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.

 

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, & 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 w/ 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 LymphoSIGHT platform or other equivalent methods w/ 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 w/ increased tracer uptake at baseline or preceding PET/CT
Standard IMWG Response Criteria
Complete response Negative serum & urine immunofixation without any soft tissue plasmacytomas & <5% plasma cells in bone marrow aspirates
Stringent complete response Complete response plus normal FLC ratio & 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 & urine M-protein detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein w/ 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 w/ 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 & 50-89% reduced 24-hour urine M-protein or ≥50% 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
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)
  • Difference between involved & uninvolved FLC levels in patients w/ no measurable serum or urine M-protein levels (absolute increase >10 mg/dL)
  • Bone marrow plasma-cell percentage irrespective of baseline status in patients w/ no measurable serum M-protein, urine M-protein, & 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 &/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 plasmacytoma 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 & 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 & 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 w/ 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

Follow Up

  • Treatment response should be evaluated after every therapy cycle (see Response Assessment)
    • CBC w/ differential & platelet count, serum creatinine level, calcium level, serum & urine M-protein level, & immunoglobulin studies should be obtained 
  • Patients receiving Carfilzomib should be closely monitored for any cardiac or lung toxicities
  • Serum FLC assay should be obtained every 2-3 months or as clinically indicated
  • Occurrence of new bone lesions should be monitored using patient history & imaging modalities (eg skeletal radiography, MRI, WBLD-CT, PET-CT)

Relapsed/Progressive Multiple Myeloma

  • Disease relapse in multiple myeloma is a common occurrence & therapy is recommended
  • Therapeutic regimen depends on patient's age, Eastern Cooperative Oncology Group (ECOG) performance status, comorbidities, & history of therapeutic agents & management strategies done
  • Treatment should be considered in patients who previously underwent SCT, patients w/ primary progressive disease after SCT, & patients ineligible for SCT w/ relapsed/progressive multiple myeloma after initial primary treatment
  • Patients post-ASCT may opt to receive another ASCT if response to previous ASCT was positive & disease progression-free for >24 months
  • Drug regimens including the newer agents Carfilzomib or Pomalidomide should be considered for refractory/resistant multiple myeloma patients

Preferred Regimens

  • Repeat administration of primary induction regimens may be considered if relapse occurs >6 months after completion of initial therapy
  • Regimens combined w/ 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 & SCT
      • May be given w/ or without pegylated Doxorubicin
    • 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
    • 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 w/ relapsed/refractory multiple myeloma previously treated w/ protease inhibitor & an IMiD agent, w/ disease progression after completion of regimen
    • Lenalidomide-based combinations:
      • Includes Daratumumab/Lenalidomide/Dexamethasone (DRd), Elotuzumab/Lenalidomide/Dexamethasone (Rd-Elo), Ixazomib/Lenalidomide/Dexamethasone (IRd) combinations
      • Preferred treatment option for multiple myeloma patients previously treated w/ at least 1 prior regimen
  • 2-drug combination regimens may be considered in elderly & frail patients

Other Recommended Regimens

  • Recommended regimens combined w/ Dexamethasone that can be considered for multiple myeloma patients w/ relapsed/refractory disease:
    • Bendamustine/Dexamethasone w/ either Lenalidomide or Bortezomib
    • Bortezomib/Dexamethasone w/ or without either liposomal Doxorubicin or Cyclophosphamide
    • Weekly Carfilzomib/Dexamethasone
    • Carfilzomib/Cyclophosphamide/Dexamethasone
    • Lenalidomide/Dexamethasone w/ or without Cyclophosphamide
    • Lenalidomide monotherapy
  • Pomalidomide/Dexamethasone w/ or without either Bortezomib, Carfilzomib, Daratumumab, or Ixazomib are treatment options for multiple myeloma patients previously treated w/ at least 2 regimens which include an IMiD & Bortezomib, w/ disease progression within 60 days after completion of therapy
  • Pomalidomide/Cyclophosphamide/Dexamethasone & Elotuzumab/Bortezomib/Dexamethasone combinations are treatment options for multiple myeloma patients previously treated w/ at least 1 regimen
  • Monotherapy w/ Daratumumab may be considered for multiple myeloma patients w/ at least 3 previously taken anti-cancer regimens which include a protease inhibitor & an IMiD agent, or who are double refractory to a protease inhibitor & an IMiD agent
  • Panobinostat-based 3-drug regimens (eg Panobinostat/Bortezomib/Dexamethasone (VD-Pano), Panobinostat/Lenalidomide/Dexamethasone) were approved for patients w/ relapsed/refractory multiple myeloma w/ history of at least 2 IMiD- & Bortezomib-containing treatments
  • The 2-drug Panobinostat-based regimen Panobinostat/Carfilzomib may be considered as a treatment option for patients w/ previously treated multiple myeloma

Conditional Regimens

  • Multi-drug regimens are preferred in patients w/ aggressive relapse even w/ prior chemotherapy used to control disease progression:
    • Dexamethasone/Cyclophosphamide/Etoposide/Cisplatin (DCEP)
    • Thalidomide/Dexamethasone/Cisplatin/Doxorubicin/Cyclophosphamide/Etoposide (TD-PACE)
    • Bortezomib/Thalidomide/Dexamethasone/Cisplatin/Doxorubicin/Cyclophosphamide/Etoposide (VTD-PACE)
  • May consider monotherapy w/ Bendamustine or high-dose Cyclophosphamide in patients w/ relapse or progressive disease
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