Allogeneic transplantation achieved graft-versus-myeloma effect

Allogeneic transplantation induced sustained remissions in patients with multiple myeloma, with the greatest survival benefit observed among those who underwent transplantation as consolidation therapy, according to study results.

Perspective from Saad Z. Usmani, MD

Patients who developed chronic graft-versus-host disease (GVHD) derived a survival benefit, whereas those who developed acute GVHD demonstrated poorer survival, results showed.

“There is indeed an immunotherapy effect of donor cells in multiple myeloma,” Michele L. Donato, MD, medical director of the blood and bone marrow collection facility at John Theurer Cancer Center, said in a press release. “Our study shows that if we transplant from a related or unrelated donor, the immune system of that donor has been shown to be able to control the disease in a great number of patients. We have proven there is a graft-versus-myeloma effect, and that has never been done before.”

Donato and colleagues evaluated data from 56 patients (median age, 52.4 years) who underwent an allogeneic transplant between 2004 and 2011.

All patients had previously undergone autologous transplantation. Twenty-six patients were undergoing transplantation as consolidation after responding to their first autograft, whereas 30 were receiving transplantation as salvage therapy.

Median follow-up was 52 months (range, 23.6-84).

Overall, 32 patients (57.1%) achieved a complete response. Twenty-one patients (37.5%) experienced progressive disease, 16 of whom received donor lymphocyte infusions or immune suppression withdrawal. Ten of these patients (62.5%) responded to these interventions.

In the entire cohort, 5-year OS was 59%. Researchers reported a markedly higher rate of 5-year OS among those who underwent allogeneic transplantation as consolidation therapy as opposed to salvage therapy (82% vs. 38%). Results of a multivariate analysis indicated receipt of transplantation as salvage treatment was significantly associated with shorter OS (HR=4.05; 95% CI, 1.25-13.11).

Grade II to grade IV acute GVHD occurred in 35.4% of patients, and 50% of patients developed chronic GVHD. Results of a multivariate analysis indicated acute GVHD was associated with shorter OS (HR=2.99; 95% CI, 1.09-8.2), whereas chronic GVHD was associated with longer OS (HR=0.26; 95% CI, 0.09-0.75). Researchers reported a higher 5-year OS among patients who developed chronic GVHD compared with those who did not (78.8% vs. 42.6%; HR=0.17; 95% CI, 0.47-0.63).

“While the vast majority of patients [with multiple myeloma] will ultimately succumb to the disease, it is a belief of mine that allogeneic transplantation has potential to change that reality,” researcher Andrew L. Pecora, MD, chief innovations officer and professor and vice president of cancer services at John Theurer Cancer Center, said in the press release. “What the study at our center revealed was that using today’s science, you can complete allogeneic transplants safely and effectively. Patients are living 5 years later without any disease detectable — potentially cured of it.”

Paul Richardson

The development of novel agents for multiple myeloma heightens the call for improved safety and efficacy of allogeneic transplantation, Paul Richardson, MD, clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute and HemOnc Today’s section editor for myeloma, wrote in an accompanying editorial.

“One of the major dilemmas facing clinicians in exploring the allogeneic approach is the remarkable success observed with not only first-generation novel agents in the management of this heterogeneous and profoundly changing disease, but also the impact of second- and third-generation proteasome inhibitors and immunomodulators, respectively, as well as monoclonal antibodies in particular, and now other small molecules, such as deacetylase inhibitors,” Richardson wrote. “The advent of novel and highly promising immunotherapeutic strategies … may allow for additional leverage of the allogeneic platform. Therefore, strategies aimed at reducing GVHD and improving the tolerability of this approach need to remain paramount, with the integration of additional novel treatment strategies to further improve patient outcome all the more vital.”

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Disclosure: Richardson reports research funding from and advisory roles with Celgene, Janssen and Millennium. The study researchers report no relevant financial disclosures.

Perspective

Saad Z. Usmani, MD

Multiple myeloma has morphed in to a chronic illness for majority of patients over the last decade. Multiple myeloma can be managed by either the sequential use or combination use of novel agents. Both approaches have practical, scientific and competing merits. Despite the plethora of emerging agents and drug classes, multiple myeloma appears to be quite a diverse group of diseases — perhaps as diverse as non-Hodgkin’s lymphoma. Allogeneic hematopoietic stem cell transplantation (HSCT) has been explored anecdotally for young or phenotypically aggressive multiple myelomas, with variable evidence toward graft-versus-multiple myeloma. Retrospective analyses from two entities — the Center for International Blood and Marrow Transplant Research and the European Society for Blood and Marrow Transplantation — compared autologous HSCT with allogeneic HSCT and demonstrated a higher sustained remission and a higher non-relapse mortality with the latter. Three randomized trials (Italian MM, EBMT-NMAM2000 and BMT-CTN-0102) compared tandem autologous HSCT with autologous HSCT followed by matched-sibling non-myeloablative allogeneic HSCT. Two trials favored the latter approach but, again, with higher non-relapse mortality.
With the emergence of novel agents, the timing and role of ASCT in multiple myeloma had become debatable until recent emerging data favoring upfront utility (Palumbo A. N Eng J Med. 2014;371:895-905.). But as we try to move toward less toxic therapies, data from Donato and colleagues highlight the utility of more intensive approaches for a subset of patients with multiple myeloma. Donato and colleagues report on 56 consecutive patients who either received a consolidation allogeneic HSCT after an upfront autologous HSCT (n=26), or as salvage at time of relapse (n=30). The important take-away messages from this study include utility of this approach for younger patients with multiple myeloma, acceptable non-relapse, the association of chronic graft-versus-host disease with sustained remissions, and utility of donor lymphocyte infusions to recapture response (evidence of graft-versus-multiple myeloma). Although we expect the novel agents and therapy approaches to further the quality of life of all patients with multiple myeloma, the goals of care may be different for a patient diagnosed at age 35 years compared with one diagnosed at age 65 years.

Saad Z. Usmani, MD

HemOnc Today Editorial Board member

Levine Cancer Institute, Carolinas HealthCare System

Disclosures: Usmani reports no relevant financial disclosures.