Multiple%20myeloma Treatment

• 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 third agent once performance status improves

• 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)
  • 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 option for patients with renal insufficiency and/or peripheral neuropathy
  • Carfilzomib/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
• 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 

Other Recommended Regimens for HCT-ineligible Patients

• Carfilzomib/Lenalidomide/Dexamethasone
  • Option for primary treatment of 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
• 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
• Bortezomib/Lenalidomide combination may be given in high-risk MM eligible for transplant
• Studies have shown improved response rates with maintenance Bortezomib

Carfilzomib/Lenalidomide

• May be considered as maintenance therapy after AHCT and in high-risk MM eligible for transplant

Daratumumab with or without Lenalidomide

• May be considered as maintenance therapy after AHCT

Ixazomib

• May be considered as maintenance therapy after AHCT
• May be substituted for Carfilzomib in select patients

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

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 first course
• A second AHCT may be considered in patients who did not achieve a VGPR or better following their first 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

• 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 first 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:
  
  • 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
  • Elotuzumab/Pomalidomide/Dexamethasone
    • Indicated for patients with relapsed/refractory MM with at least 1-3 prior therapeutic regimens unresponsive to Lenalidomide therapy
  • 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
  • Selinexor/Bortezomib/Dexamethasone
    • Indicated for patients with relapsed/refractory MM with at least 1-3 prior therapeutic regimens unresponsive to Lenalidomide therapy

Other Recommended Regimens for Early Relapsed MM

• Recommended regimens combined with Dexamethasone that can be considered for MM patients with relapsed/refractory disease:
• Bendamustine/Cyclophosphamide/Dexamethasone 
• 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/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
• Daratumumab/Cyclophosphamide/Bortezomib/Dexamethasone
  • 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
• Ixazomib/Cyclophosphamide/Dexamethasone
• Ixazomib/Lenalidomide/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 with or without either liposomal Doxorubicin
  • Weekly Carfilzomib/Dexamethasone
  • Ixazomib/Pomalidomide/Dexamethasone  
  • Lenalidomide/Dexamethasone with or without Daratumumab or proteasome inhibitor only
    • 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
• Multidrug 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/Carfilzomib/Dexamethasone
  • 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

Regimens for Late Relapsed MM

• Therapies for patients with >3 prior therapies:
  • Bendamustine
  • Bendamustine/Dexamethasone with either Lenalidomide, Carfilzomib or Bortezomib
  • High-dose/fractionated Cyclophosphamide
• Regimens indicated for patients who have received ≥4 prior regimens including an anti-CD38 monoclonal antibody, a proteasome inhibitor and an IMiD:
  • CAR T-cell therapy (preferred):
    • Ciltacabtagene autoleucel
    • Idecabtagene vicleucel
  • Bispecific antibodies (preferred):
    • Elranatamab-bcmm
    • Talquetamab-tgvs
    • Teclistamab-cqyv
  • Conditional regimen: Belantamab mafodotin-blmf
• 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