Combining an Allogeneic Graft-Vs-Myeloma Effect with High-Dose Autologous Stem Cell Rescue in the Treatment of Multiple Myeloma

Reviewer: Mary Kara Bucci, MD
University of Pennsylvania Cancer Center
Last Modified: December 9, 2001

Presenter: David G. Maloney
Presenter's Affiliation: Fred Hutchinson Cancer Research Center, Seatle, WA
Type of Session: Plenary

Background
Myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) for Multiple Myeloma has been associated with high transplant-related mortality (TRM), limiting its clinical usefulness despite its potential for cure. Autologous HSC rescue has a lower rated of TRM but does not have the curative potention of the graft-vs-tumor effect of the allograft. In order to combine the curative potential of allogeneic HSCT with the safety of autologous HSC rescue, this study followed a myeloablative autolgous HSCT with immunosuppression and an allogeneic HSC rescue, separating the high-dose conditioning regimen from the graft-vs-tumor inducing allograft by 40-120 days.

Materials and Methods
42 patients with relapsed or refractory Stage II/III myeloma received 200mg/m2 of melphalan and autologous SCR, followed 40-120 days later with a single fraction of 200 cGy total body irradiation, immunosuppression with mycophenylate mofetil x 28 days and cyclosporine at least 56 days and unmodified allogeneic stem cell transplant with peripheral blood stem cells from an HLA-identical sibling. The initial 4 patients received allografts of CD 34+ cells only; after the death of 1 patient from cytomegalovirus pneumonia, allografts were modified to CD34+ cells(8.6 x 10⁶) and CD3+ cells (4.2 x 10⁸).

Results

Autologous HSCT-related toxicities included a median of 6 days of absolute neutrophil count (ANC)< 500, ANC nadir of <50, and a platelet nadir <20K.

Following allograft, all patients engrafted with a median of 90% and 99% donor T-cell chimerism by day 28 and day 84 post-allograft, respectively.

19 patients (48%) developed acute graft-versus-host disease (GVHD) including 2 cases of Grade IV GVHD.

18 patients (45%) developed chronic GVHD.

With a median follow-up of 13 months, overall survival is 85%, progression-free survival is 83%, and 1-year TRM is 12%.

There have been 6 treatment-related deaths, one from cytomegalovirus pneumonia at day 31 post-autologous HSCT, 1 from progressive disease at day 91, 2 from acute GVHD, 1 from encephalopathy, and one from infection and chronic GVHD.

Author's Conclusions

The combined approach of myeloablative autologous SCT followed by allogeneic SCT resulted in potent anti-tumor activity and decreased treatment-related mortality despite having a relatively high median patient age (55, range 39-71).

The results of this pilot study demonstrate the need for a prospective randomized trial directly comparing this approach with conventional treatment for multiple myeloma.

Clinical/Scientific Implications
This novel combined approach to stem cell transplant may offer a safer, potentially curative treatment option for multiple myeloma patients. Older patients, who traditionally have not been offered allogeneic transplant for multiple myeloma due to their increased risk of treatment-related morbidity and mortality may be suitable candidates for this regimen.

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