Multiple Myeloma
Smouldering and active myeloma, AL amyloidosis, and POEMS
DefinitionClick to collapse
Multiple myeloma (MM) is a malignant neoplasm of plasma cells that typically accumulate in the bone marrow, leading to end-organ damage and monoclonal gammopathy. The diagnosis of symptomatic (active) MM requires either clonal bone marrow plasma cells (BMPCs) ≥10% or biopsy-proven bony or extramedullary plasmacytoma, along with at least one myeloma-defining event (MDE). MDEs include the classic CRAB criteria: hypercalcemia (serum calcium >0.25 mmol/L above the upper limit of normal or >2.75 mmol/L), renal insufficiency (creatinine clearance <40 mL/min or serum creatinine >177 μmol/L), anemia (hemoglobin >20 g/L below the lower limit of normal or <100 g/L), and bone lesions (one or more osteolytic lesions on skeletal radiography, CT, or PET-CT). Alternatively, MDEs can be biomarkers of malignancy: clonal BMPCs ≥60%, involved:uninvolved serum free light chain ratio (FLCr) ≥100, or >1 focal lesion on MRI. Smoldering (asymptomatic) MM is defined by the presence of serum monoclonal protein (M-protein) ≥3 g/dL and/or clonal BMPCs 10%–59% in the absence of MDEs or amyloidosis. Solitary plasmacytoma is a biopsy-proven solitary lesion of bone or soft tissue with clonal plasma cells, normal skeletal survey and MRI of the spine and pelvis (except for the primary lesion), absence of MDEs, and normal bone marrow with no clonal plasma cells. Solitary plasmacytoma with minimal marrow involvement has similar criteria but with clonal BMPCs <10%. Plasma cell leukemia is defined by the presence of ≥5% plasma cells in the peripheral blood. MM is a disease of the bone marrow, and while it originates from B-cell lineage, its embryological origin is not a typical descriptor in clinical guidelines.
EpidemiologyClick to collapse
SubtypesClick to collapse
Smoldering (Asymptomatic) Myeloma
A precursor state characterized by M-protein ≥3 g/dL and/or clonal BMPCs 10%–59% without evidence of end-organ damage or MDEs. It carries a risk of progression to active MM.
Active (Symptomatic) Multiple Myeloma
Defined by clonal BMPCs ≥10% or plasmacytoma plus at least one MDE (CRAB criteria or SLiM biomarkers).
Solitary Plasmacytoma
A localized clonal plasma cell neoplasm involving a single bone or soft tissue site, without systemic MM criteria.
Plasma Cell Leukemia
An aggressive variant defined by the presence of ≥5% clonal plasma cells in the peripheral blood.
High-Risk Molecular/Cytogenetic Subtypes
Subtypes defined by specific chromosomal abnormalities detected by FISH, which confer adverse prognosis.
Molecular PathogenesisClick to collapse
The molecular pathogenesis of multiple myeloma (MM) is complex and characterized by several key genomic events. The disease is initiated by the malignant transformation of a B-cell or early plasma cell in the germinal center. A hallmark is the translocation of the immunoglobulin heavy chain (IGH) gene locus at 14q32, which juxtaposes oncogenes under the control of strong enhancer elements. The most common IGH translocations are t(11;14)(q13;q32), t(4;14)(p16;q32), t(14;16)(q32;q23), and t(14;20)(q32;q12). Deletion of the short arm of chromosome 17 (del(17p13)) is a high-risk abnormality, as it encompasses the TP53 tumor suppressor gene. Mutation of TP53 is also a poor prognostic marker and requires DNA sequencing for detection. Abnormalities of chromosome 1 are frequent: gain or amplification of 1q21 is associated with disease progression and poorer outcomes, with a higher incidence in relapsed MM. Deletion of 1p32 is another high-risk cytogenetic feature. Other recurrent abnormalities include deletions of 13q and hyperdiploidy. Risk stratification based on these chromosomal aberrations, as defined by FISH on CD138-positive purified plasma cells, is critical for prognostic counseling and treatment selection. The R-ISS and the newer IMS-IMWG staging systems integrate these genetic findings with clinical markers like beta-2 microglobulin and LDH to define standard and high-risk disease. Gene expression profiling can also identify high-risk molecular signatures.
Risk FactorsClick to collapse
Age
Risk increases substantially with age, with the majority of cases diagnosed after age 65.
Race/Ethnicity
Black/African American individuals have the highest incidence rate of any racial/ethnic group, approximately twice that of other groups, and present with more severe symptoms and higher-risk disease biology.
Monoclonal Gammopathy of Undetermined Significance (MGUS)
MGUS is a precursor state with a risk of progression to MM of approximately 1% per year. The presence of MGUS confers a 25-fold increased risk of developing MM.
Smoldering (Asymptomatic) Myeloma
A higher-risk precursor than MGUS. Risk of progression to active MM varies by risk stratification: low risk (0 factors per 20/2/20 model) has a ~2-year progression risk of 6%, while high risk (2-3 factors) has a ~44% 2-year risk.
Family History
First-degree relatives of patients with MM have a 2- to 4-fold increased risk of developing MM or related plasma cell disorders.
Obesity
Elevated body mass index (BMI ≥25) has been associated with an increased risk of developing MM.
Cytogenetic Abnormalities
Specific chromosomal abnormalities (e.g., del(17p), t(4;14), 1q gain) are not causal but are high-risk prognostic factors associated with more aggressive disease and poorer outcomes.
Treatment-Related Factors (for VTE)
Use of immunomodulatory drugs (IMiDs like lenalidomide, thalidomide), high-dose dexamethasone, erythropoiesis-stimulating agents, and multiagent chemotherapy significantly increases the risk of venous thromboembolism (VTE), especially in the first 6 months after diagnosis.
Clinical FeaturesClick to collapse
Typical Presentation
Multiple myeloma (MM) is a malignant neoplasm of plasma cells that typically accumulates in the bone marrow, leading to bone destruction, elevated blood calcium, and anemia, as well as renal damage from secreted monoclonal protein (M-protein). It is most frequently diagnosed in people aged 65 to 74 years, with a median age of 69 years. The American Cancer Society estimated 36,100 new cases and 12,030 deaths in the United States in 2025 [2]. Globally, age-standardized prevalence, mortality, and disability-adjusted life years have increased from 1990 to 2021, with higher burden in males [3]. Patients often present with symptoms related to organ damage from M-protein or plasma cell infiltration, such as bone pain, fatigue, weakness, weight loss, nausea, constipation, and confusion.
Symptoms
Bone pain
A common symptom due to osteolytic lesions or fractures. Pain may be localized or diffuse.
Fatigue and weakness
Often due to anemia or renal dysfunction.
Weight loss
May occur due to metabolic changes or decreased oral intake.
Nausea and constipation
Can result from hypercalcemia or renal insufficiency.
Confusion
May be due to hypercalcemia, uremia, or hyperviscosity.
Recurrent infections
Due to immune dysfunction from abnormal plasma cells and treatment.
Signs
Bone tenderness
On palpation, indicative of lytic lesions or fractures.
Anemia
Hemoglobin <10 g/dL or >2 g/dL below normal, due to bone marrow involvement.
Hypercalcemia
Serum calcium >0.25 mmol/L (>1 mg/dL) above upper limit of normal or >2.75 mmol/L (>11 mg/dL).
Renal insufficiency
Creatinine clearance <40 mL/min or serum creatinine >177 μmol/L (>2 mg/dL).
Bone lesions
Osteolytic lesions on imaging (skeletal survey, CT, or PET-CT).
Hyperviscosity symptoms
Visual changes, headache, or bleeding due to high M-protein levels.
Red FlagsClick to collapse
Severe bone pain or new neurological deficits suggesting spinal cord compression.
Acute kidney injury with serum creatinine >2 mg/dL or rapid decline in renal function.
Hypercalcemia with serum calcium >11 mg/dL causing confusion or arrhythmias.
Anemia with hemoglobin <8 g/dL or symptomatic anemia (e.g., dyspnea, chest pain).
Recurrent or severe infections (e.g., pneumonia, sepsis) due to immune dysfunction.
Hyperviscosity symptoms (visual changes, headache, altered mental status) requiring urgent plasmapheresis.
Pathological fractures or imminent fracture risk from lytic lesions.
Plasma cell leukemia (≥5% circulating plasma cells) indicating aggressive disease.
InvestigationsClick to collapse
Diagnostic
Complete blood count (CBC) with differential and platelet count
Assess for anemia, thrombocytopenia, or leukopenia due to bone marrow infiltration.
Peripheral blood smear
Look for rouleaux formation, myeloma cells, or other abnormalities.
Serum chemistry (BUN, creatinine, electrolytes, calcium, albumin, LDH, uric acid)
Evaluate for renal dysfunction, hypercalcemia, and other metabolic abnormalities.
Serum beta-2 microglobulin
Prognostic marker and used in staging (ISS).
Serum quantitative immunoglobulins (IgG, IgA, IgM)
Detect monoclonal gammopathy and quantify M-protein.
Serum protein electrophoresis (SPEP) and serum immunofixation electrophoresis (SIFE)
Identify and quantify M-protein; immunofixation determines type.
24-hour urine for total protein, urine protein electrophoresis (UPEP), and urine immunofixation electrophoresis (UIFE)
Detect Bence Jones proteinuria and quantify urinary M-protein.
Serum free light chain (FLC) assay
Assess light chain involvement, prognostication, and response monitoring.
Unilateral bone marrow aspirate and biopsy with immunohistochemistry (IHC) and/or multi-parameter flow cytometry
Confirm clonal plasma cells, quantify bone marrow involvement, and assess phenotype.
Plasma cell FISH panel (CD138-positive selected sample)
Detect cytogenetic abnormalities for risk stratification.
Next-generation sequencing (NGS) for TP53 mutation
Identify TP53 mutation, a high-risk feature.
Staging
Whole-body FDG-PET/CT (preferred) or whole-body low-dose CT
Detect osteolytic lesions and extramedullary disease; superior to skeletal survey.
Whole-body MRI without contrast
Evaluate bone marrow infiltration, especially if FDG-PET/CT or CT is negative; discern smoldering from active MM.
Skeletal survey (X-rays of axial skeleton)
Traditional imaging but less sensitive; acceptable if advanced imaging unavailable.
Echocardiogram
Evaluate for cardiac involvement, especially if amyloidosis suspected.
Tissue biopsy of suspected plasmacytoma
Confirm diagnosis of extramedullary plasmacytoma.
Biomarkers
NT-proBNP or BNP
Assess for cardiac amyloidosis or heart failure.
Serum viscosity
Evaluate for hyperviscosity syndrome.
Hepatitis B and C testing and HIV screening
Screen for viral infections, especially before immunosuppressive therapy.
Clonotype identification or storage of bone marrow sample for MRD testing by NGS
Enable minimal residual disease monitoring.
Bone marrow biopsy for FISH, NGS, or flow cytometry
Assess for cytogenetic abnormalities and clonal plasma cells.
Renal biopsy
Evaluate for cast nephropathy, amyloidosis, or other renal pathology.
StagingClick to collapse
International Staging System (ISS), Revised ISS (R-ISS), R2-ISS, and International Myeloma Society/International Myeloma Working Group (IMS-IMWG) staging.
T Categories
| Stage |
|---|
| Not defined by TNM; staging based on ISS/R-ISS criteria. |
N Categories
| Stage |
|---|
| Not applicable; plasma cell disorders do not use nodal staging. |
M Categories
| Stage |
|---|
| Not defined by TNM; disease is systemic. |
Stage Groupings
| Group | Criteria | Clinical Meaning | Five Yr Survival | Treatment Intent |
|---|---|---|---|---|
| ISS Stage I | Serum beta-2 microglobulin <3.5 mg/L and serum albumin ≥3.5 g/dL. | Low tumor burden and better prognosis. | Median survival not reached in studies; ~80% at 5 years. | Curative intent possible with therapy. |
| ISS Stage II | Not Stage I or III (beta-2 microglobulin ≥3.5 mg/L and <5.5 mg/L, or beta-2 microglobulin <3.5 mg/L and albumin <3.5 g/dL). | Intermediate tumor burden. | ~60% at 5 years. | Curative intent with therapy. |
| ISS Stage III | Serum beta-2 microglobulin ≥5.5 mg/L. | High tumor burden and poor prognosis. | ~40% at 5 years. | Curative intent with therapy, but may consider clinical trials. |
| R-ISS Stage I | ISS stage I and standard-risk chromosomal abnormalities by FISH (no del(17p), t(4;14), or t(14;16)) and serum LDH ≤ upper limit of normal (ULN). | Low risk. | ~90% at 5 years. | Curative intent with standard therapy. |
| R-ISS Stage II | Not R-ISS stage I or III (includes most patients). | Intermediate risk. | ~60% at 5 years. | Curative intent with therapy. |
| R-ISS Stage III | ISS stage III and either high-risk chromosomal abnormalities [del(17p), t(4;14), t(14;16)] by FISH or serum LDH > ULN. | High risk. | ~40% at 5 years. | Consider aggressive therapy and clinical trials. |
| R2-ISS Low-risk (0 points) | Not ISS stage II or III, serum LDH ≤ ULN, del(17p)/t(4;14)/1q+ not detected. | Very low risk. | >90% at 5 years. | Standard therapy. |
| R2-ISS Low-intermediate risk (0.5–1 points) | ISS stage II or serum LDH > ULN or del(17p)/t(4;14)/1q+ detected. | Low-intermediate risk. | ~70-80% at 5 years. | Standard therapy. |
| R2-ISS Intermediate-high risk (1.5–2.5 points) | Any combination of high-risk features (ISS stage, LDH, del(17p), t(4;14), 1q+). | Intermediate-high risk. | ~50-60% at 5 years. | Consider more aggressive therapy. |
| R2-ISS High-risk (3–5 points) | Any combination of high-risk features totaling 3-5 points (ISS stage III, del(17p), t(4;14), 1q+, LDH > ULN). | High risk. | ~30-40% at 5 years. | Clinical trials, aggressive therapy, consider allogeneic transplant. |
| IMS-IMWG Standard Risk | All patients not meeting high-risk criteria. | Standard risk. | ~80% at 5 years. | Standard therapy. |
| IMS-IMWG High-Risk | Any of: del(17p) (>20% of plasma cells) and/or TP53 mutation; t(4;14), t(14;16), or t(14;20) co-occurring with 1q+ and/or del(1p32); monoallelic del(1p32) with 1q+ or biallelic del(1p32); high β2M (>5.5 mg/dL) with normal creatinine (<1.2 mg/dL). | High risk. | ~40% at 5 years. | Consider aggressive therapy and clinical trials. |
Staging Pearls
- Risk stratification evolves; new systems (R2-ISS, IMS-IMWG) incorporate cytogenetics and LDH for better prognostication.
- High-risk cytogenetics (del(17p), t(4;14), t(14;16)) are independent poor prognostic factors.
- 1q21 gain/amplification is common and associated with high risk, especially if co-occurring with other abnormalities.
- Plasma cell leukemia (≥5% circulating plasma cells) is a very high-risk feature.
- Staging should be performed at diagnosis and considered at relapse.
- For smoldering myeloma, risk models (Mayo 20/2/20) guide observation vs. early treatment.
Management PrinciplesClick to collapse
The management of multiple myeloma (MM) and related plasma cell disorders involves a risk-adapted, multimodal approach. Treatment decisions are guided by disease stage (e.g., solitary plasmacytoma, smoldering myeloma, symptomatic MM), risk stratification (e.g., ISS, R-ISS, R2-ISS, IMS-IMWG), patient factors (age, performance status, frailty, comorbidities), and molecular characteristics (cytogenetic abnormalities, MRD status). The primary goal for symptomatic MM is to achieve deep and durable responses, while minimizing toxicity. Supportive care, including bone-modifying agents, infection prophylaxis, and management of complications (renal impairment, hypercalcemia, VTE), is integral to improving outcomes. For asymptomatic conditions like smoldering myeloma, observation or early intervention based on risk is considered. Clinical trial participation is encouraged for all eligible patients. The NCCN Panel emphasizes equitable and inclusive clinical trial design to address disparities, particularly in Black/African American individuals who have higher myeloma incidence and distinct biological features [MYEL-F].
Curative intent
Solitary plasmacytoma (osseous or extramedullary) with minimal marrow involvement (<10% clonal plasma cells)
Radiation therapy (RT) to the involved site is the intervention of choice. Surgery may be considered for structural instability or neurologic compromise. Close surveillance for progression to MM is required [MYEL-2, MYEL-D].
Disease control/prevention of progression
Smoldering (asymptomatic) myeloma
Risk stratification using Mayo 2018/IMWG 20/2/20 criteria. Low-risk patients may be observed at 3-6 month intervals. High-risk patients may consider clinical trials or early therapy with single-agent daratumumab (category 1) or lenalidomide (category 2B) [MYEL-3].
Remission induction and deep response
Symptomatic MM (newly diagnosed)
Primary therapy with quadruplet regimens preferred for HCT-eligible patients (e.g., Dara-VRd, Isa-VRd). For HCT-ineligible or deferred, regimens like D-Rd, Dara-VRd (for non-frail patients <80 years) are preferred. Autologous HCT is standard for eligible patients. Maintenance therapy post-HCT is recommended [MYEL-4, MYEL-5, MYEL-G].
Disease control in relapsed/refractory MM
Previously treated MM
Treatment based on prior therapies, refractory status, and depth of response. Options include triplet regimens, CAR T-cell therapy (e.g., cilta-cel, ide-cel), bispecific antibodies (e.g., elranatamab, teclistamab), or clinical trials. Consider re-challenge with prior agents if relapse after >6 months [MYEL-6, MYEL-G].
Palliative care
Refractory disease with lack of treatment options
Symptom management with palliative care specialist, supportive care, and hospice initiation as appropriate [MYEL-6].
Treatment recommendations should be made after joint consultation and/or discussion by a multidisciplinary team including hematologists/oncologists, radiation oncologists, surgeons (for plasmacytomas or fractures), radiologists, pathologists, and palliative care specialists. For complex cases like CNS disease, involvement of neurologists and neurosurgeons is advised [MYEL-D, MYEL-H].
Frailty assessment should be considered in older adults using tools like the IMWG Myeloma Frailty Score Calculator. Performance status influences regimen selection: frail patients may start with 2- or 3-drug regimens with dose modifications, and steroids should be reduced or discontinued based on response and toxicity. Renal dysfunction and advanced age are not contraindications to autologous HCT but may require adjusted dosing [MYEL-F, MYEL-G].
Management PathwaysClick to collapse
Branching: site (osseous vs. extramedullary), marrow involvement (<10% clonal plasma cells), risk of progression to MM
Branching: risk stratification (Mayo 2018/IMWG 20/2/20 criteria), disease progression markers
Branching: HCT eligibility, frailty status, cytogenetic risk, patient preferences
Branching: number of prior lines, refractory status (anti-CD38, bortezomib, lenalidomide), HCT eligibility, availability of novel agents
Branching: symptom severity, CNS disease pattern (leptomeningeal vs. parenchymal), systemic disease control
Branching: cause of renal injury (plasma cell vs. lymphoplasmacytic clone), organ involvement
Branching: clone type (plasma cell vs. lymphoplasmacytic), organ damage
Branching: symptom burden (affects ADLs), clinical suspicion (high vs. low), MYD88 mutation status
Branching: disease severity, HCT eligibility, symptom burden
Pretreatment EvaluationClick to collapse
Clinical and laboratory
Imaging
Bone marrow evaluation
Additional tests
Consultations
SurgeryClick to collapse
Surgery plays a limited role in MM management, primarily for diagnosis, stabilizing fractures, or relieving spinal cord compression. It is not a primary treatment for MM but may be part of multimodality approach for solitary plasmacytomas or complications.
Procedures
Orthopedic fixation
Structural instability, fracture risk, or spinal cord compression [MYEL-I].
Vertebroplasty or kyphoplasty
Symptomatic vertebral compression fractures [MYEL-I].
Debulking surgery
Solitary plasmacytoma with spinal cord compression or neurological compromise [MYEL-2].
Radiation TherapyClick to collapse
RT is the primary treatment for solitary plasmacytomas and is used palliatively in MM for pain, impending fractures, or cord compression. It can be part of multimodality therapy for CNS involvement.
Principles
- RT is the intervention of choice for solitary plasmacytoma, providing excellent local control [MYEL-D].
- For MM, RT is primarily used for palliation of symptoms like pain, cord compression, or impending fracture [MYEL-D].
- Treatment planning should use modern principles: imaging-based delineation of GTV, CTV, PTV, and OARs. CTV expansions should include at least 0.5 cm margin for microscopic extent [MYEL-D].
- Advanced technology (IMRT, VMAT, protons) should be used to limit doses to OARs. Principles of involved-site RT (ISRT) should be followed [MYEL-D].
- Systemic therapy should not be delayed for RT; concurrent therapy can be used with careful monitoring for toxicity [MYEL-D].
Dose Frameworks
| Name | Total Dose | Dose Per Fraction | Fractions | Schedule | Indication |
|---|---|---|---|---|---|
| Solitary plasmacytoma | 40-50 Gy | 1.8-2.0 Gy | 20-25 | Daily fractions, 5 days/week | Primary treatment for solitary plasmacytoma (osseous or extramedullary) [MYEL-2, MYEL-D]. |
| Solitary plasmacytoma (<5 cm) | 35-40 Gy | 1.8-2.0 Gy | 19-22 | Daily fractions, 5 days/week | Alternative for small plasmacytomas due to high local control rates [MYEL-D]. |
Approaches
| Name | Dose Fractionation | Concurrent Chemotherapy | Indication | Key Trial | Toxicities |
|---|---|---|---|---|---|
| Palliative RT for MM | 8 Gy x 1 fraction or 20-30 Gy in 5-15 fractions | Systemic therapy can be given concurrently; monitor for additive toxicity [MYEL-D]. | Uncontrolled pain, impending pathologic fracture, or impending cord compression [MYEL-D]. | Not specified; based on panel consensus and retrospective data. | Fatigue, myelosuppression, nausea, site-specific effects (e.g., dermatitis, esophagitis) [MYEL-D]. |
| Craniospinal irradiation (CSI) for CNS disease | Variable; low-dose WBRT ≤23.4 Gy in 13 fractions may be used | May be combined with intrathecal chemotherapy and systemic therapy; avoid concurrent IT methotrexate and RT within 2 weeks [MYEL-H]. | CNS involvement with negative or controlled extra-CNS disease; as bridge to consolidation therapy [MYEL-H]. | Not specified; based on panel consensus. | Myelosuppression, neurocognitive effects, nausea [MYEL-H]. |
| Focal RT for CNS lesions | 30 Gy in 10 fractions or similar palliative regimen | Systemic therapy and intrathecal chemotherapy as per multimodality approach [MYEL-H]. | Focal neurologic deficits from localized brain, spine, or cranial nerve disease [MYEL-H]. | Not specified; based on panel consensus. | Focal edema, necrosis, cognitive changes [MYEL-H]. |
Systemic TherapyClick to collapse
Systemic therapy is the mainstay for MM, including immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), monoclonal antibodies (e.g., anti-CD38), and novel agents (e.g., bispecific antibodies, CAR T-cell therapy). Regimens are categorized as preferred, other recommended, or useful in certain circumstances based on evidence and toxicity profiles. Treatment is tailored to disease stage, risk, prior therapies, and patient factors.
Key Regimens
Treatment Response AssessmentClick to collapse
Title
Response Assessment for Multiple Myeloma
Timing
Response should be assessed after two consecutive assessments made any time before starting any new therapy. For MRD, no need for two consecutive assessments, but information after each treatment stage is recommended (e.g., after induction, HCT, consolidation, maintenance). [MYEL-E]
Response Logic
-
Use IMWG uniform response criteria for all clinical trials and practice [MYEL-E].
-
Complete response (CR): Negative immunofixation on serum and urine, disappearance of soft tissue plasmacytomas, <5% plasma cells in bone marrow [MYEL-E].
-
Stringent CR (sCR): CR plus normal FLC ratio and absence of clonal cells on bone marrow biopsy by immunohistochemistry [MYEL-E].
-
Very good partial response (VGPR): Serum and urine M-protein detectable by immunofixation but not electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein <100 mg/24 h [MYEL-E].
-
Partial response (PR): ≥50% reduction of serum M-protein plus reduction in 24-h urinary M-protein by ≥90% or to <200 mg/24 h [MYEL-E].
-
Minimal response (MR): ≥25% but ≤49% reduction of serum M-protein and reduction in 24-h urine M-protein by 50%-89% [MYEL-E].
-
Stable disease (SD): Not meeting criteria for CR, VGPR, PR, MR, or PD [MYEL-E].
-
Progressive disease (PD): Increase of 25% from lowest confirmed response value in M-protein, appearance of new lesions, or other indicators of progression [MYEL-E].
Imaging Recommendations
-
Same imaging modality used during initial workup should be used for follow-up assessments [MYEL-C].
-
Advanced whole-body imaging (FDG-PET/CT, low-dose CT, MRI without contrast) as needed. Residual focal lesions on FDG-PET/CT or MRI have adverse prognostic significance [MYEL-C].
-
Whole-body FDG-PET/CT recommended around day 100 after autologous HCT to assess for residual disease [MYEL-5].
-
For smoldering myeloma, annual imaging with same technique used at diagnosis or as clinically indicated [MYEL-C].
Biopsy Or Salvage Logic
-
Bone marrow aspirate and biopsy with FISH should be performed as clinically indicated, especially at relapse to reassess cytogenetics [MYEL-4].
-
MRD testing by next-generation flow (NGF) or next-generation sequencing (NGS) with sensitivity of 10^-5 or higher is recommended for prognostication after shared decision with patient [MYEL-E].
-
If relapse occurs, consider re-biopsy to assess for clonal evolution or new cytogenetic abnormalities [MYEL-G].
SurveillanceClick to collapse
Clinical Follow Up Schedule
| Entity | Schedule |
|---|---|
| Solitary Plasmacytoma | Every 3-6 months for at least 5 years. All plasmacytomas should be imaged yearly, preferably with the same technique used at diagnosis, for at least 5 years [MYEL-2] |
| Smoldering Myeloma | Every 3-6 months. Patients with rising parameters are considered high risk and should be closely monitored [MYEL-3] |
| Symptomatic MM (Active) | Laboratory assessments for monitoring treatment toxicities: CBC with differential and metabolic panel. Serum quantitative immunoglobulins, SPEP, SIFE. 24-hour urine for total protein, UPEP, UIFE as clinically indicated. Serum FLC assay. Bone marrow aspirate and biopsy at relapse with FISH as clinically indicated. Consider MRD testing as indicated [MYEL-4] |
Imaging Strategy
| Setting | Recommendation |
|---|---|
| Initial Diagnostic Workup | Whole-body FDG-PET/CT (preferred) or whole-body low-dose CT is recommended. Skeletal survey acceptable in certain circumstances [MYEL-C] |
| If FDG-PET/CT or LD-CT negative | Consider whole-body MRI without contrast to discern smoldering myeloma from MM [MYEL-C] |
| Solitary Osseous Plasmacytoma | Whole-body MRI (or FDG-PET/CT if MRI not available) is first choice for initial evaluation [MYEL-C] |
| Solitary Extraosseous Plasmacytoma | Whole-body FDG-PET/CT is first choice for initial and continued evaluation [MYEL-C] |
| Follow-up Smoldering Myeloma | Advanced whole-body imaging (FDG-PET/CT, low-dose CT, MRI without contrast) annually or as clinically indicated, ideally same technique used at diagnosis [MYEL-C] |
| Follow-up MM | Advanced whole-body imaging (FDG-PET/CT, low-dose CT, MRI without contrast) as needed. Patients without measurable M protein or FLC should be followed using imaging at regular intervals [MYEL-C] |
| Post-HCT | Whole-body FDG-PET/CT recommended around day 100 after autologous HCT [MYEL-5] |
Laboratory Monitoring
- CBC with differential and platelet count
- Serum chemistry: creatinine, electrolytes, liver function tests, calcium, albumin, uric acid, LDH, beta-2 microglobulin
- Serum quantitative immunoglobulins (IgG, IgA, IgM)
- Serum protein electrophoresis (SPEP) and serum immunofixation electrophoresis (SIFE)
- Serum free light chain (FLC) assay
- 24-hour urine for total protein, urine protein electrophoresis (UPEP), and urine immunofixation electrophoresis (UIFE)
- NT-proBNP/BNP for cardiac assessment
- Bone marrow aspirate and biopsy with FISH, NGS, or multi-parameter flow cytometry as clinically indicated
- MRD testing by NGF or NGS when indicated
Supportive Follow Up
- Monitor for ONJ with bisphosphonate/denosumab use
- Monitor renal function with bisphosphonate therapy
- VTE risk assessment and prophylaxis while on myeloma therapy
- Infection prophylaxis per MYEL-J guidelines
- Assess for peripheral neuropathy at each visit
- Screen for secondary primary malignancies
- Consider immunoglobulin replacement for IgG <400 mg/dL or recurrent life-threatening infections
ComplicationsClick to collapse
Disease-Related
| Complication | Management |
|---|---|
| Bone disease (osteolytic lesions, fractures, cord compression) | All patients receiving primary myeloma therapy should be given bone-targeting treatment (bisphosphonates [category 1] or denosumab). Continue for up to 2 years. Baseline dental exam recommended. Monitor for ONJ and renal dysfunction. Orthopedic consultation for impending/actual long-bone fractures or cord compression. Palliative RT for uncontrolled pain, impending pathologic fracture, or impending cord compression using 8 Gy x 1 fraction or 20-30 Gy in 5-15 fractions [MYEL-I, MYEL-D] |
| Hypercalcemia | Treat with hydration, bisphosphonates (zoledronic acid preferred), denosumab, steroids, and/or calcitonin [MYEL-I] |
| Hyperviscosity | Plasmapheresis as adjunctive therapy for symptomatic hyperviscosity [MYEL-I] |
| Anemia | Consider erythropoietin for anemic patients [MYEL-I] |
| Renal dysfunction | Pulse dexamethasone, regimens containing bortezomib and/or daratumumab. Hydration to goal urine output 100-150 cc/h. Discontinue nephrotoxic medications. Treat hypercalcemia and hyperuricemia. Dialysis if refractory. Lenalidomide dose adjustments per renal function: CrCl ≥30 to <60 mL/min: 10 mg daily; CrCl <30 mL/min not on dialysis: 15 mg every 48h; ESRD on dialysis: 5 mg once daily [MYEL-L] |
| CNS disease | Multimodality therapy (radiation and systemic therapy) with incorporation of palliative care. RT for focal neurologic deficits. WBRT ≤23.4 Gy in 13 fractions for poorly localized disease. IT chemotherapy (Thiotepa/Hydrocortisone or Methotrexate/Cytarabine/Hydrocortisone). IMiDs with CNS penetration (pomalidomide, lenalidomide). CAR-T and BsAb therapy not precluded by treated CNS disease history [MYEL-H, CNSM-1] |
| Venous thromboembolism (VTE) | VTE prophylaxis for all patients. Risk stratification by IMPEDE or SAVED score. Low risk: aspirin 81-325 mg daily. High risk: LMWH, rivaroxaban 10 mg daily, apixaban 2.5 mg BID, or warfarin (INR 2-3). Duration: indefinite while on myeloma therapy [MYEL-K] |
Supportive CareClick to collapse
Important advances have been made in adjunctive treatment/supportive care of patients with MM. This involves careful patient education about the probable side effects of each drug, the drug combinations being used, and the supportive care measures required. Supportive care can be categorized into those measures required for all patients and those that address specific drugs. Bony manifestations develop in 85% of patients with MM [MYEL-I].
Not specifically detailed in the source document beyond general supportive care references.
Not specifically detailed in the source document. Refer to NCCN Guidelines for Supportive Care.
Refer to NCCN Guidelines for Hematopoietic Growth Factors for anemia management. Erythropoietin may be considered for anemic patients, especially those with renal failure [MYEL-I].
VTE prophylaxis is administered assuming there are no contraindications to anticoagulation agents or anti-platelets. The highest risk for VTE is in the first 6 months following new diagnosis of MM. Risk stratification uses IMPEDE or SAVED scoring systems. ≤3 points IMPEDE or <2 points SAVED: aspirin 81-325 mg daily. ≥4 points IMPEDE or ≥2 points SAVED: LMWH equivalent to enoxaparin 40 mg daily, rivaroxaban 10 mg daily, apixaban 2.5 mg BID, fondaparinux 2.5 mg daily, or warfarin (INR 2-3). Duration: indefinite while on myeloma therapy or 3-6 months followed by aspirin [MYEL-K].
Palliative RT for uncontrolled bone pain. Bisphosphonates or denosumab for bone disease. Vertebroplasty or kyphoplasty for symptomatic vertebral compression fractures. Palliative care referral recommended for symptom management [MYEL-D, MYEL-I, MYEL-6].
Palliative care specialist referral recommended for symptom management in relapsed/refractory disease and at diagnosis. Discuss patient's preferences and goals of care [MYEL-4, MYEL-6].
A baseline dental exam is strongly recommended before starting bone-targeting treatment (bisphosphonates or denosumab). Monitor for osteonecrosis of the jaw (ONJ). Risk of ONJ is 9.5-fold greater with zoledronic acid compared to pamidronate [334]. Long-term ONJ rates higher with zoledronic acid (3.7%) versus clodronate (0.5%) per MRC Myeloma IX [337], [MYEL-I].
PrognosisClick to collapse
Multiple myeloma (MM) is a malignant neoplasm of plasma cells that typically accumulate in bone marrow, leading to bone destruction, elevated blood calcium, and anemia as well as renal damage secondary to the secreted monoclonal protein (M-protein). MM is most frequently diagnosed among people aged 65 to 74 years, with the median age being 69 years [1]. The American Cancer Society has estimated 36,100 new MM cases and an estimated 12,030 deaths in the United States in 2025 [2]. Globally, age-standardized prevalence and mortality rates, as well as disability-adjusted life years have all increased between 1990 and 2021, with the number of MM cases, deaths, and disability-adjusted life-years higher in males than in females [3]. Prognosis varies significantly based on disease stage, cytogenetic risk, and treatment response. The Revised International Staging System (R-ISS) integrates ISS stage with cytogenetic abnormalities and LDH levels for more refined prognostication [42]. Patients achieving minimal residual disease (MRD) negativity after treatment have significantly improved PFS and OS outcomes [155].
By Stage
| Stage | Five Yr Survival | Context |
|---|---|---|
| ISS Stage I | None | Serum beta-2 microglobulin <3.5 mg/L and serum albumin ≥3.5 g/dL |
| ISS Stage II | None | Not ISS stage I or III |
| ISS Stage III | None | Serum beta-2 microglobulin ≥5.5 mg/L |
| R-ISS Stage I | None | ISS stage I and standard risk chromosomal abnormalities by FISH and serum LDH ≤ ULN |
| R-ISS Stage II | None | Not R-ISS stage I or III; intermediate risk group |
| R-ISS Stage III | None | ISS stage III and either high-risk chromosomal abnormalities [del(17p) or t(4;14) or t(14;16)] by FISH or serum LDH > ULN |
| Smoldering Myeloma - Low Risk | None | 2-year progression rate ~6% per IMWG criteria [38] |
| Smoldering Myeloma - High Risk | None | 2-year progression rate 44% per IMWG criteria [38]; median TTP 29 months with ≥2 risk factors per Mayo 20/2/20 model [37] |
| Solitary Plasmacytoma | 74% | Five-year OS from largest retrospective study (N=258); disease-free survival 50%; local control 85% [56] |
Prognostic Factors
- R-ISS Stage III
- Extramedullary disease
- Circulating plasma cells
- Cytogenetic abnormalities: del(1p32), t(4;14), t(14;16), t(14;20), del(17p)/monosomy 17/TP53 mutation, 1q21 gain/1q21 amplification, MYC translocation
- High-risk gene expression profile
- Markers of high proliferation rate
- Two or more cytogenetic abnormalities (very high risk)
- Disease relapse within 2 years of initial therapy with HCT and maintenance
- Relapse within 18 months in case of non-transplant-based treatment
- Acquisition of 1q gain/amplification and/or del(17p)/TP53 mutation at relapse
- Extramedullary disease at relapse and/or circulating plasma cells
Follow UpClick to collapse
Post Curative Treatment
After primary therapy, patients should undergo response assessment using IMWG criteria. For HCT-eligible patients, autologous HCT is preferred after primary therapy with category 1 evidence. Whole-body FDG-PET/CT is recommended around day 100 after autologous HCT [MYEL-5]. MRD testing should be considered for prognostication after shared decision with patient. Follow-up with advanced whole-body imaging (FDG-PET/CT, low-dose CT, MRI without contrast) annually or as clinically indicated [MYEL-4, MYEL-5].
Surveillance Rationale
Residual focal lesions detected by either FDG-PET/CT or MRI have been shown to be of adverse prognostic significance [148-151]. Zamagni et al reported PFS of 44 months in patients with residual focal lesions on FDG-PET/CT versus 84 months for those without residual focal lesions [150]. In the IMAJEM trial, both PFS and OS were significantly better in patients with negative FDG-PET/CT results before maintenance therapy [151]. MRD negativity predicts improved PFS and OS, including in those who achieved CR [155].
Late Effects Screening
- Monitor for osteonecrosis of the jaw with bisphosphonate/denosumab use
- Monitor for peripheral neuropathy (especially with bortezomib-based regimens)
- Screen for secondary primary malignancies, especially with lenalidomide maintenance post-HCT
- Monitor for cardiac, renal, and pulmonary toxicity with carfilzomib
- Monitor for ocular toxicity with belantamab mafodotin-blmf
- Assess for infection risk and immune reconstitution, especially after CAR-T and BsAb therapy
- Renal function monitoring with bisphosphonate therapy
Recurrence Patterns
Disease relapse within 2 years of initial therapy with HCT and maintenance is considered high risk. Relapse within 18 months of primary induction therapy without HCT is also high risk. Solitary plasmacytoma has relatively high risk of progression into MM (14%-38% within the first 3 years of diagnosis) [49]. Patients may evolve from low-risk to high-risk smoldering myeloma over time.
Key TrialsClick to collapse
| Acronym | Full Name | Year | N | Intervention | Comparator | Population | Primary Endpoint | Key Result | Secondary Outcomes | Practice Change | Journal |
|---|---|---|---|---|---|---|---|---|---|---|---|
| PERSEUS | Daratumumab, bortezomib, lenalidomide, and dexamethasone for Multiple Myeloma | 2024 | 709 | Dara-VRd induction (4 cycles) → HCT → 2 cycles consolidation → Dara-R maintenance | VRd induction → HCT → 2 cycles consolidation → R maintenance | HCT-eligible patients with NDMM | PFS | Median PFS not reached in either arm at 47.5 months; PFS rates 84.3% vs 67.7% (HR, 0.42; 95% CI, 0.30-0.59; P < .001) | CR or better: 87.9% vs 70.1% (P < .001); MRD negativity by NGS <10^-5: 75.2% vs 47.5% (P < .001) | Established Dara-VRd as category 1 preferred regimen for HCT-eligible NDMM | N Engl J Med |
| GRIFFIN | Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with NDMM | 2023 | None | Dara-VRd → HCT → Dara-R maintenance | VRd → HCT → R maintenance | HCT-eligible patients with NDMM | sCR rate | sCR 67% vs 48% with VRd; 4-year PFS 87.2% vs 70% (HR, 0.45; 95% CI, 0.21-0.95) | Deep and durable responses with high rates of sCR and MRD negativity | Supports clinical benefit of adding daratumumab to VRd in HCT-eligible setting | Lancet Haematol |
| SWOG S0777 | Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with previously untreated myeloma | 2017 | 525 | VRd → Rd maintenance | Rd → Rd maintenance | Previously untreated MM without intent for immediate HCT | PFS | PFS 43 vs 30 months (HR, 0.712; 96% CI, 0.56-0.906); OS 75 vs 64 months (HR, 0.709; 95% CI, 0.524-0.959) | Longer-term follow-up (84 months): PFS 41 vs 29 months; OS not yet reached vs 69 months | Established VRd as category 1 regimen for HCT candidates | Lancet |
| MAIA | Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in NDMM (HCT-ineligible) | 2021 | 737 | Dara-Rd continuous until progression | Rd continuous until progression | HCT-ineligible patients with NDMM | PFS | Median PFS not reached vs 34.4 months (HR, 0.68; P < .0001); Updated (64.5 months): PFS 61.9 vs 34.4 months (HR, 0.55; P < .0001); OS not reached vs 65.5 months (HR, 0.66; P = .0003) | ≥CR 51.1% vs 30.1%; MRD negativity 32.1% vs 11.1%; Sustained MRD negativity ≥18 months: 16.8% vs 3.3% | Established Dara-Rd as category 1 preferred regimen for HCT-ineligible NDMM | Lancet Oncol |
| CEPHEUS | Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred NDMM | 2025 | 395 | Dara-VRd → Dara-R maintenance | VRd → R maintenance | HCT-ineligible or deferred NDMM patients <80 years, not frail | MRD-negativity rate at 10^-5 by NGS | MRD negativity 60.9% vs 39.4%; PFS HR 0.57 (95% CI, 0.41-0.79; P = .0005); Median PFS not reached vs 52.6 months | 54-month PFS estimates: 68.1% vs 49.5% | Established Dara-VRd as category 1 for patients <80 years who are not frail | Nat Med |
| IMROZ | Isatuximab-irfc, bortezomib, lenalidomide, and dexamethasone for MM | 2024 | 446 | Isa-VRd (4 cycles) → Isa-Rd maintenance | VRd → Rd maintenance | NDMM ≤80 years, not eligible for ASCT | PFS | PFS 63.2% vs 45.2% (HR, 0.60; 95% CI, 0.44-0.81; P = .0009) | ≥CR 74.7% vs 64.1% (P = .01); MRD negativity 55.5% vs 40.9% (P = .003) | Established Isa-VRd as category 1 preferred for HCT-deferred patients <80 years not frail | N Engl J Med |
| ENDURANCE | Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for NDMM without intention for immediate HCT | 2020 | 1053 | KRd | VRd | NDMM without high-risk features (except t(4;14)), not intending immediate HCT | PFS | Median PFS 34.4 months (VRd) vs 34.6 months (KRd); similar PFS with less neuropathy but more cardiac/pulmonary/renal toxicity with KRd | VGPR or better 65% vs 74% (P = .0015) | KRd listed as other recommended but not preferred due to similar efficacy with different toxicity profile | Lancet Oncol |
| IFM 2009 | Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma | 2017 | None | VRd → HCT | VRd alone | NDMM ≤65 years | PFS | PFS 50 vs 36 months with HCT; CR 59% vs 48% (P = .03); MRD-negative 79% vs 65% (P < .001) | OS high in both groups; HCT improved PFS but not OS | Demonstrates benefit of autologous HCT with higher rates of durable responses | N Engl J Med |
| DETERMINATION | Triplet therapy, transplantation, and maintenance until progression in myeloma | 2022 | 722 | 3 cycles VRd → stem cell collection → HCT → 2 cycles VRd → R maintenance | 3 cycles VRd → stem cell collection → 5 cycles VRd → R maintenance | NDMM | PFS | Median PFS improved by 21 months with HCT at 76-month follow-up, but no OS benefit; 5-year survival 79.2% vs 80.7% (HR for death, 1.10; 95% CI, 0.73-1.65) | MRD-negative patients had similar PFS regardless of HCT (5-year PFS 59% vs 54%; HR, 0.91) | Suggests delaying HCT is an option without negative OS effects | N Engl J Med |
| CARTITUDE-4 | Ciltacabtagene autoleucel versus standard care in lenalidomide-refractory MM | 2023 | 419 | Ciltacabtagene autoleucel (cilta-cel) | Pd or PVd standard regimens | Lenalidomide-refractory MM after 1-3 prior therapies | PFS | Median PFS not reached vs 11.8 months (HR, 0.26; 95% CI, 0.18-0.38; P < .001); CR or better 73.1% vs 21.8%; Updated: 30-month OS 76.4% vs 63.8% (HR, 0.55; P = .0009) | ORR 84.6% vs 67.3%; MRD negativity 60.6% vs 15.6% | Category 1 preferred CAR-T for after one prior line including IMiD and PI, refractory to lenalidomide | N Engl J Med |
| KarMMa-3 | Idecabtagene vicleucel versus standard regimens in relapsed and refractory MM | 2023 | 386 | Idecabtagene vicleucel (ide-cel) | Standard regimens | RRMM after 2-4 prior lines, including IMiD, anti-CD38, and PI | PFS | Median PFS 13.3 vs 4.4 months (HR, 0.49; 95% CI, 0.38-0.65; P < .001); ORR 71% vs 42% (P < .0001) | Deep responses in heavily pretreated population (95% daratumumab-refractory) | Category 1 preferred CAR-T for after two prior lines including IMiD, anti-CD38, and PI | N Engl J Med |
| ASPIRE | Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma | 2015 | 792 | KRd | Rd | Relapsed/refractory MM with 1-3 prior therapies, lenalidomide-sensitive | PFS | PFS 26.3 vs 17.6 months (HR, 0.69; 95% CI, 0.57-0.83; P = .0001) | Superior health-related quality of life with KRd | Category 1 preferred for relapsed/refractory MM | N Engl J Med |
| CANDOR | Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for relapsed/refractory MM | 2020 | None | DKd | Kd | Relapsed/refractory MM | PFS | PFS 28.6 vs 15.2 months (HR, 0.59; 95% CI, 0.45-0.78; P < .0001) | Deeper responses with daratumumab addition | Category 1 preferred for relapsed/refractory MM | Lancet |
| IKEMA | Isatuximab, carfilzomib, and dexamethasone in relapsed MM | 2021 | 302 | Isa-Kd | Kd | Relapsed/refractory MM with 1-3 prior lines | PFS | PFS 35.7 vs 19.15 months (HR, 0.53; 99% CI, 0.32-0.89; P = .0007) | Grade ≥3 TRAE 77% in Isa group vs 67% in control | Category 1 preferred for relapsed/refractory MM | Lancet |
| APOLLO | Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated MM | 2021 | 304 | Dara-Pd | Pd | Relapsed/refractory MM with ≥1 prior line | PFS | PFS 12.4 vs 6.9 months (P = .0018) | Serious adverse events 50% vs 39% | Category 1 preferred for relapsed/refractory MM after one prior line including IMiD and PI | Lancet Oncol |
| DREAMM-2 | Belantamab mafodotin for relapsed or refractory MM | 2020 | None | Belantamab mafodotin-blmf (2.5 or 3.4 mg/kg) | None | Heavily pretreated RRMM | ORR | ORR 32% and 35% in 2.5 and 3.4 mg/kg cohorts; median PFS 2.8 and 3.9 months | Median OS 15.3 and 14.0 months; Grade 3-4 keratopathy 29% and 25% | Useful in certain circumstances for after 4 prior therapies | Lancet Oncol |
| DREAMM-7 | Belantamab mafodotin plus bortezomib and dexamethasone versus daratumumab plus bortezomib and dexamethasone | 2024 | 494 | BVd (belantamab mafodotin + bortezomib + dexamethasone) | DVd (daratumumab + bortezomib + dexamethasone) | Relapsed/refractory MM after ≥1 prior line | PFS | PFS 36.6 vs 13.4 months (HR, 0.41; 95% CI, 0.31-0.53; P < .00001); Updated OS HR 0.58 (P = .0002) | MRD negativity in ≥CR: 25% vs 10% (P < .0001); Ocular events 79% vs 29% | Category 1 other recommended after ≥2 prior therapies including IMiD and PI | N Engl J Med |
| AQUILA | Daratumumab or active monitoring for high-risk smoldering multiple myeloma | 2025 | 390 | 3 years subcutaneous daratumumab monotherapy | Active monitoring | High-risk smoldering myeloma | 5-year PFS | 5-year PFS 63.1% vs 40.8%; High-risk subgroup HR 0.36 (95% CI, 0.23-0.58); 5-year OS 93% vs 86.9% (HR, 0.52; 95% CI, 0.27-0.98) | PFS benefit clear in high-risk SMM but not intermediate or low risk | Category 1 for high-risk smoldering myeloma: single-agent daratumumab | N Engl J Med |
| BOSTON | Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone | 2020 | 608 | SVd | Vd | Previously treated MM with 1-3 prior lines including PIs | PFS | PFS 13.93 vs 9.46 months (HR, 0.70; 95% CI, 0.53-0.93; P = .0075) | Grade 3-4 thrombocytopenia 39% vs 17% | Category 1 other recommended for previously treated MM | Lancet |
| MagnetisMM-3 | Elranatamab in relapsed or refractory MM | 2023 | 123 | Elranatamab-bcmm subcutaneous weekly | None | RRMM without prior BCMA-directed therapy | ORR | ORR 61.0%; ≥CR 35.0%; 80% maintained/improved response ≥6 months with biweekly dosing | Grade 3-4 AEs decreased from 58.6% to 46.6% with biweekly dosing | Preferred option for after ≥4 prior lines of therapy | Nat Med |
| CARTITUDE-1 | Ciltacabtagene autoleucel in relapsed or refractory MM | 2021 | 97 | Ciltacabtagene autoleucel | None | RRMM with ≥3 prior lines including IMiD, PI, and anti-CD38 | ORR | ORR 97%; sCR 67%; PFS 77%; OS 89%. Post-hoc analysis at 61.3 months: 33% progression-free without additional MM treatment, 96.9% achieved sCR | CRS in 95%; Grade 3-4 neutropenia 95%; anemia 68%; thrombocytopenia 60% | Preferred CAR-T option for after ≥4 prior lines | Lancet |
| MonumenTAL-1 | Talquetamab for relapsed/refractory MM | 2022 | 187 | Talquetamab-tgvs subcutaneous (weekly or biweekly) | None | RRMM with ≥4 prior systemic therapies | ORR | T-cell redirecting bispecific antibody targeting GPRC5D and CD3 | CRS (77-80%); skin-related events (67-70%); dysgeusia (63-57%) | Preferred option for after ≥4 prior lines of therapy | N Engl J Med |
| LINKER-MM1 | Linvoseltamab for relapsed/refractory MM | 2024 | 117 | Linvoseltamab-gcpt 200 mg | None | RRMM after ≥3 lines or triplet therapy | ORR | ORR 71%; 50% achieved ≥CR; estimated median DoR 29.4 months | Grade 3-4 hematologic/infectious toxicities 74%; CRS 46%; ICANS 7.7% | Preferred option for after ≥4 prior lines of therapy | J Clin Oncol |
| First-in-human Teclistamab | Teclistamab in relapsed or refractory MM | 2022 | 165 | Teclistamab-cqyv | None | Triple class refractory MM with median 5 prior lines | ORR | ORR 63%; ≥CR 39.4%; median PFS 11.3 months; median DoR 18.4 months | CRS 72.1% (grade 3: 0.6%); Grade 3-4 neutropenia 64.2%; infections grade 3-4 44.8% | Preferred option for after ≥4 prior lines of therapy | N Engl J Med |
| RedirecTT-1 | Talquetamab plus Teclistamab in relapsed/refractory MM | 2025 | 94 | Talquetamab + Teclistamab combination | None | RRMM | ORR | ORR 80% at recommended phase 2 dose (0.8 mg/kg talquetamab + 3.0 mg/kg teclistamab); 86% probability of maintaining response after 18 months | Tolerable with prophylactic tocilizumab consideration for CRS reduction | Useful in certain circumstances option; prophylactic tocilizumab may be considered | N Engl J Med |
| TOURMALINE-MM1 | Oral ixazomib, lenalidomide, and dexamethasone for MM | 2016 | 722 | IRd | Rd | Relapsed/refractory MM | PFS | PFS 20.6 vs 14.7 months (HR, 0.74; P = .01); ORR 78% vs 72%; CR 11.7% vs 6.6% | High-risk cytogenetics subgroup showed similar HR | Category 1 preferred for previously treated MM after 1-3 prior therapies | N Engl J Med |
Clinical PearlsClick to collapse
- Pearl 1: Quadruplet regimens are now preferred as standard for primary treatment of all HCT-eligible patients with MM based on improved response rates, depth of response, and PFS/OS seen in clinical trials [MYEL-G].
- Pearl 2: The 20/2/20 risk model (BMPCs >20%, M protein >2 g/dL, FLCr >20) is essential for risk stratifying smoldering myeloma; patients with ≥2 factors have high risk with median TTP of 29 months [37, MYEL-3].
- Pearl 3: Daratumumab and isatuximab-irfc may cause false-positive indirect Coombs test and interfere with serologic testing; type and screen must be performed before using these agents [MYEL-F].
- Pearl 4: Subcutaneous bortezomib is the preferred route of administration based on MMY-3021 trial data showing noninferior efficacy with significantly reduced peripheral neuropathy [78, MYEL-F].
- Pearl 5: Black/African American individuals have twice the incidence of MM, more severe symptoms at diagnosis, but superior OS with equal treatment access (7.07 vs 5.83 years; P < .001) [69,70].
- Pearl 6: Talquetamab-tgvs may be considered as a bridge to BCMA CAR-T therapy in relapsed/refractory MM, but BCMA-targeted CAR-T immediately following BCMA-targeted bispecific use may not represent optimal sequencing [MYEL-G 5 of 5].
- Pearl 7: The IMWG response criteria should be used in all clinical trials and clinical practice; MRD negativity (by NGF and/or NGS at ≥10^-5 sensitivity) predicts improved PFS and OS [147,155].
- Pearl 8: For bone disease management, continue bisphosphonates or denosumab for up to 2 years with frequency based on individual patient criteria and response; continuing beyond 2 years based on clinical judgment [MYEL-I].
Special SituationsClick to collapse
Older Adults
Black/African American Individuals
CNS Disease in MM
Solitary Plasmacytoma
Monoclonal Gammopathy of Renal Significance (MGRS)
POEMS Syndrome
Renal Impairment with MM
Guidelines ResourcesClick to collapse
NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma
NCCN Guidelines for Patients: Multiple Myeloma
NCCN Guidelines for Supportive Care
NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections
NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease
NCCN Guidelines for Systemic Light Chain Amyloidosis
NCCN Guidelines for Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma
NCCN Guidelines for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
NCCN Guidelines for Older Adult Oncology
NCCN Guidelines for Hodgkin Lymphoma
NCCN Guidelines for Management of Immunotherapy-Related Toxicities
NCCN Guidelines for Palliative Care
NCCN Guidelines for Survivorship
CDC for Use of COVID-19 Vaccines in the US
International Myeloma Working Group Consensus Criteria for Response and MRD Assessment
Protective FactorsClick to collapse
- The NCCN guidelines do not explicitly list established protective factors for the development of multiple myeloma. However, in the discussion of disparities, it is noted that Black/African American individuals have a superior median overall survival compared to White individuals despite higher incidence, which may be attributed to biological differences or differential response to therapy. This is an observation of outcome rather than a protective factor against disease development.