Multiple myeloma (MM) is caused by plasma cells that have become cancerous and subsequently overtake bone marrow. Allogeneic hematopoietic cell transplantation (allo-HCT), in which blood-forming stem cells and immune cells from a healthy donor are transferred into a recipient, can be curative for MM due to an immunologic graft-vs-myeloma (GVM) effect. Prior to reciving an allo-HCT, patients may be given very high doses of chemotherapy and sometimes radiation to completely destroy their own bone marrow and kill any remaining myeloma cells in a myeloablative allo-HCT. However, early studies using myeloablative allo-HCT resulted in high non-relapse mortality (NRM) in MM patients. In more recent studies, patients were treated with myeloablative doses of chemotherapy (melphalan) and then received their own blood-forming stem cells, which were collected before the high-dose chemotherapy. This is known as autologous HCT (auto-HCT). Auto-HCT allows patients to have longer remissions by killing off more myeloma cells than standard chemotherapy would allow, but unlike allo-HCT is not curative as it lacks the GVM effect.
In a recent study published in the journal Haematologica, Drs. Enrico Maffini and Rainer Storb of the Clinical Research Division at Fred Hutch compared the outcomes of MM patients from various treatment centers treated with tandem autologous-allogeneic HCT. Patients in this study were treated with high doses of melphalan followed by auto-HCT. Following auto-HCT recovery, a median of 75 days, patients received reduced doses of total body irradiation with or without additional conditioning chemotherapy in the form of fludarabine, and allo-HCT.
To assess the effect of treatment, the researchers looked at the time from allo-HCT until death, defined as overall survival (OS). They also looked at the time from allo-HCT until death or progression of disease, known as progression-free survival (PFS). Using these criteria, they identified a modest median PFS time of 1.9 years among all patients. Further evaluation showed that the treatment regimen was successful at treating a large group of patients when grouped according to risk: standard, high, or ultra-high. Standard- and high-risk patients benefited from autologous-allogeneic HCT, with a median PFS of 6.5 and 2.5 years, respectively. Ultra-high-risk patients, however, only had a median PFS of 0.7 years. Many of the patients survived long-term, with an OS of 75 percent and 42 percent at ten years in the standard-risk and high-risk groups respectively.
Maffini and Storb noticed that those patients who were unable to attain a complete remission before auto-HCT had significantly higher relapse risks after allo-HCT. Moreover, the researchers found that among the remaining patients, there was a group that showed signs of minimal residual disease (MRD).These patients showed no symptoms of disease, yet cancerous cells were detectable in bone marrow samples when analyzed by flow cytometry. They found that MRD positive patients faced a higher disease relapse rate than those patients with no detectable MRD.
Image provided by Dr. Enrico Maffini
Maffini explained these findings, "The GVM effect after non-myeloablative allo-HCT allowed long-term disease control in standard and high-risk patient subgroups. On the other hand, tandem autologous-allogeneic HCT was not able to overcome refractory and high-tumor burden disease states. It is pretty clear that for this patient population, there is an urgent need for alternative strategies.”
Maffini elaborated on what clinicians might change based on the conclusions of the study: “The depth of disease response to induction treatments is capital in order to achieve a long-standing clinical remission after tandem auto-allogeneic transplantation and that minimal residual disease positivity before allo-HCT was predictive of disease relapse, even among patients reaching complete remission by classical definition. Newer tools such as next generation flow cytometry and sequencing could be powerful methods to help clinicians in order to best select patients with incomplete responses prior to transplant and to candidate them to induction intensifications, with one or more new drugs available.”
Commenting further on how allo-HCT might be augmented with other treatments Maffini said, “We think that allo-HCT may serve as a solid immunological platform for post-transplant therapeutic strategies, employing different agents such as novel immunomodulatory drugs or proteasome inhibitors, NK cells infusions, bi-specific T cell engagers or even CAR-T cells in patients with very high-risk features.”
In summary, this retrospective study demonstrated the benefits of tandem autologous-allogeneic HCT in MM patients and the need for supplementing the treatment with new chemotherapeutics and other treatments for patients with refractory disease.
Funding for this study was provided by the National Cancer Institute.
Fred Hutch/UW Cancer Consortium faculty members Pamela Becker, Thomas Chauncey, Damian Green, Leona Holmberg, David Maloney, Marco Mielcarek, Brenda Sandmaier, Rainer Storb, and Barry Storer contributed to this work.
Maffini E, Storer BE, Sandmaier BM, Bruno B, Sahebi F, Shizuru JA, Chauncey TR, Hari P, Lange T, Pulsipher MA, McSweeney PA, Holmberg L, Becker PS, Green DJ, Mielcarek M, Maloney DG, Storb R. 2018. Long term follow-up of tandem autologous-allogeneic hematopoietic cell transplantation for multiple myeloma. Haematologica. doi: 10.3324/haematol.2018.200253. [Epub ahead of print].