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Multiple myeloma: Use of hematopoietic cell transplantation

Multiple myeloma: Use of hematopoietic cell transplantation
Literature review current through: Jan 2024.
This topic last updated: Jan 16, 2024.

INTRODUCTION — Autologous hematopoietic cell transplantation (HCT) remains a key component of multiple myeloma (MM) therapy in eligible patients and can be incorporated as part of the initial therapy or delayed until first relapse (algorithm 1). Although autologous HCT is not curative, it delays progression and has manageable short-term toxicities and low treatment-related mortality.

In contrast, allogeneic HCT is infrequently used outside of a clinical trial. While allogeneic HCT has the potential for cure, it has substantial treatment-related morbidity and mortality and no clear survival benefit over autologous HCT.

Practical issues regarding autologous HCT in MM are presented here, along with a brief discussion of allogeneic HCT in MM. Eligibility criteria for HCT, a comparison of HCT versus other treatment strategies, and the choice of initial chemotherapy for patients with MM are discussed separately.

(See "Multiple myeloma: Overview of management".)

(See "Multiple myeloma: Initial treatment".)

(See "Determining eligibility for autologous hematopoietic cell transplantation".)

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 "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)

INITIAL CHEMOTHERAPY — In patients who are candidates for autologous HCT, induction chemotherapy is administered for approximately four months (cycles) prior to stem cell collection to reduce the number of tumor cells in the bone marrow and peripheral blood, lessen symptoms, and reverse end-organ damage.

The ability to collect cells can be influenced by age, exposure to certain drugs, and duration of treatment prior to collection. Specifically:

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 [1-4].

Prolonged initial therapy with drugs such as lenalidomide may impair hematopoietic stem cell collection [5-8]. Therefore, hematopoietic stem cells are usually collected within the first four to six cycles of initial therapy even in patients who plan to defer HCT until later. Initial data also suggest an association between treatment regimens containing daratumumab and a decrease in the number of cells collected [8].

The specific regimen used as initial therapy is determined based on risk stratification, comorbid conditions, and resources available. Our preferred approach and data supporting this approach are discussed in more detail separately (algorithm 1), as are alternatives for resource-limited settings (algorithm 2). (See "Multiple myeloma: Initial treatment" and "Multiple myeloma: Management in resource-limited settings".)

COLLECTION OF STEM CELLS — Peripheral blood progenitor cells (PBPCs) are preferred over bone marrow cells for autologous transplantation due to quicker engraftment and a potential for less contamination of the infused cells with tumor cells. (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)

G-CSF-based stimulation — PBPCs are collected by apheresis from the peripheral blood after stimulation with granulocyte colony-stimulating factor (G-CSF), either alone or in combination with a chemokine receptor type 4 (CXCR4) inhibitor (eg, plerixafor, motixafortide), or after cyclophosphamide [9-12]. Practice varies and the specific regimen used is dependent on institutional preference and experience.

For most patients, we suggest using a risk-adapted strategy that reserves CXCR4 inhibitors for patients with a suboptimal response to single-agent G-CSF rather than using G-CSF plus a CXCR4 inhibitor as standard therapy for all patients. This preference places a high value on the low toxicity of this approach and cost savings, as approximately one-half of patients successfully collect without a CXCR4 inhibitor [13]. Some institutions use G-CSF plus a CXCR4 inhibitor as their standard.

We reserve G-CSF following cyclophosphamide for patients who are unable to collect adequate stem cells with G-CSF and plerixafor, and for patients who have had an inadequate response to induction therapy. G-CSF following 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 neutropenic fever and possible hospitalization [14]. Some institutions use G-CSF following cyclophosphamide as their standard.

Plerixafor and motixafortide are CXCR4 inhibitors that impair the binding of hematopoietic stem cells within the bone marrow microenvironment thereby aiding their release into the peripheral blood. In randomized phase 3 trials, use of plerixafor increases PBPC mobilization and decreases the number of apheresis sessions required compared with G-CSF alone [15]. Similarly, in a placebo-controlled, randomized trial, the addition of motixafortide to G-CSF decreased the number of apheresis sessions required and increased the collection of more primitive hematopoietic stem progenitor cells [16]. However, CXCR4 inhibitors are expensive, and risk-adapted ("just in time") strategies have been developed in response to its high cost and recognition that some patients will have adequate mobilization with G-CSF alone [13].

The following represents the most common strategies:

Risk-adapted strategy – At Mayo Clinic, we use the following risk-adapted strategy that is based on the response to single-agent G-CSF measured by peripheral blood CD34 (pCD34) counts and the intended number of transplants:

Patients begin single-agent G-CSF (10 mcg/kg once daily given subcutaneously), and pCD34 counts are measured after four days.

If the pCD34 count is <10/microL (if a single transplant is planned) or <20/microL (if collecting for two transplants), patients receive plerixafor the evening of the fourth day with collection initiated the next day.

In those who do not require plerixafor based on the day 4 pCD34 count, plerixafor is added if the first day collection is <1 million CD34+ cells/kg, or any subsequent day collection is <0.5 million CD34+ cells/kg. Plerixafor is typically used for no more than three days.

G-CSF plus plerixafor – Some institutions use G-CSF plus plerixafor as their standard for most patients. Patients receive daily G-CSF (10 mcg/kg per day given subcutaneously), plerixafor is added after the fourth dose of G-CSF (evening of day 4), and PBPC collection begins the next day (day 5) [17]. Daily doses of plerixafor can be repeated as needed up to a maximum of four doses. In this scenario, peripheral blood CD34 counts are not routinely performed.

G-CSF following cyclophosphamide – We use G-CSF following cyclophosphamide for a minority of patients. Intravenous cyclophosphamide is administered at a dose of 1.5 to 3 grams/m2 for one or two days, followed by daily G-CSF beginning on day 5 and pCD34 measurement on day 10.

Apheresis targets — The pCD34 count is monitored and used to guide the timing of apheresis [18]. Thresholds for initiating apheresis vary by institution, and algorithms for stem cell collection need to be established. We begin apheresis when the pCD34 count reaches ≥10 CD34 cells/microL. (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)

The collection target depends on the number of transplants planned; many patients can collect enough PBPCs for two transplants in one apheresis session.

≥6 x 106 CD34+ cells/kg if collecting for two transplants

≥3 x 106 CD34+ cells/kg if collecting for one transplant

2 x 106 CD34+ cells/kg is considered the minimum needed for one transplant

Some centers collect enough PBPCs for two transplants in all patients; one-half of the collected cells is used for the first transplant, and the other half is cryopreserved. The second half can also be used if the patient experiences graft failure or slow engraftment after the first transplant.

Others collect enough PBPCs for two transplants in younger patients (eg, <65 years) and collect for a single transplant in older patients given the very low likelihood that older patients will be eligible for a second transplant at relapse given the long progression-free survival seen with modern induction therapies and the more advanced age at relapse.

A second (tandem) transplant (using the cryopreserved stem cells) is considered for patients with high-risk MM not achieving a deep response like minimal residual disease (MRD) negativity or complete response with the first transplant. For others, the cryopreserved stem cells may be reserved for transplantation at relapse [19,20]. (See 'Tandem HCT and/or consolidation' below.)

Processing and storage of stem cells — PBPCs are cryopreserved in 5 percent dimethylsulfoxide to be thawed at the bedside at the time of infusion [21]. Non-cryopreserved, refrigerated PBPCs are used as an alternative to cryopreserved PBPCs in some centers [22].

Purging myeloma cells from PBPC collection is considered investigational; as there is no evidence of a clinical benefit with these approaches, we do not attempt to purge myeloma cells from PBPC collections outside of a clinical trial.

EARLY VERSUS LATE HCT

Our approach — After stem cell collection, patients have two main options regarding the timing of HCT:

Early HCT – Proceed with transplantation after completion of stem cell collection, followed by maintenance for at least two to three years. (See 'Maintenance' below.)

Delayed HCT – Continue induction therapy followed by maintenance until progression or as tolerated, with plans to transplant at the time of first relapse.

The choice between early versus delayed HCT is individualized with consideration of the following factors:

Patient preference

Patient age (as age approaches 70, early HCT is preferred)

MM risk stratification (early HCT is preferred in patients with high-risk MM (table 1))

Response to and tolerability of the initial chemotherapy regimen

Insurance approval (some insurers do not cover stem cell harvest and cryopreservation without immediate HCT)

The center's facilities and resources for long-term storage of stem cells

Access to effective therapies at relapse (limited access to other effective therapies favors early HCT)

MM risk stratification is of particular importance in this discussion as patients with high-risk MM tend to do less well with conventional treatment options. For those with high-risk MM, we suggest early HCT as a preferred approach irrespective of the response to induction therapy. While treatment advances have led to a higher proportion of patients with high-risk MM achieving a deep response with intensive induction therapy, it remains unclear if HCT can be deferred to the time of relapse in this population.

The preference toward early HCT and consideration of tandem HCT in patients with high-risk MM is based on the desire to obtain minimal residual disease (MRD) negativity since achievement of MRD negativity is associated with the best outcomes in these patients, even though we lack data from prospective studies on whether treatment modifications based on MRD status improve outcomes (table 2) [23].

If eligible patients defer HCT, we perform HCT at first disease progression.

Benefits of early versus late HCT — Early autologous HCT results in deeper responses and improved progression-free survival (PFS) but no clear overall survival (OS) benefit when compared with delayed HCT. The benefit of an approach that incorporates autologous HCT (early or delayed) versus chemotherapy alone is discussed in more detail separately. (See "Multiple myeloma: Overview of management", section on 'Benefits of autologous HCT versus chemotherapy alone'.)

Two large multicenter trials evaluated early versus delayed HCT in a total of 1422 patients receiving induction with bortezomib, lenalidomide, and dexamethasone (VRd) in Europe (IFM 2009 [24]) and the United States (DETERMINATION [25]). Similar results were seen in a third trial in patients receiving induction with carfilzomib, lenalidomide, and dexamethasone (FORTE [26]).

In both IFM 2009 and DETERMINATION, HCT-eligible adults with newly diagnosed MM were randomly assigned to receive one of the following treatment regimens [24,25]:

Three cycles of induction with VRd and stem cell collection, followed by five more cycles of VRd followed by lenalidomide maintenance. Delayed HCT was allowed at the time of relapse.

Three cycles of induction with VRd and stem cell collection, followed by early HCT, two more cycles of VRd, and lenalidomide maintenance.

The two trials differed in the duration of lenalidomide maintenance and the percentage of patients who received HCT at relapse. In IFM 2009, the initial protocol included one year of lenalidomide maintenance, which was subsequently changed to two years. In DETERMINATION, lenalidomide maintenance was continued until disease progression. Fewer patients in DETERMINATION received HCT at relapse (28 versus 79 percent).

In both studies, early HCT resulted in:

Deeper responses with higher rates of complete response and more patients achieving MRD negative status.

Longer median PFS (IFM 2009: 50 versus 36 months; DETERMINATION: 68 versus 46 months). In a subgroup analysis of DETERMINATION, PFS was improved among the 132 patients with high-risk MM (median PFS 56 versus 17 months; HR 1.99, 95% CI 1.21-3.26) and among the 542 patients with standard-risk MM (median PFS 82 versus 53 months; HR 1.38, 95% CI 1.07-1.79).

No detectable difference in OS (IFM 2009: 4-year OS 81 versus 82 percent; HR 1.16, 95% CI 0.80-1.68; DETERMINATION: 5-year OS 81 versus 79 percent; HR 1.10, 95% CI 0.73-1.65).

Higher rates of severe neutropenia, gastrointestinal toxicities, and infections.

No significant difference in treatment-related deaths, second malignancies, thromboembolism, or peripheral neuropathy. In IFM 2009, there were four cases of acute myeloid leukemia in the early HCT arm and one in the other arm.

In IFM 2009 and DETERMINATION, despite a transient worsening in health-related quality of life (HRQoL) directly following HCT, both groups showed clinically meaningful improvements in HRQoL from baseline [25,27].

These results suggest that early HCT delays disease progression, and that many patients who defer HCT will be able to undergo HCT at relapse. The absence of an OS benefit despite a PFS benefit and a significant percentage not undergoing HCT at relapse likely reflects the many other options available for treatment of relapse.

PREPARATIVE CHEMOTHERAPY

Choice of preparative regimen — 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 [28]. The standard conditioning regimen used for autologous HCT in MM is melphalan at a dose of 200 mg/m2 (Mel200), with dose reductions based on age and kidney function. (See 'Patients with kidney impairment' below and 'Older adults' below.)

The use of Mel200 is primarily based on two randomized trials that compared Mel200 versus lower doses 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 [29]:

Melphalan 140 mg/m2 plus 8 Gy total body irradiation versus

Melphalan 200 mg/m2 (Mel200)

Patients randomly assigned to Mel200 had 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 better in patients receiving Mel200 (66 versus 46 percent).

The second was an Italian study comparing Mel200 versus melphalan 100 mg/m2 in 298 patients <65 years of age with newly diagnosed symptomatic MM [30]. After a median follow-up of 44.6 months, patients randomly assigned to Mel200 demonstrated the following:

Improved progression-free survival (median PFS; 31.4 versus 26.2 months) and a trend toward improved estimated overall survival (OS) at five years (62 versus 48 percent).

More patients with at least one severe (grade 3 or 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.

Although further study is needed, two randomized trials suggest a potential benefit for the combination of intravenous (IV) busulfan plus a lower dose of melphalan (total dose 140 mg/m2) over the use of Mel200 alone. Longer follow-up is needed to determine whether this combination improves OS.

In a single-center randomized trial, IV busulfan plus melphalan (BuMel) improved PFS over that seen with single-agent melphalan (three year PFS 72 versus 50 percent), although with increased toxicity [31,32].

An open-label multicenter phase 3 trial (GEM12menos65) compared BuMel versus Mel200 in 397 patients with newly diagnosed MM, and initial results are available in abstract form [33]. Patients received six cycles of induction with bortezomib, lenalidomide, and dexamethasone (VRd) followed by autologous HCT and two more cycles of VRd as consolidation. They were randomly assigned to receive either Mel200 or IV busulfan (cumulative dose 9.6 mg/kg) plus melphalan 140 mg/m2 as conditioning therapy. After a median follow-up of 72 months, the two arms had similar PFS (hazard ratio [HR] 0.85; 95% CI 0.65-1.10) and OS (HR 1.03; 95% CI 0.70-1.50). However, subgroup analysis suggested that patients with International Staging System (ISS) stage 1 MM had better outcomes with Mel200 while those with ISS stage III MM and those with high-risk cytogenetics benefited more from the BuMel regimen. Higher rates of gastrointestinal toxicity and infections were seen with BuMel.

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 Mel200. Further studies are underway investigating the incorporation of other agents.

Patients with kidney impairment — The randomized trials that have shown benefit with autologous HCT compared with chemotherapy have mainly studied patients with serum creatinine <2 mg/dL. HCT in patients with kidney impairment must therefore be approached with caution. For patients with serum creatinine >2 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 kidney failure (plasma creatinine >2 mg/dL) who underwent autologous HCT [37]. 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 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 kidney failure, although it is associated with higher transplant-related mortality and greater toxicity than in those without kidney impairment [38]. Studies evaluating autologous HCT in patients with MM and kidney impairment are presented separately. (See "Determining eligibility for autologous hematopoietic cell transplantation", section on 'Kidneys'.)

Older adults — Autologous HCT can be safely performed in fit, older adults over 65 even though they were not included in the randomized trials. Our general approach to melphalan dosing in older adults is as follows:

For most patients ages 65 to <70 years, we suggest standard melphalan (200 mg/m2) (Mel200) as the conditioning regimen rather than lower doses.

For patients 70 years of age or older, we also try to administer Mel200 whenever feasible, but reduce the dose of melphalan to 140 mg/m2 (Mel140) in selected cases (eg, kidney impairment).

Case series and registry studies have reported good outcomes in older adults undergoing autologous HCT [39-42]. Mel200 and Mel140 have not been directly compared in this population, and the data from registry trials must be interpreted cautiously since patient frailty and expected tolerability confounds the choice of melphalan dose. Frailer patients are more likely to receive Mel140 and so inferior outcomes with Mel140 may reflect a frailer population.

In one study of >15,000 patients who underwent autologous HCT from 2013 to 2017, the 2092 patients ≥70 years of age had comparable outcomes to those age 60 to 69 years [41]. In a subgroup analysis of those ≥70 years, day 100 nonrelapse mortality was low (≤1 percent). When compared with those who received Mel200, the 41 percent who received Mel140 had worse estimated two-year PFS (64 versus 69 percent) and two-year OS (85 versus 89 percent).

In another analysis of this registry that focused on 360 patients ≥75 years who underwent autologous HCT in the same time period (median age 76.3 years, range 75 to 83.2 years), day 100 nonrelapse mortality was 1 percent and estimated two-year PFS and OS rates were 66 and 83 percent, respectively [42]. Preparative chemotherapy was Mel140 (71 percent) and Mel200 (29 percent). Melphalan dose used was not an independent factor in PFS.

Initial results from a subsequent randomized trial have called into question the value of Mel140 over nontransplant strategies in patients age 60 to 75 years [43]. In an abstract presentation of this trial, Mel140 did not demonstrate improved response rates or PFS versus treatment with lenalidomide and dexamethasone alone. Interpretation of these data is limited by a relatively low percentage of patients assigned to transplant proceeding to transplant (66 percent) and the use of Mel140 in a population that includes patients who would typically be considered for Mel200.

CARE DURING THE TRANSPLANTATION — Autologous HCT can be performed in both the inpatient and outpatient settings. With proper support, approximately 30 to 40 percent of patients can be managed entirely as an outpatient, with daily monitoring until engraftment [44-48].

Approximately 24 hours after completion of the preparative chemotherapy, peripheral blood progenitor cells (PBPCs) are reinfused. A period of pancytopenia follows.

The following are important factors in the care of patients during transplantation and are discussed in more detail separately:

Hematopoietic support – Red blood cell and platelet transfusions are administered as necessary while hematopoietic colony-stimulating factors (ie, G-CSF) may be used to speed neutrophil engraftment. Neutrophil engraftment usually occurs by day 12 to 14 and platelet counts are expected to recover to greater than 20,000 by day 14 to 16 [49]. Red blood cell transfusion requirements during autologous HCT are usually minimal, and HCT without transfusion support has been described [50]. (See "Hematopoietic support after hematopoietic cell transplantation".)

Infection – Patients who undergo HCT are at risk for bacterial, viral, and fungal infections, the time course of which varies in the post-transplant period, according to the degree of immune deficiency and cytopenia induced by the transplantation procedure (figure 1). Approximately 40 percent of patients with MM undergoing autologous HCT will experience febrile neutropenia [51]. 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".)

(See "Prevention of infections in hematopoietic cell transplant recipients".)

(See "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults".)

(See "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients".)

(See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)

Gastrointestinal toxicity – Gastrointestinal toxicity is a major effect of high-dose chemotherapy. Patients typically develop significant nausea, which can be controlled in most with one or more antiemetic agents. Mucositis can be seen in over half of the patients and may limit oral intake during the second week of transplant, and diarrhea is also a common symptom. (See "Early complications of hematopoietic cell transplantation".)

TANDEM 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 tandem (double) 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. Our approach to tandem HCT and consolidation is as follows:

We do not offer tandem autologous HCT or consolidation therapy routinely to most patients with MM.

Tandem HCT 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 [52,53]. If a second HCT is contemplated, it is preferable to perform the procedure within three to six months of the first transplant [54,55].

Several trials have evaluated the relative efficacy of tandem versus single autologous HCT in previously untreated patients [6,55-70].

A meta-analysis of six randomized controlled trials enrolling 1803 patients found that tandem HCT resulted in higher response rates and increased treatment-related mortality with no difference in overall survival (OS) for patients with MM as a whole [69]. 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.

In a subsequent three-arm trial in the context of modern treatments (BMTC TN 0702, STaMINA trial), 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 [56]. All three arms resulted in similar progression-free survival (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 [56,71].

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 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; HR 0.81, 95% CI 0.68-0.96) [72].

MAINTENANCE — Maintenance therapy is given for at least two years following autologous HCT; it delays progression and may improve overall survival (OS). Our preferred maintenance depends on whether the patient has standard-risk or high-risk MM (table 1). The following sections review different maintenance options for standard-risk and high-risk disease (algorithm 1).

Standard-risk disease — For standard-risk MM, we suggest maintenance therapy with lenalidomide (10 mg per day) rather than other agents (algorithm 1). We offer lenalidomide as a single agent rather than in combination with a proteasome inhibitor or anti-CD38 monoclonal antibody to minimize toxicity. We continue maintenance for at least two years and longer if well tolerated, to minimize long-term toxicity. Clinical trials suggest maintenance lenalidomide improves both progression-free survival (PFS) and OS. There is an increased risk of second cancers with lenalidomide maintenance.

Four large randomized trials compared lenalidomide maintenance versus placebo or observation in patients who underwent autologous HCT for newly diagnosed MM [73-76]. 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 [77]:

Improved PFS (median PFS 53 versus 24 months; hazard ratio [HR] 0.48, 95% CI 0.42-0.55).

Improved OS (OS at seven years 62 versus 50 percent; HR 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 [78]. The IFM 2009 and DETERMINATION trials that evaluated autologous HCT in patients following induction with bortezomib, lenalidomide, and dexamethasone (VRd) included maintenance lenalidomide. In IFM 2009, the initial protocol included one year of lenalidomide maintenance, which was subsequently changed to two years [24]. In DETERMINATION, lenalidomide maintenance was continued until disease progression [25]. Both achieved prolonged remissions. An analysis of the Myeloma XI trial that compared lenalidomide maintenance until progression versus no maintenance demonstrated continued benefit for at least four years but limited incremental benefit beyond that [79]. An ongoing randomized trial is comparing two years versus maintenance until progression.

At this point, we suggest at least two years of maintenance therapy in an effort to maximize benefit and 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 [77]. 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.

We do not routinely offer maintenance with an anti-CD38 monoclonal antibody to those who received four-drug induction therapy that included an anti-CD38 monoclonal antibody. Many of the trials that support the efficacy of these regimens in transplant-eligible patients incorporated the monoclonal antibody into the induction, consolidation, and maintenance phases of treatment (eg, GRIFFIN [80,81], PERSEUS [82], IsKia [83]). However, data from the CASSIOPEIA trial suggest that those who receive a total of six cycles of an anti-CD38 monoclonal antibody with induction do not appear to benefit from an additional two years of antibody maintenance [8,84,85]. Longer-term results from ongoing trials comparing lenalidomide with or without daratumumab or isatuximab will help answer this question. (See "Multiple myeloma: Initial treatment", section on 'Daratumumab, bortezomib, thalidomide, dexamethasone'.)

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) [86]. 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) (HR for OS 1.008; 95% CI 0.744-1.367) [87].

Two trials have evaluated the combination of lenalidomide plus carfilzomib with or without dexamethasone versus lenalidomide alone as maintenance following HCT (FORTE and ATLAS) [26,88]. In both studies, the addition of carfilzomib improved PFS. Follow-up is short and neither trial has demonstrated an OS benefit. Incorporating carfilzomib increases the complexity of care (more visits, more intensive therapy) and increases toxicity, including more infections. Given the relatively favorable course of patients with standard risk MM, we await more data before incorporating two-agent maintenance in this population.

High-risk disease — For all patients who have undergone autologous HCT, we recommend maintenance therapy for at least two years rather than observation until progression based on trials that suggest maintenance improves both PFS and OS. For patients with high-risk MM, we suggest maintenance until progression or unacceptable toxicity with a combination of a proteasome inhibitor (bortezomib or carfilzomib) plus lenalidomide rather than lenalidomide alone (algorithm 1). We reserve oral ixazomib for patients who are unable to tolerate bortezomib. We do not routinely incorporate an anti-CD38 monoclonal antibody as maintenance.

A proteasome inhibitor is added to improve on the modest PFS benefit seen with lenalidomide alone in high-risk MM. However, the impact of lenalidomide on PFS likely differs among high-risk subgroups, and other experts may opt to offer lenalidomide maintenance alone to some. In a post-hoc analysis of the Myeloma XI trial, those with isolated del(1p), del(17), or t(4;14) derived substantially greater benefit from lenalidomide maintenance than those with two or more high risk cytogenetic abnormalities [89]. These findings are limited by the post-hoc design, small numbers, and incomplete collection of cytogenetic data.

The importance of incorporating a proteasome inhibitor into the management of high-risk MM is discussed separately and is based partially on limited data that suggest that use of this class may abrogate the prognostic impact of at least some high-risk genetic markers. It remains unclear if similar effect can be achieved by combining daratumumab or isatuximab with lenalidomide for maintenance therapy. (See "Multiple myeloma: Initial treatment", section on 'High-risk myeloma'.)

Support for maintenance with a proteasome inhibitor plus lenalidomide rather than lenalidomide alone comes from two randomized trials (FORTE and ATLAS) that demonstrated improved PFS with the addition of carfilzomib to maintenance [26,88]. Limitations of both trials include their relatively short follow-up and small numbers of patients with high-risk MM.

The randomized, open-label phase 2 trial (FORTE) compared carfilzomib-based induction therapy with or without autologous HCT included a second randomization to maintenance therapy with either carfilzomib plus lenalidomide for up to two years versus lenalidomide alone until progression or intolerance [26]. Maintenance with carfilzomib plus lenalidomide improved PFS (three-year PFS 75 versus 65 percent; HR 0.64, 95% CI 0.44-0.94). The PFS benefit seen in the overall cohort did not reach statistical significance in subgroup analysis of the 83 patients with high-risk MM (HR 0.67, 95% CI 0.34-1.31). However, the number of patients with high-risk MM was small and the estimates are imprecise. Combination maintenance was associated with higher rates of grade 3 or 4 toxicity (49 versus 39 percent).

Similar results were seen in an interim analysis of a randomized, open-label, phase 3 trial (ATLAS) that compared maintenance with carfilzomib, lenalidomide, and dexamethasone (KRd) versus lenalidomide alone following autologous HCT [88]. After a median follow-up of 34 months, KRd improved PFS (median 59 versus 41 months; HR 0.51; 95% CI 0.31-0.86). As with FORTE, the benefit seen in the larger cohort did not reach statistical significance in a subgroup analysis of the 39 patients with high-risk MM (HR 0.74; 95% CI 0.30-1.86). KRd resulted in more toxicity, including higher rates of lower respiratory tract infections.

Further data come from a randomized trial that compared two years of bortezomib (1.3 mg/m2) administered every two weeks on a maintenance schedule versus thalidomide as maintenance therapy following autologous HCT [52,90]. Bortezomib maintenance appeared to improve PFS and OS for the group as a whole; however, on subgroup analysis this benefit was primarily seen in patients with high-risk MM (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 with 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 had 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 a retrospective study of a 1000 patients with newly diagnosed MM, a risk-adapted strategy using bortezomib and lenalidomide as post-HCT maintenance in high-risk MM led to median PFS of nearly four years, higher than expected compared with historical controls [91]. In addition, in a non-HCT setting, the S1211 trial utilizing bortezomib and lenalidomide maintenance following VRd induction demonstrated median PFS in high-risk MM comparable to lenalidomide alone maintenance in standard-risk MM (approximately 36 months in ENDURANCE trial) suggesting benefit for adding a proteasome inhibitor to lenalidomide [92,93].

There is less experience with ixazomib 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) [86].

We do not routinely offer maintenance with an anti-CD38 monoclonal antibody to those who received four-drug induction therapy that included an anti-CD38 monoclonal antibody. Many of the trials that support the efficacy of these regimens in transplant-eligible patients incorporated the monoclonal antibody into the induction, consolidation, and maintenance phases of treatment (eg, GRIFFIN [80,81], PERSEUS [82], IsKia [83]). However, data from the CASSIOPEIA trial suggest that those who receive a total of six cycles of an anti-CD38 monoclonal antibody with induction do not appear to benefit from an additional two years of antibody maintenance [8,84,85]. Longer-term results from ongoing trials comparing lenalidomide with or without daratumumab or isatuximab will help answer this question. (See "Multiple myeloma: Initial treatment", section on 'Daratumumab, bortezomib, thalidomide, dexamethasone'.)

MONITORING DISEASE AFTER THERAPY

Response assessment — Patients should be evaluated after autologous HCT 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. In patients with high-risk disease, we evaluate them earlier, to facilitate treatment decisions such as use of tandem transplant, further consolidation, or dual drug maintenance. (See 'Tandem HCT and/or consolidation' above.)

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".)

Significance of response to chemotherapy — Several meta-analyses have demonstrated a positive impact of minimal residual disease (MRD) negativity on progression-free survival (PFS) in patients with MM, and it appears to be similar in the context of autologous HCT and non-HCT approaches. However, the impact on overall survival (OS) has been less consistent [94]. It is unknown whether the better outcomes with MRD-negative disease simply reflect underlying disease biology (ie, a prognostic marker) or specific treatment effect. Ongoing prospective trials are evaluating the impact of additional therapy given to convert MRD-positive patients into MRD-negative. Until further data are available, we largely reserve MRD assessment for patients on clinical trials. An exception is that we target MRD negativity in patients with high-risk MM. (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 [95]. In this heterogeneous population, best response and corresponding 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

Similar results have been observed in subsequent studies of modern induction therapy and HCT, in the context of the IFM 2009 and DETERMINATION trials [24,25].

One must be careful when interpreting studies that show improved outcome in responders versus nonresponders (eg, complete response [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" [96,97]. 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, especially in the current paradigm of continued therapy. 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 [98].

SECOND AUTOLOGOUS HCT AFTER RELAPSE — For younger patients (eg, <65 years), we collect enough peripheral blood progenitor cells for two transplants; one-half of the collected cells is used for the first transplant and the other half is cryopreserved to be used for a second autologous HCT. If needed, additional stem cells can be collected at the time of relapse.

The decision to proceed with a second HCT at the time of relapse depends on many factors, including the tolerability and duration of response to the first transplant. We suggest a second HCT at the time of relapse for patients who tolerated initial transplant and experienced a sustained remission following the first HCT. This includes patients who had at least three years of progression-free survival (PFS) after HCT with maintenance or at least two years of PFS after HCT without maintenance. However, given that the PFS benefit following the second HCT is usually shorter than that seen with the first HCT [99], a non-transplant strategy is a reasonable alternative. This is particularly relevant with the increasing treatment options in myeloma.

A second autologous HCT is not considered if the relapse occurs within 36 months of the first HCT followed by maintenance therapy. If no maintenance therapy was given following the first HCT, a second HCT is not appropriate for patients who relapse within 18 to 24 months. Patients with shorter PFS 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. Young patients with high-risk relapsed MM are also offered the opportunity to discuss potential allogeneic HCT with a transplant specialist. (See "Multiple myeloma: Treatment of first or second relapse" and 'Allogeneic HCT' below.)

Two randomized trials demonstrated an improved PFS with second autologous HCT versus treatment with chemotherapy alone in patients with late relapse after a first HCT [100,101]. One directly evaluated the addition of HCT to treatment with lenalidomide plus dexamethasone (Rd) [101]. In this trial, 277 patients with relapsed MM were randomly assigned to receive three cycles of Rd followed by high-dose melphalan plus autologous HCT and lenalidomide maintenance until progression versus treatment with Rd until progression without HCT. After a median follow-up of 37 months, PFS (median 21 versus 19 months) and overall survival (three-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 (hazard ratio [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 MM who received a second autologous HCT after recurrence following initial therapy that included an autologous HCT (37 percent tandem) [102]. 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.

ALLOGENEIC HCT — Allogeneic HCT is infrequently used outside of a clinical trial. While it has the potential for cure, it has significant treatment-related morbidity and mortality and no clear survival benefit over autologous HCT.

Our recommendations regarding allogeneic HCT are consistent with those in a joint consensus statement by the American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation, and the International Myeloma Working Group [103]. A minority of patients will be eligible for allogeneic HCT, and its role in MM remains investigational.

We offer young patients with high-risk relapsed MM the opportunity to discuss the risks and benefits of allogeneic HCT with a transplant specialist. A decision to perform HCT in this population is largely driven by patient values, preferences, and risk aversion. Such transplants should ideally be conducted in the context of a clinical trial.

Allogeneic HCT can be offered to select young patients with high-risk relapsed MM who have a matched donor and are willing to accept a higher treatment-related mortality rate, morbidity of graft-versus-host disease (GVHD), and the conflicting data on the efficacy of the intervention. In highly selected patient populations, allogeneic HCT with nonmyeloablative conditioning has achieved long-term disease-free survival (DFS) in a subset of patients, although nonrelapse mortality rates can be as high as 25 percent [104-113]. Bridging chemotherapy is usually administered to control disease until allogeneic HCT. Even if allogeneic HCT can be done expeditiously, it is preferable to use chemotherapy to reduce tumor burden prior to proceeding to HCT.

Only a limited number of syngeneic (ie, identical twin donor) transplants have been performed in MM [114,115]. These reports suggest that, in the uncommon situation where an identical twin donor is available, it is reasonable to consider a syngeneic HCT in place of autologous HCT.

Available data demonstrate that, when compared with autologous HCT, nonmyeloablative allogeneic 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 largest study of allogeneic HCT as initial therapy in MM was conducted by the Bone Marrow Transplant Clinical Trials Network [116]. Of the 625 patients with standard-risk myeloma in this trial, 189 with a human leukocyte antigen (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). The main findings included:

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 to 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.

Similarly, the French IFM group failed to show a benefit from initial treatment with autologous HCT followed by reduced-intensity allogeneic HCT compared with tandem autologous HCT in patients with high-risk myeloma (deletion 13 by fluorescence in situ hybridization [FISH] or an elevated beta-2 microglobulin level) [117].

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); when compared with conventional chemotherapy alone, strategies that incorporate HCT substantially delay disease progression (algorithm 1). (See "Multiple myeloma: Overview of management".)

Induction chemotherapy before stem cell collection – Induction chemotherapy is administered for approximately four months (cycles) 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 (algorithm 1 and algorithm 2). (See "Multiple myeloma: Initial treatment".)

Stem cell collection – Peripheral blood progenitor cells are collected by apheresis after stimulation with granulocyte colony-stimulating factor (G-CSF), either alone or in combination with a chemokine receptor type 4 (CXCR4) inhibitor (eg, plerixafor, motixafortide), or after cyclophosphamide. For most patients, we suggest initiating G-CSF alone rather than G-CSF plus a CXCR4 inhibitor (Grade 2C), reserving the CXCR4 inhibitor for those who have suboptimal response to single-agent G-CSF. (See 'Collection of stem cells' above.)

Apheresis targets – We perform apheresis with a goal of collecting ≥3 x 106 CD34+ cells/kg (if a single transplant is planned) or ≥6 x 106 CD34+ cells/kg (if collecting for two transplants). While the decision is individualized, we typically collect for two transplants if the patient is <65 years of age, and one transplant if the patient is ≥65 years of age. (See 'Apheresis targets' above.)

Timing of HCT – After stem cell collection, patients have two options regarding the timing of HCT:

Early HCT – Proceed with transplantation after recovery from stem cell collection, followed by maintenance.

Delayed HCT – Continue induction therapy followed by maintenance until progression, with plans to transplant at the time of first relapse.

For those with standard-risk MM, the decision is individualized taking into account patient factors (preference, age), response and tolerability of treatment, resources, and logistics.

For those with high-risk MM, we suggest early HCT rather than delayed HCT (Grade 2C). If eligible patients defer HCT, we perform HCT at first disease progression. (See 'Our approach' above.)

Preparative chemotherapy – For most patients, we recommend a preparative regimen of high-dose melphalan (200 mg/m2) alone rather than lower-dose melphalan plus total body irradiation (Grade 1B). (See 'Preparative chemotherapy' above.)

For patients with serum creatinine >2 mg/dL at the time of transplantation, we suggest dose reduction of melphalan to 140 mg/m2 (Grade 2C). (See 'Patients with kidney impairment' above.)

For most patients age 65 to <70 years, we suggest standard melphalan (200 mg/m2) rather than lower doses (Grade 2C). For patients 70 years of age or older, we also try to administer Mel200, whenever feasible. (See 'Older adults' above.)

Consolidation and maintenance – Outside of a clinical trial, tandem (double) autologous HCT is reserved for selected patients with high-risk MM. (See 'Tandem HCT and/or consolidation' above.)

Following autologous HCT, we recommend maintenance therapy rather than observation with treatment at the time of progression (Grade 1B). 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.)

For standard-risk MM, we suggest maintenance therapy with lenalidomide rather than other agents (Grade 2C). We continue maintenance for at least two years and longer if well tolerated, to minimize long-term toxicity. (See 'Standard-risk disease' above.)

For high-risk MM, we suggest maintenance therapy with bortezomib or carfilzomib combined with lenalidomide rather than lenalidomide alone (Grade 2C). We continue maintenance until progression or unacceptable toxicity. (See 'High-risk disease' above.)

Second autologous HCT after relapse – We suggest a second HCT at the time of relapse for patients who tolerated initial transplant and experienced a sustained remission following the first HCT (Grade 2C). This includes patients who had at least three years of progression-free survival (PFS) after HCT with maintenance or at least two years of PFS after HCT without maintenance.

However, given that the PFS benefit following the second HCT is usually shorter than that seen with the first HCT, a non-transplant strategy is a reasonable alternative. A second autologous HCT is not considered if the relapse occurs within 36 months of the first HCT followed by maintenance therapy. Patients with shorter PFS 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. (See "Multiple myeloma: Treatment of first or second relapse".)

Allogeneic HCT – Allogeneic HCT is infrequently used outside of a clinical trial. While it has the potential for cure, it has significant treatment-related morbidity and mortality and no clear survival benefit over autologous HCT. We offer young patients with high-risk relapsed MM the opportunity to discuss the risks and benefits of allogeneic HCT with a transplant specialist. A decision to perform HCT in this population is largely driven by patient values, preferences, and risk aversion. Such transplants should ideally be conducted in the context of a clinical trial. (See 'Allogeneic HCT' above.)

  1. Kazmi MA, Ahsan G, Schey SA. The effects of prior induction therapy with melphalan on subsequent peripheral blood progenitor cell transplantation for myeloma. Clin Lab Haematol 2001; 23:125.
  2. Knudsen LM, Rasmussen T, Jensen L, Johnsen HE. Reduced bone marrow stem cell pool and progenitor mobilisation in multiple myeloma after melphalan treatment. Med Oncol 1999; 16:245.
  3. Wuchter P, Ran D, Bruckner T, et al. Poor mobilization of hematopoietic stem cells-definitions, incidence, risk factors, and impact on outcome of autologous transplantation. Biol Blood Marrow Transplant 2010; 16:490.
  4. de la Rubia J, Bladé J, Lahuerta JJ, et al. Effect of chemotherapy with alkylating agents on the yield of CD34+ cells in patients with multiple myeloma. Results of the Spanish Myeloma Group (GEM) Study. Haematologica 2006; 91:621.
  5. Kumar S, Giralt S, Stadtmauer EA, et al. Mobilization in myeloma revisited: IMWG consensus perspectives on stem cell collection following initial therapy with thalidomide-, lenalidomide-, or bortezomib-containing regimens. Blood 2009; 114:1729.
  6. Lemoli RM, Martinelli G, Zamagni E, et al. Engraftment, clinical, and molecular follow-up of patients with multiple myeloma who were reinfused with highly purified CD34+ cells to support single or tandem high-dose chemotherapy. Blood 2000; 95:2234.
  7. Kumar S, Dispenzieri A, Lacy MQ, et al. Impact of lenalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with newly diagnosed myeloma. Leukemia 2007; 21:2035.
  8. Moreau P, Hulin C, Perrot A, et al. Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial. Lancet Oncol 2021; 22:1378.
  9. Vesole DH, Tricot G, Jagannath S, et al. Autotransplants in multiple myeloma: what have we learned? Blood 1996; 88:838.
  10. Hosing C, Qazilbash MH, Kebriaei P, et al. Fixed-dose single agent pegfilgrastim for peripheral blood progenitor cell mobilisation in patients with multiple myeloma. Br J Haematol 2006; 133:533.
  11. Awan F, Kochuparambil ST, Falconer DE, et al. Comparable efficacy and lower cost of PBSC mobilization with intermediate-dose cyclophosphamide and G-CSF compared with plerixafor and G-CSF in patients with multiple myeloma treated with novel therapies. Bone Marrow Transplant 2013; 48:1279.
  12. Motixafortide for injection. United States prescribing information. Revised September 2023. US Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217159s000lbl.pdf (Accessed on September 20, 2023).
  13. Micallef IN, Sinha S, Gastineau DA, et al. Cost-effectiveness analysis of a risk-adapted algorithm of plerixafor use for autologous peripheral blood stem cell mobilization. Biol Blood Marrow Transplant 2013; 19:87.
  14. Gertz MA, Kumar SK, Lacy MQ, et al. Comparison of high-dose CY and growth factor with growth factor alone for mobilization of stem cells for transplantation in patients with multiple myeloma. Bone Marrow Transplant 2009; 43:619.
  15. DiPersio JF, Stadtmauer EA, Nademanee A, et al. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood 2009; 113:5720.
  16. Crees ZD, Rettig MP, Jayasinghe RG, et al. Motixafortide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma: a randomized phase 3 trial. Nat Med 2023; 29:869.
  17. Plerixafor package insert https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0ed08d2b-5051-46b2-aa37-1d6275bf9003 (Accessed on September 08, 2022).
  18. Mohty M, Hübel K, Kröger N, et al. Autologous haematopoietic stem cell mobilisation in multiple myeloma and lymphoma patients: a position statement from the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 2014; 49:865.
  19. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med 2004; 351:1860.
  20. Hari P, Pasquini MC, Vesole DH. New questions about transplantation in multiple myeloma. Oncology (Williston Park) 2006; 20:1230.
  21. Berz D, McCormack EM, Winer ES, et al. Cryopreservation of hematopoietic stem cells. Am J Hematol 2007; 82:463.
  22. Araújo AB, Soares TB, Schmalfuss T, et al. Non-cryopreserved peripheral blood stem cells as a safe and effective alternative for autologous transplantation in multiple myeloma. Transfusion 2022; 62:1967.
  23. Perrot A, Lauwers-Cances V, Corre J, et al. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. Blood 2018; 132:2456.
  24. Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma. N Engl J Med 2017; 376:1311.
  25. Richardson PG, Jacobus SJ, Weller EA, et al. Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma. N Engl J Med 2022; 387:132.
  26. Gay F, Musto P, Rota-Scalabrini D, et al. Carfilzomib with cyclophosphamide and dexamethasone or lenalidomide and dexamethasone plus autologous transplantation or carfilzomib plus lenalidomide and dexamethasone, followed by maintenance with carfilzomib plus lenalidomide or lenalidomide alone for patients with newly diagnosed multiple myeloma (FORTE): a randomised, open-label, phase 2 trial. Lancet Oncol 2021; 22:1705.
  27. Roussel M, Hebraud B, Hulin C, et al. Health-related quality of life results from the IFM 2009 trial: treatment with lenalidomide, bortezomib, and dexamethasone in transplant-eligible patients with newly diagnosed multiple myeloma. Leuk Lymphoma 2020; 61:1323.
  28. Kumar S, Dingli D, Dispenzieri A, et al. Impact of additional cytoreduction following autologous SCT in multiple myeloma. Bone Marrow Transplant 2008; 42:259.
  29. Moreau P, Facon T, Attal M, et al. Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myélome 9502 randomized trial. Blood 2002; 99:731.
  30. Palumbo A, Bringhen S, Bruno B, et al. Melphalan 200 mg/m(2) versus melphalan 100 mg/m(2) in newly diagnosed myeloma patients: a prospective, multicenter phase 3 study. Blood 2010; 115:1873.
  31. Bashir Q, Thall PF, Milton DR, et al. Conditioning with busulfan plus melphalan versus melphalan alone before autologous haemopoietic cell transplantation for multiple myeloma: an open-label, randomised, phase 3 trial. Lancet Haematol 2019; 6:e266.
  32. Saini N, Bashir Q, Milton DR, et al. Busulfan and melphalan conditioning is superior to melphalan alone in autologous stem cell transplantation for high-risk MM. Blood Adv 2020; 4:4834.
  33. Lahuerta Palacia JJ, Ubierto AJ, Rosinol L, et al. Busulfan plus melphalan vs. melphalan-200 for myeloma after induction with bortezomib, lenalidomide and dexamethasone: results of the GEM12menos65 phase III trial (abstract OAB-040). 19th Annual International Myeloma Society Meeting; August 25-27, 2022; Los Angeles, CA. 2022.
  34. Anagnostopoulos A, Aleman A, Ayers G, et al. Comparison of high-dose melphalan with a more intensive regimen of thiotepa, busulfan, and cyclophosphamide for patients with multiple myeloma. Cancer 2004; 100:2607.
  35. Fenk R, Schneider P, Kropff M, et al. High-dose idarubicin, cyclophosphamide and melphalan as conditioning for autologous stem cell transplantation increases treatment-related mortality in patients with multiple myeloma: results of a randomised study. Br J Haematol 2005; 130:588.
  36. Roussel M, Lauwers-Cances V, Macro M, et al. Bortezomib and high-dose melphalan conditioning regimen in frontline multiple myeloma: an IFM randomized phase 3 study. Blood 2022; 139:2747.
  37. Badros A, Barlogie B, Siegel E, et al. Results of autologous stem cell transplant in multiple myeloma patients with renal failure. Br J Haematol 2001; 114:822.
  38. St Bernard R, Chodirker L, Masih-Khan E, et al. Efficacy, toxicity and mortality of autologous SCT in multiple myeloma patients with dialysis-dependent renal failure. Bone Marrow Transplant 2015; 50:95.
  39. Kumar SK, Dingli D, Lacy MQ, et al. Autologous stem cell transplantation in patients of 70 years and older with multiple myeloma: Results from a matched pair analysis. Am J Hematol 2008; 83:614.
  40. Bashir Q, Chamoun K, Milton DR, et al. Outcomes of autologous hematopoietic cell transplantation in myeloma patients aged ≥75 years. Leuk Lymphoma 2019; 60:3536.
  41. Munshi PN, Vesole D, Jurczyszyn A, et al. Age no bar: A CIBMTR analysis of elderly patients undergoing autologous hematopoietic cell transplantation for multiple myeloma. Cancer 2020; 126:5077.
  42. Munshi PN, Vesole DH, St Martin A, et al. Outcomes of upfront autologous hematopoietic cell transplantation in patients with multiple myeloma who are 75 years old or older. Cancer 2021; 127:4233.
  43. Straka C, Schaefer-Eckart K, Hertenstein B, et al. Long-Term Outcome of a Prospective Randomized Trial Comparing Continuous Lenalidomide/Dexamethasone with Lenalidomide/Dexamethasone Induction, MEL140 with Autologous Blood Stem Cell Transplantation and Single Agent Lenalidomide Maintenance in Patients of Age 60-75 Years with Newly Diagnosed Multiple Myeloma. Blood 2022; 140 Supplement 1:287.
  44. Gertz MA, Ansell SM, Dingli D, et al. Autologous stem cell transplant in 716 patients with multiple myeloma: low treatment-related mortality, feasibility of outpatient transplant, and effect of a multidisciplinary quality initiative. Mayo Clin Proc 2008; 83:1131.
  45. Dunavin N, Mau LW, Meyer CL, et al. Health Care Reimbursement, Service Utilization, and Outcomes among Medicare Beneficiaries with Multiple Myeloma Receiving Autologous Hematopoietic Cell Transplantation in Inpatient and Outpatient Settings. Biol Blood Marrow Transplant 2020; 26:805.
  46. Shah N, Cornelison AM, Saliba R, et al. Inpatient vs outpatient autologous hematopoietic stem cell transplantation for multiple myeloma. Eur J Haematol 2017; 99:532.
  47. Obiozor C, Subramaniam DP, Divine C, et al. Evaluation of Performance Status and Hematopoietic Cell Transplantation Specific Comorbidity Index on Unplanned Admission Rates in Patients with Multiple Myeloma Undergoing Outpatient Autologous Stem Cell Transplantation. Biol Blood Marrow Transplant 2017; 23:1641.
  48. Graff TM, Singavi AK, Schmidt W, et al. Safety of outpatient autologous hematopoietic cell transplantation for multiple myeloma and lymphoma. Bone Marrow Transplant 2015; 50:947.
  49. Schmitz N, Linch DC, Dreger P, et al. Randomised trial of filgrastim-mobilised peripheral blood progenitor cell transplantation versus autologous bone-marrow transplantation in lymphoma patients. Lancet 1996; 347:353.
  50. Joseph NS, Kaufman JL, Boise LH, et al. Safety and survival outcomes for bloodless transplantation in patients with myeloma. Cancer 2019; 125:185.
  51. Jones JA, Qazilbash MH, Shih YC, et al. In-hospital complications of autologous hematopoietic stem cell transplantation for lymphoid malignancies: clinical and economic outcomes from the Nationwide Inpatient Sample. Cancer 2008; 112:1096.
  52. Goldschmidt H, Lokhorst HM, Mai EK, et al. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia 2018; 32:383.
  53. Cavo M, Gay FM, Patriarca F. Double autologous stem cell transplantation significantly prolongs progression-free survival and overall survival in comparison with single autotransplantation in newly diagnosed multiple myeloma: An analysis of phase 3 EMN02/HO95 study (abstract). Blood 2017; 130:401.
  54. Elice F, Raimondi R, Tosetto A, et al. Prolonged overall survival with second on-demand autologous transplant in multiple myeloma. Am J Hematol 2006; 81:426.
  55. Barlogie B, Jagannath S, Desikan KR, et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood 1999; 93:55.
  56. Stadtmauer EA, Pasquini MC, Blackwell B, et al. Autologous Transplantation, Consolidation, and Maintenance Therapy in Multiple Myeloma: Results of the BMT CTN 0702 Trial. J Clin Oncol 2019; 37:589.
  57. UK myeloma forum. British Committee for Standards in Haematology. Diagnosis and management of multiple myeloma. Br J Haematol 2001; 115:522.
  58. Lahuerta JJ, Grande C, Martínez-Lopez J, et al. Tandem transplants with different high-dose regimens improve the complete remission rates in multiple myeloma. Results of a Grupo Español de Síndromes Linfoproliferativos/Trasplante Autólogo de Médula Osea phase II trial. Br J Haematol 2003; 120:296.
  59. Fassas AB, Barlogie B, Ward S, et al. Survival after relapse following tandem autotransplants in multiple myeloma patients: the University of Arkansas total therapy I experience. Br J Haematol 2003; 123:484.
  60. Barlogie B, Tricot GJ, van Rhee F, et al. Long-term outcome results of the first tandem autotransplant trial for multiple myeloma. Br J Haematol 2006; 135:158.
  61. Barlogie B, Anaissie E, van Rhee F, et al. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3. Br J Haematol 2007; 138:176.
  62. Corso A, Mangiacavalli S, Barbarano L, et al. Limited feasibility of double transplant in multiple myeloma: results of a multicenter study on 153 patients aged <65 years. Cancer 2007; 109:2273.
  63. Tricot G, Spencer T, Sawyer J, et al. Predicting long-term (> or = 5 years) event-free survival in multiple myeloma patients following planned tandem autotransplants. Br J Haematol 2002; 116:211.
  64. Jacobson J, Barlogie B, Shaughnessy J, et al. MDS-type abnormalities within myeloma signature karyotype (MM-MDS): only 13% 1-year survival despite tandem transplants. Br J Haematol 2003; 122:430.
  65. Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 2003; 349:2495.
  66. Stadtmauer EA. Multiple myeloma, 2004--one or two transplants? N Engl J Med 2003; 349:2551.
  67. Cavo M, Tosi P, Zamagni E, et al. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol 2007; 25:2434.
  68. Naumann-Winter F, Greb A, Borchmann P, et al. First-line tandem high-dose chemotherapy and autologous stem cell transplantation versus single high-dose chemotherapy and autologous stem cell transplantation in multiple myeloma, a systematic review of controlled studies. Cochrane Database Syst Rev 2012; 10:CD004626.
  69. Kumar A, Kharfan-Dabaja MA, Glasmacher A, Djulbegovic B. Tandem versus single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: a systematic review and meta-analysis. J Natl Cancer Inst 2009; 101:100.
  70. Mai EK, Benner A, Bertsch U, et al. Single versus tandem high-dose melphalan followed by autologous blood stem cell transplantation in multiple myeloma: long-term results from the phase III GMMG-HD2 trial. Br J Haematol 2016; 173:731.
  71. Al-Ani F, Louzada M. Post-transplant consolidation plus lenalidomide maintenance vs lenalidomide maintenance alone in multiple myeloma: A systematic review. Eur J Haematol 2017; 99:479.
  72. Sonneveld P, Dimopoulos MA, Beksac M, et al. Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma. J Clin Oncol 2021; 39:3613.
  73. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 2012; 366:1782.
  74. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 2012; 366:1770.
  75. Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med 2014; 371:895.
  76. Jackson GH, Davies FE, Pawlyn C, et al. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2019; 20:57.
  77. McCarthy PL, Holstein SA, Petrucci MT, et al. Lenalidomide Maintenance After Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: A Meta-Analysis. J Clin Oncol 2017; 35:3279.
  78. Goldschmidt H, Mai EK, Dürig J, et al. Response-adapted lenalidomide maintenance in newly diagnosed myeloma: results from the phase III GMMG-MM5 trial. Leukemia 2020; 34:1853.
  79. Pawlyn C, Menzies T, Davies FE, et al. Defining the Optimal Duration of Lenalidomide Maintenance after Autologous Stem Cell Transplant - Data from the Myeloma XI Trial. Blood 2022; 140 Supplement 1:1371.
  80. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood 2020; 136:936.
  81. Voorhees PM, Sborov DW, Laubach J, et al. Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial. Lancet Haematol 2023; 10:e825.
  82. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 2023.
  83. Gay F, Roeloffzen W, Dimopoulos MA, et al. Results of the Phase III Randomized Iskia Trial: Isatuximab-Carfilzomib-Lenalidomide-Dexamethasone Vs Carfilzomib-Lenalidomide-Dexamethasone As Pre-Transplant Induction and Post-Transplant Consolidation in Newly Diagnosed Multiple Myeloma Patients (abstract 4). Blood 2023.
  84. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet 2019; 394:29.
  85. Roussel M, Moreau P, Hebraud B, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab for transplantation-eligible patients with newly diagnosed multiple myeloma (CASSIOPEIA): health-related quality of life outcomes of a randomised, open-label, phase 3 trial. Lancet Haematol 2020; 7:e874.
  86. Dimopoulos MA, Gay F, Schjesvold F, et al. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet 2019; 393:253.
  87. Ixazomib capsules, for oral use. United States prescribing information. Revised April 2022. US Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/208462s012s013lbl.pdf (Accessed on May 10, 2022).
  88. Dytfeld D, Wróbel T, Jamroziak K, et al. Carfilzomib, lenalidomide, and dexamethasone or lenalidomide alone as maintenance therapy after autologous stem-cell transplantation in patients with multiple myeloma (ATLAS): interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol 2023; 24:139.
  89. Panopoulou A, Cairns DA, Holroyd A, et al. Optimizing the value of lenalidomide maintenance by extended genetic profiling: an analysis of 556 patients in the Myeloma XI trial. Blood 2023; 141:1666.
  90. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol 2012; 30:2946.
  91. Joseph NS, Kaufman JL, Dhodapkar MV, et al. Long-Term Follow-Up Results of Lenalidomide, Bortezomib, and Dexamethasone Induction Therapy and Risk-Adapted Maintenance Approach in Newly Diagnosed Multiple Myeloma. J Clin Oncol 2020; 38:1928.
  92. Usmani SZ, Sexton R, Ailawadhi S, et al. Phase I safety data of lenalidomide, bortezomib, dexamethasone, and elotuzumab as induction therapy for newly diagnosed symptomatic multiple myeloma: SWOG S1211. Blood Cancer J 2015; 5:e334.
  93. Kumar SK, Jacobus SJ, Cohen AD, et al. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol 2020; 21:1317.
  94. Munshi NC, Avet-Loiseau H, Rawstron AC, et al. Association of Minimal Residual Disease With Superior Survival Outcomes in Patients With Multiple Myeloma: A Meta-analysis. JAMA Oncol 2017; 3:28.
  95. Kapoor P, Kumar SK, Dispenzieri A, et al. Importance of achieving stringent complete response after autologous stem-cell transplantation in multiple myeloma. J Clin Oncol 2013; 31:4529.
  96. Tannock I, Murphy K. Reflections on medical oncology: an appeal for better clinical trials and improved reporting of their results. J Clin Oncol 1983; 1:66.
  97. Rajkumar SV, Gahrton G, Bergsagel PL. Approach to the treatment of multiple myeloma: a clash of philosophies. Blood 2011; 118:3205.
  98. Hesse UJ, DeDecker C, Houtmeyers P, et al. Prospectively randomized trial using perioperative low-dose octreotide to prevent organ-related and general complications after pancreatic surgery and pancreatico-jejunostomy. World J Surg 2005; 29:1325.
  99. Shah N, Ahmed F, Bashir Q, et al. Durable remission with salvage second autotransplants in patients with multiple myeloma. Cancer 2012; 118:3549.
  100. Cook G, Williams C, Brown JM, et al. High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial. Lancet Oncol 2014; 15:874.
  101. Goldschmidt H, Baertsch MA, Schlenzka J, et al. Salvage autologous transplant and lenalidomide maintenance vs. lenalidomide/dexamethasone for relapsed multiple myeloma: the randomized GMMG phase III trial ReLApsE. Leukemia 2021; 35:1134.
  102. Sellner L, Heiss C, Benner A, et al. Autologous retransplantation for patients with recurrent multiple myeloma: a single-center experience with 200 patients. Cancer 2013; 119:2438.
  103. Giralt S, Garderet L, Durie B, et al. American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation, Blood and Marrow Transplant Clinical Trials Network, and International Myeloma Working Group Consensus Conference on Salvage Hematopoietic Cell Transplantation in Patients with Relapsed Multiple Myeloma. Biol Blood Marrow Transplant 2015; 21:2039.
  104. Efebera YA, Qureshi SR, Cole SM, et al. Reduced-intensity allogeneic hematopoietic stem cell transplantation for relapsed multiple myeloma. Biol Blood Marrow Transplant 2010; 16:1122.
  105. Patriarca F, Einsele H, Spina F, et al. Allogeneic stem cell transplantation in multiple myeloma relapsed after autograft: a multicenter retrospective study based on donor availability. Biol Blood Marrow Transplant 2012; 18:617.
  106. de Lavallade H, El-Cheikh J, Faucher C, et al. Reduced-intensity conditioning allogeneic SCT as salvage treatment for relapsed multiple myeloma. Bone Marrow Transplant 2008; 41:953.
  107. Shimoni A, Hardan I, Ayuk F, et al. Allogenic hematopoietic stem-cell transplantation with reduced-intensity conditioning in patients with refractory and recurrent multiple myeloma: long-term follow-up. Cancer 2010; 116:3621.
  108. Kröger N, Shimoni A, Schilling G, et al. Unrelated stem cell transplantation after reduced intensity conditioning for patients with multiple myeloma relapsing after autologous transplantation. Br J Haematol 2010; 148:323.
  109. Qazilbash MH, Saliba R, De Lima M, et al. Second autologous or allogeneic transplantation after the failure of first autograft in patients with multiple myeloma. Cancer 2006; 106:1084.
  110. Crawley C, Iacobelli S, Björkstrand B, et al. Reduced-intensity conditioning for myeloma: lower nonrelapse mortality but higher relapse rates compared with myeloablative conditioning. Blood 2007; 109:3588.
  111. Maloney DG, Molina AJ, Sahebi F, et al. Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 2003; 102:3447.
  112. Greil C, Engelhardt M, Ihorst G, et al. Allogeneic transplantation of multiple myeloma patients may allow long-term survival in carefully selected patients with acceptable toxicity and preserved quality of life. Haematologica 2019; 104:370.
  113. Maffini E, Storer BE, Sandmaier BM, et al. Long-term follow up of tandem autologous-allogeneic hematopoietic cell transplantation for multiple myeloma. Haematologica 2019; 104:380.
  114. Gahrton G, Svensson H, Björkstrand B, et al. Syngeneic transplantation in multiple myeloma - a case-matched comparison with autologous and allogeneic transplantation. European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 1999; 24:741.
  115. Fefer A, Cheever MA, Greenberg PD. Identical-twin (syngeneic) marrow transplantation for hematologic cancers. J Natl Cancer Inst 1986; 76:1269.
  116. Krishnan A, Pasquini MC, Logan B, et al. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol 2011; 12:1195.
  117. Garban F, Attal M, Michallet M, et al. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood 2006; 107:3474.
Topic 6656 Version 70.0

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