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. Author manuscript; available in PMC: 2015 Jul 13.
Published in final edited form as: Bone Marrow Transplant. 2013 Apr 1;48(9):1179–1184. doi: 10.1038/bmt.2013.37

Allogeneic hematopoietic cell transplantation for consolidation of VGPR or CR for newly diagnosed multiple myeloma

T Nishihori 1, JL Ochoa-Bayona 1, J Kim 2, J Pidala 1, K Shain 3, R Baz 3, D Sullivan 1, HS Jim 4, C Anasetti 1, M Alsina 1
PMCID: PMC4500071  NIHMSID: NIHMS704240  PMID: 23542223

Abstract

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative approach in patients with multiple myeloma, but its use for consolidation of first remission has not yet been fully explored. Twenty-two myeloma patients with very good partial response (VGPR) or CR received allogeneic peripheral blood grafts as consolidation from HLA-matched donors between 2007 and 2012. Conditioning regimens were fludarabine (30 mg/m2 i.v. if with bortezomib and 40 mg/m2 i.v. when without bortezomib, ×4 days) plus melphalan (70 mg/m2 intravenously ×2 days) with (n = 13) or without (n = 9) bortezomib (1.3 mg/m2). The cumulative incidence of grades 2–4 acute GVHD at day 100 was 45% (95% CI: 24–65%) and moderate-to-severe chronic GVHD at 2 years was 46% (95% CI: 19–69%). With a median follow-up of 18 (range, 2–61) months, the 2-year PFS estimate is 74.8% (95% CI: 45–90%), which compares favorably with the 52% (95% CI: 35–66%) after autologous HCT for similar patients (a median follow-up of 30 (range, 9–55) months). We are conducting a phase 2 study to assess the efficacy of allogeneic HCT as post-remission therapy.

Keywords: allogeneic hematopoietic cell transplantation, multiple myeloma, bortezomib, fludarabine, melphalan, conditioning

INTRODUCTION

Despite recent advances in treatment options and improved survival, multiple myeloma remains incurable with standard chemotherapy and autologous transplant for most patients with a median time to progression in the range of 40 months with lenalidomide post-transplant maintenance.1,2 Until now, the questions regarding the role of allogeneic hematopoietic cell transplantation (HCT) for remission consolidation could not be fully addressed, in part, due to significantly high burden of myeloma after conventional chemotherapy.3–6 However, the time to address such a question has arrived with the incorporation of bortezomib and lenalidomide into the initial systemic therapy resulting in higher rates of very good partial response (VGPR) and CR.7–9

The use of reduced-intensity conditioning preparative regimens early after initial responses in the era of novel agents might provide an avenue to explore the potent graft-versus-myeloma effect while minimizing non-relapse mortality (NRM).10–15 Therefore, we hypothesized that incorporation of allogeneic HCT early in the disease course as a consolidation therapy for the initial response would maximize the potential benefits of allografting. We report initial results of a reduced-intensity conditioning of fludarabine and melphalan with or without bortezomib in patients with multiple myeloma undergoing allogeneic HCT in their first VGPR or CR following systemic therapy containing bortezomib or lenalidomide.

PATIENTS AND METHODS

Eligibility criteria

Eligible patients for this analysis were those with treatment-responsive multiple myeloma in their first VGPR or CR at the time of allogeneic HCT after initial systemic therapy, aged between 18 and 60 years. We analyzed the outcomes of patients treated with fludarabine and melphalan ± bortezomib conditioning for allogeneic HCT during 2007–2012. Bortezomib was given with fludarabine and melphalan under the clinical protocol (MCC 15697), which was registered at Clinical Trials.gov as NCT 00948922 and approved by the Institutional Review Board (IRB) of University of South Florida (USF). Those patients without bortezomib were treated off. For some patients who were PR after initial systemic therapy, they were eligible to be treated first with autologous HCT using melphalan (100 mg/m2 i.v. ×2 days) plus bortezomib (1.3 mg/m2 i.v., given immediately after the second dose of melphalan) conditioning prior to receiving allogeneic HCT under MCC 15697. In the same time period, there were only two additional patients who achieved PR after initial systemic therapy, and who received allogeneic HCT with fludarabine and melphalan conditioning at our institution, and they were not included in the analysis. All patients signed informed consent in accordance with the Declaration of Helsinki for the study of long-term follow-up after HCT approved by the IRB of USF.

Donors were 8/8 HLA-matched (HLA-A, -B, -C and -DRB1) siblings or unrelated adults. Patients were considered eligible for allogeneic HCT if they have Karnofsky performance status of ≥60%, creatinine clearance >30 mL/min, platelet count ≥30 000/μL, ANC ≥1000/μL, left ventricular ejection fraction ≥40%, bilirubin ≤2 mg/dL, transaminases ≤2.5-times the upper limit of normal and carbon monoxide diffusion capacity ≥50%. A high-risk group by cytogenetic changes was defined by the presence of hypodiploidy, t(4;14), t(14;16), or loss of 17p13, by conventional cytogenetics or FISH. Deletion of chromosome 13q was considered high-risk only if detected by conventional cytogenetics.

Autologous cohort

To perform an exploratory comparison of efficacy between fludarabine and melphalan ± bortezomib conditioning regimen of allogeneic HCT and conventional autologous HCT in a similar patient population, we retrospectively identified a cohort of myeloma patients. From January 2006 to December 2009, there were 362 myeloma patients who underwent high-dose chemotherapy (melphalan-based) followed by autologous HCT without post-transplant maintenance therapy. Of those, 41 patients were ≤60 years of age and were in their first VGPR or CR at the time of autologous HCT, and were selected for this analysis.

Treatment plan

Fludarabine and melphalan preparative regimen consisted of fludarabine (if creatinine clearance <70 mL/min, then reduced dose) at 30 mg/m2 (with bortezomib) or 40 mg/m2 (without bortezomib) administered i.v. over 30 min on days −6, −5, −4 and −3, and melphalan 70 mg/m2 administered intravenously over 30 min on days −4 and −3. Under MCC 15697 clinical trial, bortezomib was given on day −3 at 1.3 mg/m2 i.v. push over 3–5 s followed by normal saline flush immediately after melphalan (n = 13). For those three patients who received autologous HCT (prior to allogeneic HCT) under MCC protocol 15967, conditioning regimen consisted of melphalan 100 mg/m2 administered intravenously daily over 30 min on days −4 and −3, and bortezomib at 1.3 mg/m2 administered intravenously over 3–5 s immediately after the melphalan. Two patients were enrolled to maintenance lenalidomide trial after allogeneic HCT with fludarabine and melphalan conditioning. None of the patients on the fludarabine, melphalan and bortezomib conditioning regimen protocol (MCC 15697) received post-transplant maintenance regimen nor donor-lymphocyte infusion.

GVHD prophylaxis consisted of tacrolimus/MTX, tacrolimus/mycophenolate mofetil, or tacrolimus/sirolimus, administered as per the institutional guidelines. Immunosuppression was tapered in the absence of GVHD at the discretion of the treating physician. Antibacterial, antifungal and antiviral prophylaxes were provided following the institutional standards. Myeloma disease monitoring with serum and urine protein electrophoresis, and serum-free light chain assays were performed every 3 months after allogeneic HCT until disease progression. Quality of life (QOL) was assessed using the Functional Assessment of Cancer Therapy-Blood and Marrow Transplantation (FACT-BMT) questionnaire at baseline (before allogeneic HCT), and on days +30, +90, +180, +270, +540 and +740 after allogeneic HCT under MCC 15697 (n = 12).16

Statistical endpoints

Response definition was based on International Uniform Response Criteria.17 Neutrophil engraftment was defined as the first day of ANC ≥500/μL for 3 consecutive days and platelet engraftment was defined as the first day of the platelet count ≥20 000/μL for 7 consecutive days independent of transfusions. GVHD was scored according to the published guidelines.18,19 OS and PFS were calculated using the methods of Kaplan and Meier and compared using the log-rank test.20 Cumulative incidence of grade II–IV acute GVHD and moderate to severe chronic GVHD were estimated and compared by the Gray test.21 Death and progression of disease were considered as a competing risk. Pointwise 95% confidence intervals for survival curves and cumulative incidence curves were computed using log–log transformation.

RESULTS

Patient characteristics

Patient characteristics and transplant variables are summarized in Table 1. Details of initial systemic therapy for allogeneic HCT recipients were summarized in Table 2. A total of 22 myeloma patients with first VGPR or CR received allogeneic HCT and 41 patients with VGPR or CR received autologous HCT. Three of 22 patients received autologous HCT for cytoreduction before allogeneic HCT. All patients received G-CSF-mobilized peripheral blood stem cells from 8/8 HLA-A, -B, -C and -DRB1 matched related/unrelated donors or autografts.

Table 1.

Patient demographics and transplant variables

Allogeneic HCT cohort (n = 22) Autologous HCT cohort (n = 41)
Median (range) age at HCT, years 49 (25–59) 54 (40–60)
Median time (range) from diagnosis to HCT, days 269 (141–637) 279 (144–990)
Immunoglobulin subtype
 IgG 12 (55%) 15 (37%)
 IgA 3 (13%) 11 (27%)
 IgD 0 1 (2%)
 Light chain only 7 (32%) 12 (29%)
 Non-secretory 0 2 (5%)
Durie–Salmon staging
 1A 1 (4%) 1 (2%)
 2A 2 (9%) 9 (22%)
 3A 14 (64%) 24 (59%)
 3B 5 (23%) 7 (17%)
Cytogenetics/FISH
 High-risk 7 (32%) 5 (21% = 5/24)
 Not available 0 17
Disease status at HCT
 sCR 6 (27%) 13 (32%)
 CR 4 (18%) 13 (32%)
 VGPR 12 (55%) 15 (36%)
 Number of prior therapy 1 (100%) 1 (100%)
Prior therapya
 Lenalidomide-based 2 (9%) 8 (19%)
 Bortezomib-basedb 9 (41%) 16 (39%)
 Both lenalidomide and bortezomib 11 (50%) 4 (10%)
 Other regimens 0 13 (32%)
Donor relation
 Related 9 (41%) —
 Unrelatedc 13 (59%) —
 Donor/recipient gender matching (Male/female = 25/16)
 Female/female 5 (23%) —
 Female/male 4 (18%) —
 Male/female 6 (27%) —
 Male/male 7 (32%) —
Donor/recipient CMV
 Negative/negative 6 (27%) —
 Negative/positive 7 (32%) —
 Positive/negative 3 (14%) —
 Positive/positive 6 (27%) —
GVHD prophylaxis
 Tacrolimus/MTX 8 (36%) —
 Tacrolimus/mycophenolate mofetil 6 (28%) —
 Tacrolimus/sirolimus 8 (36%) —
 Median CD34 (range) cell dose (× 106/kg)d 6.38 (1.43–10.65) 3.53 (2.02–30.06)
 Median Karnofsky performance status (range) at HCT 90 (80–100) 90 (70–100)
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Abbreviations: HCT = hematopoietic cell transplantation; sCR = stringent CR; VGPR, very good partial response

a

All patients received dexamethasone.

b

Two patients received liposomal doxorubicin containing triplet therapy and two others received CY-containing triplet therapy.

c

One donor was mismatched at DQ locus (9/10 matched)

d

Recipient who received 1.43 × 106 CD34+ cells/kg later received stem cell boost.

Table 2.

Initial systemic therapy for allogeneic HCT recipients

Regimens n
CVDD 4
Rev/Dex 2
Rev/Dex followed by RVD 3
Vel/Dex followed by RVD 2
RVD followed by Vel/Dex 1
RVD 4
DVD 2
Vel/Dex 1
Ve/Dex followed by CyBorD followed by Rev/Dex 1
CyBorD 1
Thal/Dex followed by DVD 1
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Abbreviations: CVDD = CY, bortezomib (Velcade), liposomal doxorubicin (Doxil) and dexamethasone; CyBorD = CY, bortezomib and dexamethasone; Dex = dexamethasone; DVD = liposomal doxorubicin (Doxil), bortezomib (Velcade) and dexamethasone; Rev = lenalidomide (Revlimid); RVD = lenalidomide (Revlimid), bortezomib (Velcade) and dexamethasone; Thal = thalidomide

Engraftment and chimerism

Neutrophil engraftment was achieved at medians of 15 (range, 11–19) days after transplant in allogeneic HCT recipients and 17 (range, 12–21) days after autologous HCT. Platelet engraftment was achieved at medians of 16 (range, 12–21) days after allogeneic HCT and 12 (range, 10 – 17) days after autologous HCT. At day +30, CD3- and CD33-sorted peripheral blood cells (n = 20) were medians of 100 (range, 80.99–100) % donor type and 100 (range, 98.76–100) % donor type, respectively. There were no graft failures. BM engraftment at 6 (n = 10) and 12 months (n = 8) were medians of 100 (range, 95–100) and 100 (range, 96–100) % donor type, respectively.

Response

Stringent CR (sCR) was noted in 6 patients (27%) before the allogeneic HCT, which was increased to 15 recipients (68%) at best response after the transplant. One patient progressed after achieving sCR at +446 days, while all other sCR recipients maintained their responses at the time of analysis. Of those 12 patients who were in VGPR at the time of transplant, 4 converted to CR and 5 converted to sCR at their best responses; 2 recipients remained in VGPR. In the autologous cohort, sCR was achieved in 24 patients (57%) and CR was achieved in 9 patients (21%) after autologous HCT. Cumulative incidence of relapse at 24 months was 8.3% (95% CI: 0.4%–32.4%) for the allogeneic cohort and 45.6% (94% CI: 29.4%–60.5%) for the autologous cohort.

GVGD

After allogeneic HCT, the cumulative incidence of grades II–IV acute GVHD at day 100 was 45% (95% CI: 24–65%) overall (Figure 1). The cumulative incidence of moderate-to-severe chronic GVHD at 2 years based on NIH consensus criteria was 46% (95% CI: 26–79%) (Figure 2). Of 10 patients who were treated with systemic corticosteroid for GVHD, 3 (30%) were tapered to off at the time of analysis. There were 7 patients who received tacrolimus and MTX GVHD prophylaxis with bortezomib as part of their conditioning and only 1 developed acute GVHD.

Figure 1.

Figure 1

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Cumulative incidence curve of grade 2–4 acute GVHD.

Figure 2.

Figure 2

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Moderate-to-severe chronic GVHD.

OS and PFS

After allogeneic HCT, 4 patients died of GVHD-related complications, 1 died of disease progression and 18 remained alive at the time of analysis. The 2-year PFS estimate is 74.8% (95% CI: 44.6–90.1%) with a median follow-up of 18 (range, 2–61) months for allogeneic HCT cohort, and 51.9% (95% CI: 35.4–66.1%) for the autologous HCT cohort with a median follow-up of 30 months (range, 9–55 months) (Figure 3). The 2-year OS estimate is 77.5% (95% CI: 49.7–91.1%) for allogeneic HCT cohort and 90.0% (95% CI: 75.4–96.1%) for the autologous cohort (Figure 4). There were no differences in PFS or OS when allogeneic HCT patients were stratified based on their cytogenetic risk group (P = 0.914). NRM at 6 24 months are 10.5% (95% CI: 1.6–29%) and 16.9% (95% CI: 3.8 –8%) for the allogeneic cohort, and 2.4% (95% CI: 0.2–11.2%) and 2.4% (95% CI: 0.2–11.2%) for the autologous cohort.

Figure 3.

Figure 3

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PFS.

Figure 4.

Figure 4

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OS.

Quality of life

For allogeneic HCT recipients (n = 12), mean FACT-G scores were 82.4 at baseline (n = 11), 68.9 at day +30 (n = 12), 79.1 at day +90 (n = 8), 84.4 at day +180 (n = 11), 78.6 at day +270 (n = 11), 79.3 at day +360 (n = 5), 77.3 at day +540 (n = 6) and 87.1 at day +740 (n = 3). Mean FACT-BMT total scores were 109.4 at baseline (n = 11), 92.5 at day +30 (n = 12), 106.1 at day +90 (n = 8), 115.8 at day +180 (n = 11), 106.1 at day +270 (n = 6), 106.3 at day +360 (n = 5), 102.9 at day +540 (n = 6) and 115.4 at day +740 (n = 3) (Figure 5). QOL data were not collected for autologous HCT cohort.

Figure 5.

Figure 5

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FACT-BMT Total Score.

DISCUSSION

Our study illustrates that allogeneic HCT as consolidation of VGPR or CR with fludarabine and melphalan ± bortezomib conditioning can produce excellent disease control with 2-year PFS of 74.8% (95% CI: 44.6–90.1%) and low NRM of 10.5% (95% CI: 1.6–29%) at 6 months. Thirteen patients received bortezomib with fludarabine + melphalan conditioning under the clinical trial and nine patients received fludarabine + melphalan conditioning regimen off study. There is increasing evidence to suggest that the timing of reduced-intensity transplant is crucial for lowering NRM and improving the disease control rate.22 Patients who received allografting with reduced-intensity conditioning after the failure of a previous autograft have a much higher risk of disease progression/relapse and NRM than those patients who remained in remission at the time of allogeneic HCT.23,24

Recent trends in myeloma allogeneic HCT reported by the Center for International Blood and Marrow Transplantation (CIBMTR) showed increasing recipient age (53% were >50 years) and more frequent unrelated donor grafts. OS at 1 year improved over time (63% in years 2001–2005), in part, secondary to a decrease in NRM (22%). However, relapse remains a major obstacle (58% at 5 years), especially as 29% were chemotherapy-resistant at the time of transplant.25 Multiple trials have examined the allogeneic HCT platform where cytoreduction of multiple myeloma was achieved with autologous HCT followed by reduced-intensity conditioning allogeneic HCT (tandem auto-allo HCT approach).6,10,11,26–28 A phase 3 biologic assignment trial by BMT Clinical Trial Network (BMT CTN 0102 protocol) comparing auto-allo HCT approach to tandem autologous HCT showed equivalent outcomes at 3 years in standard-risk patients, but a longer follow-up is likely required to assess the true survival benefits of this strategy.6 Initial cytoreduction remained an issue as only 42% in standard-risk and 6–32% in high-risk group, respectively, were in VGPR + CR at the time of first autologous HCT.

Achieving better response, that is, VGPR or CR, prior to HCT has been associated with at least PFS and some with OS benefits in the context of autologous HCT.29,30 Obtaining molecular response after allogeneic HCT has been demonstrated to translate into longer PFS, which further substantiates the concept of targeting deeper response in myeloma therapy in order to improve treatment outcomes.4,15,31 Another consideration would be the cost of achieving VGPR or CR by performing autologous HCT as a cytoreductive measure.32,33 Similar response may be achieved with novel inductions without autologous HCT, though the universal application of these agents could be problematic due to prohibitive developmental costs and potential toxicities.

Although there are significant interests in exploring the antimyeloma therapy to augment graft-versus-myeloma effects in the post-HCT setting, there has been no consensus on maintenance therapy after allogeneic HCT.34 The HOVON 76 trial investigated the role of lenalidomide maintenance after allogeneic HCT, but the strategy did not appear to be feasible, due to GVHD.35 Another study is currently being conducted by CIBMTR, examining lenalidomide maintenance after allogeneic HCT. Wolschke et al.36 conducted a phase I/II trial of post-allografting lenalidomide and showed significantly increased peripheral γ-IFN-secreting CD4+ and CD8+ T cells during the 1st week of lenalidomide, with subsequent rise in regulatory T cells. In addition, anti-myeloma natural killer cell activity was increased after lenalidomide in responding myeloma patients. Immunomodulatory agents with increased natural killer cell-mediated cytotoxicity warrant further investigation in order to augment graft-versus-myeloma potential after allogeneic HCT.

Dramatic improvement of initial systemic therapy with significant reduction in disease burden may obviate the need for cytoreductive autologous HCT and has set the stage for asking questions regarding the curative potential of allogeneic HCT.7,13,37 International Myeloma Working Group (IMWG) has released the statement that allogeneic HCT should be conducted under clinical trials.34 Our ongoing allogeneic HCT trial as a consolidation therapy of first response targets those myeloma patients who achieved VGPR or CR to circumvent the need for debulking and to avoid the pitfalls of early relapse.

The health-related QOL is a vital component of comprehensive peri-transplant care.38 In this small cohort of patients, the observed trajectory of reported QOL may be consistent with previously reported results.39 Following an initial decline in some patients, most returned to or exceeded pre-HCT-QOL by 6 months. These data complement the reported survival outcomes and facilitate the understanding of the patients’ experience.

CONCLUSIONS

These initial data indicate that allogeneic HCT for multiple myeloma in first VGPR or CR can be well tolerated and argues for the investigation of allogeneic HCT strategy as a consolidation therapy early in the disease course. A larger number of patients is required to assess the true efficacy of allogeneic HCT used for consolidation of remission in preventing relapse or progression of multiple myeloma.

Acknowledgments

We thank the patients, physicians, nurses and research staffs at MCC. We also thank Ms Pamela Reiersen for data collection on QOL measures.

Footnotes

CONFLICT OF INTEREST

MA is a consultant to and receives research support from Millennium Pharmaceuticals Inc.; RB, receives research support from Millennium Pharmaceuticals Inc. The remaining authors declare no conflict of interest.

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