there is a broad diversity of disease burden. The purpose of this study is to use what we consider the best agent in each class of drugs — specifically carfilzomib, lenalidomide (Revlimid, Celgene), dexamethasone and daratumumab — followed by autologous transplant for patients who are good candidates. Beyond this point, we want to tailor duration therapy or the continuation of therapy itself to the presence of minimal residual disease. Patients will continue therapy for additional cycles beyond transplant if they still have minimal residual disease present. This is a departure from the current paradigm. On the other hand, if patients have quick and complete clearance of the myeloma clone detected by next-generation sequencing minimal residual disease assay, they will have interruption of therapy and not have to undergo maintenance therapy. This is all based on the difference among patients and how quickly they clear disease.
Q: How will the study be conducted?
A: This is a single-arm, multisite, phase 2 study. We will not have a comparative study arm so we will not be able to definitively tell whether this approach is superior to the standard approach, but expect to be able to demonstrate the high rate of elimination of minimal residual disease with this combination therapy — the primary endpoint of our study.
Q: What do you expect to find?
A: The leading hypothesis is that the study will lead to a rate or 75% of minimal residual disease-negative remissions, substantially higher than what has been achieved with prior therapies for patients with newly diagnosed multiple myeloma.
Q: What is the timeline for study completion and data availability?
A: We are looking to include seven sites, and we plan to accrue 82 patients over 2 years. After this, it will be another 1.5 years to reach the primary endpoint. Although the anticipated study completion is about 3.5 years, the interest has been higher than we anticipated and the trial is accruing faster than expected, even though only two sites have been activated. We may complete this study ahead of schedule.
Q: This trial is one of the first for myeloma to use minimal residual disease as a primary endpoint , and it is the first to modify therapy based on achievement of minimal residual disease eradication . Can you elaborate on the novel design?
A: Minimal residual disease has been established as a surrogate of long-term outcomes, such as PFS and OS. We are starting to see new trials utilizing minimal residual disease as primary endpoint. The next step should be to utilize minimal residual disease to determine subsequent therapy, as utilized in our study. This is one of the first few studies to have minimal residual disease as the primary endpoint. We also want to demonstrate in an organized, standardized way that we can use minimal residual disease in decision-making and we can tailor the intensity and the duration of therapy based upon minimal residual disease clearance, which is something that has not been done before. More trials are properly utilizing minimal residual disease as a secondary endpoint or even a primary endpoint but, to my knowledge, there has not been an upfront trial that utilizes minimal residual disease as a decision-making tool. It also will be interesting to observe patients who go on to eradicate minimal residual disease and can discontinue therapy completely. We will monitor those patients using traditional parameters, but we also will survey their bone marrow at key time points to look for a molecular recurrence hopefully before clinical or a biochemical occurrence. It would be important to demonstrate that eradication of minimal residual disease is permanent, but it also would be the first seed in creating the opportunity to intervene on disease recurrence on a molecular level before patients have more abundant signs of disease.
Q: What are the clinical implications of the findings if this approach is proven successful?
A: If we are successful, we will demonstrate that the combination of carfilzomib, lenalidomide, dexamethasone and daratumumab, followed by autologous transplant, will lead to a rate of minimal residual disease elimination that is higher than what has been shown in prior studies. This would be a testimony to the feasibility of activity of this regimen. The second thing we intend to demonstrate is that we can show it is feasible to use real-time or near real-time minimal residual disease measurement to make decisions and guide therapies. The third and perhaps most exciting thing that will take us longer to find out is to demonstrate in the majority of patients that discontinuation of therapy is possible without substantial risk for recurrence. It certainly is naive to say we will cure myeloma with this trial, but we certainly are starting to take what investigators agree are necessary steps for cure, which is eradication of minimal residual disease and the discontinuation of therapy. – by Jennifer Southall
For more information:
Luciano Costa, MD, PhD, can be reached at UAB Comprehensive Cancer Center, 1824 6th Ave. South, Wallace Tumor Institute 202, Birmingham, AL 35233; email: ljcosta@uabmc.edu.
Disclosures: Amgen and Janssen are supporting this trial. Costa reports honoraria from Amgen, Celgene and Sanofi.