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Multiple myeloma: Overview of management

Multiple myeloma: Overview of management
Literature review current through: Jan 2024.
This topic last updated: Oct 17, 2023.

INTRODUCTION — Multiple myeloma (MM) is a plasma cell neoplasm characterized by clonal plasma cells that produce 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 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. As an example, patients with MGUS may have kidney failure due to diabetes or hypertension, or they may 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.

This distinction is important clinically. 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, SMM and MGUS may remain stable for prolonged periods and are managed differently.

Diagnosis of MM is based on criteria from the International Myeloma Working Group (table 1) [2]. An approach to the evaluation of suspected cases is presented in the algorithm (algorithm 1) and discussed in more detail separately. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Diagnosis'.)

The main conditions to consider in the differential diagnosis for MM include MGUS, SMM, Waldenström macroglobulinemia, solitary plasmacytoma, AL amyloidosis, POEMS syndrome, and metastatic carcinoma (table 2 and table 3). (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Differential diagnosis'.)

Clinical evaluation — The initial evaluation of patients with MM must establish the extent and sites of disease, the patient's performance status (table 4), 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 (LDH), and beta-2 microglobulin. (See "Multiple myeloma: Staging and prognostic studies".)

Serum creatinine and an estimation of glomerular filtration rate (GFR) [3]. The assessment of GFR and evaluation to determine the cause of kidney impairment are discussed separately. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation" and "Assessment of kidney function", section on 'Assessment of GFR'.)

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 [4]. (See "Comprehensive geriatric assessment for patients with cancer".)

Risk stratification — We risk stratify individual cases based on the results of FISH for specific translocations and certain other tests (table 5). 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

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 [5].

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 [6].

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 (table 6) 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 dictate 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".)

Determine transplant eligibility — All patients are assessed to determine eligibility for autologous HCT. HCT eligibility impacts the initial management of patients with MM regardless of whether they choose to proceed with HCT as part of their initial management. Clinicians should have a low threshold to refer patients to a transplant center to discuss candidacy, the role of HCT, and preferred timing.

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 7)

New York Heart Association (NYHA) functional status class III or IV (table 8)

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.

In the US, the Centers for Medicare and Medicaid Services approves reimbursement for high-dose therapy with autologous HCT in newly diagnosed patients with MM who are <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 may be necessary for older adults undergoing HCT. This is discussed in more detail separately. (See "Multiple myeloma: Use of 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 [7]. However, patients with kidney impairment can have a more complicated transplant course and increased transplant-related mortality. As such, patients and clinicians must consider the heightened risk associated with the procedure in this population, particularly if the patient has access to effective treatment options at the time of progression.

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 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 hematopoietic cell transplantation", section on 'Patients with kidney impairment'.)

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 [8]. 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'.)

INITIAL THERAPY — Patients with MM are not cured with conventional therapy. Treatment alleviates symptoms, reverses cytopenias, and decreases end-organ damage, and it aims to achieve a sustained response, improve quality of life, and prolong overall survival (OS).

Eligible for autologous transplant

Induction, stem cell collection, and timing of HCT — Patients eligible for autologous hematopoietic cell transplantation (HCT) should be referred to a transplant center to discuss candidacy, the role of HCT, and preferred timing. (See 'Determine transplant eligibility' above.)

HCT can be incorporated into the initial therapy (early HCT) or deferred until first relapse (delayed HCT). Timing is individualized taking into account age, risk stratification, response to and tolerability of initial chemotherapy, treatment options at relapse, logistic factors, and patient preference. (See "Multiple myeloma: Use of hematopoietic cell transplantation", section on 'Early versus late HCT'.)

General principles of management include:

Induction chemotherapy is administered for three to six 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 regimen used depends on risk stratification, comorbid conditions, and resources available, and limits exposure to agents that may impair stem cell collection or damage stem cells. There is no single preferred induction regimen and different experts use different regimens. Our preferred approach and data supporting this approach are discussed in more detail separately (algorithm 2) as are alternatives for resource-limited settings (algorithm 3). (See "Multiple myeloma: Initial treatment" and "Multiple myeloma: Management in resource-limited settings".)

Stem cells are collected regardless of whether the patient plans to proceed directly with HCT or store the stem cells for use at a later time. (See "Multiple myeloma: Use of hematopoietic cell transplantation", section on 'Collection of stem cells'.)

Following stem cell collection, those who choose to defer HCT continue therapy, usually with the same regimen used for induction, followed by maintenance until relapse. (See "Multiple myeloma: Initial treatment", section on 'Maintenance for patients who are ineligible for or defer HCT'.)

Benefits of 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 delayed until first relapse (delayed HCT). Patients eligible for autologous HCT should be referred to a transplant center to discuss candidacy, the role of HCT, and preferred timing. (See "Multiple myeloma: Use of hematopoietic cell transplantation", section on 'Early versus late HCT'.)

When compared with chemotherapy alone, treatment strategies that incorporate autologous HCT result in:

Superior progression-free survival (PFS), with an improvement in median PFS >20 months

Manageable short-term toxicities with a low nonrelapse mortality

Similar overall rates of second primary malignancies, and an increase in myeloid malignancies (ie, acute myeloid leukemia [AML], myelodysplastic syndrome [MDS])

Further details regarding these outcomes come from randomized trials:

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 incorporated three-drug induction therapy followed by maintenance and allowed for HCT at relapse [9-23].

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 [9]. 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; hazard ratio [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).

Did not improve OS (estimated five-year OS 81 versus 79 percent; HR 1.10, 95% CI 0.73-1.65).

A similar PFS benefit from autologous HCT was reported in two other large randomized trials that used modern three-drug induction regimens and maintenance therapy (IFM 2009 [10], FORTE [11]).

Toxicities – Autologous HCT is associated with short-term toxicities and has a low nonrelapse mortality (approximately 2 percent). In the DETERMINATION trial, when compared with VRd alone, VRd 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) [9]. 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'.)

Overall survival – The impact of autologous HCT on OS appears to depend at least partially on access to modern induction therapy, maintenance, and effective treatments at relapse. 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 [12-16]. 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 [15]. At a median follow-up of 51 months, HCT resulted in longer median PFS (43 versus 22 months; 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 [16]. 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).

In contrast, an OS benefit has not been seen in trials that used modern three-drug induction with maintenance and provided access to delayed HCT and other effective therapies at the time of relapse (DETERMINATION [9], IFM 2009 [10], FORTE [11]).

Not eligible for autologous transplant — Patients ineligible for or without access to autologous HCT are treated with 8 to 12 months of induction chemotherapy followed by maintenance until progression or unacceptable toxicity.

The chemotherapy used depends on risk stratification, performance status, comorbid conditions, and resources available. There is no single preferred induction regimen and different experts use different regimens. Our preferred approach and data supporting this approach are discussed in more detail separately (algorithm 2) as are alternatives for resource-limited settings (algorithm 3). (See "Multiple myeloma: Initial treatment" and "Multiple myeloma: Management in resource-limited settings".)

Experts differ in their approach to maintenance therapy in patients with MM who are not candidates for autologous HCT. Maintenance therapy delays progression but also requires careful monitoring for toxicities that may be associated with long-term therapy. 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 are 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 9A). 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 9B).

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. (See 'Assess eligibility for transplant' below.)  

Approximately 7 percent of patients will develop 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 MM. Patients who achieve a minimal residual disease (MRD)-negative state have superior progression-free and overall survival compared with those in whom MRD testing shows residual disease [26].

Although depth of response as assessed by MRD status 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 evaluating whether outcomes can be improved by administering additional therapy that incorporates agents to which the patient has not yet been exposed in the setting of MRD-positive disease. At present, we do not recommend that patients responding favorably to a given regimen change treatment with the goal of deepening response to achieve MRD-negative status. 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 9A-B) [27]. 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 [28-30].

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/computed 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 'Measures of tumor burden'.)

In contrast, patients without clinical relapse and with a slower rise in paraproteins may choose to defer therapy. In addition, treatment is not indicated for patients that develop oligoclonal reconstitution after autologous transplantation [30,31].

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 fluorescence in situ hybridization (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 5).

This classification is supported by retrospective studies that have demonstrated inferior survival among patients who relapse less than 12 months after initial therapy [32-34]. 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) [32].

Patients with aggressive disease at the time of relapse are best treated with a multiagent 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, multiagent combination therapy, autologous hematopoietic cell transplantation (HCT), or chimeric antigen receptor (CAR)-T cell therapy.

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 autologous 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 [35].

Assess eligibility for transplant — At the time of first relapse, previously transplant-eligible patients are assessed to determine eligibility for autologous HCT if they have not previously undergone autologous HCT. (See 'Determine transplant eligibility' above.)

Autologous HCT can achieve sustained remissions and delay progression. OS rates are similar among patients who undergo HCT as part of their initial therapy and those who delay HCT until the time of first relapse. (See 'Benefits of autologous HCT versus chemotherapy alone' above and "Multiple myeloma: Use of hematopoietic cell transplantation", section on 'Early versus late 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 [36].

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 time of first 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 hematopoietic cell transplantation".)

A second autologous HCT is an acceptable option for patients who experienced a durable benefit (at least 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 [37,38]. The attractiveness of this approach increases for those who experienced longer remissions and had an uncomplicated post-HCT course. However, the decision to proceed with a second HCT in this population is individualized and must take into consideration that there is now an abundance of other effective treatment options for relapsed disease. (See "Multiple myeloma: Use of hematopoietic cell transplantation", section on 'Second autologous HCT after relapse'.)

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 select 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 [39-48]. Allogeneic transplant is typically reserved for patients who have received standard regimens. 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.

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 [49-51]. 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 [49]. 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 [52]. (See "Plasma cell leukemia", section on 'Induction therapy'.)

CNS relapse – CNS relapse is rare and is associated with poor prognosis [53,54]. There are no good data on therapy. Most patients are treated with supportive care only, with radiation therapy to sites of localized CNS disease, 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 10), and major toxicities of selected treatment regimens (table 11).

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 4). (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 the disease is refractory to our most active agents in MM, including:  

An anti-CD38 monoclonal antibody (eg, daratumumab, isatuximab)

Lenalidomide

Pomalidomide

Bortezomib

Carfilzomib

The term penta-refractory MM is used for MM that is refractory to all five of these agents/classes.

For patients with non-penta-refractory disease, the choice of regimen is similar to that in first or second relapse, and it is driven by an understanding of drug sensitivity and expected toxicity (algorithm 4). (See "Multiple myeloma: Treatment of first or second relapse".)

Our approach to patients with penta-refractory disease is illustrated in the algorithm and described in more detail separately (algorithm 5). (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, kidney 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 [55]. The incidence of early death was 10 percent, with the most common contributors being bacterial infection (50 percent) and kidney failure (28 percent).

Skeletal lesions and bone health

Prevention – Osteoclast inhibitors (eg, bisphosphonate therapy or denosumab) are administered to prevent skeletal events in patients with one or more lesions on skeletal imaging and those with osteopenia (algorithm 6). (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 neurologic 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 have improvement of motor function with radiation therapy (RT) with longer fractionation schedules providing better relief [56].

Systemic therapy with regimens such as bortezomib, cyclophosphamide, dexamethasone (VCd) or bortezomib, lenalidomide, dexamethasone (VRd) 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 they have not been tested in a blinded fashion [57-60]. The choice between procedures depends on the available expertise. Local 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 [61]. Common indications for RT include uncontrolled pain, spinal cord or nerve root compression, impending spinal cord compression, and pathologic fractures or impending fractures [62].

Postsurgical RT after the stabilization of pathologic fractures and impending fractures of long bones can be considered [62]. Extensive radiation in this setting should be avoided because it can reduce bone marrow reserve, compromise future chemotherapy, and may impair stem cell collection for a future autologous stem cell procedure. As such, the full extent of the surgical hardware need not be covered [63].

Multiple retrospective series have evaluated various radiation dose fractionation schemes of palliative RT for MM with no clear evidence of a dose-response relationship [64-68]. Doses as low as 10 to 12 Gy in conventional fractionation can achieve effective pain control. In a phase 3 trial comparing 30 Gy in 10 fractions versus 8 Gy in 1 fraction in 101 patients with MM, the two arms had similar rates of pain relief (84.5 versus 74.4 percent, respectively) [69].

There are limited data on the safety of combining RT with novel agents in myeloma therapy. The approach appears to be generally safe, although there is a trend towards increased hematologic toxicities, especially when RT is combined with proteosome inhibitors. Concurrent RT with proteosome inhibitors should therefore be administered judiciously, especially in patients with limited marrow reserve [70-72].

Kidney impairment — All patients with MM should take measures to minimize kidney damage (eg, avoid nephrotoxins such as aminoglycosides and nonsteroidal anti-inflammatory drugs [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 7). (See "Multiple myeloma: Prevention of venous thromboembolism".)

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 [73].

The treatment of hypercalcemia depends on the calcium level, the rapidity with which it developed, and the patient's symptoms. Immediate 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 [28,74,75]. (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.

It is important to monitor closely for development of chemotherapy-related neuropathy and either modify the dose and/or schedule of the responsible agent or switch to a different drug or combination. (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 [76]. (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 [77]).

Examples of novel targets and associated agents include:

Cereblon (eg, iberdomide [78], mezigdomide [79])

GPRC5D (eg, MCARH109 [80,81])

FcRH5 (eg, cevostamab)

Kinesin spindle protein (eg, filanesib [82])

Cyclin dependent kinase (eg, dinaciclib [83])

PIM kinase (eg, PIM447 [84])

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 [85-87]. A multicenter phase 2 trial suggested that the combination of nelfinavir, bortezomib, and dexamethasone has activity in proteasome inhibitor-refractory MM [88]. Further studies are needed to confirm this finding. As another example, initial studies suggest that gamma-secretase inhibitors may be used to increase BCMA expression prior to anti-BCMA therapy [89].  

Additional trials are evaluating oncolytic viruses [90,91].

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

Verify the diagnosis – The first step in evaluating a new patient with multiple myeloma (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 (algorithm 1 and table 1 and table 2). (See 'Verify the diagnosis' above.)

All patients with confirmed MM should initiate treatment promptly. Without effective therapy, symptomatic patients have a life expectancy less than one year. Treatment is not curative; it alleviates symptoms, reverses cytopenias, decreases end-organ damage, and aims to achieve a sustained response, improve quality of life, and prolong overall survival.

Risk stratification – We risk stratify MM based on the results of fluorescence in situ hybridization (FISH) for specific translocations and certain other tests (table 5). This risk stratification has considerable prognostic value and helps guide management (algorithm 2). (See 'Risk stratification' above.)

Patients with high-risk MM are 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. (See "Multiple myeloma: Initial treatment", section on 'High-risk myeloma'.)

Determine transplant eligibility – All patients are assessed to determine eligibility for autologous hematopoietic cell transplantation (HCT). Although guidelines are provided, eligibility varies across institutions and should consider the risk-benefit assessment and the needs and wishes of the patient. (See 'Determine transplant eligibility' above.)

HCT eligibility impacts the initial management of MM regardless of whether the patient plans to proceed with HCT as part of initial management.  

Initial treatment

HCT eligible – Patients eligible for autologous HCT should be referred to a transplant center to discuss candidacy, the role of HCT, and preferred timing. Autologous HCT remains a key component of therapy; incorporation of autologous HCT delays progression and has manageable short-term toxicities. (See 'Benefits of autologous HCT versus chemotherapy alone' above.)

HCT can be incorporated into the initial therapy or deferred until first relapse. Timing is individualized based on age, risk stratification, response to and tolerability of chemotherapy, treatment options at relapse, logistic factors, and patient preference. (See "Multiple myeloma: Use of hematopoietic cell transplantation", section on 'Early versus late HCT'.)

Induction chemotherapy is administered for three to six 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. (See 'Eligible for autologous transplant' above.)

The regimen used depends on risk stratification, comorbid conditions, and resources available, and limits exposure to agents that may impair stem cell collection or damage stem cells. Practice varies, and our preferred approach is illustrated in the algorithm (algorithm 2) as are alternatives for resource-limited settings (algorithm 3). (See "Multiple myeloma: Initial treatment", section on 'Risk-stratified treatment'.)

Stem cells are collected regardless of whether the patient plans to proceed directly with HCT or store the stem cells for use at a later time. Those who choose to defer HCT continue therapy, usually with the same regimen used for induction, followed by maintenance until relapse.

HCT ineligible – Patients ineligible for or without access to autologous HCT are treated with 8 to 12 months of induction chemotherapy followed by maintenance until progression or unacceptable toxicity. (See 'Not eligible for autologous transplant' above.)

The chemotherapy used depends on risk stratification, performance status, comorbid conditions, and resources available. Practice varies and our preferred approach is illustrated in the algorithm (algorithm 2) as are alternatives for resource-limited settings (algorithm 3). (See "Multiple myeloma: Initial treatment", section on 'Risk-stratified treatment'.)

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, kidney 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 9B). Details on how to determine response to therapy are presented separately. (See "Multiple myeloma: Evaluating response to treatment".)

Relapsed or refractory 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 4 and algorithm 5). (See 'Relapsed or refractory disease' above.)

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Topic 6643 Version 69.0

References

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