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. Author manuscript; available in PMC: 2008 Apr 1.
Published in final edited form as: Biol Blood Marrow Transplant. 2007 Feb 1;13(4):423–432. doi: 10.1016/j.bbmt.2006.11.011

Nonmyeloablative Unrelated Donor Hematopoietic Cell Transplantation for the Treatment of Patients with Poor-Risk, Relapsed or Refractory Multiple Myeloma

George E Georges 1,2, Michael B Maris 1,2, David G Maloney 1,2, Brenda M Sandmaier 1,2, Mohamed L Sorror 1, Judith A Shizuru 4, Dietger W Niederwieser 5, Edward D Agura 6, Benedetto Bruno 7, Peter A McSweeney 8, Michael A Pulsipher 9, Thomas R Chauncey 1,2,3, Marco Mielcarek 1,2, Barry E Storer 1,2, Rainer Storb 1,2
PMCID: PMC1950939  NIHMSID: NIHMS20780  PMID: 17287157

Abstract

The purpose of this study was to determine long-term outcome of unrelated donor nonmyeloablative hematopoietic cell transplantation in patients with poor-risk multiple myeloma. Twenty-four patients were enrolled. Seventeen patients (71%) had chemotherapy-refractory disease and 14 patients (58%) had disease relapse or progression after prior autologous transplantation. Thirteen patients underwent planned autologous transplantation followed 43–135 days later with unrelated transplantation, while 11 proceeded directly to unrelated transplantation. All 24 patients were treated with fludarabine (90 mg/m2) and 2 Gray total body irradiation and human leukocyte antigen (HLA)-matched unrelated peripheral blood stem cell transplantation. Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil. The median follow-up was 3 years after allografting. One patient experienced non-fatal graft rejection. The incidences of acute grades II, III and chronic graft-versus-host disease were 54%, 13% and 75%, respectively. The 3-year non-relapse mortality was 21%. Complete responses were observed in 10 patients (42%) and partial responses in 4 (17%). At 3 years, overall and progression-free survival rates were 61% and 33%, respectively. Patients receiving tandem autologous-unrelated transplantation had superior overall and progression-free survivals, 77% and 51%, compared to patients proceeding directly to unrelated donor transplantation, 44% and 11%, respectively (progression-free survival p-value, 0.03). In summary, for patients with poor-risk, relapsed or refractory multiple myeloma, cytoreductive autologous transplantation followed with nonmyeloablative conditioning and unrelated hematopoietic cell transplantation is effective treatment with low non-relapse mortality, high complete remission rates and prolonged disease-free survival.

Keywords: Multiple myeloma, nonmyeloablative conditioning, allogeneic hematopoietic cell transplantation, unrelated donor, graft-versus-tumor effects, chronic graft-versus-host disease, peripheral blood stem cell transplantation

INTRODUCTION

High-dose conditioning and autologous hematopoietic cell transplantation (HCT) is effective in prolonging survival for patients with multiple myeloma; however, nearly all patients eventually relapse [1–6]. Long-term remissions and possibly cures have been described with allogeneic HCT after conventional high-dose conditioning regimens [7–9]. However, high-dose conditioning regimens for allogeneic HCT were associated with 40–50% risks of early non-relapse mortality [7–10]. Nonmyeloablative conditioning regimens for allogeneic HCT have dramatically reduced the early transplant-related mortality, and prompted interest in applying this treatment to multiple myeloma [11–21]. One particularly promising treatment has been to combine the cytoreductive benefit of high-dose melphalan and autologous “rescue” followed by the graft-versus-tumor effects of nonmyeloablative allografts, initially from HLA-matched siblings [22,23]. For patients who lack HLA-matched siblings, unrelated donor HCT is an important alternative [12]. Several reports have described reduced-intensity conditioning and unrelated donor HCT, however the number of patients with multiple myeloma studied and the duration of follow-up have been limited [12,20,23–31].

We had shown that a nonmyeloablative conditioning regimen consisting of fludarabine 30 mg/m2/day given on three consecutive days, and 2 Gy total body irradiation (TBI) combined with postgrafting immunosuppression with cyclosporine (CSP) and mycophenolate mofetil (MMF) allowed stable engraftment of unrelated hematopoietic cells in patients with various hematologic malignancies. [12] Here, we describe the clinical outcomes of 24 patients with advanced multiple myeloma who were given grafts from HLA-matched, unrelated donors with a median follow-up of 3 years. Thirteen of the 24 patients had planned autologous HCT followed by unrelated HCT while 11 proceeded directly to unrelated HCT.

PATIENTS AND METHODS

Eligibility criteria

Twenty-four patients with multiple myeloma were enrolled on three sequential phase I/II multi-institutional Fred Hutchinson Cancer Research Center unrelated HCT protocols for hematologic malignancies between May 16, 2000 and November 23, 2004 [32].

Patients were treated at 9 centers. All patients signed consent forms approved by the local institutional review boards. Inclusion criteria were the diagnosis of multiple myeloma; high risk for non-relapse mortality due to failure of prior treatment with high dose autologous HCT or preexisting comorbidities; and failure of one or more front-line therapies [12].

HLA typing and matching

Twenty-three patient-donor pairs had HLA-allele level typing performed for 10 HLA alleles (HLA-A,B,C, DRB1 and DQB1) [33]. Patient 5 did not have high-resolution typing for all 10 HLA alleles. Twenty patients were matched with their donors for 10 of 10 HLA alleles and 3 patients (patients 4, 9 and 14) had single HLA-C allele level mismatches.

Peripheral blood stem cell mobilization / high-dose melphalan / autologous transplantation

Thirteen patients underwent planned high-dose autologous HCT before unrelated donor HCT. Unless previously cryopreserved, peripheral blood stem cells (PBSCs) were collected and cryopreserved following cyclophosphamide (4 g/m2) on day 1, given with Mesna, etoposide (200 mg/m2/d) on days 1–3; dexamethasone 40 mg/d on days 1–4, and granulocyte colony stimulating factor (G-CSF; 10 μg/kg/d) from day 4 through collection [34]. Melphalan (200 mg/m2) was given >30 days after mobilization chemotherapy. Autologous PBSCs were infused 48 hours after melphalan [22]. The median CD34+ cell number was 6.1 (range, 3.5–8.8) x106/kg. Patients proceeded to allografting after recovery from autologous HCT.

Eleven patients proceeded directly to unrelated donor HCT either due to lack of availability of cryopreserved PBSC, physician preference or inability to obtain medical insurance coverage for a planned tandem autologous-unrelated HCT.

Nonmyeloablative conditioning regimen and post-transplantation immunosuppression

Conditioning included 3 doses of fludarabine 30 mg/m2/d on days –4 to –2, followed by 2 Gy TBI at rates of 0.07–0.10 Gy/min from linear accelerators on day 0. Postgrafting immunosuppression included CSP and MMF, as described [12,32]. Patients 1–7 received MMF, 15 mg/kg every 12 hours, and patients 8–24 received MMF, 15 mg/kg every 8 hours. Grading and treatment of graft-versus-host disease (GVHD) was done as described [12,35].

Collection of unrelated PBSC and supportive care

All patients received fresh G-CSF–mobilized PBSC from unrelated donors coordinated through unrelated donor registry protocols [12]. National Marrow Donor Program donors received G-CSF (10 μg/kg/d) on days –5 through –1. The median CD34+ cell number infused was 8.87 (range, 2.1 –23.1) x106/kg. Antimicrobial and cytomegalovirus prophylaxis and blood product support were administered as described [12].

Analyses of risk factors, disease responses and toxicities

Cytogenetic abnormalities were assessed at diagnosis in 14 patients using conventional karyotype G-banding (Table 1). Donor engraftment was confirmed by chimerism analyses [36].

Table 1.

Pre-transplant patient characteristics

Transplant Patient (PIN) Age (y)/Sex Known cytogentic abnormality # Regimens before Auto/Allo or URD HCT Prior local XRT Months from DX to URD HCT Failure of prior Auto HCT* Disease stage/type at HCT β2 micro-globulin at HCT CCI score Response to last preceding chemotherapy line
Planned Tandem Auto/Unrelated HCT 3 44 / F NE 4 No 8 No IIA IgGκ 1.7 0 Refractory
4 49 / M NE 5 No 14 No IIIA IgGκ 2.0 0 Refractory
7 53 / M Δ 13, complex 2 No 10 No IIIB κ 15.3 2 Refractory
14 49 / M NE 2 No 14 No IIIA IgGκ 1.5 0 Refractory
19 59 / M complex 2 No 11 No IIIA IgGκ 2.4 1 Refractory
20 51 / M Δ 13, complex 2 No 15 No IIIA IgAκ 1.5 0 PR
21 35 / F Δ 13, complex 6 No 28 No IIIA IgAλ 1.7 0 Refractory
24 51 / F none 2 Yes 8 No IIIA IgGκ 1.3 0 PR
6 31 / M NE 6 Yes 77 Yes IIIA IgAλ 3.3 0 PR
15 53 / M complex 6 Yes 57 Yes IIIA igGκ 2.6 1 Refractory
16 61 / M Δ 13, complex 10 Yes 44 Yes IIIB IgGλ 2.1 6 Refractory
17 29 / M Δ 13, complex 4 Yes 13 Yes IIIB IgAλ 2.7 1 Refractory
23 64 / M none 7 No 43 Yes IIIB κ 4.5 3 Refractory
Proceeded directly to Unrelated HCT 1 41 / M t 11;14 5 No 30 No IIIA IgGλ 4.1 0 Refractory
18 39 / M NE 3 No 17 No* IIIA κ 2.2 0 CR
2 61 / M none 5 Yes 21 Yes IIIA IgGκ 1.6 0 Refractory
5 54 / M t 1;4 4 No 22 Yes IIA IgGκ 3.2 0 Refractory
8 53 / F NE 8 Yes 130 Yes IIIA IgGκ 1.3 0 Refractory
9 57 / M complex 6 No 55 Yes IIIA IgGκ 3.9 1 Refractory
10 66 / M NE 6 Yes 108 Yes IIIA igGκ 3.5 0 Refractory
11 38 / M NE 4 No 54 Yes IIA IgGκ 2.5 0 PR
12 61 / M Δ 13, complex 4 No 29 Yes IIIA igAκ 1.3 0 CR
13 53 / M NE 4 No 12 Yes IIIA IgGλ 5.1 0 Refractory
22 52 / F NE 8 No 80 Yes IIA IgGκ 1.7 0 PR
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Patients in shaded regions had a history of disease relapse/progression after prior autologous hematopoietic cell transplantation (HCT). Dx, diagnosis; CCI, modified Charleson comorbidity index [15]; PR, partial response; CR, complete response; refractory: no CR or PR to last preceding chemotherapy line. PIN, patient identification number. PIN #1-24 assigned in chronological order by day of URD HCT.

*

Patient 18 had an autologous HCT 11 months prior to proceeding to unrelated HCT.

Patients were evaluated for disease during the two-week interval before autologous and/or unrelated HCT to estimate the baseline levels of disease activity. Disease responses were assessed using the American Bone Marrow Transplant Registry criteria [37]. Patients were considered refractory to chemotherapy if they had less than a partial response (PR) to the last regimen administered before study entry. Restaging studies were performed at 28, 56, 84 days and 6 months after unrelated HCT, then at 6-month intervals thereafter.

Medical comorbidities were evaluated using a modified Charleson comorbidity index (CCI) [15]. Pre-transplant comorbid diseases included myocardial infarction, congestive heart failure, peripheral vascular or cerebrovascular disease, hepatic disease, diabetes (with end-organ damage), pulmonary disease (moderate-severe dyspnea on exertion), and serum creatinine >2.0 mg/dl [15].

The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3 grading system was used to evaluate toxicity during the first 100 days after allografting (http://ctep.cancer.gov/reporting/ctc.html). All toxicities were graded and reported.

Statistical Methods

Overall survival and progression-free survival were estimated by the Kaplan-Meier method. Cumulative incidence estimates were calculated for acute and chronic GVHD, relapse, relapse-related mortality, and non-relapse mortality. Deaths were treated as competing events in analyses of graft rejection, GVHD, and disease progression. Disease progression and non-relapse mortality were the components of progression-free survival and were treated as competing events. Fisher’s exact test was used to compare two groups. All p values were derived from likelihood ratio statistics and were two sided. Comparisons of survival and progression-free survival were based on log-rank test. Follow-up was as of April 1, 2006.

RESULTS

Patients’ characteristics

Table 1 summarizes the clinical features of the 24 patients enrolled in the study. All patients had advanced disease at time of study enrollment. The median time from disease diagnosis to unrelated donor HCT was 25 (range 8–130) months. All patients had received therapy for their myeloma. Twenty-three (96%) were beyond first complete remission (CR1) or had never achieved CR1 despite multiple distinct chemotherapy regimens (median, 4.5, range, 2–10). Twenty-three (96%) received vincristine, adriamycin and dexamethasone for a median of 5 cycles (range, 1–11) [38], and fourteen (58%) received thalidomide-dexamethasone [39]. One patient received bortezomib, with disease progression prior to study entry. Fourteen (58%) had relapsed/progressed after prior high-dose autologous HCT at a median of 10 (range, 3–40) months before study enrollment. Seventeen (71%) had disease that was refractory to their most recent chemotherapy regimen, 5 patients (21%) had PR, and 2 patients (8%) had CR.

Planned autologous HCT

Thirteen patients received planned autologous HCT for cytoreduction a median of 75 (range, 43–135) days before unrelated HCT. After melphalan treatment, all 13 patients recovered hematopoiesis; the median number of days with neutrophils <500/μL was 9.5 (range, 7–14) and the median days with platelets <20,000/μL was 2.5 (range, 0–9).

Five patients had relapsed following a prior autologous HCT. Disease responses after planned autologous HCT were CR in 1, PR in 7 and stable disease in 5 patients.

Unrelated donor engraftment kinetics and chimerism

During the first 100 days after unrelated HCT, patients had a median duration of neutropenia of 5 (range 0–80) days. Transient severe thrombocytopenia (<20x103 platelets/μL) occurred in 6 patients (25%). Transfusion requirements were a median of 7 (range, 0–34) units of red blood cells and 0 (range, 0–45) units of platelets.

Median levels of peripheral blood CD3, CD33 and whole marrow donor chimerism at day 28 were 94%, 99% and 98%, respectively. One patient (4%) had non-fatal graft rejection by day +56, with recovery of autologous hematopoiesis. All surviving patients with engraftment eventually achieved 100% donor chimerism.

Toxicity

The regimen of fludarabine and 2 Gy TBI was well tolerated. No patients experienced mucositis, severe diarrhea or veno-occlusive disease of the liver attributable to the conditioning regimen. For the first 100 days, the median number of inpatient hospital days was 13.5 (range 0–57). Grade 4 hematologic toxicity occurred in 75% of patients, primarily due to transient neutropenia prior to donor engraftment.

Table 2 summarizes the significant non-hematologic toxicity from day 0–100. The day 100 non-relapse mortality rate was 4%. One patient, with pre-existing congestive heart failure, died of multi-organ failure. One patient (4%) developed grade 4 pulmonary toxicity, and 16 patients (67%) developed at least one grade 3 toxicity.

Table 2.

Outcomes after transplantation

Transplant Prior auto HCT Patient (PIN) % Donor CD3+ Cells Day 28 Acute GVHD Chronic GVHD Recent IST Toxicity grade, max. day 0–100 Disease response to planned auto Survival after URD HCT (days) [Cause of death] Disease outcome after URD HCT [month of CR/PR/PD/relapse]
Grade, Organ Day of onset Extensive Day of onset
Planned Tandem Auto/Unrelated HCT No 3 85–90 II S 7 Yes 85 Taper 3 PR >2030 CR [42]
No 4 100 0 — Yes 190 No 2 PR >1829 CR [12]→ Rel [27]
No 7 95 II S 59 Yes 89 — 2 PR 1105† [NRM, GVHD/OI] CR [19]
No 14 93 II S,G 9 Yes 175 Taper 3 SD >1323 SD
No 19 85 0 — Yes 420 Yes 3 CR >765 CCR
No 20 77 II S 75 No — No 3 PR >546 PR [6]
No 21 70 0 — No — No 2 SD >615 PR [12]
No 24 95 II S 47 Yes 127 Taper 2 PR >428 PR [6]
Failure of prior auto HCT 6 100 0 — Yes 455 Taper 3 PR >1498 CR [12]
15 100 II S,G 14 Yes 93 Taper 3 PR >1200 CR [3]→Rel [35]
16 95 III G 44 No — — 5 SD 57† [NRM, MOF/OI] SD
17 85–90 II G 21 No — — 3 SD 106† [PD] PD [2]
23 100 III S,G 119 Yes 190 — 3 PR 215† [NRM, GVHD/OI] CR [6]
Proceeded Directly to Unrelated HCT No 1 80–90 II S 32 No — — 3 — 89† [PD] PD [2]
Yes 18 95 0 — Yes 235 Taper 2 — >1080 CCR →Rel [22]
Failure of prior auto HCT 2 95–99 II S 29 Yes 100 — 4 — 271† [PD] PD [4]
5 100 II S 48 No — — 3 — 1030† [PD] PD [25]
8 93 II S,G 28 Yes 92 — 3 — 166† [NRM, MOF/OI] SD
9 100 III S,G,L 10 Yes 132 — 3 — 153† [NRM, GVHD/OI] SD
10 90–95 II S,G 37 Yes 123 — 3 — 290† [NRM, GVHD/OI] SD
11 5 0 — No — N/A 3 — >1124* SD*
12 95–99 II S,G 34 Yes 84 No 3 — >1356 CCR →Rel [6]
13 92 0 — Yes 418 Taper 3 — >1398 PR [12]
22 69 0 — No — No 2 — >541 CR [6] →Rel [17]
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Patients in shaded region had a history of relapse/progression after prior autologous hematopoietic cell transplantation (HCT); GVHD, graft-versus-host disease; S, skin; G, gut; L, liver; URD, unrelated donor; NRM, non-relapse mortality; OI, opportunistic infection; MOF, multi-organ failure; CR, complete response; CCR continuous CR; PR, partial response; PD, progressive disease; Rel, relapse; SD, stable disease; N/A, not applicable; Recent IST, immune suppressive therapy within 4 months of last contact date for surviving patients. PIN, patient identification number, assigned chronologically by day of URD HCT.

*

Patient 11 rejected the unrelated donor graft and proceeded to second nonmyeloablative unrelated HCT at 11.5 months. He engrafted and achieved CR at 24 months.

Summary of day 0–100 Toxicity: Patient 16 died of multi-organ failure on day 57. Patient 2 developed grade 4 pneumonitis requiring brief intubation and mechanical ventilation. Sixteen patients (67%) developed at least one grade 3 toxicity including bacteremia or fever of unknown origin treated with antibiotics, n=11; pulmonary infiltrates/ pneumonitis, n=6; transient hyperbilirubinemia, n=5; gastrointestinal nausea/ vomiting, n=4; cardiac arrhythmia or hypertension, n=2; hemorrhage, n=2; musculoskeletal pain, n=1; and renal/metabolic toxicity, n=1.

Graft-versus-host disease

Acute GVHD developed in 16 patients (67%) at a median of 33 (range, 7–119) days (Table 2, Figure 1a). Thirteen patients (54%) had grade II acute GVHD, primarily involving the skin (n=12) and the gut (n=6). All 13 responded promptly to treatment with prednisone 1 to 2 mg/kg/day. Three patients with grade III acute GVHD subsequently died at 57, 153 and 215 days, respectively. There was no grade IV GVHD.

Figure 1.

Figure 1

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Cumulative incidence after unrelated hematopoietic cell transplantation (n=24) A. Acute graft-versus-host disease (GVHD): 67% all grades of GVHD, 54% grade II, and 13% grade III GVHD by day 120. B. Chronic extensive GVHD, 75% incidence at 3 years. C. Non-relapse mortality, 21% at 3 years.

The cumulative incidence of chronic extensive GVHD was 75% (Table 2, Figure 1b). The median day of onset of chronic GVHD was 132 (range, 85–455) days.

Non-relapse mortality

Non-relapse mortality was 21% at 3 years (Figure 1c). In total, 6 patients died from non-relapse causes, at a median of 6 (range 2–37) months, 4 with stable disease and 2 in CR. Four patients died from complications associated with GVHD and opportunistic infections, due to disseminated aspergillus, parainfluenza-3 virus, klebsiella sp. and methicillin-resistant staphylococcus aureus bacteremia, respectively. One patient died of congestive heart failure (see Toxicity), and one patient died of necrotizing pancreatitis.

Disease responses

Table 2 summarizes the disease responses for each patient. Ten patients (42%) achieved or remained in CR and 4 (17%) achieved PR, for an overall response rate of 58%. Best disease responses were observed in the 13 patients given tandem autologous-unrelated HCT (p=0.01). In this group, 7 had CR and 3 had PR, for an overall response rate of 77%. In contrast, only 2 patients (18%) who proceeded directly to unrelated HCT had measurable disease responses.

There was no significant temporal association between onset of chronic extensive GVHD and subsequent disease responses, p=0.39. No patient received donor lymphocyte infusion.

Overall survival and progression-free survival

The median follow-up of surviving patients from the time of the allograft was 3 (range, 1.2–5.5) years. For all 24 patients, the estimated overall survival at 3 years was 61% and progression-free survival 33% (Figure 2a).

Figure 2.

Figure 2

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Overall survival (OS; solid line) and progression-free survival (PFS; dotted line) after nonmyeloablative conditioning and unrelated hematopoietic cell transplantation (HCT) for: A. All patients studied (n= 24). B. Recipients of tandem autologous-unrelated HCT (n=13). C. Patients proceeding directly to unrelated HCT (n=11).

The patients given tandem autologous-unrelated HCT had significantly better progression-free survival compared with patients who proceeded directly to unrelated donor HCT, p=0.03. The difference in overall survival between the two groups was not statistically significant, p=0.30. The estimated 3-year overall survival, for the 13 patients given tandem autologous-unrelated HCT, was 77% and progression-free survival 51% (Figure 2b). Of the 11 patients who proceeded directly to unrelated donor HCT, estimated overall survival at 3 years was 44% and progression-free survival 11% (Figure 2c).

Risk factors for survival

Risk factors associated with worse overall survival included significant medical comorbidities before HCT, chemotherapy-refractory disease and relapse/progression after prior autologous HCT.

Survival was worse among the 7 patients with modified CCI scores ≥1, compared to that of patients with a score of 0, p=0.03 (Figure 3a). All 3 patients with CCI scores ≥2 died from non-relapse causes. Among the 13 patients receiving tandem autologous-unrelated HCT, CCI scores ≥1 were also associated with worse overall survival (p=0.01).

Figure 3.

Figure 3

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Risk factors for overall survival after nonmyeloablative conditioning and unrelated hematopoietic cell transplantation (HCT) for all 24 patients. A. Charlson Comorbidity Index (CCI) score [15] of 0 (solid line, n=17), or ≥1 (dashed line, n=7), p = 0.03. B. Disease sensitive (solid line, n=7) or refractory (dashed line, n=17) to most recent chemotherapy regimen, p = 0.02. C. Failure of prior autologous HCT (dashed line, n=14) or no prior/no failure of prior autologous HCT (solid line, n=10), p = 0.10.

Of the 7 patients who were in PR or CR at the time of study enrollment, all (100%) were alive with follow-up to 4 years. In contrast, survival at 3 years for the 17 patients with refractory disease was 45%, p=0.02 (Figure 3b).

The 14 patients who had relapse or disease progression after a prior autologous HCT (referred to as failure of prior autologous HCT) had worse overall and progression-free survival compared with patients who did not have prior HCT or failure of prior autologous HCT, p=0.10 and p=.05, respectively, (Figure 3c). Patients who had failure of prior autologous HCT had 42% survival and 17% progression-free survival at 3 years after unrelated HCT. For these 14 patients, there was no difference in overall or progression-free survival between proceeding directly to unrelated HCT or to tandem autologous-unrelated HCT, p=0.58 and 0.98, respectively.

The presence of deletion chromosome 13 had no apparent effect on outcome, but there were few evaluable patients. Other factors, such as duration of disease and β2 microglobulin did not influence survival.

DISCUSSION

This multicenter study of patients with advanced, poor-risk multiple myeloma demonstrated that a nonmyeloablative conditioning regimen consisting of fludarabine and 2 Gy TBI followed by unrelated donor PBSC transplantation is effective treatment. Tandem autologous-unrelated HCT provided overall survival and progression-free survival of 77% and 51%, respectively, at 3 years after allografting. These results were superior to proceeding directly to unrelated HCT, which showed overall and progression-free survival of 44% and 11%, respectively. While the difference in results was likely due to patient selection, the data suggest that tandem autologous-unrelated HCT is the optimal treatment approach. However, the relatively small number of patients evaluated limits the strength of this conclusion.

Despite having poor-risk disease and advanced age, patients tolerated nonmyeloablative conditioning with fludarabine 90 mg/m2 and 2 Gy TBI well. Grades IV–V non-hematologic toxicities within the first 100 days were infrequent compared to intensive conditioning regimens in younger patients [7–10]. Consistent with recent reports, patients with significant pre-transplant medical comorbidities were at increased risk for non-relapse mortality [15]. However, non-relapse mortality was low among patients with CCI scores less than 2.

Other prognostic risk factors for worse overall survival included myeloma progression/relapse after prior autologous HCT and chemotherapy-refractory disease. Kröger et al. reported that patients who had progression/relapse after prior autologous HCT were at high risk for transplant-related mortality and disease relapse after fludarabine/melphalan conditioning, with 2-year progression-free survival less than 10% [30]. In the current study, patients with disease progression/relapse after a prior autologous HCT had 2-year progression-free survival of 34%.

Despite the advanced stage of multiple myeloma and the large proportions of patients with chemotherapy-refractory disease and comorbidities, current results compare favorably to those reported by others [24–26,29]. Furthermore, the 3-year median follow-up in our study allows for better assessment of the long-term efficacy of the unrelated donor HCT compared with earlier reports. An EBMT registry analysis of 229 patients with multiple myeloma treated with a variety of reduced-intensity conditioning regimens reported 32 patients received HLA-matched unrelated grafts [31]. The 1-year transplant-related mortality was 40% and 3-year overall survival was 17%. The authors concluded that patients who were heavily pretreated or who had chemotherapy-resistant disease did not benefit from allogeneic HCT. Our results do not support that conclusion since patients with chemotherapy-refractory disease given a tandem autologous-unrelated HCT had 70% overall survival and patients with a progression/relapse after prior autologous HCT had 40% survival at 3 years.

Although high-resolution methods for identifying HLA-matched unrelated donors were used, the cumulative incidence of chronic GVHD was 75% at 3 years. Most patients with chronic GVHD had tolerated a taper of immunosuppressive therapy, however a minority of patients required prolonged therapy. Perhaps owing to the small number of patients studied, cytoreduction provided by the autologous HCT, and the relatively high incidence of chronic GVHD, a significant association between chronic GVHD and disease response was not seen. However, in a larger cohort of patients with a variety of hematologic malignancies who received nonmyeloablative allogeneic HCT, patients with chronic GVHD had improved overall survival and progression-free survival [40]. It is likely that the sustained progression-free survival seen in our study was due to the graft-versus-myeloma benefit of chronic GVHD. Longer follow-up is needed to determine if durable remission of myeloma can be achieved.

For patients who had relapse/progression after prior autologous HCT, our study did not show that tandem autologous-unrelated HCT was superior to proceeding directly to unrelated HCT. However, since a second autologous HCT can provide effective cytoreduction with low non-relapse mortality [8,41], it is possible that select patients who have failure of prior autologous HCT may benefit from tandem autologous-unrelated HCT.

The recent development of bortezomib and lenalidomide offers patients with multiple myeloma opportunity for more effective cytoreduction before transplantation [42–44]. Despite the introduction of novel agents for myeloma, the problem of disease relapse after chemotherapy treatment will persist. Allogeneic HCT, with the immune mediated graft-versus-tumor effect, offers the possibility of definitive curative therapy. However, chronic GVHD remains a cause of significant morbidity, and future progress will require limiting the graft-versus-host reaction to myeloma-specific antigens. Due to the relatively limited toxicity of bortezomib and lenalidomide, patients with disease relapse after unrelated HCT may benefit from treatment with these agents to augment the graft-versus-tumor effect of the allograft [45].

In conclusion, the current data support the broader application of tandem autologous-unrelated HCT for patients with multiple myeloma. The low non-relapse mortality observed among patients with low CCI scores and chemotherapy-sensitive disease suggests that patients would benefit from referral for nonmyeloablative unrelated HCT at an earlier disease stage. Patients with poor-risk but chemotherapy-sensitive disease may benefit the most from this treatment approach, including those with elevated β2 microglobulin, low serum albumin, deletion of chromosome 13, or hypodiploidy [46–50]. Proceeding to tandem autologous-unrelated HCT may also be beneficial for patients with multiple myeloma for whom conventional therapy has not been effective. In addition, for patients with chemotherapy-refractory disease or who have disease progression/relapse following autologous HCT, our results suggest that a tandem autologous-unrelated HCT can offer a substantial disease-free survival benefit. Additional follow-up and treatment of increased numbers of patients in a prospective clinical trial are needed to determine if long-term cures of multiple myeloma can be achieved with this treatment approach.

Acknowledgments

The authors are very grateful to the patients and their donors who participated in this study. In addition, the authors with to thank the research nurses John Sedgwick, Mary Hinds and Steve Minor, and the data coordinator Debbie Bassuk for their invaluable help in making the study possible. We thank Drs. Leona Holmberg and William Bensinger for their thoughtful review of the manuscript. The authors also wish to thank Helen Crawford and Bonnie Larson for manuscript preparation, and all physicians, nurses, and support personnel for their very dedicated care of patients on this study.

Footnotes

Supported in part by NIH grants: CA78902, CA18029, CA15704, CA92058

Presented in part at: the American Society of Blood and Marrow Transplantation Annual Meeting, February 17, 2006.

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