multiple%20myeloma
MULTIPLE MYELOMA

Multiple myeloma is a bone marrow disease characterized by the presence of malignant plasma cells, & abnormal serum &/or urine immunoglobulin secondary to clonal plasma cell expansion.

It accounts for 1-2% of all cancers worldwide & mostly affects patients at ages 65-74 years old.

Patient usually presents with bone pain & nonspecific symptoms, or due to abnormalities in laboratory exams.

 

Multiple%20myeloma Management

Monitoring

  • Assessment of clinical response is recommended after every treatment cycle

International Myeloma Working Group (IMWG) Criteria for Response Assessment

Category Criteria
IMWG Minimal Residual Disease (MRD) Criteria
Sustained MRD-negative No MRD in the marrow as defined by next-generation flow (NGF), next-generation sequencing (NGS), or both, and in imaging*, within a minimum span of 1 year apart. Specific duration of negativity to be based on subsequent evaluations
Flow MRD-negative Phenotypically aberrant clonal plasma cells by NGF absent in bone marrow aspirate using the EuroFlow standard operating procedure for MRD detection in multiple myeloma with sensitivity of ≥1 in 105 nucleated cells
Sequencing MRD-negative Clonal plasma cells by NGS absent in bone marrow aspirate; clone present defined as <2 identical sequencing reads obtained after DNA sequencing of bone marrow aspirates by a validated equivalent methods with sensitivity of ≥1 in 105 nucleated cells
Imaging plus MRD-negative MRD-negative as defined by NGF or NGS, plus complete disappearance, decreased to less mediastinal blood pool standardized uptake values (SUV), or decreased to less than that of the surrounding normal tissue, of tracer in previous areas identified with increased tracer uptake at baseline or preceding PET/CT
Standard IMWG Response Criteria
Complete response Negative serum and urine immunofixation without any soft tissue plasmacytomas and <5% plasma cells in bone marrow aspirates
Stringent complete response Complete response plus normal FLC ratio and negative clonal cells in bone marrow biopsy by immunohistochemistry (κ/λ ratio ≤4:1 for κ or ≥1:2 for λ patients after counting ≥100 plasma cells)
Very good partial response Serum and urine M-protein detectable by immunofixation but not on serum protein electrophoresis (SPEP), or ≥90% reduction in serum M-protein with urine M-protein <100 mg/24 hours
Partial response Serum M-protein reduced by ≥50%, plus ≥90% reduction of 24-hour urinary M-protein, or <200 mg/24 hours urinary M-protein
Or ≥50% reduction in plasma cells (in place of M-protein) if with baseline bone marrow plasma cell percentage of ≥30% plus ≥50% reduction in size of soft tissue plasmacytomas if obtained at baseline
Minimal response ≥25% but ≤49% reduction in serum M-protein and 50-89% reduced 24-hour urine M-protein or 25-49% reduction in size of soft tissue plasmacytomas if obtained at baseline
Stable disease Does not meet the criteria for complete response, very good partial response, partial response, minimal response, or progressive disease
Not recommended to be used as an indicator of response
Progressive disease

25% increase from lowest confirmed response value in ≥1 of the following:
Serum M-protein (absolute increase ≥0.5 g/dL)
Serum M-protein increase ≥1 g/dL, if lowest M component was ≥5 g/dL
Urine M-protein (absolute increase ≥200 mg/24 hours)
The difference between involved and uninvolved FLC levels in patients without measurable serum or urine M-protein levels (absolute increase >10 mg/dL)
Bone marrow plasma-cell percentage irrespective of baseline status in patients with no measurable serum M-protein, urine M-protein, and involved FLC levels (absolute increase must be ≥10%)
Presence of new lesion(s), ≥50% increase from nadir in SPD† of >1 lesion, or ≥50% increase in longest diameter of previous lesion >1 cm in short axis; ≥50% increase in circulating plasma cells (≥200 cells/μL) if other tests are unavailable

Clinical relapse

≥1 of the following:

  • Presence of indicators for increasing disease and/or end-organ dysfunction (CRAB features) related to underlying clonal plasma-cell proliferative disorder
  • Presence of new soft tissue plasmacytomas or bone lesions (except osteoporotic fractures)
  • 50% or ≥1 cm increase in size of existing plasmacytomas or bone lesions serially measured by the SPD of measurable lesions
  • Hypercalcemia (>11 mg/dL)
  • Hemoglobin level decreased by ≥2 g/dL unrelated to any therapeutic regimen or other non-myeloma-related conditions
  • An increase in serum creatinine by ≥2 mg/dL during therapy initiation and attributable to myeloma
  • Hyperviscosity related to serum paraprotein
Relapse from complete response#

≥1 of the following:

  • Reappearance of serum or urine M-protein by immunofixation or electrophoresis
  • Development of ≥5% plasma cells in bone marrow
  • Appearance of any other signs of progression (eg new plasmacytoma, lytic bone lesion, hypercalcemia)
Relapse from MRD-negative#

≥1 of the following:

  • Presence of clonal plasma cell on NGF/NGS, positive for recurrence in imaging studies (loss of MRD-negative status)
  • Reappearance of serum or urine M-protein by immunofixation or electrophoresis
  • Development of ≥5% plasma cells in bone marrow
  • Appearance of any other signs of progression (eg new plasmacytoma, lytic bone lesion, hypercalcemia)

Adapted from: International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. 2016.

*Negative imaging results defined as complete disappearance, decreased to less mediastinal blood pool SUV, or decreased to less than that of the surrounding normal tissue, of tracer in previous areas identified with increased tracer uptake at baseline or preceding PET/CT

◊Validated by Freelite test

†Sum of the products of the maximal perpendicular diameters of measured lesions
#If endpoint is disease-free survival

Follow Up

  • Treatment response should be evaluated after every therapy cycle (see Response Assessment)
  • Recommended laboratory tests during follow-up or surveillance include CBC with differential and platelet count, serum creatinine level, calcium level, serum and urine M-protein level, and immunoglobulin studies should be obtained 
  • May consider the following tests as clinically indicated:
    • Serum quantitative immunoglobulins, serum protein electrophoresis (SPEP) and serum immunofixation electrophoresis (SIFE)
    • Serum FLC assay: Should be obtained every 2-3 months or as clinically indicated
    • Imaging modalities (eg whole body MRI without contrast, low-dose CT scan, WBLD-CT, whole body FDG PET/CT)
    • Bone marrow aspirate and biopsy with multiparameter flow cytometry
    • Minimal residue disease assessment
  • Patients receiving Carfilzomib should be closely monitored for any cardiac or lung toxicities
  • Occurrence of new bone lesions should be monitored using patient history and imaging modalities (eg skeletal radiography, MRI, WBLD-CT, PET-CT)
  • Follow-up bone imaging may be considered if disease progression is suspected

Relapsed/Progressive Multiple Myeloma

  • Disease relapse in multiple myeloma is a common occurrence and therapy is recommended
  • Therapeutic regimen depends on patient's age, Eastern Cooperative Oncology Group (ECOG) performance status, comorbidities, risk assessment at the time of relapse and history of therapeutic agents and management strategies done
  • Treatment should be considered in patients who previously underwent SCT, patients with primary progressive disease after SCT, and patients ineligible for SCT with relapsed/progressive multiple myeloma after initial primary treatment
  • Patients post-ASCT may opt to receive another ASCT if response to previous ASCT was positive and disease progression-free for ≥18-24 months
    • May consider nonmyeloablative alloSCT in select patients (ie young patients with high-risk myeloma with short response duration), but advantages must be weighed against treatment-related morbidity
  • Triplet therapy, which includes 2 novel agents (proteasome inhibitor, immunomodulatory drug, monoclonal antibody) plus a steroid, is recommended to be given on the 1st clinical relapse of a fit patient once confirmed, with consideration to patient's prior therapies
    • Triplet therapy, followed by 1-2 ASCTs, then a proteasome inhibitor-based maintenance treatment until disease progression is recommended for relapsed patients with genetic high-risk disease
  • Doublet therapy with 1 novel agent plus a steroid should be considered in patients with history of drug toxicity and other comorbidities
    • May start triplet therapy once with improvement of performance status
  • Use of chemotherapeutic agents and enrollment into a clinical trial should be considered in patients with repeating disease relapse

Preferred Regimens

  • Repeat administration of primary induction regimens may be considered if relapse occurs >6 months after completion of initial therapy
  • Regimens combined with Dexamethasone that are preferred options for relapsed/refractory multiple myeloma include:
    • Bortezomib/Lenalidomide/Dexamethasone
      • Studies showed that this combination was well-tolerated even by patients who received continuous high-dose treatments and SCT
      • May be given with or without pegylated Doxorubicin
    • Carfilzomib/Lenalidomide/Dexamethasone (KRd)
      • May be used in multiple myeloma patients previously given at least 1 prior therapeutic regimen
    • Daratumumab/Bortezomib/Dexamethasone (DVd)
      • Preferred option for adults with relapsed/refractory multiple myeloma previously treated with protease inhibitor and an IMiD agent, with disease progression after completion of regimen
      • Daratumumab is given with Hyaluronidase-fihj when administered subcutaneously
    • Daratumumab/Carfilzomib/Dexamethasone (DKd)
      • Indicated for patients with relapsed/refractory multiple myeloma with at least 1-3 prior therapeutic regimens
      • Daratumumab is given with Hyaluronidase-fihj when administered subcutaneously
    • Isatuximab-irfc/Pomalidomide/Dexamethasone
      • Indicated for patients with relapsed/refractory multiple myeloma who received ≥2 prior regimens including Lenalidomide and a protease inhibitor
    • Ixazomib/Pomalidomide/Dexamethasone
      • Indicated for multiple myeloma patients previously treated with at least 2 regimens which include an IMiD and a proteasome inhibitor, with disease progression on or within 60 days after completion of the last therapy
    • Pomalidomide/Bortezomib/Dexamethasone (VPd)
      • Treatment option for multiple myeloma patients previously treated with at least 2 regimens which include an IMiD and a proteasome inhibitor, with disease progression on or within 60 days after completion of the last therapy 
    • Lenalidomide-based combinations:
      • Includes Daratumumab/Lenalidomide/Dexamethasone (DRd), Ixazomib/Lenalidomide/Dexamethasone (IRd) combinations
        • Daratumumab is given with Hyaluronidase-fihj when administered subcutaneously
      • Preferred treatment option for multiple myeloma patients previously treated with at least 1 prior regimen

Other Recommended Regimens

  • Belantamab mafodotin-blmf
    • Indicated for patients who have received ≥4 prior regimens including an anti-CD38 monoclonal antibody, a proteasome inhibitor and an IMiD 
  • Recommended regimens combined with Dexamethasone that can be considered for multiple myeloma patients with relapsed/refractory disease:
    • Bendamustine/Dexamethasone with either Lenalidomide or Bortezomib
    • Bortezomib/Dexamethasone with or without either liposomal Doxorubicin or Cyclophosphamide
    • Carfilzomib/Cyclophosphamide/Dexamethasone
    • Twice-weekly Carfilzomib/Dexamethasone
      • Showed better improvement in median PFS when compared to Bortezomib/Dexamethasone combination
      • May be used in multiple myeloma patients previously given at least 1 prior therapeutic regimen-
    • Cyclophosphamide/Lenalidomide/Dexamethasone 
    • Daratumumab/Dexamethasone with Pomalidomide (DPd)
      • Treatment option for multiple myeloma patients previously treated with at least 2 regimens which include an IMiD and a proteasome inhibitor 
      • Daratumumab is given with Hyaluronidase-fihj when administered subcutaneously
    • Daratumumab/Dexamethasone/Cyclophosphamide/Bortezomib
      • Daratumumab is given with Hyaluronidase-fihj when administered subcutaneously 
    • Elotuzumab/Bortezomib/Dexamethasone
      • Treatment option for patients given at least 1 prior therapeutic regimen
    • Elotuzumab/Lenalidomide/Dexamethasone (ERd)
      • May be used for patients previously treated with 1-3 prior regimens
    • Elotuzumab/Pomalidomide/Dexamethasone
      • Treatment option for multiple myeloma patients previously treated with at least 2 regimens which include an IMiD and a proteasome inhibitor 
    • Ixazomib/Cyclophosphamide/Dexamethasone
    • Panobinostat/Bortezomib/Dexamethasone (VD-Pano)
      • Approved for patients with relapsed/refractory multiple myeloma with history of at least 2 prior therapies including IMiD- and Bortezomib-containing treatments
  • Pomalidomide/Dexamethasone with either Carfilzomib, or Cyclophosphamide are treatment options for multiple myeloma patients previously treated with at least 2 regimens which include an IMiD and a proteosome inhibitor, with disease progression on or within 60 days after completion of the last therapy

Conditional Regimens

  • Regimens combined with Dexamethasone that can be considered for multiple myeloma patients with relapsed/refractory disease:
    • Bortezomib/Dexamethasone
    • Weekly Carfilzomib/Dexamethasone
    • Ixazomib/Dexamethasone
      • Treatment option for multiple myeloma patients with history of at least 1 prior therapy
    • Lenalidomide/Dexamethasone
      • Treatment option for multiple myeloma patients with history of at least 1 prior therapy
    • Pomalidomide/Dexamethasone
      • Treatment option for multiple myeloma patients previously treated with at least 2 regimens which include an IMiD and a proteasome inhibitor, with disease progression on or within 60 days after completion of the last therapy 
  • Multi-drug regimens are preferred in patients with aggressive relapse even with prior chemotherapy used to control disease progression:
    • Carfilzomib/Cyclophosphamide/Thalidomide/Dexamethasone 
    • Dexamethasone/Cyclophosphamide/Etoposide/Cisplatin (DCEP)
    • Thalidomide/Dexamethasone/Cisplatin/Doxorubicin/Cyclophosphamide/Etoposide (TD-PACE) with or without Bortezomib (VTD-PACE)
  • Monotherapy with Daratumumab may be considered for MM patients with at least 3 previously taken anti-cancer regimens which include a protease inhibitor and an IMiD agent, or who are double refractory to a protease inhibitor and an IMiD agent
    • Daratumumab is given with Hyaluronidase-fihj when administered subcutaneously 
  • May consider monotherapy with Bendamustine or high-dose Cyclophosphamide in patients with relapse or progressive disease
  • Lenalidomide or Pomalidomide monotherapy: For steroid-intolerant patients 
  • Combination therapy with Selinexor/Dexamethasone may be considered in patients previously treated with ≥4 regimens, refractory to ≥2 protease inhibitors or IMiD agent, and an anti-CD38 monoclonal antibody
  • Venetoclax/Dexamethasone is indicated for patients with relapsed/refractory multiple myeloma with t(11;14) translocation
  • Panobinostat-based regimen (Panobinostat/Lenalidomide/Dexamethasone, Panobinostat/Carfilzomib) are approved for patients with relapsed/refractory multiple myeloma with history of at least 2 prior therapies including IMiD- and Bortezomib-containing treatments
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