Shifting the Paradigm?: Where Is Chemotherapy-and Particularly, High-Dose Therapy-Going in the Era of Biologic Agents?

Andre Goy, MD

Editor-in-Chief of

Oncology & Biotech News

Chairman and Director Lymphoma Division Chief John Theurer Cancer Center at HackensackUMC Chief Science Officer and Director of Research and Innovation Regional Cancer Care Associates Professor of Medicine, Georgetown University

The changes seen in multiple myeloma are a perfect illustration of a potentially shifting paradigm in cancer care. For decades, the standard treatment of multiple myeloma was a combination of the chemotherapy agent melphalan and prednisone (MP), reported and established by Dr Alexanian (still practicing at MD Anderson) in JAMA in 1969!¹

The poor outcome of either primary resistant or relapsed patients led to high-dose therapy and autologous stem cell transplant (ASCT), which became the new standard in younger patients. Before high-dose therapy, patients were given a variety of induction regimens (chemotherapy/cytotoxics and steroids) to debulk the tumor burden, though patients typically had significant residual disease prior to consolidation and ASCT and they frequently relapsed.

Several novel therapies have truly changed the world of multiple myeloma in the last decade, particularly proteasome inhibitors, such as bortezomib and carfilzomib, which disrupt/block the intracellular protein degradation leading to cell death, and IMiDs with thalidomide— specifically, lenalidomide and pomalidomide—which act through direct cytotoxicity, antiangiogenic effects, and activation of antitumor immunity. Other promising therapies are also being developed.

These new agents have naturally opened the door to combinations of biologics, with very impressive activity leading to high-quality responses, including complete remission in the frontline setting prior to transplantation (something that was previously accomplished in only some patients after high-dose therapy followed by ASCT).

This progress raises the question as to whether autologous transplantation will be rendered obsolete in the era of new therapies. It seems natural to think that could be the case and that patients should only be transplanted at the time of relapse once they fail these nonchemotherapy-based options, which are easily preferred by patients for their safety profile and convenience in the ambulatory care setting.

Not surprisingly, an active debate is currently ongoing in the field. Data recently published will help shed some light on this critical question. In a large trial, more than 500 patients aged ≤65 years with newly diagnosed multiple myeloma received induction therapy with lenalidomide and dexamethasone and then were randomized to either high-dose therapy with ASCT (using two tandem high-dose of melphalan) versus six cycles of standard-dose melphalan/prednisone/lenalidomide (MPR; 6 months total).2 Patients were then randomly assigned to receive no maintenance therapy or lenalidomide maintenance therapy until disease progression.

The study showed that tandem courses of high-dose chemotherapy, as compared with consolidation therapy with MPR, resulted in improved progression-free survival (the primary endpoint) and overall survival (secondary endpoint). As in previous studies, maintenance with lenalidomide was associated with improved progression-free survival after either high-dose or standard-dose consolidation therapy (but no difference in overall survival) and importantly, did not compensate in the nontransplant arm for the superior outcomes associated with high-dose therapy. Though other studies are looking at the same question using bortezomib and lenalidomide in combination, this study suggests that in multiple myeloma patients aged ≤65 years, high-dose chemotherapy with stem cell transplantation remains a standard of care associated with prolongation of progression-free and overall survival.

Induction by combination of biologics provides a high-quality response with less toxicity prior to transplant and as maintenance, might even further reduce the risk of relapse. In patients who are not eligible for high-dose therapy, combinations of biologic agents might provide an alternative to standard chemotherapy because they allow continuous therapy typically including maintenance. Of note, high-risk multiple myeloma patients (defined by poor outcomes with standard regimens) still benefit from these novel therapy combinations as induction, but might also benefit from allogenic transplantation early on, due to the now well-documented graft-versus-myeloma effect, which leads to better outcome as suggested by our group as well as others.^3,4

In summary, new therapies bring new opportunities to add to our armamentarium in cancer—as shown here in multiple myeloma—and do not replace or eliminate all prior approaches. A similar observation could be made for other agents that are radically changing the field, including BCR-targeted agents such as ibrutinib in chronic lymphocytic leukemia and some lymphoma subtypes. The goal is to build the best line of therapy early on for the longest “mileage” for a given patient. This will also involve a better characterization of patients (ie, precision medicine for relevant stratification) and will matter even more in the era of bundled payment and value-based care. The paradigm is shifting for the better…

References

1. Alexanian R, Haut A, Khan AU, et al. Treatment for multiple myeloma. Combination chemotherapy with different melphalan dose regimens. JAMA. 1969;208(9):1680-1685.
2. Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371(10):895-905.
3. Donato ML, Siegel DS, Vesole DH, et al. The graft-versus-myeloma effect: chronic graft-versus-host disease but not acute graft-versus-host disease prolongs survival in patients with multiple myeloma receiving allogeneic transplantation. Biol Blood Marrow Transplant. 2014;20(8):1211-1216.
4. Alsina M, Becker PS, Zhong X, et al. Lenalidomide maintenance for high-risk multiple myeloma after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2014;20(8):1183-1189.