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 Treatment

Principles of Therapy

  • Distinguishing active multiple myeloma from other types of multiple myeloma is imperative for proper management planning and prognosis

Smoldering (Asymptomatic) Myeloma

  • Therapeutic management is not needed but observation and routine follow-up is recommended
    • Patients with low-risk smoldering myeloma may be observed at 3- to 6-month intervals or enrolled in a clinical trial
  • Patients with high-risk smoldering multiple myeloma (with ≥2 of the following factors: >20% bone marrow plasma cells, M-protein >2 g/dL and FLCr >20) may consider joining clinical trials or started on single-agent therapy with Lenalidomide, or may be observed at 3-month intervals

Active Multiple Myeloma

  • Induction therapy followed by high-dose chemotherapy with autologous stem cell transplantation is recommended for young patients without comorbidities
  • Combination regimens with ≥3 agents is preferred over 2-drug regimens
    • Treatment with 2-drug regimens may be considered for patients ineligible for triple therapy, and may consider adding a 3rd agent once performance status improves

Pharmacotherapy

  • Induction therapy depends on patient's eligibility for stem cell transplant (SCT)
    • For SCT-eligible patients, combination of a proteasome inhibitor, an immunomodulatory drug, plus Dexamethasone is the preferred regimen prior to transplant
      • Cyclophosphamide may be considered if immunomodulatory drug is unavailable
      • Agents known to be associated with stem-cell toxicity should be avoided in SCT-eligible patients: Melphalan,>1 year Thalidomide therapy
    • For SCT-ineligible patients, combination of a proteasome inhibitor or an immunomodulatory drug, plus a steroid is preferred 
      • Studies showed improved treatment response rates, longer progression-free survival, and improved overall survival with triple therapy 

Preferred Regimens for SCT-eligible Patients

Bortezomib-based Combinations

  • 3-drug Bortezomib-based regimens Bortezomib/Lenalidomide/Dexamethasone (RVD) and Bortezomib/Cyclophosphamide/Dexamethasone (VCD) are the preferred primary therapy for SCT-eligible patients
    • Bortezomib/Lenalidomide/Dexamethasone is the preferred option for primary treatment of transplant-eligible multiple myeloma patients
    • Bortezomib/Cyclophosphamide/Dexamethasone (VCD) is the preferred option for transplant-eligible multiple myeloma patients with acute renal insufficiency
  • Herpes prophylaxis is recommended in patients receiving Bortezomib-based chemotherapeutic combinations

Other Recommended Regimens for SCT-eligible Patients

  • Carfilzomib/Lenalidomide/Dexamethasone (KRd)
    • Option for primary treatment of SCT-eligible multiple myeloma patients
  • Daratumumab/Lenalidomide/Bortezomib/Dexamethasone
    • Option for primary treatment of SCT-eligible multiple myeloma patients 
    • Daratumumab is given with Hyaluronidase-fihj when administered subcutaneously
  • Ixazomib/Lenalidomide/Dexamethasone
    • Primary regimen for patients who previously received at least 1 prior therapy, and treatment option for newly diagnosed multiple myeloma patients

Conditional Regimens for SCT-eligible Patients

  • Options for primary treatment of SCT-eligible multiple myeloma patients, but under certain circumstances:
    • Bortezomib/Doxorubicin/Dexamethasone (PAD)
    • Bortezomib/Thalidomide/Dexamethasone (VTD)
      • Showed significantly higher CR rates, near CR rates, VGPR, and overall response rate (ORR) in several studies when compared to the Bortezomib-free 2-drug regimen Thalidomide/Dexamethasone
      • Thromboprophylaxis is recommended during use
    • Cyclophosphamide/Lenalidomide/Dexamethasone
    • Daratumumab/Bortezomib/Thalidomide/Dexamethasone
      • Daratumumab is given with Hyaluronidase-fihj when administered subcutaneously
    • Daratumumab/Cyclophosphamide/Bortezomib/Dexamethasone
      • Daratumumab is given with Hyaluronidase-fihj when administered subcutaneously
  • Treatment options for patients with renal insufficiency and/or peripheral neuropathy
    • Carfilzomib/Cyclophosphamide/Dexamethasone
    • Ixazomib/Cyclophosphamide/Dexamethasone
  • Bortezomib/Dexamethasone/Thalidomide/Cisplatin/Doxorubicin/Cyclophosphamide/Etoposide (VTD-PACE)
    • Treatment option for newly diagnosed transplant-eligible multiple myeloma patients with high-risk and aggressive extramedullary disease or plasma cell leukemia

Preferred Regimens for SCT-ineligible Patients

  • 3-drug regimens are preferred due to higher response rates and recorded depth of response in various clinical studies
    • Bortezomib/Lenalidomide/Dexamethasone (VRd)
      • Studies showed significantly improved PFS and OS compared to Rd alone 
    • Bortezomib/Cyclophosphamide/Dexamethasone (VCD)
      • Preferred treatment option for SCT-ineligible multiple myeloma patients with acute renal insufficiency
      • May consider switching to 3-drug regimen Bortezomib/Lenalidomide/Dexamethasone once renal function normalizes 
    • Daratumumab/Lenalidomide/Dexamethasone
      • Daratumumab is given with Hyaluronidase-fihj when administered subcutaneously
  • 2-drug chemotherapeutic regimens should only be considered in elderly and frail patients
    • Lenalidomide/low-dose Dexamethasone (Rd)
      • Preferred option for SCT-ineligible elderly or frail multiple myeloma patients with standard-risk features
      • Thromboprophylaxis is recommended during use
      • Continuous treatment is recommended until disease progression occurs 

Other Recommended Regimens for SCT-Ineligible Patients

  • Carfilzomib/Lenalidomide/Dexamethasone
    • Option for primary treatment of newly diagnosed multiple myeloma patients not qualified for SCT 
  • Ixazomib/Lenalidomide/Dexamethasone
    • Primary treatment option for newly diagnosed multiple myeloma patients not qualified for SCT 
  • Daratumumab/Bortezomib/Melphalan/Prednisone
    • Treatment option for primary treatment of transplant-ineligible multiple myeloma patients
    • Daratumumab is given with Hyaluronidase-fihj when administered subcutaneously
  • Daratumumab/Cyclophosphamide/Bortezomib/Dexamethasone
    • Treatment option for primary treatment of transplant-ineligible multiple myeloma patients
    • Daratumumab is given with Hyaluronidase-fihj when administered subcutaneously
  • Bendamustine/Prednisone regimen may be considered for patients with suspected or confirmed neuropathy prior to initiation of MPT or VMP therapy

Conditional Regimen for SCT-ineligible Patients

  • Bortezomib/Dexamethasone (VD)
    • Primary therapeutic option for patients under certain circumstances for transplant-ineligible multiple myeloma patients 
  • Carfilzomib/Cyclophosphamide/Dexamethasone
    • Treatment option for patients with renal insufficiency and/or peripheral neuropathy
  • Cyclophosphamide/Lenalidomide/Dexamethasone
    • Therapeutic option for patients under certain circumstances for transplant-ineligible multiple myeloma patients
  • Bortezomib/Melphalan/Prednisone (VMP) and Melphalan/Prednisone/Thalidomide (MPT) are approved by the European Medicines Agency (EMA) for use in elderly patients with multiple myeloma not eligible for SCT

Maintenance Therapy

Lenalidomide

  • Recommended as maintenance therapy after autologous SCT in newly-diagnosed multiple myeloma patients
    • May also be considered as maintenance therapy in patients ineligible for SCT, but benefits should be weighed against reported adverse events (eg neutropenia, secondary malignancy) 
  • Studies showed reduced risk of disease progression or mortality, but often accompanied by grade 3-4 neutropenia
  • Further studies are needed to prove the use and safety of Lenalidomide maintenance therapy after allogeneic SCT

Bortezomib with or without Lenalidomide

  • May be considered as maintenance therapy after autologous SCT and in multiple myeloma patients who were not eligible for transplant
  • Studies have shown improved response rates with maintenance Bortezomib

Ixazomib

  • May be considered as maintenance therapy after autologous SCT

Observation and Follow-up

Smoldering (Asymptomatic) Myeloma

  • Initiation of treatment in early-stage disease is not recommended
  • Re-evaluation every 3-6 months is advised
  • Repeat complete blood count (CBC) with differential and platelet count, serum creatinine, albumin, calcium, serum quantitative immunoglobulins, SPEP, SIFE, serum FLC assay, 24-hour urine assay for total protein, UPEP, and UIFE should be conducted every follow-up if clinically indicated
  • Imaging studies (eg skeletal survey or WBLD-CT, MRI, PET-CT) is recommended annually or may be done if clinically indicated
  • Bone marrow aspirate and biopsy with FISH, SNP array, NGS panel or multiparameter flow cytometry if clinically indicated 
    • Multiparameter flow cytometry may effectively predict the risk of disease progression in patients with confirmed MGUS or smoldering myeloma

Stem Cell Transplanation

Autologous Stem Cell Transplant (ASCT)

  • Preferred management strategy for younger patients with newly diagnosed multiple myeloma, combined with chemotherapy
  • Early front-line treatment with ASCT is preferred and showed improved PFS compared to conduction of ASCT during disease relapse
  • Transplant conducted early during the course of the disease is associated with longer event-free survival rates and improved quality of life
  • Further studies are needed to compare the therapeutic effects of ASCT in multiple myeloma patients over chemotherapy

Tandem Stem Cell Transplant

  • Defined as undergoing repeat SCT with high-dose chemotherapy within 6 months after the 1st course
  • A 2nd ASCT may be considered in patients who did not achieve a VGPR or better following their 1st ASCT, with high-risk features and during disease relapse

Allogeneic Stem Cell Transplant (Allo-SCT)

  • Includes myeloablative and nonmyeloablative transplant
    • Myeloablative allo-SCT may be considered in multiple myeloma patients whose disease is responsive to primary therapy, with primary disease progression, or those with disease progression after initial ASCT
    • Nonmyeloablative is preferred over myeloablative allo-SCT due to the lesser adverse effects from the high-dose chemotherapeutic regimen
    • Avoids the contamination of re-infused autologous tumor cells and associated with reduced disease relapse brought about by its graft-versus-myeloma effect
  • Limited by scarcity of compatible donors and increased morbidity
  • Not recommended for patients with newly diagnosed disease outside of a clinical trial, with the exception of young patients with high-risk prognostic factors
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