Allogeneic Hematopoietic Stem Cell Transplantation for Multiple Myeloma

Over the past 2 decades there has been significant progress in the treatment of patients with multiple myeloma resulting in a current median survival of 3-4 years. New drugs such as Thalomid® (thalidomide), Revlimid® (linalidomide) and Velcade® (bortezomib) have shown significant activity in multiple myeloma. These new drugs, when combined with more traditional drugs, result in improved initial response rates and more effective salvage therapies.[1]

Autologus stem cell transplantation (Auto-SCT) has become the standard of care for patients 65 years of age or younger. Recent studies have also suggested that selected patients older than 65 years tolerate and benefit from Auto-SCT to the same degree as younger patients.[2] Despite these advances, therapy for multiple myeloma is still palliative and virtually all patients will ultimately relapse and die of progressive disease. This has led to studies of allogeneic stem cell transplantation (Allo-SCT) where long-term disease-free survival and possibly cure is observed in a small but significant fraction of patients.

Allo-SCT may be curative for 10-20% of patients with refractory multiple myeloma and a larger proportion of patients who are transplanted early in their disease course. The curative effects of Allo-SCT are attributed the intensive treatment regimen and to a “graft-versus-myeloma” (GVM) effect that is related to the occurrence of acute and chronic graft-versus-host disease (GVHD).[3] In contrast, SCT from autologous or syngeneic donors provide little or no GVM effect. Autologous or syngeneic SCT requires the intensive application of chemotherapy with or without radiation to accomplish eradication of disease or alternate strategies designed to duplicate or mimic the GVM effect.

Recent results suggest that Allo-SCT following myeloablative regimens for multiple myeloma may be improving. Recently, a U.S. Inter-Group Trial of early vs. late Auto-SCT was published suggesting Auto-SCT produced survival outcomes similar to standard chemotherapy when Auto-SCT was given as salvage treatment.[4] That trial, which was started in 1993, had another arm that allowed patients with HLA matched siblings to undergo Allo-SCT using an ablative cyclophosphamide (Cytoxan®) and Total body irradiation (TBI) regimen. That arm of the study was closed after 36 patients were treated, due to an excessively high treatment-related mortality (TRM) of 53%. The 7-year overall survival (OS) was identical at 39% for both Auto-SCT and Allo-SCT recipients, while the progression-free survival (PFS) was 15% for Auto-SCT recipients at 7 years compared to 22% for Allo-SCT recipients. In addition, while there is no plateau in the group that received Auto-SCT, the OS curve for the Allo-SCT group is flat with follow-up extending to 10 years suggesting the possibility of cure.

The European Bone Marrow Transplant (EBMT) Registry has reported the largest series of patients receiving Allo-SCT for multiple myeloma (n=690) following myeloablative treatment regimens.[5] The EBMT registry analysis examined transplants performed on 334 patients from 1983-93 and 356 patients from 1994-98. Of the patients transplanted during the latter period, 133 (37%) received peripheral blood stem cells (PBSC) rather than marrow. The most important observation was a marked reduction in TRM from 46% to 30% between the two time periods. The reduction in TRM was a result of fewer deaths from opportunistic infections and interstitial pneumonias. This was due, in part, to better patient selection, less prior treatment and improvements in supportive care. The OS after 3 years improved from 35% during the 1983-93 period to 56% during the 1994-98 period.

A phase II study utilizing high-dose Myleran® (busulfan) and Alkeran® (melphalan) followed by allogeneic PBSC from matched sibling donors in 30 patients with multiple myeloma, has reported a reduction in TRM.[6] The TRM was 16% at 100 days, 30% overall, with an 81% complete remission (CR) rate. Overall survival and PFS at 6 years were 65% and 70%, respectively. These studies show that improvements in patient selection and supportive care have lowered TRM of myeloablative Allo-SCT for multiple myeloma.

Although these studies show improvement in outcomes of younger patients with multiple myeloma receiving Allo-SCT there is much room for improvement. Since the majority of patients who develop multiple myeloma are greater than age 55 years and need closely HLA-matched family member or unrelated individuals to serve as stem cell donors, only a small fraction of patients are eligible for Allo- SCT. Many patients will also be considered for Allo-SCT only after failing one or two Auto-SCT. Such patients, however, are poor candidates for myeloablative Allo-SCT due to TRM that exceeds 50%.

Reduced-intensity (RIC) Allo-SCT have been proposed as a method of retaining the GVM effect of Allo-SCT while decreasing TRM. This approach should lower TRM and allow for the treatment of older patients which would be meaningful in myeloma since this is predominantly a disease of older individuals. The primary basis for adoption of RIC allo-SCT is the hypothesis that the GVM effects in multiple myeloma are potent enough to eradicate residual disease. However, most of the data suggests the GVM effects are much less potent than is observed in other hematologic diseases, such as chronic myeloid leukemia.

Reduced intensity conditioning regimens are designed more for immunosuppression than cytoreduction, with the aim of establishing consistent donor engraftment while minimizing toxicity and damage to normal host tissues. Furthermore, reduced RIC immunosuppression should minimize or eliminate the period of severe pancytopenia that always occurs after the administration of high-intensity conditioning regimens. This technique could allow donor hematopoietic and lymphoid engraftment facilitating a GVM effect while having a low TRM.

A recent review of the literature suggests that there have now been over 300 patients reported who have received Allo-SCT after RIC regimens for multiple myeloma (Personal Observations, WI Bensinger). The types of RIC regimens used vary widely and include: Alkeran 100-140 mg/m2 often with added Fludara® (fludarabine), TBI 200 cGy, with Fludara, or sometimes with added Cytoxan or low dose Myleran. Anti-thymocyte globulin (ATG) or the anti-CD52 antibody, Campath®, have been included in some regimens in order to facilitate engraftment and reduce GVHD. GVHD prophylaxis regimens have included cyclosporine or Prograf® (tacrolimus) and Myfortic® (mycophenolic acid), or methotrexate. There is currently no consensus of which of these regimens is superior in terms of toxicity or efficacy. Neupogen® (granulocyte-Colony stimulating factor) mobilized PBSC have been used for the majority of studies due to fewer graft failure/rejections and putatively better GVM effects when compared to bone marrow. Unrelated donors were utilized in more than a third of all RIC Allo-SCT. Approximately a third of these patients had the RIC Allo-SCT performed as part of a tandem strategy following a high-dose chemotherapy and Auto-SCT.

These published studies reported an incidence of acute GVHD that has ranged from 25-58% while chronic GVHD has been reported in 7-70%. Overall TRM has ranged from a low of 0% to a high of 41%. Survival has ranged from 50-100% at 1 year, 26-74% at 2 years, 36-70% at 3 years and as high as 69% at 4 years. Complete response rates have ranged from a low of 10% as high as 73%. Thus, there are a variety of approaches to the development of RIC Allo-SCT regimens with a wide range of results.

The most widely used RIC regimen was developed in Seattle based on canine transplant studies where it was shown that reliable allogeneic donor PBSC engraftment could be achieved with a very low doses of TBI of 200 cGy and a combination of two potent immunosuppressive drugs, Myfortic® and Neoral® (cyclosporine).[7] This strategy was applied to 18 patients undergoing Allo-SCT for multiple myeloma. Seven patients had refractory disease and 6 had failed a prior autograft. Two of the first 4 patients rejected the donor graft leading to the addition of Fludara, which provided additional immunosuppression.[8] There were no further occurrences of rejection following the addition of Fludara to the regimen. Although only 1 of 18 died of TRM, CRs occurred in only 2 patients and only 3 others achieved partial responses (PR). None of the responses were durable. These results suggested that in multiple myeloma, additional cytoreduction would be needed to improve the responses after an RIC allograft or alternatively patients could receive donor leukocyte infusions (DLI).

A second strategy of performing an Auto-SCT followed by a RIC Allo-SCT was evaluated in patients with multiple myeloma who had not received a prior high dose regimen.[9] Patients first had autologous PBSC collected, followed by Alkeran 200 mg/m2 and re-infusion of PBSC to provide cytoreduction and some immunosuppression. Two to 4 months’ later, after recovery from the first Auto-SCT patients’ received a RIC regimen of 200 cGy TBI, Myfortic® and Neoral® with allogeneic PBSC. Fifty-four patients, ages 29-71 years, median age 52 years, received this tandem auto-allo SCT strategy. All patients were stage II or III and 48% had refractory or relapsed disease. One patient died of CMV pneumonia after the initial Auto-SCT, 1 patient progressed after the Auto-SCT and 52 received the RIC Allo-SCT. All 52 achieved full donor chimerism with only one patient requiring DLI on day 84 for partial chimerism. The overall TRM was 22% and the CR rate was 57%. Only 4 patients developed severe acute GVHD and chronic GVHD developed in 60%. With a follow-up of 48 months after RIC Allo-SCT, OS was 69%, and the PFS was 45%.

One study utilized Alkeran 100 mg/m2 to prepare 45 patients prior to RIC Allo-SCT. These patients had either failed 2 or 3 prior Auto-SCT, or received RIC Allo-SCT as part of a tandem autologous-allogeneic transplant strategy.[10] Patients in this study had a median age of 56 years and donors were all HLA matched; 12 were unrelated volunteer donors. TBI and Fludara were added to the regimens of patients receiving transplants from unrelated donors. The day 100 TRM was 15%, overall TRM 38% and 64% achieved CR or near CR. Overall survival at 3 years was 36%. However, there was a significantly better survival for patients transplanted as part of the planned tandem strategy vs. after failed autografts, 86% v. 31%.

Several other studies of RIC Allo-SCT from family members or unrelated donors have confirmed that results are poor when patients have failed a prior Auto-SCT or have chemotherapy resistant disease.[11] Two German studies and a study from the M.D. Anderson Cancer Center confirmed 2-year survivals of 26-50% for patients who had failed 1 or more Auto-SCT.

Recent studies have suggested that increased immunosuppression in RIC regimens can abrogate the GVM effect. In one study, Campath was added to TBI and Fludara in 20 patients with multiple myeloma undergoing RIC Allo-SCT as part of front-line therapy.[12] Fourteen of 20 were given DLI post transplant for residual or progressive disease. Although TRM and survival at 2 years were acceptable at 15% and 71%, respectively, the CR rate of 10% was disappointing. The low response rate may have been due to the addition of Campath, which may have interfered with the GVM effect.

In another study, ATG was added to a Myleran-Fludara regimen. The incidences of TRM and GVHD were low at 17% and 27%, respectively, but the CR rate was also relatively low at 24%.[13] Both studies suggest that antibodies such as Campath or ATG to prevent GVHD must be used cautiously and probably at reduced doses since these antibodies may also abrogate the GVM effect.

Recently the European Group for Blood and Marrow Transplant (EBMT) has summarized registry data containing 229 patients undergoing RIC Allo-SCT in 33 centers.[14] The regimens varied widely, but almost all utilized Fludara with a large majority receiving either low-dose TBI, Alkeran or Cytoxan. Approximately 50% of the RIC regimens also contained ATG or Campath. Eighty percent of patients were transplanted with PBSC. Acute GVHD grades 2-4 occurred in 31% of patients and extensive chronic GVHD was reported in 25%. Although the TRM was low at 22% the 3-year OS and PFS were disappointing at 41% and 22%, respectively. Disease status, duration of disease, and the use of Campath for conditioning were found in multivariate analysis to be adverse risk factors for TRM, PFS and OS. The development of limited chronic GVHD was associated with better OS and PFS, 84% and 46%, respectively. However, patients with extensive chronic GVHD had poorer outcome with OS and PFS of 58% and 30%, respectively. Interestingly, patients with no chronic GVHD had the worst outcomes with an OS and PFS of 29% and 12%, respectively. These data fit the concept that GVHD is necessary for the GVM effect, but severe GVHD can compromise survival.

Patients who receive one Auto-SCT and progress can be treated with a second Auto-SCT or a RIC-Allo-SCT. They could also receive a myeloablative regimen, but the TRM would be over 50%. One trial comparing Auto-SCT to RIC Allo-SCT following relapse from a prior Auto-SCT found no differences in PFS or OS between the two treatments.[15] A more recent study has demonstrated that a second Auto-SCT after relapse or progression can result in major responses with prolonged survival[16] Thus, it remains to be determined whether or not an RIC Allo-SCT or a second Auto-SCT is the best choice once patients have failed a prior Auto-SCT. Conversely, CR rates and early survivals were very good when a planned Auto-SCT was followed by a RIC Allo-SCT.[17]

There are a number of studies reported or underway comparing tandem Auto-SCT to a tandem Auto-SCT followed by RIC Allo-SCT. The randomization for these studies was “genetic,” in that patients with available related donors were typed and if an HLA identical donor was identified, they were offered a RIC Allo-SCT as the second transplant. While not truly randomized, these studies will provide some comparative data on the relative risks and benefits of the two approaches.

A French trial compared outcomes in 284 patients with multiple myeloma who were high risk by virtue of elevated beta-2-micoglobulin and deletion of chromosome 13 by FISH.[18] All patients first had an Auto-SCT following high-dose Alkeran. The 65 patients with HLA matched donors underwent an RIC Allo-SCT after conditioning with Myleran, Fludara and a high dose of ATG 12.5 mg/kg. Outcomes were compared to 219 patients without donors who then had a second Auto-SCT following Alkeran 220 mg/m2. TRM was 5% for the tandem auto group compared to 11% for the auto-allo group. The CR and very good PR rates were 51% and 62%, respectively, for the tandem auto and auto-allo groups. With relatively short follow-up, median 2 years, OS and event free survivals (EFS) were not statistically different: OS 35% vs. 41%, and EFS 25% v. 30% for the tandem auto and auto-allo studies, respectively. Although these results indicate that patients with high-risk features do not benefit from a tandem auto-allograft approach, the regimen utilized a high dose of ATG 12.5 mg/kg. This resulted in a low incidence of chronic GVHD (7%) but a relatively low CR rate (33% of evaluable patients). This study agrees with another report analyzing the outcome of RIC Allo-SCT in patients with or without del13.[19] This study demonstrated that del13 was an independent, adverse risk factor for OS and PFS after RIC Allo-SCT due primarily to a greater risk of relapse.

In a more recent study reported at the 2005 meeting of the American Society of Hematology, an Italian consortium compared 54 patients with multiple myeloma undergoing tandem Auto-SCT to 54 patients with multiple myeloma who had a tandem auto-allo approach using the Seattle regimen.[20] The CR rate was 26% with the tandem auto and 54% with the auto-allo group. The TRM was 4% and 11% for the tandem auto and auto-allo groups, respectively. With a 38-month median follow-up, 42% of the tandem auto patients had died, mostly from relapse, compared to only 17% of the auto-allo patients. Overall survivals were 62% and 84%, for the tandem auto v. auto-allo groups, respectively. These early results suggest a possible advantage for the auto-allo approach, although longer follow-up is needed and questions remain about patient selection bias in this trial.

The EBMT has compared RIC Allo-SCT with standard ablative conditioning for allografting in multiple myeloma. (Crawley, C, personal communication) Between 1998 and 2002, 196 patients conditioned with ablative regimens were compared with 321 patients undergoing RIC conditioning. TRM was significantly lower for the RIC group, p=0.001. There was, however, no statistical difference in OS between the 2 groups and PFS was inferior for patients receiving RIC regimens, p=0.009. This was due to a rate of relapse for the RIC group that was more than double the rate for standard conditioning patients, p= 0.0001.

Currently, no prospective randomized trials are comparing ablative Allo-SCT with RIC Allo-SCT for patients with multiple myeloma. One of the major reasons for this is the reluctance to subject older patients with multiple myeloma to more intensive regimens. However, several transplant teams appear to be increasing the dose-intensity of RIC regimens to add a greater anti-myeloma effect without increasing the TRM. One such approach has been to eliminate the Cytoxan in the Myleran-Cytoxan regimen while keeping the dose of Myleran at a high level.

Future studies of allogeneic SCT in multiple myeloma should focus on regimens that are less toxic but able to preserve anti-tumor effects, which would include radioisotopes linked to bone seeking chelates and dose adjusted chemotherapy.[21] It should be relatively easy to combine targeted radiotherapy and dose adjusted chemotherapy to create a more tolerable transplant regimen. Such treatments could be combined with infusions of allogeneic donor lymphocytes or subsets of lymphocytes in the form of “engineered grafts”, for example CD4 lymphocytes, which may have a GVM effect without increasing GVHD. [22] It may be worthwhile to exploit monoclonal antibodies targeting myeloma cells such as the CD40 antigen, in order to increase the ability of donor allogeneic cells to eliminate residual host disease.[23] It may also be possible to exploit killer-immunoglobulin-like mismatching between donor and recipient, which has been shown to result in improved PFS due to a reduced rate of relapse. [24]

Of all the treatment modalities employed to control multiple myeloma only allogeneic SCT is potentially curative, due in large part to a GVM effect. While patients who receive either allogeneic or autologous stem cell transplants for multiple myeloma have similar 3-5 year survival, only allograft recipients appear to enjoy long-term disease free survival. High TRM associated with allogeneic stem cell transplantation is currently the major limitation to wider use of this potentially curative modality. This high mortality has been the major impetus for exploration of RIC regimens designed to allow engraftment of allogeneic stem cells. With follow-up now extending to 7 years, it is clear that when compared to myeloablative transplants, RIC allografts are associated with lower TRM, however, reduced mortality comes at a cost of higher rates of disease progression and relapse.

Strategies designed to improve the therapeutic index of Allo-SCT include the use of more intensive, yet still non-myeloablative conditioning regimens, tandem autologous plus RIC allografts, peripheral blood cells rather than bone marrow, graft engineering to improve the GVM effect, post transplant maintenance and targeted conditioning therapies such as bone seeking radioisotopes.

[2]Jantunen E, Kuittinen T, Penttila K, et al. High-dose melphalan (200 bg/m2) supported by autologous stem cell transplantation is safe and effective in elderly (>65 years) myeloma patients: comparison with younger patients treated on the same protocol. Bone Marrow Transplanation . 2006;37:917-922.

[3]Aschan J, Lonnqvist B, Ringden O, et al. Graft-versus-myeloma effect (Letter). Lancet . 1996;348:346.

[4]Barlogie B, Kyle RA, Anderson KC, et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol . 2006;24(6):929-36.

[5]Gahrton G, Svensson H, Cavo M, et al. Progress in allogeneic bone marrow and peripheral blood stem cell transplantation for multiple myeloma: a comparison between transplants performed 1983 - 93 and 1994 - 98 at European Group for Blood and Marrow Transplantation centres. Br J Haematol . 2001;113:209-16.

[6]Majolino I, Corradini P, Scimè R, et al. Allogeneic transplantation of unmanipulated peripheral blood stem cells in patients with multiple myeloma. Bone Marrow Transplant . 1998;22:449-55.

[7]Storb R, Yu C, Sandmaier B, et al. Mixed hematopoietic chimerism after hematopoietic stem cell allografts. Transplant Proc . 1999;31:677-8.

[8]McSweeney PA, Niederwieser D, Shizuru JA, et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood . 2001;97(11):3390-400.

[9] Maloney DG, Molina AJ, Sahebi F, et al. Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood . 2003;102(9):3447-54.

[10] Lee C-K, Badros A, Barlogie B, et al. Prognostic factors in allogeneic transplantation for patients with high-risk multiple myeloma after reduced intensity conditioning. Exp.Hematol . 2003;31(1):73-80.

[11] Einsele H, Schafer HJ, Hebart H, et al. Follow-up of patients with progressive multiple myeloma undergoing allografts after reduced-intensity conditioning. Br J Haematol . 2003;121(3):411-8.

[12] Peggs KS, Mackinnon S, Williams CD, et al. Reduced-intensity transplantation with in vivo T-cell depletion and adjuvant dose-escalating donor lymphocyte infusions for chemotherapy-sensitive myeloma: Limited efficacy of graft-versus-tumor activity. Biol Blood Marrow Transplant . 2003;9(4):257-65.

[13] Mohty M, Boiron JM, Damaj G, Michallet AS, Bay JO, Faucher C, Perreau V, Bilger K, Coso D, Stoppa AM, et al. Graft-versus-myeloma effect following antithymocyte globulin-based reduced intensity conditioning allogeneic stem cell transplantation. Bone Marrow Transplant . 2004;34(1):77-84.

[14]Crawley C, Lalancette M, Szydlo R, et al. Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT. Blood. 2005;105(11):4532-9.

[15] Qazilbash MH, Saliba R, de Lima M. et a. Second autologous or allogeneic transplantation after the failure of first autograft in patients with multiple myeloma. Cancer . 2006;106(5):1084-9.

[16] Elice F, Raimondi R, Tosetto A, D'Emilio A, Di Bona E, Piccin A, Rodeghiero F. Prolonged overall survival with second on-demand autologous transplant in multiple myeloma. Am J Hematol . 2006;81(6):426-31.

[17] Galimberti S, Benedetti E, Morabito F, et al. Prognostic role of minimal residual disease in multiple myeloma patients after non-myeloablative allogeneic transplantation. Leuk Res . 2005;29(8):961-6.

[18] Garban F, Attal M, Michallet M, Hulin C, Bourhis JH, Yakoub-Agha I, Lamy T, Marit G, Maloisel F, Berthou C, et al. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood . 2006;107(9):3474-80.

[19] Kroger N, Schilling G, Einsele H, et al. Deletion of chromosome band 13q14 as detected by fluorescence in situ hybridization is a prognostic factor in patients with multiple myeloma who are receiving allogeneic dose-reduced stem cell transplantation. Blood . 2004;103(11):4056-61.

[20] Bruno B, Rotta M, Patriarca F, et al. Double autologous transplant versus tandem autologus-non myeloablative allogeneic transplant for newly diagnosed multiple myeloma. Blood . 2005;206:18a, abstract 46.

[21] Deeg HJ, Storer B, Slattery JT, et al. Conditioning with targeted busulfan and cyclophosphamide for hemopoietic stem cell transplantation from related and unrelated donors in patients with myelodysplastic syndrome. Blood. 2002;100(4):1201-7.

[22] Champlin R, Giralt S, Gajewski J, Hester J, Körbling M, Deisseroth A. CD8 depleted donor lymphocytes for CML relapsing post BMT. ISEH. 1995;23:939

[23] Hussein MA, Berenson JR, Niesvizky R, et al. A phase I humanized anti-CD-40 monoclonal antibody (SGN-40) in patients with multiple myeloma. Blood . 2005;106:723a, abstract # 2572.

[24] Kroger N, Shaw B, Iacobelli S, et al. Comparison between antithymocyte globulin and alemtuzumab and the possible impact of KIR-ligand mismatch after dose-reduced conditioning and unrelated stem cell transplantation in patients with multiple myeloma. Br J Haematol . 2005;129(5):631-43.