The prognosis for patients diagnosed with multiple myeloma has dramatically improved over the past fifteen years due to the availability of more effective therapies. The proteasome inhibitors (bortezomib, carfilzomib, ixazomib) and immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide) are the cornerstones of myeloma therapy, while the histone deacetylase inhibitor panobinostat, as well as the monoclonal antibodies elotuzumab and daratumumab, are important recent additions to the therapeutic armamentarium for this disease.
As is true with many other malignancies, myeloma is most often treated with regimens incorporating multiple agents from different drug classes that possess synergistic pharmacologic mechanisms. A team from the Jerome Lipper Multiple Myeloma Program led by Paul Richardson, MD, and Ken Anderson, MD, pioneered a regimen incorporating both lenalidomide (Revlimid) and bortezomib (Velcade) plus dexamethasone (RVD) over 10 years ago (Richardson et al. JCO 2009, Richardson et al. Blood 2010). Results from early trials were very promising, and over time the regimen has been accepted as a standard of care. Development of the RVD regimen culminated in a randomized phase 3 clinical trial comparing the 3-drug combination of RVD to Rd in newly diagnosed myeloma (Durie BG et al. Lancet 2017). The recently published results of this study demonstrated superiority of RVD to Rd with respect to overall response rate and quality of response, and most importantly, both median progression free and overall survival.
Members of the Dana-Farber Multiple Myeloma program have also led the development of the monoclonal antibodies elotuzumab and daratumumab. With favorable safety profiles and unique anti-tumor mechanisms, these agents have proven to be effective therapeutic partners with immunomodulatory drugs and proteasome inhibitors. Indeed, elotuzumab is approved by the Food and Drug Administration for use with lenalidomide and dexamethasone, while daratumumab is approved as a single agent and in combination with lenalidomide and dexamethasone; pomalidomide and dexamethasone; and bortezomib and dexamethasone.
In collaboration with other sites within the ALLIANCE Cooperative Group, we are now conducting a clinical trial evaluating the effectiveness and safety of daratumumab in combination with RVD in transplant-eligible patients with newly diagnosed myeloma (NCT02874742). Patients are randomized to receive induction therapy with either standard RVD or daratumumab plus RVD. All patients receive four cycles of induction followed by high-dose therapy and autologous transplant, two cycles of post-transplant consolidation with RVD, and lenalidomide maintenance. Patients in the daratumumab group also receive daratumumab as part of consolidation and maintenance therapy. The primary objective of the study is to determine the rate of stringent complete response following completion of post-transplant consolidation. Response to therapy will also be characterized through minimal residual disease assessments using the highly sensitive technique of next-generation DNA sequencing.
This important trial will allow further refinement of treatment for patients with newly diagnosed multiple myeloma, building on the encouraging advances of recent years to improve clinical outcomes for our patients still further.
For more information about this trial, call 617-632-4218 or email jacobp_laubach@dfci.harvard.edu.