Multiple myeloma: Evaluating response to treatment

INTRODUCTION — Patients with multiple myeloma (MM) are evaluated periodically to determine how the disease is responding to therapy and to assess for potential treatment-related and disease-related complications (table 1).

This assessment focuses on several aspects:

●Tumor response to treatment as demonstrated by measures of tumor burden

●Signs and symptoms of disease progression or development of other disease-related complications (eg, development of amyloidosis)

●Toxicities related to treatment and whether they call for any treatment modifications

It is important that we accurately measure the efficacy of treatments applied in order to ensure that the goals are met for the individual patient and to develop optimal treatment strategies for patients in general. This requires a standard set of criteria that can be uniformly applied to all patients, creating unbiased comparison of different treatment approaches in the research setting and allowing their implementation in routine practice.

The International Myeloma Working Group (IMWG) has developed uniform response criteria (table 2), which are used to measure treatment efficacy in routine patient care and clinical trials. These criteria are described in detail here along with the IMWG's proposed definitions of survival endpoints to be used in reporting clinical research.

The diagnosis of MM and the tests used to measure monoclonal proteins in the blood and urine are discussed in detail separately, as are the indications for and choice of therapy.

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

●(See "Laboratory methods for analyzing monoclonal proteins".)

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

CLINICAL ASSESSMENT — Prior to each treatment cycle, we perform a directed history, physical examination, and targeted bloodwork with the goal of identifying:

●Toxicities related to treatment and whether they call for any treatment modifications

●Signs and symptoms of disease progression or development of other disease-related complications (eg, development of amyloidosis)

For most patients, this bloodwork includes a complete blood count with differential, blood glucose and electrolytes, and a chemistry screen that includes measurements of serum creatinine and calcium. Myeloma-specific tests to assess tumor burden are discussed separately. (See 'Timing and choice of test(s)' below.)

Treatment- and disease-related complications of particular interest include:

●Anemia

●Hypercalcemia

●Kidney impairment

●Infection

●Skeletal lesions

●Extramedullary plasmacytomas

●Thrombosis

●Neuropathy

We monitor for additional drug-specific toxicities based on the specific regimen used. Notable toxicities by drug class are illustrated in the table (table 3).

Patients with multiple myeloma may develop concurrent AL amyloidosis. Symptoms and signs suggestive of amyloidosis include macroglossia, nephrotic range proteinuria, restrictive cardiomyopathy, unexplained elevated NT-proBNP, and/or hepatomegaly. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

Administration considerations for common therapies and the management of treatment- and disease-related complications are discussed separately. (See "Multiple myeloma: Administration considerations for common therapies" and "Multiple myeloma: Overview of management", section on 'Prevention and management of complications'.)

ASSESSING TUMOR RESPONSE

Timing and choice of test(s) — In most clinical trials, tumor burden is assessed prior to each treatment cycle. In routine clinical practice, these assessments can be done every few cycles once it has been confirmed that the patient is responding to the treatment regimen applied.

The preferred tests to monitor tumor response for a given patient depend on the results of baseline studies indicating the best markers to follow and on the suspected degree of response [1].

Routine monitoring

Patients with measurable M protein — Most patients will have a serum monoclonal (M) protein level ≥1 g/dL and/or urine M protein level ≥200 mg/day at baseline (ie, measurable M protein). For such patients managed in routine practice (ie, outside of a trial), we offer the approach described below. Additional details regarding the specific tests are presented separately. (See 'Measures of tumor burden' below.)

Those on clinical trials require more frequent and specialized testing as detailed by trial protocol and guidelines from the International Myeloma Working Group (IMWG) (table 1 and table 2) [2].

●Baseline measurement – Baseline tumor burden is measured prior to therapy using the serum protein electrophoresis (SPEP), 24-hour urine protein electrophoresis (UPEP), and the serum free light chain (FLC) assay.

●Monitoring disease – Initially, tumor burden is monitored at the start of each treatment cycle. Once it has been confirmed that the disease is responding, these assessments can be done every few cycles. Tumor burden is measured using the SPEP and either the serum FLC assay or the UPEP. Many patients and clinicians find the serum FLC assay to be more convenient than the UPEP, although the correlation between these tests is not perfect.

Serum M protein measurements cannot be used alone because some patients who had detectable serum M protein on presentation will only show light chains on UPEP or serum FLC assay at the time of relapse. This is called "light chain or Bence Jones escape" [2,3].

In patients followed preferentially with SPEP and serum FLC assay, the UPEP should still be performed periodically (eg, every six months) for validation and to check for other renal issues such as albuminuria.

Serum and urine immunofixation should be done in addition once the serum and urine electrophoresis, respectively, shows no measurable protein.

Bone marrow biopsy and imaging are reserved for the investigation of suspected complete response or progressive disease.

●Adjustments for special conditions – The laboratory should be notified if the patient has received a therapeutic monoclonal antibody (eg, daratumumab, isatuximab, elotuzumab). IgG kappa monoclonal antibodies like these may be detected on SPEP and immunofixation assays. The laboratory may be able to modify the assay or use another assay to better estimate the M protein level in this scenario. (See 'Serum and urine tests' below.)

Quantitative immunoglobulins may be used to follow tumor burden in certain circumstances (eg, patients with IgA monoclonal protein). (See 'Serum and urine tests' below.)

Serum M protein <1 g/dL and urine M protein <200 mg/day — A subset of patients will have a serum monoclonal (M) protein level <1 g/dL and urine M protein level <200 mg/day at baseline (ie, no measurable M protein on SPEP and UPEP). For such patients managed in routine practice (ie, outside of a trial), we offer the approach described below. Details regarding the specific tests are presented separately. (See 'Measures of tumor burden' below.)

Those on clinical trials require more frequent and specialized testing as detailed by trial protocol and guidelines from the IMWG (table 1 and table 2) [2].

●No measurable M protein, measurable FLC – Serum free light chain (FLC) assay can be used as the primary measure of tumor burden in patients with an abnormal FLC ratio and an involved serum FLC level ≥10 mg/dL (ie, measurable FLC) [4]. (See 'Serum and urine tests' below.)

In such patients, SPEP, serum immunofixation, UPEP, and urine immunofixation are reserved for confirmation of complete response and very good partial response.

Bone marrow biopsy and whole body FDG positron emission tomography-computed tomography [PET/CT] are reserved for the investigation of suspected complete response or progressive disease.

●No measurable M protein or FLC – A minority of patients (2 to 5 percent) will have no measurable M protein or measurable FLC at baseline. In such patients, tumor burden is assessed by periodic bone marrow aspirate and biopsy (if ≥30 percent plasma cells on bone marrow evaluation) or whole body FDG PET/CT [1,5].

The frequency of these studies depends on other clinical parameters (eg, hemoglobin, calcium, and creatinine); patients who are felt to be responding well based on improvement in end-organ function will need bone marrow and imaging assessments less frequently compared with those in whom the response status is less clear. (See 'Bone marrow aspirate and biopsy' below.)

Although not readily available at most centers, mass spectrometry can quantitate low level M proteins and studies are evaluating whether it can be used to follow disease activity in a subset of these patients [6]. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Mass spectrometry'.)

●Plasmacytoma – Rarely, patients with no M protein or FLC measurable will have biopsy-proven plasmacytoma. If such patients have at least one lesion on whole body PET/CT that has a single diameter of ≥2 cm, tumor burden can be followed with whole body PET/CT every three to four cycles until a plateau or complete response is attained. (See 'Imaging' below.)

Suspected complete response — When a complete response (CR) is suspected, the standard evaluation includes:

●SPEP and serum immunofixation

●24-hour UPEP and urine immunofixation

●Serum FLC assay

●Bone marrow aspirate and biopsy

●Cross-sectional imaging (eg, whole body FDG PET/CT) only if plasmacytomas present at baseline.

Serum and urine studies are required regardless of whether the disease at baseline was measurable on serum, urine, both, or neither. Outside of a clinical trial, urine immunofixation can be omitted in the CR evaluation of patients with measurable serum M protein at diagnosis. In one study of patients achieving negative serum immunofixation, the urine immunofixation was also negative in all of the patients with serum M protein only at diagnosis and 98.6 percent of those with serum and urine M protein at diagnosis [7].

The bone marrow evaluation uses morphologic evaluation and visual quantitation to assess the percentage of plasma cells. Assessment of the bone marrow for minimal residual disease (MRD) using next-generation flow cytometry or next-generation sequencing is usually reserved for patients on clinical trials. (See 'Imaging' below and 'Minimal residual disease assessment' below.)

A CR requires confirmation of these studies on two consecutive assessments made at any time before the institution of any new therapy except for bone marrow assessments, which do need not be confirmed.

Suspected progression — When disease progression is suspected based on clinical or biochemical findings, the standard evaluation includes:

●Measures of tumor burden – SPEP, serum immunofixation, 24-hour UPEP, serum FLC

●Measures of end organ damage – Hemoglobin, serum calcium, and creatinine

In addition, imaging studies such as PET/CT, MRI, or whole body low dose CT may be needed if there are concerns for new or worsening bone lesions or plasmacytomas [8]. A bone marrow aspirate and biopsy are not always necessary but should be performed if there is doubt about the disease status to determine if change in the cytogenetic characteristics has occurred, or to determine eligibility for clinical trials.

IMWG response categories — 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 2) [1,9,10].

Complete response criteria (CR, sCR, MRD negative) — The IMWG uniform response criteria define complete response, stringent complete response, and minimal residual disease negativity, as described below (table 2) [1,9,10].

The response criteria require confirmation of testing on two consecutive assessments made at any time before the institution of any new therapy except for bone marrow assessments and minimal residual disease assessments (if performed), which do need not be confirmed.

●Complete response (CR) – Requires all of the following:

•Serum and urine immunofixation – No monoclonal (M) protein

•Bone marrow aspirate and biopsy – <5 percent clonal plasma cells

•Cross sectional imaging – No evidence of soft tissue plasmacytoma (if present at baseline); no known evidence of progressive or new bone lesions if imaging performed

For patients who lack measurable M protein in the serum and urine at baseline being monitored using the free light chain (FLC) assay, CR requires normalization of the FLC ratio in addition to the above criteria [11].

●Stringent complete response (sCR) – Requires all of the following:

•Meets criteria for CR

•FLC ratio – Normal

•Bone marrow aspirate and biopsy – No clonal cells by bone marrow immunohistochemistry or immunofluorescence. This is achieved if there is a kappa/lambda ratio of ≤4:1 or ≥1:2 after examination of a minimum of 100 plasma cells.

●Minimal residual disease (MRD) negative – Requires both of the following:

•Meets criteria for CR (defined above)

•Absence of aberrant clonal plasma cells by next-generation flow cytometry or next-generation sequencing on bone marrow aspirates with a minimum sensitivity of 1 in 10⁵ nucleated cells or higher.

Partial response criteria (VGPR, PR) — The IMWG uniform response criteria define partial response and very good partial response, as described below (table 2) [1,9,10].

The response criteria require confirmation of testing on two consecutive assessments made at any time before the institution of any new therapy except for bone marrow assessments, which do need not be confirmed.

●Partial response (PR) – Requires all of the following:

•Serum M protein – ≥50 percent decrease in serum M protein

•24-hour urine M protein – ≥90 percent decrease or absolute urine M protein <200 mg/24 hours

•Cross sectional imaging – ≥50 percent decrease in size of soft tissue plasmacytoma (if present at baseline); no known evidence of progressive or new bone lesions if imaging performed

For patients who lack measurable M proteins in the serum and urine at baseline being monitored using the FLC assay, PR requires ≥50 percent decrease in the difference between involved and uninvolved FLC levels.

If the FLC levels were also unmeasurable at baseline, a 50 percent reduction in bone marrow plasma cells is an acceptable measure of PR as long as the original bone marrow contained at least 30 percent plasma cells.

●Very good partial response (VGPR) – In addition to the PR requirements above, VGPR requires one of the following:

•Serum and urine M protein detectable by immunofixation but not on electrophoresis

•≥90 percent decrease in serum M protein with a urine M protein <100 mg/24 hours

In patients who lack measurable M proteins in the serum and urine at baseline being monitored using the FLC assay, VGPR requires >90 percent decrease in the difference between involved and uninvolved FLC levels [11].

Minimal response or stable disease — The IMWG uniform response criteria includes criteria for minimal response or stable disease, as described below (table 2) [1,9,10].

The response criteria require confirmation of testing on two consecutive assessments made at any time before the institution of any new therapy except for bone marrow assessments, which do need not be confirmed.

●Minimal response (MR) – Requires all of the following:

•Serum M protein – ≥25 but ≤49 percent reduction of serum M protein

•24-hour urine M protein – 50 to 89 percent decrease in urine M protein

•Cross sectional imaging – ≥50 percent decrease in size of plasmacytoma (if present at baseline); no known evidence of progressive or new bone lesions if imaging performed

●Stable disease (SD) – Requires both of the following:

•Does not meet criteria for complete response, very good partial response, partial response, or progressive disease

•No known evidence of progressive or new bone lesions if radiographic studies were performed

The IMWG advises that stable disease not be used as an indicator of response in multiple myeloma trials [1]. Time-to-progression is a better estimate of disease stability. (See 'Survival end points' below.)

Progressive disease — The IMWG uniform response criteria define progressive disease as described below (table 2) [1,9,10]. Progressive disease should be confirmed on two consecutive assessments made at any time before the institution of any new therapy. Bone marrow assessments do need not be repeated to confirm progressive disease.

Any of the following is considered evidence of progressive disease:

●Serum M protein – ≥25 percent increase from lowest value (absolute increase must be ≥0.5 g/dL). A serum M protein increase ≥1 g/dL is sufficient to define relapse if starting M-protein is ≥5 g/dL [10].

●24-hour urine M protein – ≥25 percent increase from lowest value (absolute increase must be ≥200 mg/24 hours).

●Cross sectional imaging – ≥50 percent increase in the size or development of new bone lesions or soft tissue plasmacytomas.

●FLC assay – Difference in the kappa and lambda FLC with ≥25 percent increase from lowest value (absolute increase must be >10 mg/dL). This FLC criterion should only be used for patients with unmeasurable M protein in the serum and urine.

●Bone marrow plasma cell percentage – ≥25 percent increase in bone marrow plasma cell percentage from lowest value (absolute increase must be ≥10 percent). This bone marrow criterion should only be used if serum M protein, urine M protein, and FLC are unmeasurable at baseline.

●Clinical relapse – A clinical relapse can be documented based on the development of one or more of the following attributable to the myeloma: a serum calcium >11.5 mg/dL, decrease in hemoglobin of ≥2 g/dL, rise in serum creatinine ≥2 mg/dL, hyperviscosity related to the serum paraprotein.

Patients who had achieved complete response may become immunofixation positive at variable time points prior to meeting criteria for progression, as defined before. Lost immunofixation negativity in these patients, often referred to relapse from CR is occasionally used as a trial endpoint, depending on the goals of the trial.

Renal response — For patients who have myeloma-associated kidney impairment at the time of diagnosis, changes in kidney function with treatment should be documented. For those who require dialysis, conversion to dialysis independence is a strong marker of treatment efficacy.

The IMWG has proposed the following criteria for renal response in those who are not dialysis-dependent based on baseline estimated glomerular filtration rate (eGFR) and best attained creatinine clearance (CrCl) [12-14]:

●Complete response – Baseline eGFR <50 mL/min/1.73 m², improved to CrCl ≥60 mL/min

●Partial response – Baseline eGFR <15 mL/min/1.73 m², improved to 30 to 59 mL/min

●Minor response – Baseline eGFR <15 mL/min/1.73 m², improved to 15 to 29 mL/min; or baseline eGFR 15 to 29 mL/min/1.73 m², improved to CrCl 30 to 59 mL/min

The management of kidney impairment in patients with myeloma is discussed separately. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Treatment and prognosis".)

MEASURES OF TUMOR BURDEN

Serum and urine tests — For most patients with multiple myeloma (MM), tumor burden can be monitored using a combination of serum and urine tests. The preferred timing and choice of test is discussed in detail above. (See 'Timing and choice of test(s)' above.)

●Serum protein electrophoresis (SPEP) – SPEP quantifies serum M protein using densitometry. Serum M protein levels must be ≥1 g/dL at baseline to be monitored with SPEP. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Serum protein electrophoresis (SPEP)'.)

Serum M protein measurements cannot be used alone to follow disease because some patients who had detectable serum M protein on presentation will only show light chains on UPEP or serum FLC assay at the time of relapse. This is called "light chain or Bence Jones escape" [2,3].

Daratumumab, isatuximab, and elotuzumab are immunoglobulin G (IgG) kappa monoclonal antibodies that can be detected on SPEP and immunofixation assays. As such, they may obfuscate the response assessment in patients with IgG kappa myeloma protein. The laboratory may be able to modify the assay or use another assay to better estimate the M protein level in this scenario. As an example, a daratumumab-specific immunofixation electrophoresis reflex assay has been developed [15]. This assay uses a murine anti-daratumumab antibody to shift the migration of daratumumab on electrophoresis to allow for differentiation between it and native IgG kappa. Where available, mass spectrometry-based assessment can also allow discrimination of therapeutic antibodies for the monoclonal protein.

●24-hour urine protein electrophoresis (UPEP) – UPEP quantifies urine M protein using densitometry. Urine M protein levels must be ≥200 mg/day at baseline to be monitored with UPEP. (See "Laboratory methods for analyzing monoclonal proteins", section on '24-hour urine protein electrophoresis (UPEP)'.)

●Serum and urine immunofixation – Immunofixation can be used to monitor tumor burden once protein electrophoresis shows no measurable protein. Immunofixation is more sensitive than protein electrophoresis but cannot estimate the size of the M protein. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Serum immunofixation' and "Laboratory methods for analyzing monoclonal proteins", section on 'Urine immunofixation'.)

●Serum free light chain (FLC) assay – To be assessable, the FLC assay must demonstrate an abnormal FLC ratio, and the baseline level of the involved light chain isotype (kappa or lambda) must be ≥10 mg/dL. In patients with a low FLC kappa/lambda ratio, lambda is the "involved" light chain and kappa is the "uninvolved" light chain. Conversely, in patients with a high FLC ratio, kappa is the "involved" light chain and lambda is the "uninvolved" light chain. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Serum free light chains'.)

In patients achieving CR, the prognostic impact of an abnormal FLC ratio is maintained even when flow cytometry is unable to detect clonal bone marrow plasma cells (ie, MRD-negative cases) [16]. An important exception is that an abnormal FLC ratio solely due to suppression of one or both light chains (eg, secondary to treatment) does not appear to impact prognosis.

●Quantitative immunoglobulins – Quantitative measurement of the immunoglobulins, typically IgG, IgA and IgM can also provide an estimate of the monoclonal protein depending on the isotype. While this does not distinguish between the tumor secreted, monoclonal immunoglobulin from normal immunoglobulins secreted by the plasma cells, it may be easier to follow in certain circumstances. In patients with IgA monoclonal protein, quantitative IgA may be more accurate, especially at the lower levels of monoclonal protein, given its migration pattern on electrophoresis and consequent inability to gate the monoclonal component [17]. Similarly, at high levels of monoclonal protein, the electrophoresis may underestimate the M spike and quantitative immunoglobulin levels may provide a more accurate estimation. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Quantitation of immunoglobulins'.)

Bone marrow aspirate and biopsy — Bone marrow aspirate and biopsy is part of the assessment of suspected CR. In addition, periodic bone marrow aspirate and biopsy may be used in the evaluation of response in patients who lack measurable M protein in the serum and urine, and also have either a normal FLC ratio or involved FLC level <10 mg/dL.

To follow disease activity, the baseline bone marrow plasma cell percentage must be significant, typically ≥30 percent. When using bone marrow to assess response, the percentage of plasma cells is usually determined by a morphologic evaluation and visual quantitation.

The importance of including a bone marrow examination in the accurate estimation of CR rates was perhaps best demonstrated in a study of 92 patients with previously measurable disease who had achieved negative serum and urine immunofixation following treatment [18]. After evaluation of a bone marrow biopsy, 79 patients (86 percent) demonstrated less than 5 percent plasma cells, while 13 patients (14 percent) had 5 percent or greater plasma cells, 11 of whom demonstrated monoclonality. When only patients with a normal serum FLC ratio and negative immunofixation of the urine and serum were analyzed, 3 of 26 patients (10 percent) demonstrated 5 percent or greater plasma cells in the bone marrow.

While generally reserved for the research setting, quantitative assessment of MRD in the bone marrow may also be performed using next-generation sequencing or next-generation flow cytometry. The clinical value of these more sensitive tests is yet to be determined but is an area of active research. (See 'Minimal residual disease assessment' below.)

Imaging — Imaging with a whole body combined ¹⁸F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET/CT) is part of the assessment of suspected CR and used in the evaluation of response in patients with extramedullary plasmacytoma [1,8]. (See 'Suspected complete response' above.)

The PET component provides a measure of tumor burden (including extramedullary sites) through tumor metabolic activity, while the CT component localizes the metabolic activity and is a sensitive measure of bone lesions. Numerous studies have demonstrated the value of PET in assessing treatment response during therapy [5,19-24].

The International Myeloma Working Group response criteria defines a negative whole body PET/CT as the disappearance of every area of increased tracer uptake found at baseline, or on a preceding PET/CT; or a decrease to less than the mediastinal blood pool standardized uptake value (SUV); or a decrease to less than that of surrounding normal tissue [1]. Initial studies suggest that background liver activity (ie, Deauville criteria) may be used as a comparison to define response in the bone marrow and focal lesions [25]. Validation in additional cohorts is needed before applying this measure in standard practice.

Studies suggest that magnetic resonance imaging (MRI) is more sensitive than PET when used for initial staging; however, MRI appears to have a higher false positive rate than PET when used for response assessment, partially due to its inability to distinguish between bone remodeling versus residual disease in this setting [5,23,26-29]. MRI is slower to normalize following treatment. Ongoing studies are evaluating the use of PET/MRI for response assessment [30].

Minimal residual disease assessment — We typically reserve MRD assessment for patients on clinical trials [1]. MRD status is prognostic and has been proposed as a surrogate marker for progression-free survival (PFS) and overall survival (OS) in clinical trials. However, its clinical use outside of trials is unclear as it does not yet inform treatment decisions.

Interpretation of studies evaluating MRD is complicated by heterogeneity in the methods used, timing of samples, and reported outcomes. The most robust data come from bone marrow samples; peripheral blood assays need further validation.

There are two main techniques, each of which has strengths and weaknesses [1,31]:

●Next-generation flow cytometry – A method standardized by the EuroFlow consortium can be performed in a few hours using automated software that minimizes subjectivity. A baseline sample is not required, but the study must be performed on a fresh sample.

●Next-generation VDJ sequencing – One assay using this method, the ClonoSEQ assay, has been US Food and Drug Administration approved for MRD assessment in myeloma. A baseline sample is required to identify the dominant clonotype, but the study can be performed on both fresh and stored samples. It is not impacted by therapeutic monoclonal antibodies.

Mass spectrometry is also being evaluated in this setting, although it is less widely available [32]. It is likely that mass spectrometric methods will complement the marrow based MRD testing given the significant variability in terms of monoclonal protein secretion by plasma cells.

Meta-analyses of prospective studies using different MRD assessment techniques have demonstrated an association between achieving undetectable MRD and improved PFS and OS [33-36]. As an example, a meta-analysis combined data from >2500 patients enrolled on four phase 3 trials that used next-generation sequencing on bone marrow to assess MRD (POLLUX, CASTOR, ALCYONE, and MAIA) [34]. Patients who achieved a CR or better with undetectable MRD had superior PFS when compared with patients who did not achieve a CR and/or had detectable MRD (estimated 48-month PFS 70 versus 24 percent; HR 0.20; 95% CI 0.16-0.24). When the analysis was limited to patients with a CR or better, achieving undetectable MRD improved PFS over that seen in patients with detectable MRD (estimated 48-month PFS 70 versus 52 percent; HR 0.52, 95% CI 0.41-0.66).

The prognostic value of MRD status may differ according to the duration of response and aggressiveness of disease. Some studies suggest that the magnitude of PFS benefit may be even greater when undetectable MRD status is sustained over 6 to 12 months, and that reemergence of MRD may predict clinical relapse [37,38]. Others suggest that patients with more indolent disease may have good long-term disease control despite having detectable MRD [39].

While patients with undetectable MRD do better than those with detectable MRD, it is not known whether altering therapy based on MRD status will improve outcomes. As always, one must be careful when interpreting studies that show improved outcome in responders versus non-responders (eg, detectable MRD versus undetectable MRD) since such comparisons have inherent methodologic flaws that cannot be overcome by increasing the sample size. In general, whether or not a treatment works, "responders" will typically appear to do better than "non-responders." One way of overcoming the bias that exists when comparing responders with non-responders is to perform landmark analysis at time points that ensure that almost all patients have had time to reach the response level being studied.

Several trials are investigating the use of MRD to guide treatment decisions (eg, escalation and de-escalation of care). As we await results, MRD status cannot drive decisions on whether to continue, alter, or resume therapy. MRD negativity is also not indicative of cure. A subset of patients with sustained MRD negative status for a prolonged period of time may be cured, but longer follow-up of patients in clinical trials is needed to confirm this hypothesis.

In the future, the preferred test for MRD detection, optimal timing of assessment, and the best MRD threshold to use will likely vary depending on availability and the reason MRD is being measured (eg, prognostic marker, goal of therapy, indicator of cure).

SURVIVAL END POINTS — Retrospective reviews have found that the amount of time that lapses before progression of myeloma may be a stronger predictor of a patient's survival when compared with the depth of their initial response to chemotherapy [40]. Overall survival is markedly shortened for patients who experienced disease progression early after initial treatment (typically 18 to 24 months or less from start of initial treatment). The rapidity with which the best response is obtained is also not necessarily a predictor for the duration of the subsequent response.

As the importance of this response time is better understood, the International Myeloma Working Group has proposed uniform definitions of survival end points. Recommended end points are defined as follows [1,9,10]:

●Progression-free survival – Time from start of treatment to disease progression or death from any cause.

●Time to progression – Time from start of treatment to disease progression. Deaths due to causes other than progression are censored, but not included in this calculation.

●Duration of response – For patients who have achieved a partial or greater response, this is the time from when the response was first noted until the time of disease progression. Deaths due to causes other than progression are censored but not included in this calculation.

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 5^th to 6^th 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 10^th to 12^th 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 treatment (Beyond the Basics)" and "Patient education: Multiple myeloma symptoms, diagnosis, and staging (Beyond the Basics)" and "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)")

●The Basics (see "Patient education: Multiple myeloma (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical assessment – Prior to each treatment cycle, we assess for potential treatment-related and disease-related complications.

This assessment includes a directed history and physical examination in addition to a complete blood count with differential, blood glucose and electrolytes, and a chemistry screen that includes measurements of serum creatinine and calcium. (See 'Clinical assessment' above.)

●Assessing tumor burden – Initially, we also assess tumor burden prior to each treatment cycle. Once it is confirmed that the disease is responding, these assessments can be done every few cycles. The studies used depend on the disease detected at baseline and on the suspected degree of response (table 1). (See 'Timing and choice of test(s)' above.)

•Measurable M protein – Most patients will have measurable M protein defined as a serum monoclonal (M) protein level ≥1 g/dL and/or urine M protein level ≥200 mg/day at baseline before treatment. In such patients, baseline tumor burden is measured using the serum protein electrophoresis (SPEP), 24-hour urine protein electrophoresis (UPEP), and the serum free light chain (FLC) assay. (See 'Patients with measurable M protein' above.)

At follow-up, tumor burden is measured using the SPEP and either the serum FLC assay or the UPEP. In patients followed preferentially with SPEP and serum FLC assay, the UPEP should still be performed periodically (eg, every six months) for validation and to check for other renal issues such as albuminuria. Serum and urine immunofixation are used once the electrophoresis shows no measurable protein.

•No measurable M protein – A subset of patients without measurable M protein at baseline will have an involved serum FLC level ≥10 mg/dL. In such patients, FLC levels are used as the primary measure of tumor burden with each cycle of therapy.

Patients without measurable M protein or abnormal FLC can be followed with periodic bone marrow aspirate and biopsy or whole body FDG PET/CT. (See 'Serum M protein <1 g/dL and urine M protein <200 mg/day' above.)

•Suspected complete response – When a complete response (CR) is suspected in clinical practice, the evaluation should include SPEP, serum immunofixation, 24-hour UPEP, urine immunofixation, serum FLC, and bone marrow aspirate and biopsy. A whole body FDG PET/CT is also performed if plasmacytomas were present at baseline. (See 'Imaging' above.)

•Suspected progression – When disease progression is suspected, the standard evaluation includes:

-Measures of tumor burden – SPEP, serum immunofixation, 24-hour UPEP, and serum FLC

-Measures of end organ damage – Hemoglobin, serum calcium, and creatinine

Bone marrow studies are not always necessary but should be performed if there is doubt about the disease status, to investigate changes in cytogenetics, or to determine eligibility for clinical trials.

●Limited role for MRD monitoring – Assessment of the bone marrow for minimal residual disease (MRD) using next-generation flow cytometry or next-generation sequencing is usually reserved for patients on clinical trials. While MRD status is prognostic, data from randomized trials are not available to support using MRD results to guide treatment decisions. (See 'Minimal residual disease assessment' above.)

●Response criteria – The International Myeloma Working Group response criteria are used to define response to therapy as stringent complete, complete, very good partial, and partial (table 2). (See 'IMWG response categories' above.)

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