INTRODUCTION — Allogeneic hematopoietic cell transplantation (HCT) may be the only treatment for patients with multiple myeloma (MM) that has a chance of producing cure. Its use, however, is limited since even ideal candidates who undergo allogeneic HCT have a high rate of treatment-related mortality, and because its efficacy compared with autologous HCT is not fully established. The treatment-related mortality associated with allogeneic HCT is decreasing with the advent of nonmyeloablative preparative regimens. At the same time, new chemotherapeutic agents (eg, bortezomib, lenalidomide) are being incorporated into the initial treatment of MM, and survival with chemotherapy alone or with autologous HCT is improving. As such, the role of allogeneic HCT in the treatment of MM is not clear.
The use of allogeneic HCT in the management of patients with MM will be reviewed here. The process of determining the appropriate initial therapy for patients with MM, eligibility guidelines for HCT, and response criteria used to evaluate the treatment of MM are discussed separately, as is a comparison of allogeneic HCT to autologous HCT and chemotherapy. (See "Multiple myeloma: Overview of management" and "Multiple myeloma: Initial treatment" and "Multiple myeloma: Evaluating response to treatment".)
The term "hematopoietic cell transplantation" (HCT) will be used throughout this review as a general term to cover transplantation of progenitor (stem) cells from any source (eg, bone marrow, peripheral blood, cord blood). Otherwise, the source of such cells will be specified (eg, autologous peripheral blood progenitor cell transplantation). (See "Sources of hematopoietic stem cells".)
MYELOABLATIVE HCT — Myeloablative allogeneic HCT requires hematopoietic cells from an HLA-matched donor, which are given after the patient receives high dose chemotherapy and total body radiation. Allogeneic HCT has two advantages over autologous HCT: the graft does not contain tumor cells; and the transplant can produce a graft-versus-myeloma effect [1,2]. Less than 5 to 10 percent of patients with MM are candidates for this approach due to its high toxicity. A detailed discussion on eligibility guidelines is presented separately. (See "Multiple myeloma: Overview of management", section on 'Autologous versus allogeneic HCT'.)
In earlier studies, allogeneic HCT for myeloma was associated with an early mortality of at least 20 percent and an overall mortality of 30 to 50 percent, due to fungal infections, interstitial pneumonitis, and graft-versus-host disease [3-8]. This mortality rate limited the use of myeloablative allogeneic HCT [9]. Although there is a suggestion that the mortality rates are lower in more recent years, data are lacking. (See "Multiple myeloma: Overview of management", section on 'Autologous versus allogeneic HCT'.)
The outcome after allogeneic HCT is best in patients with a low initial tumor burden who go into complete remission after first-line chemotherapy [3]. However, myeloma usually relapses after allogeneic HCT, even in complete responders. In a series of 80 patients in Seattle who underwent allogeneic HCT, only five were alive without evidence of disease four to seven years after HCT [5]. However, the majority of these patients had chemotherapy-resistant disease, which may have contributed to the relatively poor long-term outcome.
At this time, standard myeloablative transplants are not routinely performed in newly diagnosed myeloma outside of a clinical trial setting [10]. Myeloablative allogeneic transplantation is considered (typically as an option at first relapse) in selected patients (age less than 60 to 65 years) with high risk relapsed myeloma who have a matched donor and are willing to accept a high early treatment-related mortality. Myeloablative allogeneic transplantation can be considered in selected patients with relapsed refractory myeloma with a good performance status in whom other treatment options appear limited, but in this setting the risks are higher and the probability of a durable remission is low. Options for conditioning regimens for a myeloablative allogeneic transplantation in myeloma include Mel200 (melphalan 200 mg/m2), Mel/TBI (melphalan 140 mg/m2 plus total body radiation 12 Gy), and BuMel (busulphan, melphalan).
SYNGENEIC HCT — Only a limited number of syngeneic (ie, identical twin donor) transplants have been performed in MM.
●The European Group for Blood and Marrow Transplantation performed a case-matched analysis on 25 syngeneic transplants (24 using bone marrow and one using peripheral blood stem cells) and compared the results with 125 patients who underwent autologous transplantation and another 125 who underwent allogeneic transplantation [11]. Only two twins died of transplant-related toxicity. Overall survival for the twins was 73 months, significantly better than that of the case-matched autologous transplants (44 months); both groups outperformed the allogeneic transplants.
●The Seattle Marrow Transplant Team performed syngeneic transplants on five patients with MM [12]. Four patients responded to therapy, while one patient died one month after transplant from cytomegalovirus-associated interstitial pneumonitis. Response durations for these four patients were 6, 17, 18, and more than 72 months.
These reports support the use of syngeneic HCT in place of an autologous HCT if a twin donor is available. If an identical twin donor is available, it is reasonable to consider a syngeneic HCT in place of autologous HCT.
T CELL DEPLETED ALLOGENEIC HCT — The use of T cell-depleted peripheral blood stem cells decreases the incidence of graft-versus-host disease (GVHD) and reduces transplant mortality, issues which are especially important in patients with MM. However, in some of the available studies, treatment-related mortality has been appreciable, while in others relapse may be more frequent, due in part to lessening of graft-versus-myeloma effect [1,13].
As an example, a study of 53 patients with previously untreated MM and an HLA-identical sibling received induction therapy followed by a partially T cell-depleted myeloablative allogeneic HCT [14]. Although the overall response rate was 89 percent, treatment-related mortality was 34 percent and 26 percent of patients died from progressive myeloma. At a median follow-up of 38 months, only 3 of the 20 surviving patients were in long-term complete remission.
The use of a T cell-depleted allogeneic HCT, combined with late donor lymphocyte infusion (DLI) to increase the graft-versus-myeloma effect is an approach currently under investigation. In one study, treatment-related toxicity was appreciable; only 14 of the 24 patients were able to receive a T cell-depleted HCT plus DLI [15]. However, patients completing the full program had an estimated two-year progression-free survival of 65 percent.
At this time, T cell-depleted transplants are not recommended outside of a clinical trial setting [10].
NONMYELOABLATIVE ALLOGENEIC HCT — Nonmyeloablative preparative regimens use less intensive chemotherapy or irradiation alone prior to the infusion of donor hematopoietic stem cells. This approach relies more on donor cellular immune effects and less on the cytotoxic effects of the preparative regimen to control the underlying disease. Nonmyeloablative allogeneic HCT and reduced intensity HCT are associated with lower rates of treatment-related toxicity and treatment-related mortality, but higher rates of relapse compared with rates previously seen with myeloablative allogeneic transplantation [16-22]. (See "Preparative regimens for hematopoietic cell transplantation", section on 'NMA and RIC regimens'.)
The importance of the graft-versus-tumor effect is supported by studies that show improved survival in patients who develop chronic GVHD [23]. As with myeloablative allografts, the best outcomes are seen in patients transplanted early in the course of their disease when the disease is in remission. As such, several groups are pursuing protocols in which an autologous HCT is followed by a nonmyeloablative allogeneic HCT [24-26].
The prospective trials that have investigated nonmyeloablative HCT have conflicting data regarding survival rates, but are consistent in their treatment-related mortality rates (11 to 18 percent at five years) and rates of extensive GVHD (50 to 74 percent). New strategies are needed to improve the safety and efficacy of nonmyeloablative HCT. Until such improvements are demonstrated, this strategy is not recommended for most patients with newly diagnosed myeloma outside of a clinical trial setting [10,27].
Autologous followed by nonmyeloablative allogeneic HCT in newly diagnosed myeloma — The strategy of autologous HCT followed by nonmyeloablative allogeneic HCT is not recommended for patients with newly diagnosed myeloma outside of a clinical trial setting, except perhaps in those with high-risk prognostic factors (ie, del(13), hypodiploidy, t(14;16), del(17p), or a plasma cell labeling index of ≥3 percent). Even in such patients the role of allogeneic HCT approaches is investigational, especially given the superior results that are being obtained with newer induction regimens.
Randomized trials of allogeneic HCT have not been feasible for patients with myeloma. Instead, investigators have relied on a "biologic randomization" in which patients are assigned to treatment with or without allogeneic HCT based on the presence or absence of an HLA-matched sibling donor. Patients without an HLA-matched sibling are assigned to treatment with maintenance therapy or observation, depending on the trial design. Results are then evaluated by an intention-to-treat analysis for "donor" and "no donor" (available) treatment groups. As with randomized trials, not all patients in the "donor" group ultimately receive an allogeneic HCT, but they would still be included in the "donor" group for the statistical analysis.
The results of donor versus no donor trials have been mixed. While they all demonstrate lower relapse rates and higher rates of nonrelapse mortality among allogeneic HCT recipients, the majority suggests that this does not translate into a survival benefit. Of importance, options for the treatment of relapsed myeloma have increased dramatically since many of these trials were conducted. The most recent trials, some of which allowed for the use of novel agents (eg, bortezomib) at relapse, have not demonstrated a survival benefit with allogeneic HCT.
A 2013 meta-analysis included data from 1822 patients with previously untreated myeloma enrolled on six prospective trials comparing double autologous HCT versus a single autologous HCT followed by nonmyeloablative allogeneic HCT [28]. When compared with double autologous HCT, allogeneic HCT was associated with greater treatment-related mortality (relative risk [RR] 3.3; 95% CI 2.2-4.8) and a greater likelihood of attaining a complete response (RR 1.4; 95% CI 1.1-1.8), but similar overall survival both during the first 36 months (hazard ratio [HR] 1.15; 95% CI 0.91-1.45) and beyond 36 months (HR 0.74; 95% CI 0.53-1.04).
The following is a brief summary of the largest trials conducted in this setting:
●The largest study was conducted by the Bone Marrow Transplant Clinical Trials Network [29]. Of the 625 patients with standard-risk myeloma in this trial, 189 with an HLA-identical sibling donor were assigned to receive a myeloablative autologous HCT followed by a nonmyeloablative allogeneic HCT (completed in 83 percent). The 436 patients without a sibling donor were assigned to double autologous HCT (completed in 84 percent) followed by a second randomization to maintenance thalidomide/dexamethasone or observation. At a median follow-up of 40 months, double autologous HCT resulted in similar rates of progression-free (46 versus 43 percent) and overall (80 versus 77 percent) survival at three years when compared with autologous HCT followed by nonmyeloablative allogeneic HCT. In the nonmyeloablative allogeneic HCT arm, grade II–IV acute GVHD occurred in 26 percent of patients by day 100. The cumulative incidence of chronic GVHD was 47 percent at one year and 54 percent at two years. As with standard-risk myeloma, a subgroup analysis of the 85 patients enrolled in this trial with high-risk myeloma found no benefit to autologous HCT followed by nonmyeloablative allogeneic HCT. Thalidomide maintenance did not improve progression-free or overall survival.
●In the HOVON-50 MM study, 260 patients who had received an autologous HCT were genetically assigned to receive a reduced intensity conditioning allogeneic HCT from a sibling donor (122 patients) or maintenance therapy with thalidomide or interferon alfa [30]. After a median follow-up of 77 months, when compared with maintenance therapy, allogeneic HCT was associated with similar rates of progression-free (28 versus 22 percent) and overall (55 percent) survival at six years.
●In another trial, the French IFM group demonstrated that patients with high-risk myeloma (deletion 13 by FISH or an elevated beta-2 microglobulin level) showed no benefit with autologous HCT followed by reduced intensity allogeneic HCT compared with tandem autologous HCT [31].
●The Spanish PETHEMA group prospectively compared the use of autologous (85 patients) or reduced-intensity allogeneic (25 patients) HCT in 110 patients with myeloma who failed to achieve a complete or near complete remission after an initial autologous HCT [32]. At a median follow-up after second transplantation of 5.2 years of patients who received an allogeneic HCT there was no difference in event-free or overall survival rates.
●In contrast to the above four studies, an Italian study that enrolled 162 consecutive patients with newly diagnosed myeloma who were ≤65 years of age and had at least one sibling found a survival benefit with nonmyeloablative allogeneic transplantation [26]. When compared with patients undergoing auto-auto HCT, patients undergoing auto-allo HCT had the following significant outcomes [26,33]:
•A higher two-year cumulative incidence of treatment-related mortality (10 versus 2 percent)
•A lower cumulative incidence of disease-related mortality at a median follow-up of 45 months (43 versus 7 percent)
•Cumulative incidences of grades II to IV GVHD and grade IV GVHD of 43 and 4 percent, respectively
•A longer median overall survival (not yet reached at a median follow-up of seven years versus 4.25 years; HR 0.51, 95% CI 0.34-0.76)
●One other study, a prospective study from the European Bone Marrow Transplantation, has also shown survival benefit. In this study, 357 patients with newly diagnosed myeloma who underwent autologous HCT followed by reduced-intensity allogeneic HCT (for those who had a sibling donor, 108 patients), by a second autologous HCT (104 patients), or by observation (145 patients) [34]. At a median follow-up of 61 months, patients who underwent allogeneic HCT had significantly higher rates of progression-free (35 versus 18 percent) and overall (65 versus 58 percent) survival at 60 months; a higher rate of nonrelapse mortality at 24 months (12 versus 3 percent); and clinically significant cumulative incidences of grade II to IV acute GVHD (20 percent), limited chronic GVHD (31 percent), and extensive chronic GVHD (23 percent). The survival benefit persisted at eight years in the population as a whole (49 versus 36 percent) and on subgroup analysis of patients with del(13) (47 versus 31 percent) [35].
Together, the available data demonstrate that nonmyeloablative HCT is associated with a higher cumulative incidence of nonrelapse mortality and a lower incidence of relapse; however, this does not appear to translate into a survival benefit in the setting of novel agents. Therefore, nonmyeloablative allogeneic transplantation in newly diagnosed myeloma remains investigational. The treatment-related mortality is approximately 10 to 20 percent and the rates of acute and chronic GVHD are high. It is also unclear what impact nonmyeloablative HCT will have, given the major changes in induction therapy using novel agents.
Of importance, the HOVON 76 trial evaluated nonmyeloablative allogeneic HCT followed by lenalidomide maintenance in 35 patients with newly diagnosed myeloma [36]. Lenalidomide maintenance was poorly tolerated and patients also had rapid onset of GVHD. Lenalidomide maintenance is not recommended after allogeneic HCT. (See "Multiple myeloma: Use of autologous hematopoietic cell transplantation", section on 'Standard-risk disease'.)
Nonmyeloablative allogeneic HCT in relapsed myeloma — As with myeloablative HCT, the use of nonmyeloablative HCT can be considered in selected young patients with high-risk relapsed myeloma who have a matched donor and are willing to accept a high treatment-related mortality rate and the conflicting data on the efficacy of the intervention.
The choice between myeloablative versus nonmyeloablative HCT often depends on the expertise of the institution where the procedure is done, and in some cases based on the age and functional status of the patient.
The following studies have evaluated nonmyeloablative allogeneic transplantation in patients relapsing after autologous HCT [33,37-42]:
●In the largest study, the European Group for Blood and Marrow Transplantation evaluated 413 patients with myeloma relapsing or progressing after prior autologous HCT who underwent reduced intensity conditioning followed by related (62 percent) or unrelated allogeneic HCT [43]. In this cohort, 45 percent had undergone two or more prior autologous HCTs. Median progression-free survival and overall survival from the time of transplant were 9.6 and 24.7 months, respectively. Cumulative nonrelapse mortality at one year was 22 percent. The five-year survival rate was approximately 30 percent, but there did not appear to be a plateau in the survival curves. Grade II to IV acute GVHD and extensive chronic GVHD were reported in 33 and 27 percent, respectively.
●In a study of 53 patients, 33 of whom had relapsed after one or more prior autologous transplants, complete remission was attained in 62 percent [37]. Transplant-related mortality was 13 percent and grade III to IV acute GVHD and chronic GVHD were noted in 5 and 64 percent, respectively. At a median follow-up of 22 months, three-year estimated overall and progression-free survivals were 45 and 37 percent, respectively.
●In a larger study of 68 patients, 65 of whom had relapsed after a prior autologous HCT, complete remission rate (35 and 34 percent) and treatment-related mortality (24 and 18 percent) were similar for those with or without chromosome 13 deletion, while two-year overall survivals were 18 and 67 percent, respectively [38]. The higher relapse rate in patients with chromosome 13 deletion (HR 3.3, 95% CI 1.3-8.2) suggested the need for additional post-remission treatment, such as donor lymphocyte infusion. (See 'Donor lymphocyte infusion' below.)
●A retrospective analysis of 50 patients with relapsed or refractory MM treated with a fludarabine/melphalan-based conditioning regimen followed by the infusion of a graft from a related (27 patients) or unrelated donor reported a nonrelapse mortality rate of 26 percent with a median follow-up time of 6.4 years. Overall and progression-free survival rates were 34 and 26 percent, respectively [41].
Longer term follow-up of these studies is awaited [10].
MONITORING REMISSION POST-ALLOGENEIC HCT — Patients should be evaluated at approximately day 100 after transplantation to determine how their disease has responded to therapy. The preferred method is the measurement of monoclonal (M) protein in serum and urine. Free light chain (FLC) measurements are primarily reserved for patients with unmeasurable M-protein in the serum and urine. Among patients without an M protein in serum or urine and normal FLC ratio, further evaluation includes bone marrow immunohistochemistry or immunofluorescence and plasma cell labeling index. Blood counts, renal function, and serum calcium are also monitored. After day 100, tests for monitoring response to therapy and to detect relapse are performed every three months.
The International Myeloma Working Group has developed uniform response criteria, which are used to measure the effect of treatment for MM. These criteria are described in detail separately. (See "Multiple myeloma: Evaluating response to treatment".)
Allogeneic HCT and minimal residual disease negative state — Outcome after HCT may be better assessed by evaluating the patient for achievement of a minimal residual disease (MRD) negative state (complete remission by molecular methods) [44]. This issue was addressed in a series of 48 patients in complete clinical remission (CCR) following allogeneic HCT [45]. Durable polymerase chain reaction (PCR) negativity for clone-specific markers, mixed negativity and positivity, or positivity were noted in 33, 40, and 27 percent, respectively. The cumulative risks for disease relapse at five years were zero, 33, and 100 percent, respectively. However, testing for MRD negativity at present is experimental and is not available in most centers.
In a study of 229 patients with MM, CCR was attained in 38 and 22 percent following allogeneic or autologous HCT, respectively [44]. For those attaining CCR following allogeneic or autologous HCT, 50 and 16 percent, respectively, were considered to be MRD negative, as defined by repeated PCR negativity. Median relapse-free survivals for those who did or did not attain MRD negativity were 110 and 35 months, respectively [44]. Corresponding relapse rates were 16 and 41 percent, respectively.
These results support the concept, as shown in other hematologic malignancies, that a deeper response is associated with longer relapse-free survival and reduced relapse rates. However, as noted above, the achievement of a complete response by molecular methods (MRD negativity) does not equate with cure. In one study of 14 patients with MM in complete remission by the EBMT criteria following high dose melphalan and autologous HCT, all were PCR negative on follow-up bone marrow examination [46]. However, 8 of the 14 have since relapsed, all with the original immunoglobulin rearrangement present at disease presentation. The main limitations are that MRD testing is not widely available and not fully standardized.
Similar results can perhaps be obtained by monitoring for the presence of neoplastic plasma cells in bone marrow aspirates post-HCT, using flow cytometry [47]. In one study, the 12 patients in the "low risk" group (ie, no malignant cells at both three and six months post-transplant) had a five-year overall survival of 100 percent, while the 23 patients in the "high risk" group (ie, either malignant cells at three months or no malignant cells at three months reverting to malignant cells at six months) had a five-year survival of 54 percent.
TREATMENT OF RELAPSE AFTER HCT — Treatment options for relapsed MM after an allogeneic HCT include donor lymphocyte infusion or treatment with salvage chemotherapy.
Donor lymphocyte infusion — Donor lymphocyte infusion (DLI) produces significant clinical benefit in many patients with MM relapsing after allogeneic HCT [48]. In a series of 54 patients, DLI yielded overall and complete response rates of 52 and 17 percent, and acute and chronic graft-versus-host disease (GVHD) in 57 and 47 percent, respectively [49]. Progression-free survival was 20 months for partial responders, and had not been reached for those achieving complete remission. Predictive factors for response to DLI were remission before allogeneic HCT and the occurrence of acute or chronic GVHD. Of interest, deletion of chromosome 13 did not influence response or outcome following DLI. (See "Immunotherapy for the prevention and treatment of relapse following allogeneic hematopoietic cell transplantation".)
In one exploratory study, use of prophylactic DLI with CD4+ cells at six months following HCT enhanced reconstitution of donor T cells and conversion to full donor hematopoiesis, as well as promoting antitumor immunity [50].
●In 18 patients with progressive or residual disease and prior ineffective DLI after allogeneic HCT, adoptive therapy with low dose thalidomide plus DLI achieved an overall response rate of 67 percent with a low incidence of acute and chronic GVHD [51].
●In a second study, objective responses to salvage treatment with thalidomide were noted in 9 of 31 patients with myeloma progressing after allogeneic HCT [52].
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple myeloma".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Allogeneic bone marrow transplant (The Basics)")
●Beyond the Basics topics (see "Patient education: Multiple myeloma symptoms, diagnosis, and staging (Beyond the Basics)" and "Patient education: Multiple myeloma treatment (Beyond the Basics)" and "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●At present, patients with multiple myeloma (MM) should be aware of the availability, and encouraged to undergo, autologous hematopoietic cell transplantation (HCT) if they are eligible for the procedure. (See "Multiple myeloma: Overview of management", section on 'Determining transplant eligibility'.)
●Myeloablative allogeneic HCT is not routinely performed in newly diagnosed myeloma outside of clinical trials. Myeloablative allogeneic HCT is considered (usually at first relapse) in selected patients (age less than 60 to 65 years) with high-risk myeloma who have a matched donor and are willing to accept a high early treatment-related mortality. Myeloablative allogeneic HCT is also considered in selected patients with relapsed refractory myeloma with a good performance status in whom other treatment options appear limited.
●Efforts to reduce allogeneic HCT-related mortality with the use of nonmyeloablative regimens remain investigational. Nonmyeloablative HCT can be considered in selected patients with relapsed myeloma who have a matched donor and are willing to accept a high treatment-related mortality. (See "Prevention of graft-versus-host disease" and "Preparative regimens for hematopoietic cell transplantation", section on 'NMA and RIC regimens'.)
●The use of maintenance therapy, dendritic cells, and vaccines following allogeneic HCT is under investigation.
