Transplant in Myeloma Ups Survival, but Is Underutilized

Alexander M. Castellino, PhD

June 14, 2018

Another study has confirmed that autologous hematopoietic stem cell transplant (aHSCT) improves survival in patients with multiple myeloma (MM).

A retrospective analysis of California databases showed that overall survival (OS) for patients with MM who received a transplant was 73 months, significantly longer than the 48 months for those who did not.

The study, from researchers at the University of California, Davis, was published online June 11 in the Journal of the National Cancer Institute.

"There's still a debate within the oncology community whether stem cell transplant should always be used, should always be avoided, or how we should choose patients," commented lead author Aaron Rosenberg, MD, assistant professor in the Division of Hematology and Oncology. He noted that the debate has intensified in recent years with the advent of several new drugs.

"We showed there's a significant improvement in survival in those patients who get a stem cell transplant compared to those who don't," he said in a statement. "Transplants decreased the risk of dying by almost 20%."

However, the team also found that only 20% of MM patients overall received aHSCT and that utilization was substantially lower among patients aged 60 years or older, at 11.5%, vs 37.6% for younger patients.

"As the median age of diagnosis of MM is 69 years, this study suggests that the utilization rate of ASCT for most patients in California is remarkably low," commented John P. Chute, MD, from the Division of Hematology/Oncology at the University of California, Los Angeles, in an accompanying editorial.

"This low rate of utilization of ASCT over the past two decades is surprising," he commented, considering that a randomized European trial in 1996 and a comparative US trial in 1997 demonstrated superior overall survival in MM patients treated with ASCT compared to those treated with standard therapy. Subsequently, two prospective, randomized studies showed that ASCT increases overall survival in MM patients (Lancet Oncol. 2015;16:1617-1629; New Engl J Med. 2014;37110:895-905).

In addition, the recently completed Intergroupe Francophone du Myelome (IFM) 2009 study demonstrated a statistically significant increase in progression-free survival in MM patients who underwent ASCT compared to patients who underwent more modern standard therapy (N Engl J Med. 2017;37614:1311-1320).

Study Details

For their study, Rosenberg and colleagues analyzed data from the California Cancer Registry, the California Patient Discharge Database, and the Ambulatory Surgery Database for the period 1998-2012. They found that nearly 13,494 patients were newly diagnosed with MM, of whom 20.8% underwent aHSCT.

The patients who underwent aHSCT were younger (median age at diagnosis was 56 years compared with 67 years for the non-ASCT group), had fewer comorbidities, and were less likely to be hospitalized 2 years prior to diagnosis.

Of patients who received aHSCT, 2% were aged 70 to 79 years at the time of diagnosis, 21% were aged 60 to 69 years, and 38% were younger than 60 years.

The median time from diagnosis to aHSCT was 9.4 months; 66% of patients received aHSCT within 12 months of diagnosis (n = 1843), and 89% received aHSCT within 2 years (n = 2486).

The median time from diagnosis to aHSCT was not substantially different over the years: 9.2, 10, and 8.9 months for those diagnosed in the periods 1998-2002, 2003-2007, and 2008-2012, respectively.

With a hazard ratio (HR) of 0.83 (95% confidence interval [CI], 0.75 - 0.92), aHSCT was associated with a significant reduction in risk for death. The association between aHSCT and OS was similar over time and across all age groups.

"If the newer agents were making the transplants less relevant, you would expect to see a decrease in efficacy across various areas of treatment, and we didn't see that at all," said Rosenberg. "Stem cell transplants are at least as effective as they were in the early 2000s."

Chute concurs, and points out that the period covered by this study (1998-2012) "represents an important era, noteworthy for the development and implementation of several new classes of efficacious myeloma therapies, including immunomodulatory agents (eg, lenalidomide) and proteasome inhibitors (eg, bortezomib)." He adds that the launch of these new agents "called into question the role of autologous stem cell transplantation as consolidation for myeloma patients following induction therapy."

Possible Explanation for Low Utilization of aHSCT

Chute also notes that the proportion of MM patients who underwent transplant in this study was similar to that reported for other studies, including the Center for International Blood and Marrow Transplant Research review (CIBMTR), in which 13% of patients underwent aHSCT.

However, Rosenberg and colleagues note that late transplants (12 months or longer after diagnosis) may not provide as much benefit as early transplants (<12 months after diagnosis). Late aHSCT was associated with a 33% increased risk for death (HR, 1.33; 95% CI, 1.16 - 1.51).

The researchers further investigated the timing of the transplants and found that non-Hispanic whites were more likely to receive early transplants and that African Americans were more likely to receive late transplants.

However, in his editorial, Chute notes that the retrospective nature of this analysis does not take into account variables that likely contribute to this difference. Limitations include a lack of critical information on disease stage, cytogenetics, minimal residual disease status, treatment regimens, and responses — all variables that affect outcomes.

Another study (IFM 2009) suggests that in the era of modern chemotherapy agents, late transplants may provide comparable survival benefits as early transplants, Chute notes.

Why Is There Underutilization?

So why is it that more patients with newly diagnosed MM do not receive aHSCT?

Chute points out that the failure of induction therapy, which is used prior to patients receiving a transplant, is not a likely explanation. "[Given] that combination therapies...produce high response rates in 77% to 88% of patients, this would appear to account for a small fraction of patients," he writes.

Chute notes that the CIBMTR review also showed that utilization of transplant differed among groups, with lowest utilization for African Americans. Other variables that are likely to affect use of aHSCT include noncompliance, socioeconomic barriers, and physician/patient concerns over toxicities associated with transplant, he suggests.

A previously published report notes that younger patients and those with fewer comorbidities and private insurance (compared with those with governmental insurance or those who have no insurance) were more likely to undergo aHSCT. Noting that aHSCT is utilized infrequently, Rosenberg and colleagues indicate that future studies focusing on access and barriers to aHSCT are warranted.

"[This study] is ongoing evidence the procedure is important and useful in an era when newer treatments are available. Patients still need to be considered for stem cell transplant," said Rosenberg. "It's not for everyone, but that decision needs to be made with a keen eye towards the benefits and risks."

"This study reinforces the powerful role for high-dose therapy and ASCT in the practical management of patients with MM," concurs editorialist Chute.

The study was supported by the California Department of Public Health, the Centers for Disease Control and Prevention's National Program of Cancer Registries, the National Cancer Institute's Surveillance, Epidemiology and End Results Program, and the Public Health Institute. Dr Rosenberg is on the speakers bureau for Amgen. The other study authors and Dr Chute have disclosed no relevant financial relationships.

J Natl Cancer Inst. Published online June 11, 2018. Abstract, Editorial

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