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Multiple myeloma: Staging and prognostic studies

Multiple myeloma: Staging and prognostic studies
Literature review current through: Jan 2024.
This topic last updated: Sep 25, 2023.

INTRODUCTION — Plasma cell myeloma is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin and can present as a single lesion (solitary plasmacytoma) or multiple lesions (multiple myeloma [MM]). This clone of plasma cells proliferates in the bone marrow and often results in extensive skeletal destruction with osteolytic lesions, osteopenia, and/or fractures. Additional disease-related complications include hypercalcemia, kidney impairment, anemia, and infections.

This topic review will discuss the staging and prognostic studies used in MM. The pathogenesis, clinical manifestations, diagnosis, and the different modalities used for therapy are discussed separately.

(See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)

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

(See "Multiple myeloma: Pathobiology".)

OVERVIEW — While multiple myeloma (MM) is considered an incurable form of cancer, patient outcomes continue to improve in terms of both the duration and quality of life [1]. With modern therapy, the median overall survival exceeds eight years, and varies from a few months in patients with ultra-high-risk features to more than 15 years in patients with lower risk features. In patients who are eligible for hematopoietic cell transplantation, median overall survival exceeds 12 years with standard risk myeloma and is over 6 years in high risk myeloma [2,3].

MM is a heterogeneous disease; some patients present with rapidly progressive symptoms and organ dysfunction whereas others have a more indolent clinical presentation (figure 1). The prognosis of patients with MM is dependent on four key factors:

Staging (disease characteristics)

Patient factors (host characteristics)

Disease biology (clinical characteristics, including plasmablastic morphology and the presence of extramedullary involvement)

Availability and response to therapy

Of these four key factors, information on staging, patient factors, and disease biology can be identified by prognostic studies at the outset and are discussed in this topic. On the other hand, response to therapy can only be known after the patient has started therapy and is complicated by the fact that rapidity and completeness of the response may not always correlate with good long-term outcome. Most of the data regarding prognostic studies in patients with MM come from evaluations at the time of diagnosis. It is unclear how many of these factors may affect outcomes in previously treated patients. In addition, it is not clear how the prognostic value of these factors will change with the emergence of new therapies.

Prognostic studies have numerous benefits in both the clinical and research setting [4]. As examples, they:

Provide the patient and physician with a better understanding of the aggressiveness of disease and chance of survival

Lead to a better understanding of the patient population studied in a particular trial

Allow for a gross comparison between patient populations in different trials

May help guide therapy selection

Identify new targets for therapy

An individual finding may be a prognostic marker, a predictive marker, or both [5,6]. Prognostic markers are associated with clinical outcomes independent of therapy received. Such markers usually reflect tumor burden, distribution, and growth rate. In contrast, predictive markers inform the likelihood of response to a given treatment and therefore impact choice of therapy. Such markers may be the target of the treatment or may modify the expression and/or function of the target. Identifying predictive markers will facilitate a move towards precision medicine, which uses genetic or molecular profiling to tailor therapy for the individual patient.

STAGING — The Revised International Staging System (R-ISS) (table 1) is the preferred staging system for MM.

The R-ISS has replaced earlier systems including Durie-Salmon (table 2) [7], the International Staging System (ISS) [8], and the International Myeloma Working Group (IMWG)-2014 staging system [9].

Staging systems are used to guide treatment decisions and to stratify patients enrolled in clinical trials and allow clinicians to better interpret data from such trials. They should be used only in patients with symptomatic, overt MM; they should not be used in patients with smoldering myeloma or monoclonal gammopathy of undetermined significance, since their value in such populations is not known.

Revised International Staging System (R-ISS) — The R-ISS uses serum beta-2 microglobulin (B2M), serum albumin, serum lactate dehydrogenase (LDH), and bone marrow FISH results to stratify patients into three risk groups (table 1). It provides more robust prognostic information than that from the original ISS which did not include information on LDH and FISH [8].

R-ISS is calculated as follows:

Stage I – B2M <3.5 mg/L, serum albumin ≥3.5 g/dL, normal LDH, and no del(17p), t(4;14), or t(14;16) by FISH

Stage II – neither stage I nor stage III

Stage III – B2M ≥5.5 mg/L and elevated LDH - and/or - del(17p), t(4;14), or t(14;16) by FISH

The R-ISS was developed based on 3060 patients with newly diagnosed MM enrolled onto one of 11 international trials [10]. Treatment included autologous hematopoietic cell transplantation (65 percent), immunomodulatory agents (66 percent), and proteasome inhibitors (44 percent). Patients were stratified into three risk groups with significantly different estimated rates of overall survival (OS) and progression-free survival (PFS) at five years (figure 2):

R-ISS I (n = 871) – Estimated OS and PFS at five years were 82 and 55 percent, respectively. Median OS was not reached. Median PFS was 66 months.

R-ISS II (n = 1894) – Estimated OS and PFS at five years were 62 and 36 percent, respectively. Median OS and PFS were 83 and 42 months.

R-ISS III (n = 295) – Estimated OS and PFS at five years were 40 and 24 percent, respectively. Median OS and PFS were 43 and 29 months.

On subset analysis, the R-ISS provided prognostic value independent of patient age and therapy received. The R-ISS has been validated in several separate cohorts using different treatment approaches [11-13].

CYTOGENETIC ABNORMALITIES — Fluorescence in situ hybridization (FISH) is performed at time of initial diagnosis to help determine the revised International Staging System (R-ISS) stage and to guide therapy (algorithm 1). Metaphase cytogenetics have long been a mainstay of the diagnostic evaluation for patients with MM. However, the sensitivity of metaphase cytogenetics is limited in comparison to FISH, and thus the approach has less overall utility. Next-generation sequencing techniques are being evaluated and hold promise as a diagnostic tool in myeloma management as well. At present, we rely primarily upon FISH for prognostic purposes. (See "Multiple myeloma: Overview of management", section on 'Risk stratification' and 'Revised International Staging System (R-ISS)' above.)

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 therapy [14,15]. Due to their prognostic value and the widespread availability of probes for FISH testing, t(4;14), t(14;16), and del17p are considered high-risk cytogenetics in the R-ISS [10]. (See 'Specific IgH translocations' below and 'Del(17p)' below.)

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 detected by FISH [16].

The most widely used preferred method for detecting cytogenetic abnormalities in MM is through interphase FISH studies on bone marrow plasma cells [4,17,18]. The preferred FISH techniques are either interphase FISH in purified plasma cells or light chain-restricted plasma cell cytoplasmic immunoglobulin enhanced FISH [4]. A more advanced and sensitive alternative to FISH is next-generation sequencing methods such as RNAseq, but these are not widely available. These tests also maintain sensitivity in the context of hemodilution of the bone marrow aspirate sample.

Using FISH, MM can be molecularly classified into unique cytogenetic entities (table 3) [4,15,19]. Some cytogenetic subtypes, such as t(11;14) and t(6;14) and trisomies of odd numbered chromosomes, are considered to indicate standard-risk myeloma. By contrast, the detection of t(4;14), t(14;16), t(14;20), del17p13, gain 1q, and/or del1p32 are associated with poor prognosis in MM when treated with standard therapy (table 4). The poor outcomes seen in patients with t(4;14) by FISH were shown to be at least partially overcome by therapy that incorporates the early use of bortezomib-containing regimens and hematopoietic cell transplantation (HCT). (See "Multiple myeloma: Initial treatment", section on 'High-risk myeloma'.)

The prognostic value of these chromosomal translocations and deletions detected by FISH analysis has been shown in numerous studies [20-23]. Additional details concerning these abnormalities and their prognostic significance are described in the sections below.

Specific IgH translocations — The most common chromosomal translocations in MM involve 14q32, the site of the immunoglobulin heavy chain (IgH) locus and are referred to as "primary IgH translocations." Of these, t(11;14) is the most common. t(4;14) and t(14;16) are considered high-risk cytogenetics in the R-ISS staging system. (See 'Revised International Staging System (R-ISS)' above.)

Primary IgH translocations seen in MM include:

t(11;14)(q13;q32)

t(4;14)(p16.3;q32.3)

t(6;14)(p25;q32)

t(8;14)(q24;q32)

t(14;16)(q32.3;q23)

These translocations place an oncogene next to the IgH locus such that the active promoter region of the IgH gene induces overexpression of the oncogene. The products of these translocations then act as transcription factors, growth factor receptors, and cell cycle mediators to promote growth and replication. 

t(11;14)(q13;q32) is the most common and defines a subgroup of MM with a particular clinicopathologic phenotype [24]. The incidence of t(11;14) ranges from 10 to 31 percent in patients with IgG, IgA, IgD, and light chain MM [24,25]; it is increased in patients with non-secretory MM (83 percent), as well as in IgM (7 of 8) and IgE (2 of 2) MM [25,26]. Patients with MM and t(11;14) are more likely to have lower levels of serum M proteins and lymphoplasmacytic or small mature plasma cell morphology, CD20 expression, and lambda light chains [24,27-29]. While categorized as "standard risk" disease, patients with t(11;14) have lower response rates and reduced progression-free survival (PFS) and overall survival (OS) than other standard-risk patients [30-34]. (See "Multiple myeloma: Pathobiology", section on 'Immunoglobulin heavy chain translocations'.)

The t(4;14), t(14;16), and t(14;20) translocations are associated with poor prognosis [14,20,35]. Of note, while t(4;14) is associated with chemotherapy-sensitive disease, it was previously associated with a high rate of relapse, even in those undergoing high dose chemotherapy followed by autologous HCT [36-38]. While t(4;14) is considered a high-risk genetic abnormality, there is evidence that bortezomib can overcome the adverse prognosis associated with this finding [39].

While not widely available, next-generation sequencing (NGS) can identify prognostically different subsets of MM with t(4;14) based on the coordinates of the translocation breakpoints in the NSD2 gene. In a large cohort study that used NGS, median overall survival (OS) differed by breakpoint location [40]:

"Late disruption" - Breakpoint within the NSD2 gene downstream of the translation start site (median OS 28.6 months; 31 percent of population)

"Early disruption" - Breakpoint between the transcription and translation start site (median OS 59.4 months; 24 percent of population)

"No disruption" - Breakpoint upstream of the NSD2 gene (median OS 75.1 months; 45 percent of population)

These results were validated in an independent dataset.

Initial series evaluating the prognostic impact of t(14;16) had mixed results, likely reflecting the small numbers of patients in each cohort due to the rarity of this translocation [20,41,42]. The poor outcomes in patients with t(14;16) were confirmed in an international study that included 223 patients with t(14;16) and reported short median PFS (2.1 years) and OS (4.1 years) [43].

Del(17p) — Deletions of 17p, including 17p13, the TP53 gene locus, are found in 10 percent of MM patients and are associated with a shorter survival after both conventional chemotherapy and HCT [14,20,35,44-48]. Del(17p) is considered a high-risk cytogenetic finding in the R-ISS staging system. (See 'Revised International Staging System (R-ISS)' above.)

Del(17p) is highly associated with a low rate of complete response, rapid disease progression, plasma cell leukemia, and central nervous system involvement [49-51]. As an example, a study of 59 patients with previously untreated MM reported that those patients with a TP53 gene deletion (present in 33 percent) had shorter median survival (14 versus 39 months from the time of diagnosis) [52]. (See "Multiple myeloma: Pathobiology", section on 'Drivers of progression from MGUS to MM'.)

The presence of mutated TP53 on the other allele ("double hit") likely impacts the prognosis of patients with del(17p). One study evaluated patients with uniformly treated newly diagnosed MM for del(17p) and TP53 mutations and reported the following PFS and OS outcomes by genetic findings [53]:

Intact 17p (2505 patients) – median PFS 44 months, median OS 152 months

del(17p) with wild type TP53 (76 patients) – median PFS 27.2 months, median OS 52.8 months

del(17p) with mutated TP53 (45 patients) – median PFS 18.1 months, median OS 36 months

These results confirm the negative impact of del(17p) on prognosis and identify cases with TP53 mutation on the other allele as having a particularly poor prognosis.

Trisomies — Hyperdiploidy is a well-recognized predictor of favorable outcomes in MM. Hyperdiploidy occurs in MM typically due to trisomies of odd numbered chromosomes [54].

There are conflicting data on whether the presence of trisomies can ameliorate some of the adverse prognostic effects of high-risk cytogenetic abnormalities [19,55]. We do not downgrade our risk assignment for those with trisomies.

In one retrospective study of 484 patients with newly diagnosed symptomatic MM, a trisomy was present in approximately 60 percent of all patients and 40 percent of patients with high-risk myeloma as defined by FISH showing t(4;14), t(14;16), t(14;20), or loss of p53 [19]. The OS for patients with trisomy in the setting of high-risk MM was similar to that of patients with standard-risk MM defined by FISH. In comparison, patients with high-risk MM without trisomy had shorter survival.

The impact of trisomy on prognosis may be dependent on the chromosome involved. In another retrospective study of 965 patients with MM, a survival benefit was seen in patients with trisomy 3 and those with trisomy 5, but not in those with trisomy 7, 9, 11, 15, 17, 18, or 19 [56]. In contrast, trisomy 21 was associated with inferior survival.

Other cytogenetic lesions — Several other cytogenetic lesions have been associated with adverse prognosis in MM. These include:

Chromosome 1 abnormalities – Abnormalities in both the short and long arms of chromosome 1 have been associated with shorter survival [57-63]. In general, 1q gain (three copies), 1q amplification (four or more copies), and 1p deletion, and 1q21 aberrations are associated with both disease progression and poor prognosis [57,64-70]. As an example, in a study of 1195 patients with MM, chromosome 1p32 deletions were identified in 85 cases (7 percent) and were associated with inferior PFS (14 versus 34 months) and OS (27 versus 97 months) [61]. We consider 1q gain and 1q amplification to be associated with adverse prognosis (table 4).

12p deletions – Initial studies have suggested that 12p deletions are associated with short event-free survival (EFS) and OS rates, but this needs further confirmation [60].

MYC rearrangements – The MYC oncogene is located at 8q24.21. In one series, translocations involving MYC were detected by FISH in 8 percent of newly diagnosed MM [71]. MYC translocations were associated with a higher disease burden and shorter OS.

DISEASE BIOLOGY — In MM, prognosis can be markedly different in patients with similar staging and host factors. These disparities are driven primarily by differences in underlying disease biology, which can greatly influence the aggressiveness of the clinical course. Some of the most important markers of adverse prognosis include atypical bone marrow plasma cell immunophenotype, increased plasma cell proliferative rate, plasmablastic morphology, increased circulating plasma cells, and the presence of extramedullary involvement.

Plasma cell morphology and immunophenotype — Plasma cell morphology and immunophenotype may serve as markers for disease aggressiveness. Morphology and immunophenotype more closely resembling normal, reactive plasma cells may be associated with a better prognosis. In contrast, outcomes are worse for patients with MM that exhibits plasmablastic morphology or an atypical immunophenotype.

A plasmablastic morphology is seen in approximately 8 percent of patients with MM and is associated with highly proliferative disease with shorter event-free survival (EFS) and overall survival (OS) following conventional chemotherapy [72,73].

The malignant plasma cells in MM generally express cytoplasmic immunoglobulin, CD38, CD56 (neural cell adhesion molecule), and CD138 [74]. About 15 to 20 percent of patients will have cells that express CD20; such patients are likely to have t(11;14) along with lymphoplasmacytic or small mature plasma cell morphology. Absence of CD56 expression is often seen in plasma cell leukemia [75]. (See "Plasma cell leukemia", section on 'Prognosis' and 'Specific IgH translocations' above.)

Patients with plasma cells in the bone marrow that demonstrate an immunophenotype resembling normal, reactive plasma cells or a plasma cell immunophenotype generally observed in monoclonal gammopathy of undetermined significance (MGUS) may have a better prognosis when compared with patients whose bone marrow contains plasma cells with an immunophenotype more typical of MM [76-78]. As an example, a prospective series of 685 patients with newly diagnosed MM uniformly treated on protocol found that patients who expressed CD28 or lacked CD117 had significantly shorter progression-free survival (PFS) and OS than patients who expressed CD117 and lacked CD28 [77]. The clinical use of bone marrow plasma cell immunophenotyping studies to help determine prognosis needs further clarification.

Extramedullary disease — While uncommon, presentation with or development of extramedullary plasmacytoma, secondary plasma cell leukemia (PCL), or central nervous system (CNS) involvement is associated with worse outcomes [79-84].

The true incidence of extramedullary disease at the time of diagnosis is not known. In one large study, extramedullary disease was documented in <5 percent of patients at the time of diagnosis, and at higher rates over the disease course [79]. The most common sites of extramedullary disease were the skin and soft tissue, paraspinal area, lymph nodes, and liver. Other sites of involvement included the kidney, spleen, testes, CNS, and lung. Extracellular disease was more common in MM defined as high risk by gene expression profiling.

Leptomeningeal myelomatosis along with abnormal cerebrospinal fluid findings is uncommon but denotes a poor prognosis [50,85-89]. It is usually associated with high-risk cytogenetics. Historically, survival in this patient population was measured in months [88], although outcomes appear to be improving since the incorporation of immunomodulatory drugs and proteasome inhibitors into first-line therapy [83,90].

The presence of circulating plasma cells is associated with adverse prognosis in MM. The impact differs by the method of detection:

Peripheral blood smear – Patients with MM who have ≥5 percent monoclonal plasma cells on conventional peripheral blood smear meet the diagnostic criteria for plasma cell leukemia (PCL) [91]. Lower levels of circulating plasma cells (eg, 2 to 4 percent) on conventional peripheral smear may also be associated with highly proliferative and aggressive MM [92-94]. PCL is discussed separately. (See "Plasma cell leukemia", section on 'Prognosis'.)

Multicolor flow cytometry – Circulating plasma cells can be detected by multicolor flow cytometry of the blood in most patients with MM at the time of diagnosis due to the high sensitivity of the assay [95-97]. Several prospective studies have shown that high levels of circulating plasma cells detected by flow cytometry is associated with worse progression-free survival and overall survival independent of other prognostic factors, including the R-ISS [95-97]. Limitations include limited access outside of academic institutions, expense, uncertainty regarding the optimal threshold, and need for a fresh sample. Further studies are also needed to determine the prognostic impact of circulating plasma cells detected by next generation sequencing.

Monoclonal protein — The clinical course of MM may be influenced in part by the type of monoclonal (M) protein produced:

Patients with light chain or IgD MM have a higher incidence of renal failure and associated amyloidosis, a smaller serum M-component, and a higher rate of light chain excretion than those with IgG or IgA MM [98,99]. IgD MM typically has a lambda light chain. (See "Overview of amyloidosis".)

Patients with a cryoglobulin (type I cryoglobulinemia) may develop renal disease or other symptoms related to the presence of a cold-insoluble protein. (See "Overview of cryoglobulins and cryoglobulinemia", section on 'Type I cryoglobulinemia' and "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation", section on 'Less common causes of AKI'.)

It is not clear whether the survival of patients with light chain MM is adversely affected. In three large reviews, light chain MM was reported to be not associated with a difference in prognosis [100], or a significant reduction in survival [8]. A significant reduction in survival occurs only if light chain MM is accompanied by renal impairment at presentation [101].

Serum free light chain ratio — The serum kappa/lambda free light chain (FLC) assay is a sensitive method for the detection of excess FLCs, and an abnormal kappa/lambda FLC ratio is used as a surrogate marker for clonal expansion. The presence of an abnormal (monoclonal) kappa/lambda FLC ratio in the serum is associated with a higher risk of disease progression in patients with MGUS, solitary plasmacytoma, or smoldering MM. (See "Clinical course and management of monoclonal gammopathy of undetermined significance", section on 'Risk stratification to estimate risk of progression'.)

The FLC ratio may also have prognostic value in patients with newly diagnosed symptomatic MM when used in conjunction with the International Staging System (ISS). As an example, one study evaluated the serum FLC ratio measurement that was available from 790 out of 1027 patients with newly diagnosed MM seen at a large referral center [102]. Patients with abnormal FLC ratio (<0.03 or >32) had a significantly shorter median survival when compared with patients with a FLC ratio between 0.03 and 32 (30 versus 39 months, respectively). Further study is needed to assess impact on patients staged with the revised ISS (R-ISS).

Further details regarding serum FLC measurement and its use in response assessment is discussed separately. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Serum free light chains' and "Multiple myeloma: Evaluating response to treatment", section on 'Serum and urine tests'.)

Gene expression profiling — Gene expression profiling (GEP) has been utilized to aid in the discrimination between plasma cells from normal subjects and those with MGUS, MM, AL amyloidosis, and extramedullary plasmacytomas [59,103-109], as well as to identify patients with high-risk myeloma [110-116]. While GEP is not part of the standard risk stratification of patients with MM, patients found to have a high-risk signature on GEP are considered to have high-risk MM on risk stratification (table 4).

Multiple GEP models are at various stages of development. The following commercially available GEP models have been validated in clinical trials:

The Myeloma Prognostic Risk Signature (MyPRS) – A 70-gene expression profiling signature developed by the Myeloma Institute for Research and Therapy at Little Rock, Arkansas [112-115].

The SKY92 Multiple Myeloma Profiler – A 92-gene expression profiling signature developed at Erasmus University Medical Center in the Netherlands [117-119].

This technology, as well as comparative genomic hybridization, whole genome sequencing, tumor-associated antigens, and multiparameter flow cytometry may ultimately have utility for diagnostic, therapeutic, and prognostic purposes [120-128]. Further studies in this area will be necessary to more firmly establish the role of these approaches in management of MM. (See "Multiple myeloma: Pathobiology".)

Plasma cell proliferative rate — An increased bone marrow plasma cell proliferative rate is associated with adverse prognosis in MM [129-131]. However, plasma cell proliferative rate may not improve risk stratification beyond that calculated based on R-ISS and age [132].

Initial methods to measure plasma cell proliferation relied on slide-based immunofluorescence assays, but now proliferation is assessed by measuring the percentage of cells in S phase on flow cytometry.

PATIENT FACTORS — The clinical outcome for patients with MM depends on a complex interaction between biologic features of the plasma cell clone and patient-specific factors such as age, performance status, and comorbidities. Patients with comorbidities that limit their ability to withstand treatment will have a poor outcome even if they have MM with features commonly associated with a better prognosis. While much of the research evaluating prognosis in MM has focused on the biologic properties of the malignant clone, large case series have identified numerous prognostic factors, some of which are patient-dependent factors.

As an example, univariate analysis of a series of 1027 patients with MM seen at the Mayo Clinic between 1985 and 1998 uncovered the following significant adverse prognostic risk factors for survival (relative risks [RR] in parentheses) [100]:

Performance status 3 or 4 (table 5) (1.9)

Serum albumin <3 g/dL (1.7)

Age ≥70 years (1.5)

Serum creatinine ≥2 mg/dL (1.5)

Platelet count <150,000/microL (1.5)

Beta-2 microglobulin >4 mg/L (1.5)

Plasma cell labeling index ≥1 percent (1.5)

Serum calcium ≥11 mg/dL (1.3)

Hemoglobin <10 g/dL (1.3)

Bone marrow plasma cell percentage ≥50 percent (1.2)

Among these, patient factors such as performance status, albumin concentration, and age appear to have as much or higher prognostic value than many of the disease-related factors.

Geriatricians commonly measure functional status by evaluating basic activities of daily living (ADLs, (table 6)), instrumental activities of daily living (IADLs, (table 7)), and the Charlson comorbidity index (CCI, (table 8)). ADLs are the skills that are necessary for basic living and include feeding, grooming, transferring, and toileting. IADLs are required to live independently in the community and include activities such as shopping, managing finances, housekeeping, preparing meals, and taking medications. The CCI is a measure of comorbidities. (See "Comprehensive geriatric assessment for patients with cancer".)

A study by the International Myeloma Working Group used ADLs, IADLs, CCI, and age to quantitate patient frailty in 869 patients with MM (median age 74 years) enrolled on three trials of initial therapy that did not incorporate transplantation [133]. This evaluation discriminated three groups (fit, intermediate frail, frail). When compared with fit patients, frail patients had significantly inferior overall survival (hazard ratio [HR] 3.57), shorter progression-free survival (HR 1.68), higher rates of treatment discontinuation (HR 2.27), and more grade 3/4/5 non-hematologic toxicity (HR 1.74). Prospective studies are needed to better define how these measures can be incorporated into clinical practice.

Another analysis of 10,549 patients reported that patients older than 50 years had significantly shorter survival when treated with either chemotherapy alone or high dose therapy followed by transplantation [134]. While younger patients tended to present with more favorable features, age at diagnosis itself was an independent predictor of overall survival. A subsequent analysis of the same patient cohort with a median follow-up time of 3.25 years reported mean overall survival times of 6.3, 6.4, 5.3, 4.3, 3.4, and 2.5 years for those patients <40, 40 to 49, 50 to 59, 60 to 69, 70 to 79, and ≥80 years at the time of diagnosis, respectively, indicating that although younger patients have better survival, the number of years of life lost was greater [135].

IMAGING STUDIES — A discussion of the role of imaging studies in patients with MM and effect on prognosis is presented separately. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Imaging'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple myeloma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: Multiple myeloma symptoms, diagnosis, and staging (Beyond the Basics)")

SUMMARY

Heterogeneity of disease – Multiple myeloma (MM) is a heterogeneous disease; some patients present with rapidly progressive symptoms and organ dysfunction whereas others have a more indolent clinical presentation. Distinction between these groups is important so that treatment can be initiated in appropriate patients and postponed in those who do not need it. (See 'Overview' above.)

Staging – The revised International Staging System (R-ISS) (table 1) is calculated using serum beta-2 microglobulin, serum albumin, lactate dehydrogenase, and a select group of chromosomal abnormalities detected by fluorescence in situ hybridization (FISH), and it stratifies patients into three risk groups with differing expected disease tempo and overall survival (figure 2). (See 'Revised International Staging System (R-ISS)' above.)

Importance of cytogenetic features – Due to their prognostic value and the widespread availability of probes for FISH testing, t(4;14), t(14;16), and del17p are considered high-risk cytogenetics in the R-ISS. Other cytogenetic findings consistently associated with poor outcomes include t(14;16) and gain 1q by FISH. (See 'Cytogenetic abnormalities' above.)

Disease biology – Differences in disease biology can influence the clinical course and result in markedly different outcomes in patients with similar staging and host factors. Some of the most important markers of adverse prognosis are the atypical bone marrow plasma cell immunophenotype, increased plasma cell proliferative rate, plasmablastic morphology, increased circulating plasma cells, and the presence of extramedullary involvement. (See 'Disease biology' above.)

Impact of patient factors – The clinical outcome for patients with MM depends on a complex interaction between biologic features of the plasma cell clone and patient-specific factors such as age, performance status, and comorbidities. Patients with comorbidities that limit their ability to withstand treatment will have a poor outcome even if they have MM with features commonly associated with a better prognosis. (See 'Patient factors' above.)

Risk stratification for treatment – Individual cases are stratified into either high-risk or standard-risk MM based on the results of FISH for specific translocations and certain other tests (table 4). This risk stratification helps to determine prognosis and impacts treatment choice (algorithm 1). (See "Multiple myeloma: Overview of management".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges extensive contributions of Robert A Kyle, MD to earlier versions of this topic review.

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Topic 6658 Version 54.0

References

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