INTRODUCTION — Multiple myeloma (MM) is characterized by the neoplastic proliferation of clonal plasma cells producing a monoclonal immunoglobulin. These plasma cells proliferate in the bone marrow and can result in extensive skeletal destruction with osteolytic lesions, osteopenia, and/or pathologic fractures. Additional disease-related complications include hypercalcemia, kidney impairment, anemia, and infections.
This topic reviews the overall treatment strategy for patients with MM. Further details regarding the selection of initial therapy, the treatment of relapsed and/or refractory disease and the use of hematopoietic cell transplantation are discussed separately.
●(See "Multiple myeloma: Initial treatment".)
●(See "Multiple myeloma: Treatment of first or second relapse".)
●(See "Multiple myeloma: Treatment of third or later relapse".)
●(See "Multiple myeloma: Use of autologous hematopoietic cell transplantation".)
●(See "Multiple myeloma: Management in resource-limited settings".)
●(See "Multiple myeloma: The use of osteoclast inhibitors".)
●(See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Treatment and prognosis".)
PRETREATMENT EVALUATION
Verify the diagnosis — The first step in evaluating a new patient with MM is to verify the diagnosis since the premalignant stages of myeloma, namely monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), may be easily misdiagnosed as MM if one is not careful (table 1 and algorithm 1). As an example, patients with MGUS may have renal failure due to diabetes or hypertension, or have bone lesions from other cancers. Such patients may be misdiagnosed with MM if these findings are incorrectly attributed to the plasma cell dyscrasia. Therefore, every effort should be made to determine whether the observed "end-organ damage" is truly secondary to the underlying plasma cell disorder or to an unrelated process. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Diagnosis'.)
Unlike persons with MGUS and SMM, all patients with a confirmed diagnosis of MM require treatment. Without effective therapy, symptomatic patients die within a median of six months [1]. In contrast, patients with SMM may remain stable for prolonged periods. As such, if there is doubt about whether the patient has SMM or MM, a reasonable approach is to re-evaluate the patient in two or three months and to delay therapy until the correct diagnosis is evident. The patient should be instructed to monitor for symptoms related to MM and contact the provider immediately should there be a change in his or her condition. (See "Smoldering multiple myeloma".)
Clinical evaluation — The initial evaluation of patients with MM must establish the extent and sites of disease, the patient's performance status (table 2), and comorbid conditions that could complicate overall management. In addition, specific tests are performed for risk stratification and to determine eligibility for autologous hematopoietic cell transplantation (HCT). Particular attention should be paid in the history and physical examination to constitutional symptoms, bone pain, neurologic findings, and infections.
Our pretreatment evaluation also includes the following studies, some of which are performed as part of the diagnostic evaluation (see "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Evaluation'):
●A complete blood count and differential with examination of the peripheral blood smear.
●A chemistry screen plus measurements of serum calcium, albumin, lactate dehydrogenase, and beta-2 microglobulin. (See "Multiple myeloma: Staging and prognostic studies".)
●Serum creatinine and an estimation of glomerular filtration rate [2]. The assessment of GFR and evaluation to determine the cause of renal dysfunction is discussed separately. (See "Assessment of kidney function", section on 'Assessment of GFR' and "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation".)
●Serum free light chain (FLC) assay.
●A serum protein electrophoresis (SPEP) with immunofixation and quantitation of immunoglobulins. A routine urinalysis and a 24-hour urine collection for protein electrophoresis (UPEP) and immunofixation. (See "Laboratory methods for analyzing monoclonal proteins".)
●Bone marrow aspiration and biopsy with immunophenotyping and fluorescence in situ hybridization (FISH). FISH should include probes that identify t(11;14), t(4;14), t(6;14), t(14;16), t(14;20), del17p13, gain 1q, and trisomies of odd numbered chromosomes. FISH for del1p32 can provide additional prognostic information, if available. (See "Multiple myeloma: Staging and prognostic studies", section on 'Other cytogenetic lesions'.)
●Cross sectional imaging (eg, CT, PET/CT, or MRI) for the detection of bone involvement. The choice of imaging modality is discussed separately. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Choice of modality'.)
A comprehensive geriatric assessment may be useful in assessing comorbidity and functional status in the older patient with MM, thus permitting the formulation of an appropriate, individualized treatment plan [3]. (See "Comprehensive geriatric assessment for patients with cancer".)
Risk stratification — We risk stratify individual cases based on the results of fluorescence in situ hybridization (FISH) for specific translocations and certain other tests (table 3). This risk stratification helps to determine prognosis and impacts treatment choice (algorithm 2):
●High-risk myeloma – We consider patients with at least one of the following clinical or pathologic criteria to have high-risk MM:
•t(4;14), t(14;16), t(14;20), del17p13, or gain 1q by FISH
•Lactate dehydrogenase (LDH) levels ≥2 times the institutional upper limit of normal
•Features of primary plasma cell leukemia (defined as ≥5 percent circulating plasma cells on a manual differential count) (see "Plasma cell leukemia")
While patients with a high-risk signature on gene expression profiling (GEP) are considered to have high-risk myeloma, this test is not recommended on a routine basis.
●Standard-risk myeloma – We consider patients who lack all of the high-risk abnormalities described above to have standard-risk MM. This includes patients with trisomies, t(11;14), and t(6;14).
Our risk stratification has evolved over time and will continue to change as our understanding regarding the prognostic value of specific cytogenetic findings in MM improves. While we test for all of the FISH markers described above, some are not available in some regions of the world. The Revised International Staging System, which takes into account the international availability of specific FISH probes, considers patients with any of the following as having high-risk MM: t(4;14), t(14;16), and del17p [4].
Support for our risk stratification comes from the following (see "Multiple myeloma: Staging and prognostic studies"):
●Patients with t(4;14), t(14;16), t(14;20), del17p13, or gain 1q by FISH account for approximately 25 percent of MM and have a shortened median survival with standard treatment [5].
●While deletion 13 and hypodiploidy have been considered adverse prognostic factors when detected by conventional cytogenetics, these are not independent predictors of poor outcome when FISH results are taken into account.
●There are conflicting data on whether the presence of trisomies can ameliorate some of the adverse prognostic effects of high-risk cytogenetic abnormalities. We do not downgrade our risk assignment for those with trisomies.
●Elevated LDH is a marker of adverse prognosis in myeloma. Elevated LDH is included in the calculation of the revised International Staging System (R-ISS) and is used as an inclusion criterion for trials investigating novel therapies for patients with high-risk MM.
●Patients with a high-risk signature on GEP are also considered to have high-risk MM, but this test is not recommended on a routine basis.
The underlying genetic abnormalities in the myeloma clone dictates disease biology and are a major predictor of outcome. Prognosis also depends on host factors (age, performance status, comorbidities), stage, and response to therapy. Staging and prognosis is discussed in more detail separately as is the impact of specific cytogenetic findings. (See "Multiple myeloma: Staging and prognostic studies".)
Determining transplant eligibility — Following diagnosis and risk stratification, all patients are assessed to determine eligibility for autologous hematopoietic cell transplantation (HCT). When compared with chemotherapy alone, autologous HCT appears to prolong both event-free and overall survival.
Stem cell collection should occur early in the treatment course for all eligible patients regardless of whether the plan is for HCT to be incorporated into the initial treatment or postponed until the time of first relapse.
The initial chemotherapy given to patients who are candidates for HCT should limit agents that may impair stem cell collection or damage stem cells. Eligibility criteria are discussed in the following section. Practical issues regarding the use of autologous HCT in myeloma are presented separately. (See "Multiple myeloma: Use of autologous hematopoietic cell transplantation".)
A minority of patients will be eligible for allogeneic HCT, but the role of allogeneic approaches in MM remains investigational and controversial. (See "Multiple myeloma: Use of allogeneic hematopoietic cell transplantation" and "Determining eligibility for allogeneic hematopoietic cell transplantation".)
●General eligibility requirements – Eligibility for autologous HCT in MM varies across countries and institutions. In most European countries, transplantation for MM is offered primarily to patients younger than 65 years of age. In the United States (US), a strict age limit is not used. Instead, decisions are made on a case-by-case basis based on "physiologic age" and vary across institutions. (See "Determining eligibility for autologous hematopoietic cell transplantation".)
In most centers in the US, patients with one or more of the following factors are not usually considered eligible for autologous HCT in myeloma:
•Age >77 years
•Frank cirrhosis of the liver
•Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain (table 4)
•New York Heart Association functional status Class III or IV (table 5)
These are guidelines and the decision on transplant eligibility should be made based on a risk-benefit assessment and the needs and wishes of the patient. There is insufficient evidence at this time that the newer chemotherapeutic programs (eg, bortezomib, lenalidomide) will result in a reduced need for HCT.
In the US, the Centers for Medicare and Medicaid Services approves reimbursement for high-dose therapy with autologous HCT in newly diagnosed patients with myeloma who are less than 78 years old and have Durie-Salmon stage II or III disease, and for selected patients who have been previously treated. Additional details are available on the Centers for Medicare and Medicaid Services website at www.cms.gov. Studies that have evaluated the impact of age on transplant efficacy are described in more detail separately. (See "Determining eligibility for autologous hematopoietic cell transplantation", section on 'Age'.)
Dose adjustment of the conditioning regimen is often necessary for older adults undergoing HCT. This is discussed in more detail separately. (See "Multiple myeloma: Use of autologous hematopoietic cell transplantation", section on 'Older adults'.)
●Kidney function – Autologous HCT may be safely performed among patients with all stages of kidney disease, even among patients on dialysis. Kidney impairment appears to have no adverse effect on either the quality of stem cell collection or engraftment following autologous HCT [6].
The randomized trials that have shown benefit with HCT compared with chemotherapy have mainly studied patients with serum creatinine <2 mg/dL (177 micromol/L). Patients with higher creatinine levels can have a more complicated transplant course and must be approached with care. The conditioning regimen should use a reduced dose of melphalan since toxicity is increased with standard doses in this population. (See "Multiple myeloma: Use of autologous hematopoietic cell transplantation", section on 'Patients with renal insufficiency'.)
Retrospective series suggest that HCT in patients with MM and dialysis-dependent kidney failure is associated with a relatively high transplant-related mortality (15 percent) and greater toxicity than in those without kidney dysfunction [7]. 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'.)
Kidney 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 micromol/liter]) can undergo HCT as an outpatient [8].
INITIAL THERAPY
Induction therapy — The initial therapy of patients with symptomatic MM depends on risk stratification, eligibility for autologous hematopoietic cell transplantation (HCT), and resources available (algorithm 2). There is no general agreement as to the preferred induction regimen and different experts use different regimens. Our preferred approach and data supporting this approach are discussed in more detail separately, as are alternatives for resource-poor settings. (See "Multiple myeloma: Initial treatment" and "Multiple myeloma: Management in resource-limited settings".)
The duration of induction therapy depends on the regimen used and whether the patient will proceed with HCT:
●Patients eligible for HCT receive induction therapy for three to six cycles of induction therapy 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. During this time, specific arrangements for the subsequent HCT can be made to ease the transition of therapy. Stem cells are collected at this time regardless of whether an early or delayed transplant strategy is used. Those who choose to delay HCT until first relapse complete a total of 8 to 12 cycles of initial therapy followed by maintenance until relapse. (See 'HCT eligible' below.)
●Patients ineligible for HCT receive 8 to 12 cycles of initial therapy with a triplet regimen followed with maintenance therapy until progression unless there is significant toxicity. In patients who are frail and are not felt to be candidates for triplet therapy, we offer 8 to 12 cycles of doublet therapy with lenalidomide and low dose dexamethasone followed by maintenance with single-agent lenalidomide. (See 'HCT ineligible' below.)
Post-induction therapy
HCT eligible — Following induction therapy and stem cell collection, patients who are eligible for HCT must choose among the following approaches:
●Early transplant strategy – Proceed with autologous HCT (single or double) directly after recovery from stem cell collection
●Delayed transplant strategy – Continued therapy, usually with the same regimen used for induction, reserving autologous HCT until first relapse
●Allogeneic HCT
For most patients, the preferred approach is induction chemotherapy followed by early or delayed autologous HCT rather than allogeneic HCT. The incorporation of autologous HCT into the treatment strategy improves progression-free survival (PFS) and overall survival (OS) over that seen with standard doses of chemotherapy alone. Studies evaluating early and delayed transplant strategies have demonstrated similar survival rates so either option is acceptable for most patients. Although allogeneic HCT offers a chance for cure, its use in initial therapy is limited by high early mortality rates and morbidity. (See "Multiple myeloma: Use of allogeneic hematopoietic cell transplantation".)
The choice between early and delayed HCT is individualized. The factors that influence this decision include:
●Patient preference
●Risk stratification (early HCT is preferred for high-risk MM)
●Patient age (as age approaches 70, early HCT is preferred)
●Response and tolerability to the initial chemotherapy regimen
●Insurance approval (some insurers do not cover stem cell harvest and cryopreservation without immediate transplantation)
●Center facilities and resources for long-term storage of stem cells
Importantly, patients who choose to delay transplant may have an event or complication that makes them ineligible for transplant in the future. This is discussed in more detail separately. (See "Multiple myeloma: Use of autologous hematopoietic cell transplantation", section on 'Timing of HCT'.)
Autologous HCT versus chemotherapy alone — Autologous HCT remains a key component of myeloma therapy in eligible patients and can be incorporated as part of the initial therapy (early HCT) or at the time of first relapse (delayed HCT), depending on risk stratification:
●For standard-risk MM, either early or delayed HCT is reasonable and the decision is individualized based upon patient preference and other logistics.
●For high-risk MM, we prefer early HCT based on data that such an approach has generally yielded the best long-term survival results [9].
For eligible patients with MM, we recommend early or delayed autologous HCT rather than conventional chemotherapy alone. When compared with chemotherapy alone, autologous HCT results in:
●Improved OS
●Superior PFS, with an improvement in median PFS >20 months
●Manageable short-term toxicities with a low nonrelapse mortality
●Similar rates of second primary malignancies, with a potential increase in myeloid malignancies (ie, acute myeloid leukemia [AML], myelodysplastic syndrome [MDS])
Further details regarding these outcomes come from randomized trials described below.
●Overall survival – Improved OS with autologous HCT was shown in randomized trials that compared autologous HCT versus chemotherapy alone and did not allow for HCT at the time of relapse [10-14]. Many of these trials used older induction therapies and none used a triplet regimen. Two incorporated lenalidomide into the induction regimen:
•In one trial, 273 patients received four cycles of lenalidomide plus dexamethasone (Rd) followed by stem cell collection and were then randomly assigned to consolidation with melphalan, prednisone, lenalidomide (MPR) or with high dose melphalan plus autologous HCT [13]. At a median follow-up of 51 months, HCT resulted in longer median PFS (43 versus 22 months; hazard ratio [HR] 0.44; 95% CI 0.32-0.61) and OS (82 versus 65 percent at four years; HR 0.55; 95% CI 0.32-0.93).
•In a second trial, 256 patients underwent induction with Rd followed by stem cell collection and were randomly assigned to consolidation with Rd plus cyclophosphamide or with high dose melphalan plus autologous HCT [14]. After a median follow-up of 52 months, those assigned to chemotherapy without HCT had shorter PFS (median 29 versus 43 months; HR 2.51; 95% CI 1.60-3.94) and OS (73 versus 86 percent at four years; HR 2.40; 95% CI 1.32-4.38).
Several additional randomized trials comparing early HCT versus chemotherapy allowed for HCT after relapse and have not found an OS benefit [15-23]. These studies are more difficult to interpret since they do not directly address the value of HCT as a modality versus chemotherapy alone. However, given the OS benefit seen in a few randomized trials and the marked limitations of the studies that did not show a benefit, we believe that there is a significant OS benefit to autologous HCT when compared with chemotherapy alone. However, for standard-risk MM, it appears that OS is similar whether HCT is performed as part of initial therapy (early HCT) or at the time of first relapse (delayed HCT) [23].
●Progression-free survival – Autologous HCT delays progression by >20 months. This PFS benefit has been a consistent finding across randomized trials of induction therapy followed by early HCT versus chemotherapy alone, including those trials that have allowed HCT after relapse [10-23].
In the largest trial using modern triplet therapy (DETERMINATION), 722 patients received three cycles of induction with bortezomib, lenalidomide, and dexamethasone (VRd) followed by stem cell collection and were randomly assigned to an additional five cycles of VRd consolidation versus high dose melphalan plus autologous HCT plus two cycles of VRd consolidation, each followed by lenalidomide maintenance until progression or unacceptable toxicity [22]. At the time of relapse, autologous HCT was recommended but not mandated for those assigned to VRd alone; HCT was performed in 78 of 279 (28 percent) patients relapsing after VRd alone. After a median follow-up of 76 months, incorporation of autologous HCT:
•Improved PFS (median PFS 68 versus 46 months; HR 1.53, 95% CI 1.23-1.91).
•On subgroup analysis, this benefit was seen among the 132 patients with high-risk myeloma (median PFS 56 versus 17 months; HR 1.99, 95% CI 1.21-3.26) and among the 542 patients with standard-risk myeloma (median PFS 82 versus 53 months; HR 1.38, 95% CI 1.07-1.79).
•Longer follow-up is needed to evaluate OS as median OS was not reached in either arm and the five year estimates have a wide confidence interval (estimated five-year OS 81 versus 79 percent; HR 1.10, 95% CI 0.73-1.65).
●Toxicities – In the DETERMINATION trial, when compared with RVd alone, RVd plus HCT increased grade 3 or higher toxicities overall (94 versus 78 percent), including cytopenias (90 versus 62 percent), infection (18 versus 10 percent), gastrointestinal disorders (19 versus 8 percent), and fatigue (6 versus 3 percent) [22]. There was a temporary decrease in quality of life at the time of HCT followed by a return to baseline and further improvement during maintenance.
Second primary malignancies were similar overall (10.7 versus 10.4 percent), although there were more cases of AML/MDS (10 cases with HCT versus none). Deaths due to adverse events were consistent with other modern HCT trials (5 versus 1 death).
Another analysis of autologous HCT in 1156 patients with MM reported a one-year nonrelapse mortality of 2 percent (95% CI 1-4 percent) [24]. Approximately 25 percent of patients in this study were alive 15 years after first autologous HCT [25]. (See "Determining eligibility for autologous hematopoietic cell transplantation", section on 'Functional status and comorbid illnesses'.)
Further details regarding timing of HCT are discussed separately. (See "Multiple myeloma: Use of autologous hematopoietic cell transplantation", section on 'Timing of first HCT'.)
Autologous versus allogeneic HCT — A minority of patients will be eligible for allogeneic HCT, but the role of allogeneic approaches 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. (See "Multiple myeloma: Use of allogeneic hematopoietic cell transplantation".)
Although allogeneic HCT may be a potentially curative treatment for MM, initial treatment with high dose chemotherapy followed by allogeneic HCT is not commonly employed. This is due to many factors including the fact that a majority of patients are ineligible due to older age or comorbidities and because it is associated with high rates of overall mortality and symptoms of graft-versus-host disease. Moreover the higher probability of cure compared with autologous transplantation remains unproven. We do not recommend myeloablative allogeneic HCT for standard-risk MM at this time due to the excessively high mortality rate and toxicity and lack of proven benefit compared with autologous HCT [15,26]. It may be considered, ideally in the context of a clinical trial, in selected young patients with high-risk relapsed MM.
Both prospective and retrospective studies have evaluated the use of nonmyeloablative HCT in MM. Nonmyeloablative HCT relies primarily on a graft-versus-myeloma effect, which is unfortunately often accompanied by the detrimental effects of graft-versus-host disease. Outcomes with this therapeutic approach have been mixed. Due to conflicting results, high treatment-related mortality, and toxicity [27], nonmyeloablative allogeneic HCT is not advised for patients with newly diagnosed myeloma outside of a clinical trial setting, except in selected young patients with high-risk relapsed MM. This is discussed in more detail separately. (See "Multiple myeloma: Use of allogeneic hematopoietic cell transplantation".)
Maintenance after HCT — Since virtually all patients who receive autologous HCT for MM eventually develop relapsed disease, trials have investigated the use of chemotherapeutic and biologic agents in an attempt to eliminate residual malignant cells after HCT. Our preferred treatment approach uses lenalidomide maintenance for standard-risk patients, and proteasome-inhibitor-based maintenance for high-risk patients (algorithm 2). The use of maintenance therapy after HCT is discussed in more detail separately. (See "Multiple myeloma: Use of autologous hematopoietic cell transplantation", section on 'Maintenance'.)
HCT ineligible — There is ongoing debate regarding the role of maintenance therapy in patients with MM who are not candidates for autologous HCT and experts differ in their approach. We suggest maintenance therapy for most patients; this preference places a high value on delaying progression and the potential for an as yet unproven survival benefit, and places a lower value on the risks associated with continued therapy. The type of maintenance depends on risk stratification and comorbidities (algorithm 2). This is discussed in more detail separately. (See "Multiple myeloma: Initial treatment", section on 'Maintenance for patients who are ineligible for or defer HCT'.)
EVALUATING RESPONSE TO TREATMENT
Response criteria and monitoring for relapse — Patients should be evaluated before each treatment cycle to determine how the disease is responding to therapy (ie, tumor burden) and to assess for potential treatment-related and disease-related complications. Details of this evaluation are presented separately. (See "Multiple myeloma: Evaluating response to treatment" and 'Prevention and management of complications' below.)
Briefly, the preferred method for assessing tumor burden in a given patient depends on the results of baseline studies and on the suspected degree of response (table 6A). The International Myeloma Working Group (IMWG) uniform response criteria are the preferred criteria to determine the patient's best response to treatment and to define when a relapse has occurred (table 6B).
The rationale for monitoring disease response is to modify therapy if needed, adjust doses based on response and toxicity, and to identify transplant candidates with resistant disease. In such patients, early hematopoietic cell transplantation (HCT) may be preferred. (See "Multiple myeloma: Use of autologous hematopoietic cell transplantation".)
Approximately 7 percent of patients will develop a secondary monoclonal gammopathy of undetermined significance (MGUS) defined as a new monoclonal protein that has an isotype (heavy and/or light chain) distinct from the original clone (eg, IgM MGUS in a patient with IgG MM). This is discussed in more detail separately. (See "Diagnosis of monoclonal gammopathy of undetermined significance", section on 'Secondary MGUS'.)
Significance of response to chemotherapy — The depth of response has prognostic value in myeloma. Patients who achieve a minimal residual disease (MRD)-negative state have superior progression-free and overall survival compared to those in whom MRD testing shows residual disease [28]. However, there are no data from randomized trials evaluating whether outcomes can be improved by administering additional therapy to patients with MRD-positive disease. Thus, although the depth of response has prognostic value, we need more data on whether better outcomes can be achieved by altering therapy based on the extent of response. Randomized trials are being conducted to address this question. MRD assessment is discussed in more detail separately. (See "Multiple myeloma: Evaluating response to treatment", section on 'Minimal residual disease assessment'.)
RELAPSED OR REFRACTORY DISEASE — Most patients with MM will have an initial response to treatment. However, conventional therapy is not curative and MM will ultimately relapse. In addition, a minority will have primary refractory disease that does not respond to initial treatment.
Indications for therapy — Progression is usually identified by a rise in monoclonal (M) protein in the serum or urine or in the serum free light chain ratio (table 6A-B) [29]. However, not all patients with progression on laboratory testing need immediate treatment. (See "Multiple myeloma: Evaluating response to treatment".)
Therapy for relapsed disease is indicated if there is a clinical relapse, extramedullary disease, or a rapid rise in paraproteins [30-32].
●Clinical relapse – Development of CRAB symptoms (hypercalcemia, renal insufficiency, anemia, or new bone lesions), using the same definitions as for the diagnosis of MM. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Diagnostic criteria'.)
●Extramedullary plasmacytoma – Plasma cell tumors that arise outside of the bone marrow. If extramedullary relapse is suspected clinically, we evaluate the extent of disease with a whole body combined fluorine-18-labeled fluorodeoxyglucose positron emission tomography/computerized tomography (18F-FDG PET/CT). (See 'Extramedullary relapse' below and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Imaging'.)
●Rapid rise in paraproteins – Salvage therapy is clearly indicated if there is a doubling of the M protein over two to three months, with an increase in the absolute levels of M protein of ≥1 g/dL in the serum or of ≥500 mg per 24 hours in the urine, confirmed by two consecutive measurements. (See "Multiple myeloma: Evaluating response to treatment", section on 'Assessing tumor burden'.)
In contrast, patients without clinical relapse and with a slower rise in paraproteins may choose to defer salvage therapy. In addition, treatment is not indicated for patients that develop oligoclonal reconstitution after autologous transplantation [32,33].
Selection of therapy
General principles
Identify aggressive disease (risk stratification) — The duration of response can be used to identify patients with clinically aggressive disease:
●Patients who relapse less than 12 months from first-line therapy or relapse on full doses of first-line therapy (ie, refractory disease) are considered to have aggressive disease even if evaluation by FISH previously classified their disease as standard risk.
●Patients previously diagnosed with high-risk disease by FISH who relapse more than two years from initial therapy can be considered as having standard-risk disease at the time of relapse in the absence of new additional high-risk cytogenetic abnormalities (table 3).
This classification is supported by retrospective studies that have demonstrated inferior survival among patients who relapse less than 12 months after initial therapy [34-36]. As an example, a retrospective analysis of 102 patients with relapsed MM reported that patients who had a time to first progression ≤12 months had a shorter median overall survival (OS) when compared with those who had a time to first progression after 12 months (20 versus 59 months, respectively) [34].
Patients with aggressive disease at the time of relapse are best treated with a multi-agent chemotherapy regimen, preferably in the context of a clinical trial. These are the patients who will be the least likely to respond to conventional therapies and likely require more intensive treatment, which may include prolonged maintenance therapy, multi-agent combination therapy, autologous hematopoietic cell transplantation (HCT), chimeric antigen receptor (CAR)-T cell therapy, or allogeneic HCT.
Assess eligibility for clinical trials — There is no single standard therapy for relapsed or refractory MM and practice varies widely; as such, we encourage eligible patients to participate in clinical trials. This is especially important for patients with high-risk disease and patients with multiply relapsed disease who have been exposed to most available agents. (See 'Investigational agents and accessing clinical trials' below.)
When a clinical trial is not available or if a patient does not want to participate in a trial, the choice of therapy depends on eligibility for HCT, what agents have been used previously, how the disease responded to this therapy, aggressiveness of the relapse, side effect profiles, and patient comorbidities. Our approach is generally consistent with that proposed by the International Myeloma Working Group [37].
Assess eligibility for transplant — At the time of relapse, all patients are assessed to determine eligibility for autologous HCT and allogeneic HCT. Eligibility for HCT is primarily determined based on the patient's age, performance status, and/or the presence of comorbid conditions. (See 'Determining transplant eligibility' above.)
Prospective randomized trials have shown that autologous HCT results in superior event-free survival (EFS) and OS rates when compared with combination chemotherapy in patients with previously untreated MM. In addition, at least one randomized trial found similar OS rates among patients who underwent HCT as part of their initial therapy and those who delayed HCT until the time of relapse. As such, after initial chemotherapy and collection of stem cells, patients can either proceed directly to autologous HCT or can opt for delayed autologous HCT at the time of relapse. This is discussed in more detail separately. (See "Multiple myeloma: Use of autologous hematopoietic cell transplantation", section on 'Timing of HCT'.)
Our recommendations regarding 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 [38].
●For those patients who are eligible for HCT but did not undergo HCT as part of their initial treatment, we recommend high-dose chemotherapy followed by autologous HCT at relapse. Patients who are initially refractory to induction chemotherapy (primary refractory disease) can achieve a good response to subsequent autologous HCT, and lack of response to initial therapy does not preclude transplantation. Support for the use of autologous HCT in MM and practical details on the performance of autologous HCT are presented separately. (See "Multiple myeloma: Use of autologous hematopoietic cell transplantation".)
●A second autologous HCT is an acceptable option for patients who experienced a durable benefit (at least 18 to 24 months) with the first HCT. Retrospective studies suggest that these patients can attain a progression-free survival (PFS) following second HCT of at least nine months [39,40]. The attractiveness of this approach increases for those who experienced longer remissions and had an uncomplicated post-HCT course. (See "Multiple myeloma: Use of autologous hematopoietic cell transplantation", section on 'Treatment of relapse after HCT'.)
●For patients in whom cryopreserved stem cells are available, the need for bridging chemotherapy prior to autologous HCT for relapsed MM is based on the clinical need and the anticipated delay to arrange for HCT. If patients have symptomatic relapse or a delay to arrange for transplant of more than a few weeks is anticipated, chemotherapy is administered to control the disease. For patients in whom cryopreserved stem cells are not available, a chemotherapy regimen to reduce tumor burden is almost always needed prior to stem cell mobilization, and autologous HCT.
●Allogeneic HCT can be offered to selected young patients with high-risk relapsed MM who have a matched donor and are willing to accept a high treatment-related mortality rate and the conflicting data on the efficacy of the intervention. In highly selected patient populations, allogeneic HCT with reduced intensity 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 [41-50]. 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. (See "Multiple myeloma: Use of allogeneic hematopoietic cell transplantation".)
Extramedullary relapse — Patients with extramedullary plasmacytoma, secondary plasma cell leukemia (PCL), or central nervous system (CNS) involvement at the time of relapse require special consideration:
●Extramedullary plasmacytoma and secondary PCL – The development of extramedullary disease or secondary PCL is associated with adverse prognosis and is difficult to treat [51-53]. A multicenter retrospective study of 101 patients with secondary PCL reported a median OS of 4.2 months with a one-year OS of 19 percent among patients who received therapy [51]. Response rates were higher among those who underwent autologous HCT and/or received proteasome inhibitors. If the patient is able to tolerate aggressive therapy, we usually offer multidrug regimens (such as VDT-PACE) for one to two cycles to control disease, and then offer standard three-drug regimens used in the treatment of relapsed myeloma [54]. (See "Plasma cell leukemia", section on 'Induction therapy'.)
●CNS relapse – CNS relapse is rare, and is associated with poor prognosis [55,56]. There are no good data on therapy. Most patients are treated with supportive care only, or occasionally intrathecal chemotherapy regimens used in the treatment of CNS lymphoma. (See "Secondary central nervous system lymphoma: Treatment and prognosis".)
First or second relapse — There are many approved treatment combinations for patients with relapsed and/or refractory MM. Most patients experience serial relapses over time and will ultimately receive most if not all available agents at some point during their disease course. Accompanying tables provide active drugs by class (table 7), and major toxicities of selected treatment regimens (table 8).
The choice of therapy for relapsed MM must consider prior therapy, response, and likelihood of the disease being sensitive or refractory to prior agents. In general, refractory disease is defined as progressing on or within 60 days of receiving standard doses of a specific therapy.
Whether a patient is lenalidomide sensitive or lenalidomide refractory represents an important determinant of second- or third-line therapy, since many of the regimens that have regulatory approval for this indication incorporate lenalidomide. Our approach is therefore structured according to disease status as it relates to sensitivity or refractoriness to lenalidomide (algorithm 3). (See "Multiple myeloma: Treatment of first or second relapse".)
Third or later relapse — For patients with third or later relapse, our approach depends on whether their disease is refractory to our most active agents in MM (penta-refractory), including:
•An anti-CD38 monoclonal antibody (eg, daratumumab, isatuximab)
For patients with non-penta-refractory disease, the choice of regimen is similar to that in first or second relapse, and driven by an understanding of drug sensitivity and expected toxicity (algorithm 3).
Our approach to patients with penta-refractory disease is illustrated in the algorithm and described in more detail separately (algorithm 4). (See "Multiple myeloma: Treatment of third or later relapse".)
PREVENTION AND MANAGEMENT OF COMPLICATIONS — In addition to therapy directed at the malignant clone, the management of most patients with MM includes preventative measures to reduce the incidence of skeletal events, renal damage, infections, and thrombosis.
The importance of these complications was highlighted in a study of death within 60 days of diagnosis in patients with myeloma entering onto the United Kingdom's Medical Research Council (MRC) trials. The incidence of early death was 10 percent, with the most common contributors being bacterial infection (50 percent) and renal failure (28 percent) [57].
Skeletal lesions and bone health
●Prevention – Osteoclast inhibitors (eg, bisphosphonate therapy) are administered to prevent skeletal events in patients with one or more lesions on skeletal imaging and those with osteopenia (algorithm 5). (See "Multiple myeloma: The use of osteoclast inhibitors".)
●Spinal cord compression – Spinal cord compression is a clinical emergency and should be suspected in patients with severe back pain, weakness, or paresthesias of the lower extremities, or bladder or bowel dysfunction or incontinence.
Prompt diagnosis and immediate treatment are critically important in the preservation of neurological function in patients with spinal cord compression. In patients with neurologic symptoms directly due to cord compression, radiation therapy is given along with dexamethasone, and up to half of patients may have improvement of motor function with radiotherapy with longer fractionation schedules providing better relief [58].
Systemic therapy with regimens such as bortezomib, cyclophosphamide, dexamethasone (VCD) or bortezomib, thalidomide, dexamethasone (VTD) work rapidly and can be used instead of radiation in selected patients if there is minimal neurologic deficit. Surgical decompression is necessary only if the neurologic deficit does not improve or if the compression is due to retropulsed bone. Details regarding the treatment of neoplastic spinal cord compression are presented separately. (See "Treatment and prognosis of neoplastic epidural spinal cord compression".)
●Pathologic and impending fractures – Pathologic fractures or impending fractures of long bones require stabilization. Although the decision to stabilize lytic lesions is made by an orthopedic surgeon and depends in part upon the location of the lesions, a usual rule of thumb is that if there is 50 percent or more destruction of cortical bone thickness, surgical fixation is required. (See "Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma".)
Vertebral fractures may benefit from kyphoplasty or vertebroplasty. Most pain related to lytic lesions can be controlled with the combination of analgesics and active myeloma chemotherapy. (See "Management of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma".)
Kyphoplasty and vertebroplasty have been associated with pain relief in prospective trials in patients with myeloma, but have not been tested in a blinded fashion [59-62]. The choice between procedures depends on the available expertise. Local radiation therapy (RT) is rarely needed after these procedures except in rare cases in which the patient has myeloma refractory to systemic therapy.
●Palliative radiation therapy – Up to 40 percent of patients with myeloma will require RT to control disease at some point in their disease course [63]. Common indications for RT include:
•Pain control of lytic lesions that are refractory to systemic therapy.
•Treatment of spinal cord compression from plasmacytoma.
•Primary treatment of solitary plasmacytoma.
•Local control of MM relapse involving a limited area.
Post-surgical RT after stabilization of impending fractures is rarely needed [64]. Extensive radiation should be avoided because it can reduce bone marrow reserve, compromise future chemotherapy, and may prevent a future autologous stem cell procedure. Most patients can get equally rapid pain relief and reduction in tumor mass with systemic therapy for myeloma.
Our approach is in contrast to a joint recommendation for RT after stabilization surgery for patients with pathologic fracture of the femur from the Musculoskeletal tumor society (MSTS), American Society for Radiation Oncology (ASTRO), and American Society of Clinical Oncology (ASCO) [65]. The MSTS/ASTRO/ASCO recommendation is a consensus statement based on a 1995 retrospective analysis of mostly solid tumor metastases [66], and aims to reduce pain, improve functional status, and reduce the need for further intervention. The high response rates with systemic therapy and major advances in the treatment of MM question the applicability of these study results to today's patients with MM.
The dose of RT used varies according to the clinical situation. Palliation of lytic bone lesions may be accomplished with 20 to 30 Gy administered in 5 to 10 fractions while higher doses are required for the treatment of solitary plasmacytoma (in which the intent is curative) or spinal cord compression [67]. Whether radiation is more effective when given in conjunction with chemotherapy is unclear [68].
There are limited data regarding the ideal dose of palliative RT for bone lesions. A retrospective single institution study of 101 patients administered palliative radiation to 306 symptomatic bone sites reported at least partial symptom relief in 98 percent of sites receiving 10 or greater Gy of radiation with no dose response demonstrated [68]. A minority of sites had complete symptom control (26 percent).
Kidney impairment — All patients with MM should take measures to minimize kidney damage (eg, avoid nephrotoxins such as aminoglycosides and NSAIDs and maintain adequate hydration). Many medications used for myeloma require dose adjustment for kidney impairment (eg, lenalidomide, zoledronic acid). Treatment of kidney impairment is directed at the underlying cause. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Treatment and prognosis".)
Infection — Prophylactic measures that may minimize infection in patients with MM include yearly influenza vaccines, pneumococcal vaccine at the time of diagnosis, prophylactic antibiotics during the first months of induction chemotherapy, and intravenous immune globulin for selected patients who have recurrent, serious infections. (See "Infections in patients with multiple myeloma" and "Immunizations in adults with cancer".)
Patients suspected of having an infection should be treated promptly with empiric antibiotics covering encapsulated bacteria and gram-negative micro-organisms. (See "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications".)
Thromboembolism — Patients with MM are at increased risk of having comorbidities known to be risk factors for the development of venous thromboembolism (VTE) in the general population. In addition, treatment with immunomodulatory drugs (eg, lenalidomide, pomalidomide, thalidomide) has been associated with high rates of VTE. All patients with MM should have an assessment of their VTE risk so that appropriate prophylaxis may be employed (algorithm 6). (See "Multiple myeloma: Prevention of venous thromboembolism in patients receiving immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide)".)
Other complications — Patients with MM may also require specific interventions for the management of hypercalcemia, anemia, neuropathy, and, rarely, hyperviscosity.
●Hypercalcemia – Patients with hypercalcemia may be asymptomatic or present with anorexia, nausea, vomiting, polyuria, polydipsia, constipation, weakness, confusion, or stupor. Hypercalcemia can also contribute to the development of kidney impairment.
In most patients with MM the diagnosis of hypercalcemia does not require measurement of the ionized calcium. However, if a patient presents with an elevated serum calcium level but no associated symptoms, the ionized calcium should be measured to confirm hypercalcemia prior to the initiation of treatment since rarely the monoclonal protein binds to calcium [69].
The treatment of hypercalcemia depends on the calcium level, the rapidity with which it developed, and the patient's symptoms. Emergent treatment with hydration, glucocorticoids, bisphosphonates, and/or hemodialysis/calcitonin is indicated for symptomatic patients. (See "Treatment of hypercalcemia".)
●Anemia – The treatment of anemia associated with myeloma depends on the severity of the anemia, the presence or absence of symptoms related to anemia, and whether the patient is undergoing active chemotherapy. Patients with significant symptoms should be considered for red blood cell transfusion. Erythropoiesis-stimulating agents are generally reserved for patients receiving chemotherapy with a hemoglobin level of 10 g/dL or less [30,70,71]. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer".)
●Neuropathy – Patients with MM can develop peripheral neuropathy related to the disease itself or as a toxicity of treatment (eg, bortezomib, thalidomide). When it occurs, the painful sensory neuropathy can interfere with quality of life and with performance of activities of daily living, and it may require dose modification and/or treatment discontinuation. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Bortezomib' and "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Thalidomide and related agents'.)
●Hyperviscosity – Rarely patients with MM develop the hyperviscosity syndrome. This syndrome is characterized by oronasal bleeding, blurred vision, neurologic symptoms, confusion, and heart failure. Serum viscosity measurements do not correlate well with symptoms or the clinical findings. Plasmapheresis promptly relieves the symptoms and should be performed regardless of the viscosity level if the patient is symptomatic [72]. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)
INVESTIGATIONAL AGENTS AND ACCESSING CLINICAL TRIALS — Often, there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).
Ongoing trials are evaluating traditional agents in new combinations and evaluating newer agents with different mechanisms of action, novel targets, or more refined targets (eg, additional anti-CD38 monoclonal antibodies [73]).
Initial studies show impressive response rates with novel therapies directed against B cell maturation antigen (BCMA), including both standard and "off the shelf" chimeric antigen receptor T cells (eg, idecabtagene vicleucel and ciltacabtagene autoleucel) and bispecific T cell engagers (BiTEs, eg, teclistamab, AMG 701, CC93269) [74-83].
Use of the anti-BCMA antibody drug conjugate belantamab mafodotin and BCMA-directed chimeric antigen receptor T cell therapy are discussed separately. (See "Multiple myeloma: Treatment of third or later relapse", section on 'Targeting BCMA'.)
Agents with novel targets include "CELMoDs" that target cereblon (eg, iberdomide, CC92480), BiTEs such as talquetamab (targeting GPRC5D and CD3) and cevostamab (targeting FcRH5 and CD3), filanesib (kinesin spindle protein inhibitor), dinaciclib (cyclin dependent kinase inhibitor), and LGH-447 (pan PIM kinase inhibitor).
Some studies are evaluating the addition of agents aimed at restoring drug sensitivity. As an example, initial studies suggest that the protease inhibitor nelfinavir impairs proteasome activity and may have synergistic effects when combined with bortezomib [84-86]. A multicenter phase 2 trial suggested that the combination of nelfinavir, bortezomib, and dexamethasone has activity in proteasome inhibitor-refractory MM [87]. Further studies are needed to confirm this finding.
Additional trials are evaluating oncolytic viruses [88,89].
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 1), 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 info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Multiple myeloma (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
●Verification of the diagnosis – The first step in evaluating a new patient with MM is to verify the diagnosis since the premalignant stages of myeloma, namely monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), may be easily misdiagnosed as MM if one is not careful (table 1 and algorithm 1). (See 'Verify the diagnosis' above.)
•Management of SMM is dependent upon risk stratification (algorithm 7). (See "Smoldering multiple myeloma".)
•Patients who have end-organ damage attributable to the underlying plasma cell disorder or other myeloma-defining biomarker require therapy.
•All patients with confirmed MM should initiate treatment promptly. Without effective therapy, symptomatic patients have a life expectancy less than one year.
●Risk stratification – We risk stratify individual cases based on the results of fluorescence in situ hybridization (FISH) for specific translocations and certain other tests (table 3). This risk stratification has considerable prognostic value and also helps guide the selection of initial therapy (algorithm 2).
•High-risk myeloma: Includes patients with t(4;14), t(14;16), t(14;20), del17p13, or gain1q by FISH, those with lactate dehydrogenase (LDH) ≥2 times the institutional upper limit of normal, and those with features of primary plasma cell leukemia.
•Standard-risk myeloma: Includes patients without any of the high-risk cytogenetic abnormalities or features. This includes patients with trisomies, t(11;14) and t(6;14).
●Determining transplant eligibility – All patients are assessed to determine eligibility for autologous hematopoietic cell transplantation (HCT), which appears to prolong both event-free and overall survival when compared with non-transplant strategies. Eligibility for HCT varies across institutions. Although guidelines are provided, eligibility should consider the risk-benefit assessment and the needs and wishes of the patient. (See 'Determining transplant eligibility' above.)
Patients eligible for HCT receive induction therapy for three to 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. Following recovery from stem cell collection, patients may proceed directly to autologous HCT (early transplant strategy) or continue therapy, usually with the same regimen used for induction, reserving autologous HCT until first relapse (delayed transplant strategy). (See 'HCT eligible' above.)
●Approach to therapy in standard-risk myeloma – Treatment of standard-risk MM depends on HCT eligibility and comorbidities (algorithm 2):
•Patients with standard-risk MM who are eligible for HCT are treated with a triplet regimen for three to six cycles prior to stem cell collection. The choice of triplet regimen is discussed in more detail separately. (See "Multiple myeloma: Initial treatment".)
•Following stem cell collection, we recommend early or delayed autologous HCT rather than either chemotherapy alone or allogeneic HCT (Grade 1B). (See 'Autologous HCT versus chemotherapy alone' above.)
•Studies evaluating early and delayed transplant strategies have demonstrated similar survival rates so either option is acceptable for most patients. The decision is individualized taking into account patient preference, age, response to and tolerability of initial chemotherapy, and logistic factors. Importantly, patients who choose to delay transplant may have an event or complication that makes them ineligible for transplant in the future. (See "Multiple myeloma: Use of autologous hematopoietic cell transplantation", section on 'Timing of HCT'.)
•Those who proceed with early transplant are offered at least two years of maintenance therapy post-transplant. Those who choose to delay HCT until first relapse complete a total of 8 to 12 cycles of triplet therapy followed by maintenance with single-agent lenalidomide until relapse.
•For most patients ineligible for HCT, we offer a bortezomib-based triplet regimen for 8 to 12 cycles followed by maintenance with single-agent lenalidomide. Doses and schedules of triplet regimens can be modified for use in frail patients. In patients who are not felt to be candidates for triplet therapy, we offer 8 to 12 cycles of lenalidomide and low dose dexamethasone followed by maintenance with single-agent lenalidomide. (See 'HCT ineligible' above.)
●High-risk myeloma – Patients with high-risk MM should be encouraged to enroll in a clinical trial investigating novel therapeutic strategies, since they tend to do less well with conventional treatment options. Outside of a clinical trial, data are limited and experts differ in their approach. For transplant-eligible patients, we suggest induction therapy followed by early autologous HCT and two-drug maintenance (algorithm 2) (Grade 2C). Transplant-ineligible patients are offered 8 to 12 cycles of triplet-based induction therapy followed by two-drug maintenance. (See "Multiple myeloma: Initial treatment", section on 'High-risk myeloma'.)
●Complementary therapy – In addition to therapy directed at the malignant clone, the management of most patients with MM includes preventative measures to reduce the incidence of skeletal events, renal damage, infections, and thrombosis. Patients with MM may also require specific interventions for the management of hypercalcemia, anemia, and neuropathy. (See 'Prevention and management of complications' above.)
●Evaluating response – Patients should be evaluated before each treatment cycle to determine how their disease is responding to therapy (table 6B). Details on how to determine response to therapy are presented separately. (See "Multiple myeloma: Evaluating response to treatment".)
●Relapsed disease – Relapsed or refractory MM is usually identified on routine surveillance. Treatment is individualized based on prior therapy, response, and likelihood of the disease being sensitive or refractory to prior agents (algorithm 3 and algorithm 4). (See 'Relapsed or refractory disease' above.)
