multiple%20myeloma
MULTIPLE MYELOMA
Treatment Guideline Chart

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 hematopoietic cell transplantation (AHCT) is recommended for young patients without comorbidities
    • High-dose Melphalan is the standard conditioning regimen prior to autologous stem cell transplantation (ASCT)
  • 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 hematopoietic cell transplant (HCT)
    • For HCT-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 HCT-eligible patients: Melphalan,>1 year Thalidomide therapy
    • For HCT-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 HCT-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 HCT-eligible patients
    • RVD is the preferred option for primary treatment of transplant-eligible multiple myeloma (MM) patients
    • VCD is the preferred option for transplant-eligible MM patients with acute renal insufficiency
  • Herpes prophylaxis is recommended in patients receiving Bortezomib-based chemotherapeutic combinations

Other Recommended Regimens for HCT-eligible Patients

  • Carfilzomib/Lenalidomide/Dexamethasone (KRd)
    • Option for primary treatment of HCT-eligible MM patients
  • Daratumumab/Lenalidomide/Bortezomib/Dexamethasone
    • Option for primary treatment of HCT-eligible MM 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 MM patients

Conditional Regimens for HCT-eligible Patients

  • Options for primary treatment of HCT-eligible MM patients, but under certain circumstances:
    • Bortezomib/Cyclophosphamide/Dexamethasone (VCD)
      • Preferred treatment option for MM patients with acute renal insufficiency
      • May consider switching to 3-drug regimen Bortezomib/Lenalidomide/Dexamethasone once renal function improves 
    • 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/Carfilzomib/Lenalidomide/Dexamethasone
      • Reserved for patients with aggressive MM
      • 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 MM patients with high-risk and aggressive extramedullary disease or plasma cell leukemia

Preferred Regimens for HCT-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 
    • Daratumumab/Lenalidomide/Dexamethasone
      • Daratumumab is given with Hyaluronidase-fihj when administered subcutaneously

Other Recommended Regimens for HCT-ineligible Patients

  • Carfilzomib/Lenalidomide/Dexamethasone
    • Option for primary treatment of newly diagnosed MM patients not qualified for HCT 
  • Ixazomib/Lenalidomide/Dexamethasone
    • Primary treatment option for newly diagnosed MM patients not qualified for HCT 
  • Daratumumab/Bortezomib/Melphalan/Prednisone
    • Treatment option for primary treatment of transplant-ineligible MM patients
    • Daratumumab is given with Hyaluronidase-fihj when administered subcutaneously
  • Daratumumab/Cyclophosphamide/Bortezomib/Dexamethasone
    • Treatment option for primary treatment of transplant-ineligible MM patients
    • Daratumumab is given with Hyaluronidase-fihj when administered subcutaneously

Conditional Regimen for HCT-ineligible Patients

  • Bortezomib/Cyclophosphamide/Dexamethasone (VCD)
    • Preferred treatment option for HCT-ineligible MM patients with acute renal insufficiency
    • Consider switching to 3-drug regimen Bortezomib/Lenalidomide/Dexamethasone once renal function improves 
  • Bortezomib/Dexamethasone (VD)
    • Primary therapeutic option for patients under certain circumstances for transplant-ineligible MM patients 
  • Bortezomib/Lenalidomide/Dexamethasone (VRD-lite)
    • Treatment option for HCT-ineligible frail MM patients
  • Bendamustine/Prednisone regimen may be considered for patients with suspected or confirmed neuropathy prior to initiation of Bortezomib/Melphalan/Prednisone (VMP) or Melphalan/Prednisone/Thalidomide (MPT) therapy 
  • 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 MM patients
  • Lenalidomide/low-dose Dexamethasone (Rd)
    • Preferred option for HCT-ineligible elderly or frail MM patients with standard-risk features
    • Thromboprophylaxis is recommended during use
    • Continuous treatment is recommended until disease progression occurs 
  • VMP and MPT are approved by the European Medicines Agency (EMA) for use in elderly patients with MM not eligible for HCT

Maintenance Therapy

Lenalidomide

  • Recommended as maintenance therapy after autologous HCT (AHCT) in newly-diagnosed MM patients
    • May also be considered as maintenance therapy in patients ineligible for HCT, 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 HCT

Bortezomib with or without Lenalidomide

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

Ixazomib

  • May be considered as maintenance therapy after AHCT

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 as needed
  • Bone marrow aspirate and biopsy with FISH, SNP array, NGS panel or multiparameter flow cytometry as needed 
    • Multiparameter flow cytometry may effectively predict the risk of disease progression in patients with confirmed MGUS or smoldering myeloma

Hematopoietic Cell Transplantation (HCT)

Autologous Hematopoietic Cell Transplant (AHCT)

  • Preferred management strategy for younger patients with newly diagnosed multiple myeloma, combined with chemotherapy
  • Early front-line treatment with AHCT is preferred and showed improved PFS compared to conduction of AHCT 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 AHCT in multiple myeloma patients over chemotherapy

Tandem Autologous Hematopoietic Cell Transplant

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

Allogeneic Hematopoietic Cell Transplant (Allo-HCT)

  • Includes myeloablative and nonmyeloablative transplant
    • Myeloablative allo-HCT 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 AHCT
    • Nonmyeloablative is preferred over myeloablative allo-HCT 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

Relapsed/Progressive Multiple Myeloma

  • Disease relapse in multiple myeloma (MM) 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 HCT, patients with primary progressive disease after HCT, and patients ineligible for HCT with relapsed/progressive MM after initial primary treatment
  • Patients post-AHCT may opt to receive another AHCT if response to previous AHCT was positive and disease progression-free for ≥18-24 months
    • May consider nonmyeloablative allo-HCT 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 AHCTs, 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 for Early Relapsed MM

  • 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 early relapsed/refractory MM include:
    • Bortezomib/Lenalidomide/Dexamethasone
      • Studies showed that this combination was well-tolerated even by patients who received continuous high-dose treatments and HCT
      • May be given with or without pegylated Doxorubicin
    • Carfilzomib/Lenalidomide/Dexamethasone (KRd)
      • May be used in MM patients previously given at least 1 prior therapeutic regimen
    • Daratumumab/Bortezomib/Dexamethasone (DVd)
      • Preferred option for adults with relapsed/refractory MM 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 MM with at least 1-3 prior therapeutic regimens
      • Daratumumab is given with Hyaluronidase-fihj when administered subcutaneously
    • Daratumumab/Pomalidomide/Dexamethasone (DPd)
      • Treatment option for MM patients previously treated with at least 2 regimens which include Lenalidomide and a proteasome inhibitor
      • Daratumumab is given with Hyaluronidase-fihj when administered subcutaneously
    • Isatuximab-irfc/Carfilzomib/Dexamethasone
      • Preferred treatment option for MM patients previously treated with at least 1 prior regimen 
    • Isatuximab-irfc/Pomalidomide/Dexamethasone
      • Indicated for patients with relapsed/refractory MM who received ≥2 prior regimens including Lenalidomide and a protease inhibitor
    • Ixazomib/Pomalidomide/Dexamethasone
      • Indicated for MM 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 MM 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:
      • Include 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 for Early Relapsed MM

  • Recommended regimens combined with Dexamethasone that can be considered for MM 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 MM patients previously given at least 1 prior therapeutic regimen
    • Cyclophosphamide/Lenalidomide/Dexamethasone 
    • 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 MM patients previously treated with at least 2 regimens which include Lenalidomide and a proteasome inhibitor 
    • Ixazomib/Cyclophosphamide/Dexamethasone
    • Panobinostat/Bortezomib/Dexamethasone (VD-Pano)
      • Approved for patients with relapsed/refractory MM with history of at least 2 prior therapies including IMiD- and Bortezomib-containing treatments
    • Selinexor/Bortezomib/Dexamethasone
  • Pomalidomide/Dexamethasone with either Carfilzomib, or Cyclophosphamide are treatment options for MM 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 for Early Relapsed MM

  • Regimens combined with Dexamethasone that can be considered for MM patients with relapsed/refractory disease:
    • Bortezomib/Dexamethasone
    • Weekly Carfilzomib/Dexamethasone
    • Ixazomib/Dexamethasone
      • Treatment option for MM patients with history of at least 1 prior therapy
    • Lenalidomide/Dexamethasone
      • Treatment option for MM patients with history of at least 1 prior therapy
    • Pomalidomide/Dexamethasone
      • Treatment option for MM 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 
    • Venetoclax/Dexamethasone
      • Indicated for patients with relapsed/refractory MM with t(11;14) translocation
  • 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)
    • Dexamethasone/Thalidomide/Cisplatin/Doxorubicin/Cyclophosphamide/Etoposide (DT-PACE) with or without Bortezomib (VTD-PACE)
    • Selinexor/Daratumumab/Dexamethasone
    • Selinexor/Pomalidomide/Dexamethasone
      • Treatment option for MM 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
  • 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/fractionated Cyclophosphamide in patients with relapse or progressive disease
  • Lenalidomide or Pomalidomide monotherapy: For steroid-intolerant patients 
  • Panobinostat-based regimen (Panobinostat/Lenalidomide/Dexamethasone, Panobinostat/Carfilzomib) are approved for patients with relapsed/refractory MM with history of at least 2 prior therapies including IMiD- and Bortezomib-containing treatments

Regimens for Late Relapsed MM

  • Regimens indicated for patients who have received ≥4 prior regimens including an anti-CD38 monoclonal antibody, a proteasome inhibitor and an IMiD:
    • Belantamab mafodotin-blmf
    • Idecabtagene vicleucel
    • Melphalan flufenamide/Dexamethasone
  • 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
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