Introduction

There has been significant progress in the treatment of multiple myeloma, a plasma cell malignancy with a current median survival of 3–4 years. New drugs such as thalidomide and botezomib have shown significant activity in multiple myeloma, and when these new agents are combined with more traditional drugs, the response and complete remission (CR) rates are as high as responses achieved with autologous stem cell transplantation (ASCT).^{1, 2} ASCT has become the standard of care for many patients with multiple myeloma. Despite these advances, long-term survival with the new drugs or ASCT is rare and virtually all patients recur.

Stem cell transplantation (SCT) from allogeneic donors may be curative for 10–20% of patients with refractory hematologic malignancies and a larger proportion of patients who are transplanted in remission. A graft-versus-myeloma (GVM) effect may be associated with allogeneic SCT in patients with multiple myeloma.^{3, 4, 5} In contrast, SCT from autologous or syngeneic donors provide little or no GVM effect. Autologous or syngeneic SCT requires the intensive application of chemotherapyradiation to accomplish eradication of disease or alternate strategies designed to duplicate or mimic the GVM effect.

Although treatment with high-dose chemoradiotherapy followed by allogeneic SCT is capable of producing remissions and long-term survival for patients with multiple myeloma, the transplant-related mortality (TRM) of 25–50%, even in 'good-risk' patients, limits the application of this approach. Furthermore, as the majority of patients who develop multiple myeloma are older than 55 years and need closely human lymphocyte antigen (HLA)-matched family member or unrelated individuals to serve as stem cell donors, less than 10% of patients are even eligible for allogeneic SCT. Patients who have failed a prior autologous transplant are generally poor candidates for a full-dose allogeneic SCT owing to treatment-related mortality that exceeds 50%.

Graft-versus-myeloma

The entire basis for adoption of reduced intensity conditioning (RIC) allografting is the hypothesis that the GVM effects in multiple myeloma are potent enough to eradicate residual disease. Owing to small patient numbers and heterogeneity of risk factors in registry data, only a few conventional transplant studies to date have been able to identify a GVM effect. A small retrospective report of 37 patients who received conventional allografts for multiple myeloma found that among 15 patients who achieved CR, 11 had chronic graft-versus-host disease (cGVHD), whereas four did not.⁶ Individual case reports have documented a GVM effect in association with GVHD when immunosuppression was withdrawn.⁷ Small series of patients with multiple myeloma who developed post-allograft relapses and who subsequently were infused with allogeneic leukocytes from their original stem cell donors (donor lymphocyte infusion (DLI)) have clearly demonstrated a GVM effect that was associated with GVHD.^{3, 4, 5, 8, 9} In initial studies, 50–70% of patients receiving DLI for relapsed multiple myeloma have been reported to achieve CR.^{5, 10, 11} A more recent survey of 25 patients at 15 centers reported CR in only seven (28%) patients who received one or more DLI infusions.⁹ In a review of DLI for relapsed multiple myeloma, a GVM effect was noted in 18 of 22 patients who developed GVHD compared to only two of seven patients who did not develop GVHD (P=0.02).¹² These studies suggest that although clinical GHVD may not be essential for GVM, the relationship between the two is very strong. Retrospective studies of RIC transplants have shown a strong linkage between the development of cGVHD and a diminished risk of relapse (hazard ratio (HR), 0.37, P=0.02)¹³ (Einsele H et al. Blood 2002; 100(Part 1): 635a, abstract). Furthermore, when one compares response rates to DLI among different diseases, it appears that the 'graft-versus-leukemia' effect in patients with multiple myeloma is less potent than other diseases such as chronic myeloid leukemia, chronic lymphocytic leukaemia, mantle cell or follicular lymphoma (Cwynarski K et al. Blood 1999; 94(Suppl 1): 669a, abstract).^{14, 15} This suggests that RIC allografting for multiple myeloma is unlikely to be successful unless patients can first be treated to a state of minimal disease. Subsequent studies have confirmed this prediction.

Non-ablative allogeneic transplants

The high intensity conditioning regimens customarily used before allogeneic transplants are designed to produce cytoreduction and immunosuppression sufficient to allow establishment of the donor graft. The demonstrated efficacy of DLI in relapsed allograft patients suggests that the allogeneic GVM effect plays an important role in the cure. This has led to the exploration of RIC regimens, designed more for immunosuppression rather than cytoreduction, with the aim of establishing consistent donor engraftment with while minimizing toxicity and damage to normal host tissues. Furthermore, reduced intensity immunosuppression should minimize or eliminate the period of severe pancytopenia that always occurs after high intensity conditioning. This technique could in theory, once donor engraftment is achieved, allow the GVM effect to operate while avoiding the high TRM.

The most widely used RIC regimen was developed in Seattle based on canine transplant studies where it was shown that reliable allogeneic donor peripheral blood stem cell (PBSC) engraftment could be achieved with a very low dose of total body irradiation (TBI) of 200 cGy and a combination of two potent immunosuppressive drugs including mycophenolic acid (MMF) and cyclosporine.¹⁶ This strategy was applied to 18 patients undergoing allogeneic transplant for multiple myeloma. Seven patients had refractory disease and six had failed a prior autograft. Two patients of the first four rejected the donor graft leading to the addition of fludarabine, which provided additional immunosuppression.¹⁷ There were no further occurrences of rejection following the addition of fludarabine to the regimen. Although only one of 18 died of transplant-related toxicities (TRM), complete responses occurred in only two patients and only three others achieved partial responses. 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.

A second strategy of performing an autologous stem cell transplant followed by an RIC allograft was evaluated in patients with multiple myeloma who had not received a prior high-dose regimen. Patients first have autologous PBSC collected, followed by melphalan 200 mg/m² and reinfusion of PBSC to provide cytoreduction and some immunosuppression. Two to 4 months later, after recovery from the first autologous stem cell transplant, patients' received an RIC regimen of 200 cGy TBI, MMF and cyclosporine with allogeneic PBSC. Fifty-four patients aged 29–71 years, median age 52 years, received this tandem auto–allo transplant strategy. All patients were stage II or III and 48% had refractory or relapsed disease. One patient died of cytomegalovirus pneumonia after the initial ASCT, one patient progressed after the ASCT and 52 received the RIC allograft. 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 four patients developed severe acute GVHD (grades 3–4) and cGVHD developed in 60%.¹⁸ With a follow-up of 48 months after allograft, the survival at 48 months was 69% and the progression-free survival (PFS) was 45%.

There are approximately 370 patients who have received allogeneic stem cell transplants after RIC regimens for multiple myeloma with results reported in full manuscript or abstract form in 13 phase 2 studies (Tables 1 and 2). The types of RIC regimens used varied widely and include melphalan 100–140 mg/m² often with added fludarabine, TBI 200 cGy, with fludarabine, or sometimes with added cyclophosphamide or low-dose busulfan. Anti-thymocyte globulin (ATG) or the anti-CD52 antibody alemtuzumab have been included with some regimens in order to facilitate engraftment and reduce GVHD. GVHD prophylaxis regimens have included cyclosporine or tacrolimus and MMF or methotrexate. There is currently no consensus on which of these regimens is superior in terms of toxicity or efficacy. Granulocyte colony-stimulating factor-mobilized PBSC have been used for the majority of studies owing to fewer graft failure/rejections and putatively better GVM effects when compared to bone marrow. Unrelated donors were utilized in 99 transplants. Approximately, 120 of these patients had the RIC allograft performed as part of a tandem strategy following an ablative autologous transplant.

Table 1 - Phase 2 trials of reduced intensity allogeneic transplantation from related and unrelated donors for the treatment of multiple myeloma.

Full table

Table 2 - Prospective studies comparing tandem autologous transplant with autologous+reduced intensity allografting.

Full table

Acute GVHD grades 2–4 occurred in 25–58% of patients. cGVHD was reported in 7–70% of patients. Overall, TRM has ranged from a low of 0% to a high of 41%. Survival has ranged from 50 to 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% to as high as 73%.

One study utilized melphalan 100 mg/m² to prepare 45 patients before RIC allografting. These patients had either failed two or three prior autologous transplants, or received the allograft as part of a tandem autologous–allogeneic transplant strategy (n=12). The patients had a median age of 56 years and donors were all HLA matched; 12 were unrelated volunteer donors. TBI and fludarabine 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 (OS) at 3 years was poor, only 36%. There was a significantly better survival for patients transplanted as part of the planned tandem strategy versus failed autografts, 86 versus 31%, P=0.01.¹⁹ Several other studies of RIC allografts from family members or unrelated donors have confirmed that results are poor when patients have failed a prior autologous transplant or have chemotherapy-resistant disease (Hoepfner S et al. Blood 2002; 100(Part 1): 859a, abstract).^{20, 21} Two German studies and a study from MD Anderson confirmed 2-year survivals of 26–50% for patients who had failed one or more autologous transplants. A study combining data from several centers including approximately 120 patients found that relapse from a prior autologous transplant was the most significant risk factor for TRM (HR 2.80; P=0.02), relapse (HR 4.14; P<0.001) and death (HR 2.69; P=0.005).¹³ At least one trial comparing autologous to RIC allograft following relapse from a prior autologous transplant found no differences in PFS and OS.²² A more recent study has demonstrated that a second autologous transplant performed only after relapse or progression can result in major responses with prolonged survival.²³ Thus, it remains to be determined whether or not an RIC allograft or a second autograft is the best choice once patients have failed a prior autograft. Conversely, CR rates and early survivals were very good when a planned tandem, reduced intensity allograft approach was utilized as part of the initial treatment.^{18, 24, 25, 26}

In one study, the anti-CD52 antibody, alemtuzumab was added to TBI and fludarabine in 20 patients with multiple myeloma undergoing RIC allografting as part of front-line therapy.²⁷ 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 alemtuzumab, which may have interfered with the GVM effect. In another study, ATG at doses of 2.5–12.5 mg/kg were added to a busulfan–fludarabine regimen. The incidences of TRM and GVHD were low at 17 and 27%, respectively, but the CR rate was also relatively low at 24%.²⁸ Both the studies of Peggs and Mohty suggest that antibodies such as alemtuzumab or ATG to prevent GVHD must be used cautiously and probably at reduced doses as 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 allogeneic stem cell transplants in 33 centers.²⁹ The regimens varied widely but almost all utilized fludarabine with a large majority receiving either low-dose TBI, melphalan or cyclophosphamide. Approximately, 50% of the RIC regimens also contained ATG or alemtuzumab. Eighty percent of patients were transplanted with PBSC. Acute GVHD grades 2–4 occurred in 31% of patients and extensive cGVHD was reported in 25%. Although the TRM was low at 22%, the 3-year OS and PFS were disappointing at 41 and 22%. Disease status and duration at transplant, and the use of alemtuzumab for conditioning were found in multivariate analysis to be adverse risk factors for TRM, PFS and OS. The development of limited cGVHD was associated with better OS and PFS, 84 and 46%, respectively, whereas patients with extensive cGVHD had an OS and PFS of 58 and 30%, respectively. Interestingly, patients with no cGVHD had the worst outcomes with an OS and PFS of 29 and 12%, respectively.

More recently, the EBMT has compared RIC with standard ablative conditioning for allografting in multiple myeloma. (C Crawley, 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 two 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.

Randomized trials

Currently no prospective randomized trials exist comparing ablative with non-ablative conditioning regimens for the transplant of patients with multiple myeloma. There are, however, a number of studies reported or underway comparing tandem autologous transplants to a tandem autologous-non-ablative allograft approach. 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 non-ablative transplant as the second transplant. Although not truly randomized, they provide some comparative data on the relative risks and benefits of the two techniques.

A French trial compared outcomes in 284 patients with multiple myeloma who were at high risk by virtue of elevated beta-2-micoglobulin and deletion of chromosome 13 by fluorescent in situ hybridization.³⁰ All patients first had an autologous transplant with high-dose melphalan. The 65 patients with HLA-matched donors underwent an allogeneic transplant after conditioning with busulfan, fludarabine and a high dose of ATG 12.5 mg/kg. They were compared to 219 patients without donors who then had a second autologous transplant with melphalan 220 mg/m². TRM was 5% for the tandem auto group compared to 11% for the auto–allo group. The CR and very good partial remission (PR) rates were 51 and 62%, respectively, for the tandem auto and auto–allo groups. With relatively short follow-up, median 2 years, the OSs and event-free survivals (EFSs) were not statistically different, OS 35 versus 41%, and EFS 25 versus 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-reduced intensity allograft approach, the regimen utilized a high dose of ATG 12.5 mg/kg. This resulted in a low incidence of cGVHD (7%) but a relatively low CR rate (33% of evaluable patients). This study agrees with another report analyzing the outcome of RIC allografting in patients with or without del13.³¹ This study demonstrated that del13 was an independent, adverse risk factor for OS and PFS after RIC allografting due primarily to a greater risk of relapse. Whether or not an RIC allograft can overcome this adverse risk factor remains to be determined.

In a more recent study reported at the American Society of Hematology 2005, an Italian consortium compared 54 patients with multiple myeloma undergoing tandem autologous transplant to 54 patients with multiple myeloma who had a tandem auto–allo approach using the Seattle regimen (Bruno B et al. Blood 2005; 106(Part 1): 18a, abstract). 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. OSs were 62 and 84% for the tandem auto versus auto–allo groups, respectively, P=0.003. 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.

RIC allogeneic transplant regimens can result in reliable donor engraftment with relatively low TRM compared to high-dose regimens. It appears, however, that substantial cytoreduction pre-allografting is necessary owing to a limited GVM effect. Preliminary results suggest the tandem auto/RIC allogeneic strategy can result in CRs in at least 50% of patients with multiple myeloma; similar to what can be achieved with a high-dose conditioning regimen. Reduced intensity regimens are another promising strategy to ensure reliable engraftment, low mortality and high response rates, as well as the ability to expand this technique to older patients or patients with co-morbid conditions. It will be important, however, to have longer follow-up of patients transplanted with non-ablative regimens in order to document the durability of these remissions and to document the rates and severity of cGVHD.

Patients who relapse after RIC allografting have very limited options. DLI can result responses for 30–50% of patients but few achieve durable responses. In one report, only three of 21 patients given DLI for relapsed multiple myeloma after RIC allografts achieved CRs with another four achieving PRs.³² DLI also carries significant risk of acute and cGVHD. More recently, it has been shown that thalidomide or bortezomib given along with DLI can improve response rates with very promising OS and PFS at 2 years of 100 and 84% with only a minimal risk of GVHD.^{33, 34} These results suggest that early maintenance with novel agents are worth further exploration in an attempt to reduce relapse rates after RIC allografting.

Revisiting ablative allografts

Recently, a US intergroup trial of early versus late autologous transplant was published suggesting autologous transplant produced survival outcomes similar to standard chemotherapy when autologous transplant could be given as salvage treatment.³⁵ That trial, which was started in 1993, had another arm that allowed patients with matched siblings to undergo allogenic transplant using an ablative cyclophosphamide and TBI regimen. That arm of the study was closed after 36 patients were treated, owing to an excessively high TRM of 53%. With follow-up, the 7-year OS is identical at 39% for both autologous and allogeneic recipients, whereas the PFS is 15% for autologous recipients at 7 years compared to 22% for allogeneic recipients. Additonally, although there is no plateau in the group that received autologous transplant, the OS curve for the allogeneic group is flat with follow-up extending to 10 years.

The EBMT Registry has reported the largest series of patients receiving allogeneic transplants for multiple myeloma (n=690) following marrow ablative treatment regimens.³⁶ The EBMT registry analysis examined transplants performed on 334 patients from 1983 to 1993 and 356 patients from 1994 to 1998. Of the patients transplanted during the latter period, 133 (37%) received 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 mortality was a result of fewer deaths from opportunistic infections and interstitial pneumonias. This was due, in part, to better patient selection with less prior treatment and improvements in supportive care. The improvement in results did not appear to be a result of the introduction of PBSC. The OS after 3 years improved from 35% during the 1983–1993 period to 56% during the 1994–1998 period. A phase 2 study utilizing high-dose busulfan and mephalan followed by allogeneic PBSC from matched sibling donors in 30 patients with multiple myeloma, has reported a reduction in TRM.³⁷ The TRM was 16% at 100 days, 30% overall with an 81% CR rate. Survival and PFS at 6 years were 65 and 70%, respectively. Thus, improvements in patient selection and supportive care have narrowed the differences in TRM between ablative (30%) and RIC (20%) allogeneic stem cell transplants. This suggests that there may be strategies to make ablative regimens more tolerable, which would still preserve the cytoreductive benefits of an allograft.

Additional areas of research

Another technique for improving the ability to eradiate residual host myeloma involves the use of targeted radiation delivered by antibodies or chemically specific uptake. High-energy, short-acting radioisotopes linked to bone-seeking compounds have been utilized in this manner. Holmium-166 (¹⁶⁶Ho), a beta-emitting radiometal with a half-life of 26 h has been linked to DOTMP, a tetra phosphonate chelate to achieve rapid and specific uptake in bone and bone surfaces. In phase 1–2 trials, increasing doses of ¹⁶⁶Ho-DOTMP were given, along with high-dose melphalan, followed by autologous SCT.³⁸ A CR rate of 38% was observed with a median OS in excess of 48 months. Sammarium-153, another high-energy isotope was linked to EDTMP, another tetraphosphonate chelate and studied in 18 patients with multiple myeloma, who received melphalan 200 mg/m² following the isotope.³⁹ CR resulted in five patients with a very good PR in another seven. The samarium isotope has also been given to nine patients in a pilot study along with cyclophophamide as a preparative regimen for allografting in multiple myeloma.⁴⁰ Tolerance was very good with only one patient dying from TRM. Responses were disappointing with only two CRs. Further development and studies with targeted radioisotopes are needed.

One probable reason for the high TRM after allografting for patients with multiple myeloma may be related to the primary immunodeficiency in this disease. Thus, improved sources of stem cells such as PBSC that result in earlier engraftment and immune reconstitution⁴¹ should reduce infectious complications.

Future studies of allogeneic marrow transplantation in multiple myeloma should focus on regimens that are less toxic but able to preserve antitumor effects such as radioisotopes linked to bone-seeking chelates⁴² or dose-adjusted chemotherapy.⁴³ It should be relatively easy to combine targeted radiotherapy and dose-adjusted chemotherapy to create a more tolerable regimen. The studies using RIC regimens appear to effectively reduce the early complications and mortality of allogeneic transplants, but are relatively ineffective at eradicating residual disease unless accompanied by cytoreduction delivered with a prior autograft. 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.⁴⁴ It may also be possible to exploit killer-immunoglobulin-like mismatching between donor and recipient, which has been shown to result in improved PFS owing to a reduced rate of relapse.⁴⁵ Finally, 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 (Hussein MA et al. Blood 2005; 106(Part 1): 723a, abstract).

At present, allogeneic transplants (ablative and RIC) cannot be recommended outside the context of a clinical trial. If patients are not eligible for trials, RIC regimens should be utilized for elderly patients or patients with co-morbid conditions that preclude an ablative regimen. In most cases, this will require a tandem autologous transplant or novel cytoreductive techniques to most effectively prepare patients for the allograft. In younger, fit patients, the choice of ablative or RIC regimens should ideally be determined by appropriate research priorities within the medical institutions. If studies are not available and the patients or physicians wish to proceed with an allogeneic transplant, current data indicate that an ablative regimen would be preferred.

References

1. Kumar S, Anderson KC. Drug insight: thalidomide as a treatment for multiple myeloma (review). Nat Clin Pract Oncol 2005; 2: 262–270. | Article | PubMed | ChemPort |
2. Anderson KC, Shaughnessy Jr JD, Barlogie B, Harousseau J-L, Roodman GD. Multiple myeloma. In: Broudy VC, Abkowitz JL, Vose JM (eds). Hematology 2002: American Society of Hematology Education Program Book. American Society of Hemtology: Washington, DC, 2002, pp 214–240.
3. Tricot G, Vesole DH, Jagannath S, Hilton J, Munshi N, Barlogie B. Graft-versus-myeloma effect: proof of principle. Blood 1996; 87: 1196–1198. | PubMed | ISI | ChemPort |
4. Verdonck LF, Lokhorst HM, Dekker AW, Nieuwenhuis HK, Petersen EJ. Graft-versus-myeloma effect in two cases. Lancet 1996; 347: 800–801. | Article | PubMed | ChemPort |
5. Aschan J, Lonnqvist B, Ringden O, Kumlien G, Gahrton G. Graft-versus-myeloma effect (letter). Lancet 1996; 348: 346. | Article | PubMed | ChemPort |
6. Le Blanc R, Montminy-Métivier S, Bélanger R, Busque L, Fish D, Roy D-C et al. Allogeneic transplantation for multiple myeloma: further evidence for a GVHD-associated graft-versus-myeloma effect. Bone Marrow Transplant 2001; 28: 841–848. | Article | PubMed | ChemPort |
7. Libura J, Hoffmann T, Passweg J, Gregor M, Favre G, Tichelli A et al. Graft-versus-myeloma after withdrawal of immunosuppression following allogeneic peripheral stem cell transplantation. Bone Marrow Transplant 1999; 24: 925–927. | Article | PubMed | ChemPort |
8. Bertz H, Burger JA, Kunzmann R, Mertelsmann R, Finke J. adoptive immunotherapy for relapsed multiple myeloma after allogeniec bone marrow transplantation (BMT): evidence for a graft-versus-myeloma effect. Leukemia 1997; 11: 281–283. | Article | PubMed | ISI | ChemPort |
9. Salama M, Nevill T, Marcellus D, Parker P, Johnson M, Kirk A et al. donor leukocyte infusions for multiple myeloma. Bone Marrow Transplant 2000; 26: 1179–1184. | Article | PubMed | ISI | ChemPort |
10. Collins Jr RH, Shpilberg O, Drobyski WR, Porter DL, Giralt S, Champlin R et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 1997; 15: 433–444. | PubMed | ISI |
11. Alyea E, Ritz J. Induction of graft versus myeloma by donor lymphocyte infusions following allogeneic bone marrow transplant. In: Anderson KC (ed). VI International Workshop on Multiple Myeloma 1997, 1997.
12. Mehta J, Singhal S. Graft-versus-myeloma (review). Bone Marrow Transplant 1998; 22: 835–843. | Article | PubMed | ChemPort |
13. Kroger N, Perez-Simon JA, Myint H, Klingemann H, Shimoni A, Nagler A, et al. Relapse to prior autograft and chronic graft-versus-host disease are the strongest prognostic factors for outcome of melphalan/fludarabine-based dose-reduced allogeneic stem cell transplantation in patients with multiple myeloma. Biol Blood Marrow Transplant 2004; 10: 698–708. | Article | PubMed | ISI | ChemPort |
14. Dazzi F, Szydlo RM, Cross NC, Craddock C, Kaeda J, Kanfer E et al. Durability of responses following donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood 2000; 96: 2712–2716. | PubMed | ISI | ChemPort |
15. Helg C, Starobinski M, Jeannet M, Chapuis B. Donor lymphocyte infusion for the treatment of relapse after allogeneic hematopoietic stem cell transplantation (review). Leukemia Lymph 1998; 29: 301–313. | ChemPort |
16. Storb R, Yu C, Sandmaier B, McSweeney P, Georges G, Nash R, Woolfrey A. Mixed hematopoietic chimerism after hematopoietic stem cell allografts. Transplant Proc 1999; 31: 677–678. | Article | PubMed | ChemPort |
17. McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001; 97: 3390–3400. | Article | PubMed | ISI | ChemPort |
18. Maloney DG, Molina AJ, Sahebi F, Stockerl-Goldstein KE, Sandmaier BM, Bensinger W et al. Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 2003; 102: 3447–3454. | Article | PubMed | ISI | ChemPort |
19. Lee C-K, Badros A, Barlogie B, Morris C, Zangari M, Fassas A et al. Prognostic factors in allogeneic transplantation for patients with high-risk multiple myeloma after reduced intensity conditioning. Exp Hematol 2003; 31: 73–80. | Article | PubMed | ISI |
20. Giralt S, Bensinger W, Goodman M, Podoloff D, Eary J, Wendt R. ¹⁶⁶Ho-DOTMP plus melphalan followed by peripheral blood stem cell transplantation in patients with multiple myeloma: results of two phase 1/2 trials. Blood 2003; 102: 2684–2691. | Article | PubMed | ISI | ChemPort |
21. Einsele H, Schafer HJ, Hebart H, Bader P, Meisner C, Plasswilm L et al. Follow-up of patients with progressive multiple myeloma undergoing allografts after reduced-intensity conditioning. Br J Haematol 2003; 121: 411–418. | Article | PubMed | ISI |
22. Qazilbash MH, Saliba R, de Lima M, Hosing C, Couriel D, Aleman A et al. Second autologous or allogeneic transplantation after the failure of first autograft in patients with multiple myeloma. Cancer 2006; 106: 1084–1089. | Article | PubMed |
23. Elice F, Raimondi R, Tosetto A, D'Emilio A, Di Bona E, Piccin A et al. Prolonged overall survival with second on-demand autologous transplant in multiple myeloma. Am J Hematol 2006; 81: 426–431. | Article | PubMed |
24. Kroger N, Schwerdtfeger R, Kiehl M, Sayer HG, Renges H, Zabelina T et al. Autologous stem cell transplantation followed by a dose-reduced allograft induces high complete remission rate in multiple myeloma. 2002; 100: 755–760.
25. Kroger N, Sayer HG, Schwerdtfeger R, Kiehl M, Nagler A, Renges H et al. Unrelated stem cell transplantation in multiple myeloma after a reduced-intensity conditioning with pretransplantation antithymocyte globulin is highly effective with low transplantation-related mortality. Blood 2002; 100: 3919–3924. | Article | PubMed | ISI | ChemPort |
26. Galimberti S, Benedetti E, Morabito F, Papineschi F, Callea V, Fazzi R et al. Prognostic role of minimal residual disease in multiple myeloma patients after non-myeloablative allogeneic transplantation. Leuk Res 2005; 29: 961–966. | Article | PubMed | ChemPort |
27. Peggs KS, Mackinnon S, Williams CD, D'Sa S, Thuraisundaram D, Kyriakou C 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: 257–265. | Article | PubMed | ChemPort |
28. Mohty M, Boiron JM, Damaj G, Michallet AS, Bay JO, Faucher C et al. Graft-versus-myeloma effect following antithymocyte globulin-based reduced intensity conditioning allogeneic stem cell transplantation. Bone Marrow Transplant 2004; 34: 77–84. | Article | PubMed | ISI | ChemPort |
29. Crawley C, Lalancette M, Szydlo R, Gilleece M, Peggs K, Mackinnon S 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: 4532–4539. | Article | PubMed | ISI | ChemPort |
30. Garban F, Attal M, Michallet M, Hulin C, Bourhis JH, Yakoub-Agha I 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: 3474–3480. | Article | PubMed | ChemPort |
31. Kroger N, Schilling G, Einsele H, Liebisch P, Shimoni A, Nagler A 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: 4056–4061. | Article | PubMed | ISI | ChemPort |
32. Ayuk F, Shimoni A, Nagler A, Schwerdtfeger R, Kiehl M, Sayer HG et al. Efficacy and toxicity of low-dose escalating donor lymphocyte infusion given after reduced intensity conditioning allograft for multiple myeloma. Leukemia 2004; 18: 659–662. | Article | PubMed | ISI | ChemPort |
33. Kroger N, Shimoni A, Zagrivnaja M, Ayuk F, Lioznov M, Schieder H et al. Low-dose thalidomide and donor lymphocyte infusion as adoptive immunotherapy after allogeneic stem cell transplantation in patients with multiple myeloma. Blood 2004; 104: 3361–3363. | Article | PubMed | ISI | ChemPort |
34. van de Donk NW, Kröger N, Hegenbart U, Corradini P, Miguel JF, Goldschmidt H et al. Remarkable activity of novel agents bortezomib and thalidomide in patients not responding to donor lymphocyte infusions following nonmyeloablative allogeneic stem cell transplantation in multiple myeloma. Blood 2006; 107: 3415–3416. | Article | PubMed | ISI | ChemPort |
35. Barlogie B, Kyle RA, Anderson KC, Greipp PR, Lazarus HM, Hurd DD 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: 929–936. | Article | PubMed | ChemPort |
36. Gahrton G, Svensson H, Cavo M, Apperley J, Bacigalupo A, Björkstand B 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: 209–216. | Article | PubMed | ISI | ChemPort |
37. Majolino I, Corradini P, Scim R, Santoro A, Tarella C, Cavallaro AM et al. Allogeneic transplantation of unmanipulated peripheral blood stem cells in patients with multiple myeloma. Bone Marrow Transplant 1998; 22: 449–455. | Article | PubMed | ChemPort |
38. Giralt S, Bensinger W, Goodman M, Podoloff D, Eary J, Wendt R et al. ¹⁶⁶HO-DOTMP plus melphalan followed by peripheral blood stem cell transplantation in patients with multiple myeloma: results of two phase 1/2 trials. Blood 2003; 102: 2684–2691. | Article | PubMed | ISI | ChemPort |
39. Dispenzieri A, Wiseman GA, Lacy MQ, Litzow MR, Anderson PM, Gastineau DA et al. A Phase I study of 153Sm-EDTMP with fixed high-dose melphalan as a peripheral blood stem cell conditioning regimen in patients with multiple myeloma. Leukemia 2005; 19: 118–125. | Article | PubMed | ChemPort |
40. Kennedy GA, Durrant S, Butler J, Morton J, Western R, Bartlett ML et al. Outcome of myeloablative allogeneic stem cell transplantation in multiple myeloma with a 153Sm-EDTMP-based preparative regimen. Leukemia 2005; 19: 879–880. | Article | PubMed | ChemPort |
41. Bensinger WI, Martin PJ, Storer B, Clift R, Forman SJ, Negrin R et al. Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med 2001; 344: 175–181. | Article | PubMed | ISI | ChemPort |
42. Macfarlane DJ, Durrant S, Bartlett ML, Allison R, Morton AJ. 153Sm EDTMP for bone marrow ablation prior to stem cell transplantation for haematological malignancies. Nucl Med Commun 2002; 23: 1099–1106. | Article | PubMed | ChemPort |
43. Deeg HJ, Storer B, Slattery JT, Anasetti C, Doney KC, Hansen JA 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: 1201–1207. | Article | PubMed | ISI | ChemPort |
44. Champlin R, Giralt S, Gajewski J, Hester J, Körbling M, Deisseroth A. CD8 depleted donor lymphocytes for CML relapsing post BMT. Int Soc Exp Hematol 1995; 23: 939.
45. Kroger N, Shaw B, Iacobelli S, Zabelina T, Peggs K, Shimoni A et al. Comparison between antithymocyte globulin, alemtuzumab, the possible impact of KIR-ligand mismatch after dose-reduced conditioning, unrelated stem cell transplantation in patients with multiple myeloma. Br J Haematol 2005; 129: 631–643. | Article | PubMed | ChemPort |
46. Gerull S, Goerner M, Benner A, Hegenbart U, Klein U, Schaefer H et al. Long-term outcome of nonmyeloablative allogeneic transplantation in patients with high-risk multiple myeloma. Bone Marrow Transplant 2005; 36: 963–969. | Article | PubMed | ChemPort |
47. Ma SY, Lie AK, Au WY, Chim CS, Kwong YL, Liang R. Non-myeloablative allogeneic peripheral stem cell transplantation for multiple myeloma. Hong Kong Med J 2004; 10: 77–83. | PubMed | ChemPort |
48. Perez-Simon J, Martino R, Alegre A, Tomas J, De Leon A, Caballero D et al. Chronic but not acute graft-versus-host disease improves outcome in multiple myeloma patients after non-myeloablative allogeneic transplantation. Br J Haematol 2003; 121: 104–108. | Article | PubMed | ISI |

Acknowledgements

This work was supported in part by Grants CA-18029, CA-47748, CA-18221, CA-15704 from the National Cancer Institute, and HL 36444 from the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, The Jose Carreras Foundation Against Leukemia, Barcelona, Spain.