Those of us who’ve lived with cancer understand the necessity and value of clinical trials. Without them cancer care would never change; treatment would always remain the same.
I’ve worked with several ongoing committees and groups to help design and formulate myeloma clinical trials, and am still astounded by the dedication required to get them accomplished. Hundreds of unpaid hours of work by PIs (Principle Investigators) are expended before a trial is even presented to a patient as a possible treatment option.
A myeloma trial which will soon open is MASTER, an exciting combination of effective drugs for newly diagnosed patients. It has been designed and championed by Dr. Luciano J. Costa of UAB (University Alabama at Birmingham). Dr. Costa and his colleagues have devoted hundreds of hours of time over the last two years to write the trial, discuss and negotiate it with pharma companies, and re-shape it based on those discussions. Those of us working with him over these two years have shared numerous emails and face to face interactions. Each step, including FDA and Pharma discussions, has taken weeks or months of time.
MASTER is an acronym for “Monoclonal Antibody-Based Sequential Therapy for Deep Remission in Multiple Myeloma”. To find this clinical trial on SparkCures, click here:
This trial is still undergoing final contracting agreements with the companies involved, a process which I’ve learned takes an inordinately long time.
There are many things to like about this trial. It combines four potent anti-myeloma drugs to initiate therapy for 82 newly diagnosed patients. MASTER is a single arm trial which means that everyone will receive the designed treatment plan. There will be no randomization of patients against their will, so each participant will receive all four drugs. Best of all perhaps is the fact that Carfilzomib and Daratumumab will be provided at no cost to patients thanks to support from Amgen and Janssen. Once the trial is officially open, I predict that it will accrue patients quite quickly.
MASTER will assess the safety and efficacy of an induction therapy using the combination of dexamethasone, lenalidomide (Revlimid), daratumumab (Darzalex) and carfilzomib (Kyprolis) to treat patients with newly diagnosed multiple myeloma. The therapy with KRdD (Kyprolis, Revlimid, dexamethasone, Darzalex) will be followed by autologous hematopoietic cell transplantation (auto-HCT) and KRdD consolidation. The hypothesis is that the KRdD therapy particularly in combination with the auto-HCT will be safe and lead to deep remission.
The trial will also monitor for minimal residual disease (MRD) to determine duration of therapy, if continuous therapy is needed, and if therapy needs to be reinstituted before patients have clinical relapse.
The study has four cycles (28-days each) of drug therapy prior to patients being evaluated for auto-HCT. After the completion of induction therapy, each patient will be evaluated for a transplant of their own hematopoietic stem cells. If, after the transplant, the patient still has detectable multiple myeloma, they will proceed to a series of consolidation blocks, up to three, consisting of four cycles of the KRdD at specified dosages and time frames. Patients who eliminate MRD (“deep remission”) will discontinue consolidation and be observed without any maintenance. For patients with still detectable MRD after completion of consolidation therapy, maintenance therapy will begin until disease progression or until a patient develops intolerance of their treatment. The anticipated start date, if all paperwork can be completed, is April 1, 2018.
This trial will utilize response adapted therapy, and each patient’s intensity and duration of therapy will be individualized to achieve the desired endpoint of MRD (-) status. There are several points along the treatment schema at which patients may discontinue treatment, the earliest occurring after receiving Melphalan for their auto-transplant if they are MRD (-). Auto-tx is still the best known inducer of MRD negativity. Clinical trials for upfront treatment of MM in young patients typically have fixed induction, transplant, and consolidation/maintenance schedules. Each person follows the same schedule, irrespective of response. While some patients require indefinite therapy, others may reach deep remissions that may allow for complete treatment discontinuation without recurrence. Those reaching deep remissions upfront may be able to safely discontinue therapy, sparing toxicity and cost. Patients want flexibility and a chance to stop continuous therapy but are afraid of relapse. Close follow-up of MASTER MRD- patients will help ease this fear. MASTER trial’s primary endpoint will be achievement of MRD < 10^-5.
MRD in Multiple Myeloma
Traditional response criteria based on protein detection and marrow morphology has not been adequate to recognize true disease eradication. However we finally have better tools to detect 1 cancerous plasma cell in 100,000 cells or even 1 in 1,000,000 cells. This remarkable elimination of myeloma cells, this MRD- state, is a strong predictor of long term outcomes. MRD – status needs validation as a treatment endpoint. To date no study has ever been performed validating MRD to determine subsequent therapy, and in myeloma we have been missing a reliable endpoint for response-adapted therapy. Sustained MRD eradication (< 10-5) may be just that!
As with any treatment or diagnostic advancement the devil is in the details. How is MRD defined? How can accuracy be assured? MRD data obtained and evaluated at 10-4 is very different than data defining MRD as 10-6. When it comes to curing myeloma, achievement of deep MRD negativity is an absolute must. Achieving CR without reaching MRD (-) is no better than a response of VGPR or PR. In MASTER trial MRD will be measured by next generation sequencing using ClonoSEQ, a registered proprietary test.
To summarize this important clinical trial, the goal will be achievement of well-defined MRD (-) state of <10-5 in two consecutive assessments, followed by discontinuation of therapy and careful monitoring for relapse. MRD clearance might occur anywhere in the continuum of treatment, after Melphalan, during or after consolidation, or during maintenance. Discontinuation of therapy will occur with confirmed MRD eradication, and active surveillance of MRD resurgence will continue for patients who discontinue therapy. If MASTER is successful it will demonstrate that MRD-based response adapted therapy is feasible. The future may bring randomized studies of “response-adapted” vs. standard therapy, as seen for example in Hodgkin Lymphoma. It will also help position Dara-KRd as a lead upfront regimen for a subsequent Phase III randomized trial. A limitation of MASTER is that MRD assessment based on marrow samples may miss extra-medullary or focal disease. PET will be done in MRD negative patients.