Discoveries and Contributions of Total Therapy Trials
Since initiating the first Total Therapy trial in 1989, doctors and researchers at the Myeloma Institute for Research and Therapy have made significant discoveries and observations that have led to life-saving practices and therapies. Notable examples include the following:
- Showed that tandem transplants are a safe way to reduce myeloma tumors. In Total Therapy 1, complete response* was achieved by 40% of patients; 25% survived at least 20 years, and 15% reached 20-year event-free survival.**
- Discovered and established, with Total Therapy 2, that rates of complete response, event-free survival, and overall survival significantly improved when thalidomide was incorporated from the very beginning of treatment for patients with advanced or refractory myeloma.
- Distilled prognostic variables that indicate short- and long-term outcomes. These variables include cytogenetic abnormalities, high levels of lactate dehydrogenase enzyme, molecularly defined risk (determined by gene expression profiling), deletion of the TP53 gene, and proliferation index.
- Recognized that, while complete response is an important first objective for treatment, patients who achieve only partial response*** can also reach long-term event-free survival. In these cases, the partial (rather than complete) response reflects a remaining condition—monoclonal gammopathy of undetermined significance (MGUS)—that can remain stable for long periods of time.
- Discovered that achieving and sustaining complete response is critically important for achieving positive outcomes for patients with high-risk myeloma.
- Introduced bortezomib and immunomodulatory drugs (functionally similar to thalidomide) in Total Therapy 3, with unprecedented success in the 85% of patients with low-risk disease, 90% of whom sustained complete response for at least 5 years.
- Documented, through mathematical modeling, significant cure fractions in Total Therapy 1 and extended cure fractions in Total Therapy 2 and Total Therapy 3.
- Initiated personalized therapy for myeloma by assigning patients to separate protocols designed for molecularly defined low-risk (Total Therapy 4) or high-risk (Total Therapy 5) disease.
- Discovered that MRI and PET-CT imaging delineate the full extent of both bone marrow and extramedullary myeloma, leading to the novel objective of improving clinical success by achieving resolution of focal lesions that persist long after documented clinical complete response.
*Complete response: No abnormal monoclonal proteins (M-proteins) in the blood serum or urine, disappearance of any soft-tissue plasmacytomas (malignant plasma-cell tumors), less than 5% plasma cells in bone marrow.
**Event-free survival: Survival without experiencing any myeloma-related event.
***Partial response: At least 50% reduction in the size of soft-tissue plasmacytomas, at least 50% reduction of serum M-proteins and less than 200 mg of urine M-proteins in a 24-hour period. For situations in which M-proteins are immeasurable, additional requirements involve reductions in free light chain levels and bone marrow plasma cells.