1. Nalley, Catlin

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NEW YORK CITY-Early autologous stem cell transplantation (SCT) plus high-dose chemotherapy has been considered the standard of care for multiple myeloma for the past 20 years; however, with a growing number of innovative therapies for newly diagnosed patients, does this standard hold true?

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An expert panel debated this question during the Chemotherapy Foundation Symposium, held Nov. 8-10.


Standard Treatment

Autologous stem cell transplantation is performed either at the time of initial diagnosis or at relapse and is often the treatment of choice for younger patients (less than 70 years of age) with recently diagnosed multiple myeloma (Blood 2009;114:1729).


While neither transplantation nor chemotherapy offers patients a cure, research has shown that event-free and overall survival are prolonged following transplantation compared with treatment with conventional chemotherapy alone.


However, with the advent of new chemotherapeutic agents, patients have seen an improvement in survival when receiving chemotherapy alone. Whether the use of these newer agents, alone or in combination, will delay or eliminate the need for transplantation in multiple myeloma patients is under investigation.


Current Research

In the U.S., RVD (lenalidomide, bortezomib, and dexamethasone) is the most commonly utilized induction regimen for the treatment of multiple myeloma. Given the efficacy of this treatment option, researchers have started to question the role and timing of high-dose chemotherapy with autologous stem cell transplantation.


A recent study demonstrated that RVD when used in combination with SCT, followed by two cycles of RVD and lenalidomide maintenance for 1 year, led to superior response rates and progression-free survival compared to an approach that excluded SCT (N Engl J Med 2017; doi:10.1056/NEJMoa1611750). However, overall survival at 4 years was comparable between the two treatment arms.


Study authors concluded that the progression-free survival benefits, "must be weighed against the increased risk of toxic effects associated with high-dose chemotherapy plus transplantation, especially since we found that later transplantation might be as effective as early transplantation in securing long-term survival.


"Our results suggest that the use of a combination therapy that incorporates newer proteasome inhibitors, next-generation immunomodulatory drugs, and potent monoclonal antibodies along with transplantation tailored according to minimal residual disease (MRD) detection could further improve outcomes among adults up to 65 years of age who have multiple myeloma."


Ongoing Debate

So where does the oncology community stand when it comes to utilizing SCT in multiple myeloma? There was a consensus among the panel at the Chemotherapy Foundation Symposium: transplantation still has a role in treatment, but the discussion is ongoing as new agents become available.


"Up until now, early autologous transplant has been the standard of care for patients with newly diagnosed multiple myeloma who are eligible and fit for transplant. With so many new, effective novel therapies for multiple myeloma, physicians may question whether a delayed transplant would have the same overall survival outcome as the traditional early transplant," Pamela Crilley, DO, Chair, Department of Medical Oncology, Cancer Treatment Centers of America, told Oncology Times. "This study, to date, shows that early transplant showed a higher rate of complete remission with more patients achieving lower minimal residual disease status and longer median time to progression, although as yet, no improvement in overall survival."


During the discussion, Crilley emphasized the improvements in transplantation, "The old thought that SCT is difficult and full of toxicities is not so much the case anymore." With an improvement in antibiotics and the use of outpatient transplantation, "the fear of toxicities for these patients has been taken away, so I would still come down on the side of consideration for transplants in patients with multiple myeloma."


"In the frontline, induction plus transplant remains the standard of care," noted Ruben Niesvizky, MD, Professor of Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York. "However, I have the reputation of not being in favor of transplants. I would vote that the patient who is MRD-negative before the transplant may be able to defer the transplant since there is no significant improvement in [overall survival]."


He emphasized that this is an ongoing discussion in his practice and he always discusses the current options and their relationship to progression-free survival and overall survival with his patients so they can make the right decision for themselves.


"The data pretty clearly shows the [progression-free survival] benefit in the majority of patients," reiterated Hearn Jay Cho, MD, PhD, Associate Professor of Medicine, Hematology and Medical Oncology, The Mount Sinai Hospital, New York City. "However, there is need in high-risk patients and I think focusing on further research on how we can improve outcomes in transplantation, particularly in consolidation, is a very critical area of need."


Edward A. Stadtmauer, MD, Section Chief of Hematologic Malignancies, Division of Hematology & Oncology, Perelman Center for Advanced Medicine, Philadelphia, expressed his agreement with the fellow panelists, noting that every time a new therapy is developed this question regarding the role and timing of transplant is discussed, but based on current data, he believes it is "here to stay."


There is also the question of the lack of overall survival benefit in the study. Some argue that these results may differ if lenalidomide maintenance in both treatment arms is continued until progression. The U.S. arm of the study has included this in its design.


Commenting on this question, Cho noted, "We do not know yet since the U.S. results are not available." In regards to the recently published study in the New England Journal of Medicine, Cho said, "Four years is a very early landmark in the modern era of myeloma therapy. So, we don't know whether the transplantation upfront or at relapse is going to change the course of the patient's history down the road, because if we have patients living 8-10 years we won't know for a long time if that is actually going to make a difference. But the preponderance of data suggests that at least in terms of progression-free survival there is a well-defined benefit."


And the oncologists attending the event agreed with an overwhelming majority of 96 percent saying that stem cell transplantation is still relevant in the treatment of multiple myeloma.


Catlin Nalley is associate editor.