INTRODUCTION — High-dose therapy followed by autologous hematopoietic cell transplantation (HCT), performed either at the time of initial diagnosis or at relapse, is considered the standard of care for younger patients (less than 70 years of age) with newly diagnosed multiple myeloma (MM) (algorithm 1). Although high-dose therapy with autologous HCT is not curative, event-free survival and overall survival are prolonged compared to treatment with standard-dose myeloma treatments alone.
Allogeneic HCT has the potential for cure but has high treatment-related mortality without a clear benefit over autologous HCT. This has greatly limited the role of allogeneic HCT in the treatment of MM. The use of allogeneic HCT for MM is discussed in detail separately. (See "Multiple myeloma: Use of allogeneic hematopoietic cell transplantation".)
Practical issues regarding the use of autologous HCT in myeloma are presented here. Eligibility criteria for HCT, a comparison of HCT with other treatment strategies, and the initial chemotherapy choices for patients with myeloma are discussed separately. (See "Multiple myeloma: Overview of management", section on 'Autologous HCT versus chemotherapy alone' and "Multiple myeloma: Initial 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".)
INITIAL CHEMOTHERAPY — In patients who are candidates for HCT, induction chemotherapy is administered for approximately four months prior to stem cell collection in order to reduce the number of tumor cells in the bone marrow and peripheral blood, lessen symptoms, and mitigate end-organ damage. Initial therapy consists of regimens such as bortezomib, lenalidomide, dexamethasone (VRd) or bortezomib, cyclophosphamide, dexamethasone (VCd) (algorithm 1). Melphalan-containing regimens should be avoided prior to the collection of stem cells, since their use has been associated with damage to the hematopoietic stem cell compartment as well as an increased risk of myelodysplasia following transplantation.
Prolonged initial therapy may impair hematopoietic stem cell collection [1]. Therefore hematopoietic stem cells are usually collected within the first four cycles of initial therapy even in patients in whom a delayed autologous HCT is contemplated.
The specific regimen used as initial therapy is determined based on patient characteristics, induction-related early mortality and morbidity, ease of administration, and side effect profiles. The choice of initial chemotherapy is discussed in detail separately. (See "Multiple myeloma: Initial treatment".)
COLLECTION OF STEM CELLS — Hematopoietic progenitor (stem) cells should be collected before the patient is exposed to alkylating agents [2]. Hematopoietic stem cells can be harvested directly from the bone marrow or collected by apheresis from the peripheral blood after stimulation with granulocyte colony-stimulating factor (G-CSF) or with the addition of chemotherapy. Peripheral blood progenitor cells (PBPCs) are preferable to bone marrow cells for transplantation due to quicker engraftment and a potential for less contamination of the infused cells with tumor cells. The various sources of hematopoietic stem cells are discussed in detail separately. (See "Hematopoietic support after hematopoietic cell transplantation", section on 'Autologous PBPC transplantation' and "Sources of hematopoietic stem cells", section on 'PBPC mobilization'.)
G-CSF alone and G-CSF plus cyclophosphamide are the most common regimens used for stem cell mobilization [3-5]. The usual dose of G-CSF is 10 mcg/kg per day subcutaneous. Cyclophosphamide is usually administered at a dose of 1.5 to 6 grams/m2 intravenous for two days. The choice between the two methods is mainly dependent on institutional preference and experience. There are no randomized trials comparing the two approaches.
At Mayo Clinic, we prefer G-CSF alone (10 mcg/kg once daily), and reserve G-CSF plus cyclophosphamide for patients who fail to collect adequate stem cells with G-CSF alone, and for patients who have had an inadequate response to induction therapy. This is supported by the observation that patients with a high tumor burden demonstrate delayed platelet recovery when transfused with PBPCs collected following growth factor treatment alone [6]. Some institutions use G-CSF plus cyclophosphamide as their standard. G-CSF plus cyclophosphamide has the advantage of providing much higher PBPCs than G-CSF alone, but it also carries the risk of longer time to start collection and the risk of neutropenia.
Plerixafor, a chemokine receptor type 4 inhibitor that acts to impair the binding of hematopoietic stem cells within the bone marrow microenvironment, is also available for use in combination with G-CSF in patients with MM [7,8]. Initial reports suggest this agent may improve stem cell collection [9]. We reserve plerixafor primarily for patients who fail stem cell collection with either G-CSF or G-CSF plus cyclophosphamide [1,10-12]. (See "Sources of hematopoietic stem cells", section on 'Plerixafor'.)
Following initiation of one of the mobilization regimens discussed above, patients are monitored by peripheral blood CD34 counts [13]. We begin apheresis when the peripheral CD34+ counts reach 10 CD34 cells/microL, however, thresholds for initiating apheresis vary by institution and algorithms for stem cell collection need to be established. (See "Sources of hematopoietic stem cells".)
Apheresis is performed with a goal of collecting at least 3 x 106 CD34+ cells/kg if only one transplant is being considered, or at least 6 x 106 CD34+ cells/kg if two transplants are being considered. A minimum of 2 x 106 CD34+ cells/kg is considered essential for one transplant. In general, we harvest enough PBPCs for two transplantations; a single transplantation is done with one-half of the collected cells and the other half are cryopreserved. A second (tandem) transplant (using the cryopreserved stem cells) is considered for patients not achieving complete or near complete response with the first transplant. For patients achieving complete or near complete response with the first transplant, the cryopreserved stem cells may be reserved for transplantation at relapse [14,15].
PROCESSING AND STORAGE OF STEM CELLS — Peripheral blood progenitor cells (PBPCs) are cryopreserved in 5 percent dimethylsulfoxide to be thawed at the bedside at the time of infusion [16].
Infused peripheral blood stem cells or bone marrow are inevitably contaminated by myeloma cells or their precursors, and may contribute to relapse [17]. In a xenotransplant mouse model, injection of G-CSF mobilized cells from patients with minimal myeloma resulted in the development of myeloma (including lytic bone lesions) in the recipients [18].
This observation suggested that purging these cells prior to transplantation might be beneficial, although attempts at purging are technically difficult and clinically disappointing even after removal of 2 to 3 logs of tumor cells [2,19,20]. In addition, delayed engraftment may [21] or may not [22] occur with stem cell selection.
Two main strategies of purging myeloma cells have been tried:
●Positive selection: the desired hematopoietic stem cells are identified and isolated either by CD34+ cell selection or by isolation of CD34+/Thy1+ stem cells by high speed cell sorting [22-24].
●Negative selection: neoplastic cells are removed using a combination of monoclonal antibodies [25].
However, there is no evidence of a clinical benefit with these approaches, and we do not attempt to purge myeloma cells from PBPC collections outside of a clinical trial.
TIMING OF HCT
Timing of first HCT — After adequate numbers of hematopoietic stem cells have been collected and stored, patients have two main options for further treatment:
●Proceed with transplantation after recovery from stem cell collection (early transplant)
●Continue induction therapy with plans to transplant at the time of early relapse (delayed transplant)
In randomized trials, early transplantation results in deeper responses and improved progression-free survival (PFS), but no clear overall survival (OS) benefit. The choice between early and delayed HCT must be made individually with consideration of the following factors:
●Patient preference
●Patient age (as age approaches 70, early transplantation is preferred)
●Genetic risk profile (early transplantation is preferred in patients with high-risk disease)
●Response to and tolerability of the initial chemotherapy regimen
●Insurance approval (some insurers do not cover stem cell harvest and cryopreservation without immediate transplantation)
●The center's facilities and resources for long-term storage of stem cells
There have been several randomized trials comparing early versus delayed transplant, only one included patients receiving induction with an immunomodulatory agent and a proteasome inhibitor. In this multicenter trial (IFM 2009), 700 adults ≤65 years of age with symptomatic newly diagnosed myeloma were randomly assigned to receive one of the following treatment regimens [26]:
●Three cycles of induction with bortezomib, lenalidomide, and dexamethasone (VRD) and stem cell collection, followed by five more cycles of VRD and a year of lenalidomide maintenance. Delayed transplant was allowed at the time of relapse.
●Three cycles of induction with VRD and stem cell collection, followed by early transplant, two more cycles of VRD, and a year of lenalidomide maintenance.
Delayed transplant was performed at the time of progression in 136 (79 percent) patients in the first arm. Transplant was not pursued in 36 patients at the time of progression, largely due to disease refractoriness. Early transplant was associated with a higher rate of complete response (CR; 59 versus 48 percent), a lower rate of minimal residual disease (65 versus 79 percent), and a longer median PFS (50 versus 36 months). At a median follow-up of 44 months, there was no significant difference in OS (OS at four years 81 versus 82 percent), a finding that was maintained in a preliminary report with longer follow-up (OS at eight years 60 versus 62 percent [27]). As expected, early transplant was associated with higher rates of severe neutropenia, gastrointestinal toxicities, and infections. There was no significant difference in treatment-related deaths, second malignancies, thromboembolism, or peripheral neuropathy. There were four cases of acute myeloid leukemia in the early transplant arm and one in the other arm. Despite a transient worsening in health-related quality of life (HRQoL) directly following HCT, both groups showed clinically meaningful improvements in HRQoL from baseline [28].
These results suggest that early transplant delays disease progression, that the majority of patients who defer transplant will be able to undergo transplant at relapse, however a significant percentage cannot and that this delay does impact PFS but does not appear to impact OS likely related to the many other treatments that are available to these patients.
Early HCT may be even more important for patients with high-risk disease (table 1) [29]. The outcome of patients with high-risk disease has not improved significantly even with the arrival of new agents. Median survival is approximately two to three years despite standard treatment. As such, these patients should be strongly encouraged to participate in clinical trials and considered for novel therapeutic strategies, since they do poorly with all conventional treatment options. (See "Multiple myeloma: Initial treatment", section on 'High-risk myeloma'.)
For patients with high-risk MM, we target CR as a goal of therapy (table 2). We proceed with early autologous HCT in eligible patients as a preferred approach, especially if not in CR after initial induction therapy. Following HCT, all patients are given maintenance for at least two to three years. In eligible patients who did not receive initial transplantation, we perform autologous HCT at first disease progression.
Timing of second HCT — Selected patients with high-risk MM may be candidates for a second autologous HCT. If a second HCT is contemplated, it is preferable to perform the procedure within 6 to 12 months of the first transplant [30]. The efficacy of tandem (double) transplantation is discussed in detail separately. (See 'Double HCT and/or consolidation' below.)
PREPARATIVE CHEMOTHERAPY
General — A preparative (conditioning) regimen consisting of high-dose chemotherapy is given to eradicate malignant cells prior to rescue of the hematopoietic system with a peripheral blood progenitor cell (PBPC) infusion [31]. The standard conditioning regimen used for HCT in MM is melphalan at a dose of 200 mg/m2, with dose reductions based on age and renal function. (See 'Patients with renal insufficiency' below and 'Older adults' below.)
The use of this dose is primarily based on two randomized trials that have compared melphalan 200 mg/m2 with a lower dose of melphalan in preparation for HCT.
The first was a French cooperative study that compared the two most common preparative regimens at that time in 282 newly diagnosed symptomatic patients <65 years of age [32]:
●Melphalan 140 mg/m2 plus 8 Gy total body irradiation versus
●Melphalan 200 mg/m2
Patients randomly assigned to melphalan 200 mg/m2 had significantly faster hematologic recovery, less transfusion requirements, shorter hospitalizations, and a lower incidence of severe mucositis (30 versus 50 percent). While the median duration of event-free survival (EFS) was similar in both arms (21 months), survival at 45 months was significantly better in patients receiving melphalan 200 mg/m2 (66 versus 46 percent).
The second was an Italian study comparing melphalan 200 mg/m2 with melphalan 100 mg/m2 as preparative regimens for HCT in 298 newly diagnosed symptomatic patients <65 years of age [33]. After a median follow-up of 44.6 months, patients randomly assigned to melphalan 200 mg/m2 demonstrated the following:
●A significantly longer median progression-free survival (PFS; 31.4 versus 26.2 months) and a trend toward improved projected overall survival (OS) at five years (62 versus 48 percent).
●A significantly higher percent of patients with at least one severe (grade 3/4) nonhematologic event (45 versus 30 percent). Greater gastrointestinal toxicity (11 versus 1 percent), mucositis (17 versus 3 percent), need for intravenous broad-spectrum antibiotics (41 versus 29 percent), and need for platelet transfusions (56 versus 38 percent).
●Treatment-related mortality was 3 percent in both groups.
In other randomized studies, the use of more intensive preparative regimens, such as thiotepa, busulfan, and cyclophosphamide [34]; high-dose idarubicin, cyclophosphamide, and melphalan [35]; or bortezomib plus melphalan [36] did not result in better outcomes than melphalan at a dose of 200 mg/m2. A potential exception is with the combination of busulfan and melphalan. In a single-center randomized trial, intravenous busulfan plus melphalan improved PFS over that seen with single-agent melphalan (three year PFS 72 versus 50 percent), although with increased toxicity [37,38]. Further follow-up of this trial and other trials investigating this combination (eg, NCT019162520) are needed to determine whether this combination improves OS.
Further studies are underway investigating the incorporation of other agents.
Patients with renal insufficiency — The randomized trials that have shown benefit with HCT compared with chemotherapy have mainly studied patients with serum creatinine <2.0 mg/dL. HCT in patients with renal failure must therefore be approached with caution. For patients with serum creatinine >2.0 mg/dL, we suggest that the dose of melphalan used as the conditioning regimen be reduced to 140 mg/m2.
Support for this dose adjustment comes from a retrospective review of 81 patients with MM and renal failure (plasma creatinine >2 mg/dL) who underwent autologous HCT [39]. Sixty patients received melphalan 200 mg/m2. After excessive toxicity was noted in these patients, the subsequent 21 patients received melphalan 140 mg/m2. The patients who received melphalan 200 mg/m2 had significantly higher rates of severe pulmonary toxicity (57 versus 17 percent) and mucositis (93 versus 67 percent). Treatment-related mortality, EFS, and OS were not significantly different between the two melphalan doses.
Retrospective series suggest that HCT is feasible in patients with MM and dialysis-dependent renal failure, although it is associated with higher transplant-related mortality and greater toxicity than in those without renal dysfunction [40]. Studies evaluating autologous HCT in patients with MM and renal impairment are presented separately. (See "Determining eligibility for autologous hematopoietic cell transplantation", section on 'Kidneys'.)
Renal function can also be used to determine eligibility for an outpatient HCT. In our experience and that of others, more than one-half of patients with a serum creatinine <2 mg/dL (177 micromol/L) (or <3 mg/dL [265 µmol/liter]) can undergo HCT as an outpatient [41].
Older adults — For patients over 65 years of age who are candidates for HCT, we suggest a single dose of melphalan (200 mg/m2) as the conditioning regimen rather than tandem intermediate-dose melphalan 100 mg/m2. However, for patients 70 years of age or older, we usually reduce the dose of melphalan to 140 mg/m2 [42,43].
In order to reduce toxicity in patients over 65 years of age, two sequential courses of an intermediate dose of melphalan (100 mg/m2) followed by hematopoietic stem cell rescue (MEL100) has been studied as an alternative to high-dose melphalan 200 mg/m2. One prospective single arm study and two randomized trials have supported the tolerability of MEL 100 [44-46]. However, the results of the two randomized trials that used intermediate-dose melphalan conditioning differed in efficacy when compared with standard-dose melphalan-based regimens.
●A prospective, single arm study evaluated the use of up to three sequential courses of MEL100 followed by PBPC infusion in 71 patients, of whom 53 were >60 years of age [44]. Rates of complete remission following the first, second, and third courses of MEL100 were 19, 34, and 47 percent, respectively. There were no treatment-related deaths.
●A multicenter trial of 194 previously untreated patients evaluated the use of two initial "debulking" courses of vincristine, doxorubicin, and dexamethasone (VAD) followed by randomly assigned treatment with either two consecutive (tandem) courses of autologous HCT employing MEL100 or conventional treatment with melphalan plus prednisone (MP) [45]. At a median follow-up of 39 months, the administration of MEL100 produced the following significant results in the subgroup of 80 patients aged 65 to 70:
•Higher rates of near complete plus partial remissions (47 versus 16 percent)
•Longer median EFS (28 versus 16 months) and OS (58 versus 37 months)
•Higher short-term toxicity (eg, mucositis, fever, need for red cell or platelet transfusions)
●The French Intergroupe Francophone du Myelome (IFM) group reported on 447 previously untreated patients with myeloma age 65 to 75 years who were randomly assigned to treatment with melphalan, prednisone, and thalidomide (MPT) versus melphalan and prednisone alone (MP) versus tandem autologous HCT using MEL100 [46]. Treatment with MPT was associated with significantly longer median OS when compared with treatment with either MP or tandem autologous HCT. There was no difference in median OS between the MP and transplant arms. This study suggests that an intermediate dose of melphalan may not be the optimal conditioning regimen. Further details on the regimens and results of this trial are presented separately. (See "Multiple myeloma: Management in resource-limited settings".)
CARE DURING THE TRANSPLANTATION — Autologous HCT has been performed in both the inpatient and outpatient settings. Approximately 24 hours after completion of the preparative chemotherapy, peripheral blood progenitor cells (PBPCs) are reinfused. A period of pancytopenia follows. Red blood cell and platelet transfusions are administered as necessary while hematopoietic colony-stimulating factors (ie, G-CSF) are used to speed neutrophil engraftment. Neutrophil engraftment usually occurs by day 12 and platelet counts are expected to recover to greater than 20,000 by day 16 [47]. Red blood cell transfusion requirements during autologous HCT are usually minimal and HCT without transfusion support has been described [48]. Approximately 30 to 40 percent of patients can undergo autologous transplantation entirely as an outpatient, with daily monitoring until engraftment [49]. (See "Hematopoietic support after hematopoietic cell transplantation".)
Patients who undergo HCT are at risk for bacterial, viral, and fungal infections, the time course of which varies in the posttransplant period, according to the degree of immune deficiency and cytopenia induced by the transplantation procedure (figure 1). Approximately 40 percent of patients with multiple myeloma undergoing autologous HCT will experience febrile neutropenia [50]. As a result, prophylactic therapies to prevent infection including antiviral and antifungal drugs are recommended during the period of increased risk. In addition, all markers of potential infection must be investigated thoroughly. These issues are discussed in detail separately. (See "Overview of infections following hematopoietic cell transplantation" and "Prevention of infections in hematopoietic cell transplant recipients" and "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults" and "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients" and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)
DOUBLE HCT AND/OR CONSOLIDATION — Given the survival benefits observed with autologous HCT, trials have evaluated the use of additional intensive chemotherapy followed by a second HCT, a procedure termed double (tandem) autologous HCT. They have also evaluated the use of consolidation therapy (eg, two to four cycles of bortezomib, lenalidomide, dexamethasone [VRd]) after HCT and prior to maintenance therapy. However, neither approach has shown clear benefit for standard-risk MM in the context of modern induction therapies. We do not offer double autologous HCT or consolidation therapy routinely to most patients with myeloma. Double transplant may be considered for selected patients with high-risk MM (especially those with del17p13), given that these patients have worse outcomes than standard-risk MM, although evidence supporting this approach is of low quality [51,52].
Several randomized and non-randomized trials have evaluated the relative efficacy of double versus single autologous HCT in previously untreated patients [2,53-68].
●A meta-analysis of six randomized controlled trials enrolling 1803 patients found that double HCT resulted in higher response rates and increased treatment-related mortality with no difference in OS for patients with MM as a whole [67]. However, this meta-analysis was limited in that it included one publication that was subsequently retracted and two that were never published as full manuscripts. As such, it is still possible that a subgroup of patients might benefit from a double HCT.
●In a subsequent three-arm trial performed in the United States (BMTC TN 0702, STaMINA trial) in the context of modern treatments, 758 patients undergoing a first autologous HCT were randomly assigned 1:1:1 to receive a second autologous HCT followed by lenalidomide maintenance; four cycles of bortezomib, lenalidomide, and dexamethasone (VRD) followed by lenalidomide maintenance; or lenalidomide maintenance alone [53]. All three arms resulted in similar PFS and OS at 38 months.
For patients who undergo induction therapy with a lenalidomide-containing triplet regimen (eg, VRd) followed by a single autologous HCT, consolidation with additional cycles of the same triplet regimen offers no benefit above that attained with lenalidomide maintenance alone. This was illustrated in the STaMINA trial described above and a meta-analysis of post-transplant consolidation plus lenalidomide maintenance versus lenalidomide maintenance alone [53,69].
In contrast, a modest benefit from consolidation may be seen in patients who undergo induction therapy with regimens other than VRd, and if options for salvage therapy at relapse are limited. This was illustrated in a European trial (EMN02/HO95) of patients who underwent induction with bortezomib, cyclophosphamide, dexamethasone (VCd), which demonstrated a moderate PFS benefit for the addition of two cycles of VRd consolidation (median 59 versus 43 months; hazard ratio 0.81, 95% CI 0.68-0.96) [70].
Based on these data, we do not routinely offer double HCT or consolidation therapy. We consider double autologous HCT for patients with high-risk MM (specifically del 17p13). An example of this approach involves the administration of melphalan (200 mg/m2) for the first transplant and the same dose of melphalan for the second transplant [3]. In a double transplant approach, the second transplant should be performed within six months after completion of the first [55].
MAINTENANCE — Since virtually all patients who received autologous HCT for MM eventually develop relapsed disease, trials have investigated the use of consolidation or maintenance therapy following HCT. Maintenance therapy refers to the prolonged administration of agents with low toxicity profiles in an attempt to prevent progression of disease.
Maintenance therapy can prolong progression-free survival (PFS) in MM and may improve overall survival (OS). The following sections review different maintenance options for standard-risk and high-risk disease (table 1). For all patients, we recommend at least two years of maintenance rather than observation after transplant (algorithm 1). For standard-risk patients, we suggest maintenance with lenalidomide rather than other agents. For high-risk patients, we suggest maintenance with a proteasome inhibitor based regimen. (See "Multiple myeloma: Initial treatment", section on 'Risk stratified treatment'.)
Standard-risk disease — Randomized trials have suggested that maintenance lenalidomide prolongs PFS and OS in patients with standard-risk MM who have undergone autologous HCT. Based on the randomized trials described below, we recommend maintenance therapy rather than observation until progression for all patients after HCT (algorithm 1). For patients with standard-risk myeloma, we suggest two years of maintenance with lenalidomide (10 mg per day) rather than longer courses of lenalidomide or maintenance with other agents. There is an increased risk of second cancers with lenalidomide maintenance. (See "Multiple myeloma: Initial treatment", section on 'Risk stratified treatment'.)
Four large randomized trials compared lenalidomide maintenance versus placebo or observation in patients who underwent autologous HCT for newly diagnosed MM [71-74]. In all four studies, there was a clear improvement in the primary endpoint of PFS, but estimates in OS were imprecise. In a meta-analysis using primary source patient data from the >1200 patients enrolled on three of these trials, post-transplant maintenance with lenalidomide resulted in the following, when compared with placebo or observation [75]:
●Improved PFS (median PFS 53 versus 24 months; hazard ratio 0.48; 95% CI 0.42-0.55)
●Improved OS (OS at seven years 62 versus 50 percent; hazard ratio 0.75; 95% CI 0.63-0.90)
●Higher rates of second primary malignancy occurring before and after progression (6.1 versus 2.8 percent)
●Discontinuation due to treatment-emergent adverse events in 29 percent (including neutropenia, thrombocytopenia)
●Although lenalidomide maintenance showed a survival benefit in most subgroups, a beneficial effect could not be demonstrated in patients with high-risk cytogenetics (in an analysis of the 567 patients in whom risk status could be ascertained)
The ideal duration of lenalidomide maintenance is under investigation. In one randomized trial, continuing lenalidomide maintenance for two years after HCT improved OS beyond that seen with stopping lenalidomide upon achievement of a complete response [76]. An ongoing randomized trial is comparing two years versus maintenance until progression. At this point, we suggest two years of maintenance therapy in an effort to minimize long-term toxicity. The increased risk of second cancers must be discussed with the patient. In the meta-analysis described above, the risk of progressive disease was higher than the risk of developing an invasive second primary malignancy regardless of whether the patient received lenalidomide maintenance or not [75]. In addition, the meta-analysis was unable to demonstrate an impact of lenalidomide maintenance on the time to death as a result of a second primary malignancy or adverse event.
Maintenance with the oral proteasome inhibitor ixazomib is reserved for patients enrolled on clinical trials. Ixazomib has been studied as maintenance therapy following HCT in a randomized placebo-controlled trial (TOURMALINE-MM3) [77]. This trial compared two years of maintenance ixazomib versus placebo in 656 patients who had achieved an at least partial response following induction therapy and a single autologous HCT. Ixazomib improved PFS (median 27 versus 21 months; HR 0.72, 95% CI 0.58-0.89). There were no unexpected toxicities. The PFS benefit with ixazomib was much less than what has been consistently reported with lenalidomide. Further, the package insert reported unpublished data showing numerically more deaths in the ixazomib arm (105 of 395 patients, 27 percent) versus the placebo arm (69 of 261 patients, 26 percent) (hazard ratio for OS 1.008; 95% CI 0.744-1.367) [78].
High-risk disease — Following autologous HCT, proteasome-inhibitor-based maintenance is associated with improved PFS and OS in patients with high-risk myeloma. Based on the randomized trials described above, we recommend maintenance therapy rather than observation until progression for all patients after HCT (algorithm 1). For patients with high-risk myeloma, we suggest at least two years of maintenance therapy with a proteasome inhibitor, such as bortezomib, following transplant. The importance of incorporating proteasome inhibitors into the management of high-risk myeloma is discussed separately. (See "Multiple myeloma: Initial treatment", section on 'High-risk myeloma'.)
There are no trials comparing maintenance with proteasome inhibitors versus lenalidomide in this population. A randomized trial compared bortezomib (1.3 mg/m2) administered every two weeks on a maintenance schedule versus thalidomide as maintenance therapy following autologous HCT for two years [51,79]. Bortezomib maintenance appeared to improve PFS and OS for the group as a whole; however, on subset analysis this benefit was primarily seen in patients with high-risk myeloma (median OS not reached at 54 months versus 24 months; HR 0.36, 95% CI 0.18-0.74). Bortezomib maintenance also appeared to improve OS in patients with t(4;14) translocation compared to previous reports. One limitation of this trial was that the induction regimen was also different between the two arms, making it difficult to assess the value of maintenance therapy. Nevertheless, since previous trials have not shown an impact on OS based on small differences in induction regimens, the survival benefits in high-risk patients are likely attributable to bortezomib maintenance.
In the randomized trial of ixazomib maintenance (TOURMALINE-MM3), the PFS benefit seen in the overall cohort did not reach statistical significance in subgroup analysis of the 115 patients with high-risk cytogenetics (HR 0.63; 95% CI 0.38-1.02) [77].
Based on these data, we suggest proteasome-inhibitor-based maintenance for patients with high-risk myeloma following HCT. We reserve oral ixazomib for patients who are unable to tolerate bortezomib. The duration of maintenance has not been well studied. At this point we suggest at least two years of maintenance therapy.
MONITORING DISEASE AFTER THERAPY — Patients should be evaluated after transplantation to determine how their disease has responded to therapy. We typically assess patients on day 100 following HCT and, if doing well, we reassess every three to four months thereafter.
The International Myeloma Working Group has developed uniform response criteria, which are used to measure the effect of treatment for MM (table 2). These criteria are described in detail separately. (See "Multiple myeloma: Evaluating response to treatment".)
Investigators have also examined the use of multiparameter flow cytometry (MFC) or immunoglobulin gene rearrangement high throughput sequencing as a measurement of minimal residual disease (MRD) and predictor of outcome in patients after autologous HCT. As an example, a prospective analysis of 295 patients with newly diagnosed MM evaluated the use of MFC of bone marrow samples obtained at day 100 following autologous HCT [80]. At a median follow-up of 57 months, patients who had no evidence of MRD had significantly longer median progression-free (71 versus 37 months, respectively) and overall survival (not reached versus 89 months, respectively) when compared with patients who had MRD. However, at this time, the importance of monitoring for MRD and the impact of MRD on the timing of further treatment requires further prospective studies.
Significance of response to chemotherapy — The relationship between survival and the degree of response (complete versus partial) to initial therapy is controversial [81]. While some studies have suggested a survival benefit from attaining a deeper response [26,82-84], it is unknown whether this just reflects underlying disease biology (ie, a prognostic marker) or specific treatment effect. (See "Multiple myeloma: Overview of management", section on 'Significance of response to chemotherapy'.)
A survival benefit from attaining a deeper response was demonstrated in a retrospective study of 445 patients with MM who underwent autologous HCT between 2002 and 2008 with a median follow-up of 77 months from HCT [85]. In this heterogeneous population, best response and corresponding overall survival (OS) after transplant were:
●Stringent complete response (25 percent) – Median OS not reached; 80 percent survival at five years
●Complete response (8 percent) – Median OS 81 months; 53 percent survival at five years
●Near complete response (20 percent) – Median OS 60 months; 47 percent survival at five years
●Very good partial response (14 percent) – Median OS 64 months (5.3 years)
●Partial response (25 percent) – Median OS 59 months (4.9 years)
●Stable disease (5 percent) – Median OS 56 months (4.6 years)
●Progressive disease (4 percent) – Median OS nine months
This study supports the universal reporting of stringent complete response (CR) separate from CR in prospective trials. The heterogeneity of initial therapy and of salvage therapy available over the time period studied limit the extrapolation of these data to determine goal of therapy. One must be careful when interpreting studies that show improved outcome in responders versus nonresponders (eg, CR versus no CR) since such comparisons have inherent methodologic flaws that cannot be overcome by increasing the sample size. In general, whether a treatment works or not, "responders" will typically appear to do better than "nonresponders" [86,87]. One way of overcoming the bias that exists when comparing responders with nonresponders is to perform landmark analysis at time points that ensure that almost all patients have had time to reach the response level being studied.
Another factor to consider when assessing the significance of response to chemotherapy or HCT is whether a maximum response has been attained at the time of assessment. While patients are conventionally tested at day 100 following HCT to determine disease response, monoclonal protein levels will continue to decline in a significant percentage of patients. As an example, in one study of 430 patients with MM who underwent autologous HCT within one year of their diagnosis and had not attained a CR at day 100, 167 patients (39 percent) showed a deepening of their response after day 100 without further treatment [88].
TREATMENT OF RELAPSE AFTER HCT — The prognosis of patients who relapse after autologous HCT appears to differ depending on the timing of the relapse [89-93]. As an example, a retrospective analysis of 494 patients who had relapsed after HCT found that those who relapse within the first 12 months have a shorter median overall survival (OS; approximately 20 versus 83 months from HCT) when compared with those who relapse after 12 months [89]. Treatment options for relapsed MM after an autologous HCT include a second autologous HCT, nonmyeloablative allogeneic HCT as part of a clinical trial, or treatment with salvage chemotherapy.
In general, a second autologous HCT is not recommended for patients who relapse within 12 to 18 months (if no maintenance therapy was given) of the first, since the progression-free survival (PFS) following the second HCT will most likely be even shorter than the benefit seen with the first transplant [94]. In patients who received lenalidomide maintenance, a second autologous HCT is not considered if the relapse occurs within 36 months of the first HCT. These patients are best treated with active agents that they have not received before or have had good responses to in the past as well as clinical trials investigating novel therapies.
As mentioned above, we routinely harvest enough stem cells at initial chemotherapy for two transplantations; a single transplantation is done with one-half of the collected cells and the other half is cryopreserved. A second (tandem) transplant (using the cryopreserved stem cells) is considered for patients not achieving complete or near complete response with the first transplant, and is followed by maintenance [95]. For patients achieving complete or near complete response with the first transplant, we suggest reserving the cryopreserved stem cells are for a second autologous HCT to be used at the time of relapse [14,15]. (See 'Timing of second HCT' above.)
Two randomized trials compared second autologous HCT versus treatment with chemotherapy alone in patients with late relapse after a first HCT [96,97]. In one, patients with first progressive or relapsed disease at least 18 months after prior autologous HCT were treated with bortezomib, doxorubicin, and dexamethasone (PAD) followed by peripheral blood stem cell collection [96]. The 174 patients with adequate stem cells were randomly assigned to further treatment with either high-dose melphalan plus autologous HCT or to oral cyclophosphamide (400 mg/m2 weekly for 12 weeks). There was poor accrual and the trial was stopped early for benefit. After a median follow-up of 31 months, second autologous HCT resulted in a longer median time to progression (19 versus 11 months; hazard ratio 0.36); further follow-up is necessary to assess OS. In the other, 277 patients with relapsed MM were randomly assigned to receive three cycles of lenalidomide plus dexamethasone (Rd) followed by high-dose melphalan plus autologous HCT followed by lenalidomide maintenance until progression or to receive Rd until progression. After a median follow-up of 37 months, PFS (median 21 versus 19 months) and OS (3 year OS 72 percent each) were similar in the two treatment arms on intention-to-treat analysis. However, approximately 30 percent of those assigned to HCT did not receive HCT and a disproportionate number of patients in the HCT arm progressed during the initial three months of Rd. A post-hoc landmark analysis beginning at the time of HCT suggested an OS benefit for HCT (HR 0.56; 95% CI 0.32-0.99), a finding that suggests a potential benefit for the 70 percent of patients that could undergo HCT.
Further experience comes from a single institution retrospective analysis of 200 patients with myeloma who received a second autologous HCT after recurrence following initial therapy that included an autologous HCT (37 percent tandem) [98]. A partial or greater response was seen in 80 percent by day 100. At a median follow-up of 57 months, the median PFS and OS times following second autologous HCT were 15 and 42 months, respectively. Outcomes were worse among patients who had an initial remission duration <18 months and those who had less than a partial response to reinduction therapy prior to HCT.
For patients who have already undergone a second HCT as part of a double (tandem) HCT or patients who were unable to collect enough progenitor (stem) cells for a second HCT, we discuss the possibility of allogeneic HCT or salvage chemotherapy. However, very few such patients are candidates for allogeneic HCT. These two options are discussed in detail separately. (See "Multiple myeloma: Use of allogeneic hematopoietic cell transplantation", section on 'Autologous followed by nonmyeloablative allogeneic HCT in newly diagnosed myeloma' and "Multiple myeloma: Treatment of first or second relapse".)
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 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. Additionally, immunocompromised patients are candidates for a modified vaccination schedule (figure 2), other preventive strategies (including pre-exposure prophylaxis), and the early initiation of COVID-directed therapy. 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 education" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Autologous 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
●Role in care – Autologous hematopoietic cell transplantation (HCT) is a standard part of the treatment of younger patients with multiple myeloma (MM) due to improvements in event-free and overall survival when compared with conventional chemotherapy alone (algorithm 1). The principal characteristics that determine eligibility for HCT are age, performance status, and/or the presence and severity of certain comorbid conditions. (See "Multiple myeloma: Overview of management".)
●Induction chemotherapy before stem cell collection – In patients who are candidates for HCT, induction chemotherapy is administered for approximately four months prior to stem cell collection in order to reduce the number of tumor cells in the bone marrow and peripheral blood, lessen symptoms, and mitigate end-organ damage. Recommendations for specific induction chemotherapy regimens are presented separately. (See "Multiple myeloma: Initial treatment".)
●Stem cell collection – Peripheral blood progenitor cells (PBPCs) are the preferred source of stem cells due to quicker engraftment and a potential for less contamination with tumor cells. We use apheresis to collect PBPCs with a goal of collecting 6 x 106 CD34+ cells/kg, which is considered sufficient for two transplants. We do not attempt to purge myeloma cells from PBPCs. (See 'Collection of stem cells' above and 'Processing and storage of stem cells' above.)
●Timing of HCT – The choice between proceeding with HCT after recovery from stem cell collection (early transplant) versus reserving HCT for the time of first relapse (delayed transplantation) is individualized and must take into account patient factors (preference, age), disease factors (early HCT preferred for high-risk patients), and logistics. Early transplant prolongs progression-free survival, but has not demonstrated an overall survival benefit. (See 'Timing of HCT' above.)
●Preparative chemotherapy – For most patients undergoing autologous HCT for MM, we recommend a preparative regimen of high-dose melphalan (200 mg/m2) rather than lower-dose melphalan plus total body irradiation or more intensive preparative regimens (Grade 1A). (See 'Preparative chemotherapy' above.)
For patients with serum creatinine >2.0 mg/dL at the time of transplantation, we suggest that the dose of melphalan used as the conditioning regimen be reduced to 140 mg/m2 (Grade 2C). (See 'Patients with renal insufficiency' above.)
For patients over 65 years of age who are candidates for HCT, we suggest a single dose of melphalan (200 mg/m2) as the conditioning regimen rather than tandem intermediate-dose melphalan 100 mg/m2 (Grade 2C). For patients 70 years of age or older, we usually reduce the dose of melphalan to 140 mg/m2. (See 'Older adults' above.)
●Risk for infections – Patients who undergo HCT are at risk for bacterial, viral, and fungal infections. A detailed discussion on the prophylaxis and treatment of infections in this patient population is presented separately. (See "Overview of infections following hematopoietic cell transplantation" and "Prevention of infections in hematopoietic cell transplant recipients" and "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults" and "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients" and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)
●Consolidation and maintenance – Outside of a clinical trial, second (tandem) autologous HCT is reserved for selected patients with high-risk MM. (See 'Double HCT and/or consolidation' above.)
Following autologous HCT, we recommend maintenance therapy rather than observation with treatment at the time of progression (Grade 1B). For standard-risk patients, we suggest maintenance therapy with lenalidomide rather than other agents (Grade 2B). For high-risk patients, we suggest maintenance therapy with bortezomib rather than other agents (Grade 2C). The duration of maintenance must weigh a potential survival benefit against the risk of toxicities, including the development of a second malignancy. (See 'Maintenance' above.)
●Response assessment – The International Myeloma Working Group has developed uniform response criteria, which are used to measure the effect of treatment for MM (table 2). These criteria are described in detail separately. (See "Multiple myeloma: Evaluating response to treatment".)
●Managing relapse after HCT – Treatment options for relapsed MM after an autologous HCT include a second autologous HCT, allogeneic HCT as part of a clinical trial, or treatment with other therapies used for MM. A second autologous HCT is a reasonable approach for transplant-eligible patients who achieved a response duration longer than 18 months (without maintenance therapy) or more than 36 months (with maintenance therapy). For eligible patients less than 65 with a suitable matched donor, we discuss the possibility of non-myeloablative allogeneic HCT or other therapies. These two options are discussed in detail separately. (See "Multiple myeloma: Use of allogeneic hematopoietic cell transplantation", section on 'Autologous followed by nonmyeloablative allogeneic HCT in newly diagnosed myeloma' and "Multiple myeloma: Treatment of first or second relapse".)
