Multiple Myeloma Management

Evaluation

Definition of Monoclonal Gammopathy of Undetermined Significance (MGUS)  

Non-IgM monoclonal gammopathy of undetermined significance is defined as a serum monoclonal protein <3 g/dL, clonal BMPCs <10%, and the absence of CRAB criteria or amyloidosis attributable to plasma cell proliferative disorder.  

IgM monoclonal gammopathy of undetermined significance is defined as a serum monoclonal protein <3 g/dL, <10% bone marrow lymphoplasmacytic infiltration and absence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, hepatosplenomegaly, or other end-organ damage attributable to plasma cell proliferative disorder.  

Light-chain monoclonal gammopathy of undetermined significance is defined as an increased κ FLC ratio of >1.65 and increased λ FLC ratio of <0.26, Ig heavy chain expression absent on immunofixation, absence of CRAB criteria or amyloidosis attributable to plasma cell proliferative disorder, clonal BMPCs <10%, and urinary monoclonal protein <500 mg/24 hours.  

Staging Systems  

International Staging System (ISS)  

ISS is a risk stratification algorithm based on serum beta-2 microglobulin level and serum albumin. It is the preferred and most widely used staging system for the determination of prognosis in patients with multiple myeloma.  

The revised ISS (R-ISS) includes the parameters for ISS plus results from serum lactate dehydrogenase (LDH) and FISH measurements. This newer staging system can effectively predict the progression-free survival (PFS) and overall survival (OS) rates in multiple myeloma patients. The R2-ISS classification utilizes a numerical value that is assigned to each risk factor based on their influence on OS.

Reference: National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: multiple myeloma. Version 2.2027. Sep 2026. 
*Standard-risk findings by FISH defined as the absence of any high-risk chromosomal abnormality
**High-risk findings by FISH include the presence of del(17p) and/or translocation t(4;14) and/or translocation t(14;16)  

International Myeloma Society (IMS)-International Myeloma Working Group (IMWG) High-Risk Factors for Multiple Myeloma

• Del(17p) (>20% of plasma cells) and/or TP53 mutation
• Translocations t(4;14), t(14;16) or t(14;20) co-occurring with 1q+ and/or del(1p32)
• Monoallelic del(1p32) along with 1q+ or biallelic del(1p32)
• High beta-2 microglobulin (>5.5 mg/L) with normal creatinine (<1.2 mg/dL)

High-risk factors for newly diagnosed multiple myeloma patients include: 

• R-ISS III
• Extramedullary disease
• Circulating plasma cells
• Cytogenetic abnormalities: del(1p32), t(4;14), t(14;16), t(14;20), del(17p), monosomy 17, TP53 mutation, 1q21 gain or 1q21 amplification, MYC translocation
• High-risk gene expression profile
• Markers of high proliferation rate

High-risk factors for relapsed multiple myeloma:

• Presence of disease relapse within 2 years after initial therapy in patients using transplant and maintenance therapy
• Relapse within 18 months in patients undergoing nontransplant-based treatment
• Acquisition of 1q gain or amplification and/or del(17p) or TP53 mutation
• Extramedullary disease at relapse and/or circulating plasma cells

Principles of Therapy

Distinguishing active multiple myeloma from other types of multiple myeloma is imperative for proper management planning and prognosis. The patient’s preferences and goals of care through a shared decision-making process should be taken into great consideration at all stages of treatment. Frailty assessment tools (eg Myeloma Frailty Calculator developed by the IMWG) should be used to guide regimen intensity especially in elderly and non-transplant patients.

Smoldering (Asymptomatic) Multiple Myeloma

Therapeutic management depends on risk; however, 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% BMPCs, M-protein >2 g/dL and FLCr >20) may consider joining clinical trials or may be 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 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 ≥4 agents are preferred over 2- or 3-drug regimens. Treatment with 2-drug regimens may be considered for patients ineligible for triple therapy (eg poor performance status, frail, elderly) and may consider adding a third agent once performance status improves. Dose modifications should be considered based on functional status and age. It must be noted that patients with CNS involvement should be managed using multimodality therapy (eg radiation therapy, intrathecal chemotherapy, systemic therapy). Supportive care is recommended for symptom management and referral to a palliative care specialist should be considered. 

Relapsed or Progressive or Refractory Multiple Myeloma

Disease relapse in multiple myeloma is a common occurrence and therapy is recommended. The choice of therapeutic regimen depends on the 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 hematopoietic cell transplantation, patients with primary progressive disease after hematopoietic cell transplantation, and patients ineligible for hematopoietic cell transplantation with relapsed or refractory or progressive multiple myeloma after initial primary treatment. 

Patients post-autologous hematopoietic cell transplantation may opt to receive another autologous hematopoietic cell transplantation if the response to the previous autologous hematopoietic cell transplantation was positive and disease progression-free for ≥18-24 months. Nonmyeloablative allo- hematopoietic cell transplantation may be considered in select patients (ie young patients with high-risk myeloma with short response duration), but advantages must be weighed against treatment-related morbidity.  

If feasible, refer all patients to a T-cell therapy-capable center at first relapse. T-cell redirecting therapy (eg Teclistamab +/- Daratumumab, Ciltacabtagene autoleucel) is a preferred option after 1-3 prior lines. Discuss patient preferences and goals of care at each reassessment and refer to palliative care for symptom management.

Triplet therapy, which includes 2 novel agents (PI, IMiD, monoclonal antibody) plus a steroid, is recommended to be given on the first clinical relapse of a fit patient once confirmed, with consideration to the patient's prior therapies. Drug or drug classes which the patient has not been exposed to or not exposed within 6 months should be included. Triplet therapy, followed by 1-2 autologous hematopoietic cell transplantation, then a PI-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 a history of drug toxicity and other comorbidities. Triplet therapy may be started once with an improvement in performance status. Patients with disease refractory to the novel drug in the doublet backbone should be considered for triplet therapy which does not contain the drug the patient is progressing on.   

The use of chemotherapeutic agents and enrollment into a clinical trial should be considered in patients with repeating disease relapse. 

Pharmacological therapy

Induction therapy depends on the patient's eligibility for hematopoietic cell transplantation. A quadruplet regimen is now preferred; based on functional status, patients may start a 2- or 3-drug regimen with drugs added as performance status improves. Cyclophosphamide may be considered if an IMiD is unavailable. Limit exposure to myelotoxic agents (eg alkylating agents, nitrosoureas) prior to harvest. Harvesting within the first 6 cycles before prolonged Lenalidomide and/or Daratumumab exposure is considered; collect enough for two transplants, and strongly consider collecting and storing if hematopoietic cell transplant is deferred.

For hematopoietic cell transplantation-ineligible patients, a combination of a PI or an IMiD, plus a steroid is preferred. Studies showed improved treatment response rates, longer PFS, and improved OS with triple therapy. It must be noted that renal dysfunction and advanced age are not contraindicated to transplant.

Subcutaneous (SC) is the preferred method of administration of Bortezomib. This results in a significant reduction in peripheral neuropathy. Weekly dosing of Bortezomib is preferred over twice-weekly dosing.
 

Preferred Regimen for Hematopoietic Cell Transplantation-Eligible Patients  
 
Bortezomib/Lenalidomide/Dexamethasone (VRD) plus Daratumumab¹ is the preferred primary therapy for hematopoietic cell transplantation-eligible multiple myeloma patients. Bortezomib/Lenalidomide/Dexamethasone (VRD) plus Isatuximab-irfc is also a preferred primary therapy for hematopoietic cell transplantation-eligible patients. 

Other Recommended Regimens for Hematopoietic Cell Transplantation-Eligible Patients  

• Carfilzomib/Lenalidomide/Dexamethasone plus Daratumumab¹
• Carfilzomib/Lenalidomide/Dexamethasone plus Isatuximab-irfc

Conditional Regimens for Hematopoietic Cell Transplantation-Eligible Patients  

Other options for primary treatment of hematopoietic cell transplantation-eligible multiple myeloma patients, but under certain circumstances include the following:

• Bortezomib/Cyclophosphamide/Dexamethasone (VCD)
  • Preferred initial treatment option for multiple myeloma patients with acute renal insufficiency
  • May consider switching to a 3-drug regimen Bortezomib/Lenalidomide/Dexamethasone (VRD) once renal function improves
  • May be an option for patients without access to Bortezomib/Lenalidomide/Dexamethasone (VRD) regimen
• Bortezomib/Cyclophosphamide/Dexamethasone plus Daratumumab¹
• Bortezomib/Cyclophosphamide/Lenalidomide/Dexamethasone plus Daratumumab¹
• Bortezomib/Lenalidomide/Dexamethasone (VRD)
  
  • Herpes prophylaxis is recommended in patients receiving Bortezomib-based chemotherapeutic combinations
• Carfilzomib/Cyclophosphamide/Dexamethasone
  
  • Treatment option for patients with renal insufficiency and/or peripheral neuropathy
  • May be an option for patients without access to Carfilzomib/Lenalidomide/Dexamethasone regimen
• Carfilzomib/Lenalidomide/Dexamethasone (KRd)
  • Carfilzomib may be substituted with Ixazomib in select patients
• Dexamethasone/Thalidomide/Cisplatin/Doxorubicin/Cyclophosphamide/Etoposide/Bortezomib (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 Hematopoietic Cell Transplantation-Ineligible Patients  

A quadruplet regimen is now preferred; based on functional status, patients may start a 2- or 3-drug regimen with drugs added as performance status improves. Bortezomib/Lenalidomide/Dexamethasone (VRD) plus Daratumumab¹ is for patients <80 years old who are not frail. Bortezomib/Lenalidomide/Dexamethasone (VRD) plus Isatuximab-irfc is preferred for patients <80 years old who are not frail. Lenalidomide/Dexamethasone plus Daratumumab1 combination may also be used in hematopoietic cell transplantation-ineligible patients.

Other Recommended Regimens for Hematopoietic Cell Transplantation-Ineligible Patients  

Studies showed that Bortezomib/Lenalidomide/Dexamethasone (VRD) significantly improved PFS and OS compared to Rd alone. Carfilzomib/Lenalidomide/Dexamethasone is an option for primary treatment of newly diagnosed multiple myeloma patients not qualified for hematopoietic cell transplantation. Lenalidomide/Dexamethasone plus Isatuximab-irfc is also recommended.

Conditional Regimens for Hematopoietic Cell Transplantation-Ineligible Patients  

Bortezomib/Cyclophosphamide/Dexamethasone (VCD) is a treatment option for patients with renal insufficiency and/or peripheral neuropathy. Consider switching to a 3-drug regimen Bortezomib/Lenalidomide/Dexamethasone (VRD) once renal function improves. It is also a treatment option for patients without access to a PI in combination with Lenalidomide/Dexamethasone. 

Bortezomib/Cyclophosphamide/Dexamethasone plus Daratumumab¹ is a treatment option for the primary treatment of transplant-ineligible multiple myeloma patients with renal insufficiency.

Bortezomib/Dexamethasone (VD) is a primary therapeutic option for patients under certain circumstances for transplant-ineligible multiple myeloma patients. Bortezomib/Lenalidomide/Dexamethasone (VRD-lite) is a treatment option for hematopoietic cell transplantation-ineligible frail multiple myeloma patients.  

Carfilzomib/Cyclophosphamide/Dexamethasone is a treatment option for hematopoietic cell transplantation-ineligible multiple myeloma patients with acute renal insufficiency and/or peripheral neuropathy. Consider switching to a 3-drug regimen Carfilzomib/Lenalidomide/Dexamethasone once renal function improves. This regimen  is a treatment option for patients with renal insufficiency and/or peripheral neuropathy. It is also a treatment option for patients without access to a PI in combination with Lenalidomide/Dexamethasone.

Carfilzomib/Lenalidomide/Dexamethasone plus Isatuximab-irfc is a therapeutic option for patients under certain circumstances for transplant-ineligible multiple myeloma patients. Ixazomib/Lenalidomide/Dexamethasone is also recommended. Lenalidomide/Cyclophosphamide/Dexamethasone is a therapeutic option for patients under certain circumstances for transplant-ineligible multiple myeloma patients. 

Lenalidomide/low-dose Dexamethasone (Rd) is a preferred option for hematopoietic cell transplantation-ineligible elderly or frail multiple myeloma patients with standard-risk features; thromboprophylaxis is recommended during use. Continuous treatment is recommended until disease progression occurs.  

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 hematopoietic cell transplantation.  

¹Daratumumab is given with Hyaluronidase-fihj when administered subcutaneously.  

Maintenance Therapy  

Lenalidomide  

Lenalidomide is recommended as maintenance therapy after autologous hematopoietic cell transplantation in newly-diagnosed multiple myeloma patients. It may also be considered as maintenance therapy in patients ineligible for hematopoietic cell transplantation, but benefits should be weighed against reported adverse events (eg neutropenia, secondary malignancy).  

Studies showed a 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 hematopoietic cell transplantation.  

Bortezomib with or without Lenalidomide  

Bortezomib with or without Lenalidomide may be considered as maintenance therapy after autologous hematopoietic cell transplantation. Bortezomib/Lenalidomide combination may be given in high-risk multiple myeloma patients who are eligible for transplant. Studies have shown that maintenance therapy with Bortezomib improved response rates.  

Carfilzomib/Lenalidomide  

Carfilzomib/Lenalidomide may be considered as maintenance therapy after autologous hematopoietic cell transplantation and in high-risk multiple myeloma patients eligible for transplant.  

Daratumumab  

Daratumumab may be considered as maintenance therapy after autologous hematopoietic cell transplantation.

Daratumumab/Lenalidomide  

Daratumumab/Lenalidomide may be considered as maintenance therapy after autologous hematopoietic cell transplantation and recommended for high-risk multiple myeloma patients eligible for transplant. 

Ixazomib  

Ixazomib may be considered as maintenance therapy after autologous hematopoietic cell transplantation. It may also be substituted for Carfilzomib in select patients. 

Smoldering (Asymptomatic) Multiple Myeloma  

Select patients at high risk may be given Daratumumab or Lenalidomide. 

Multiple Myeloma with CNS Disease  

Regimes below may be used as part of multimodal therapy.  

Intrathecal Chemotherapy  

Intrathecal chemotherapy includes Methotrexate, Thiotepa/Hydrocortisone, and Methotrexate/Cytarabine/Hydrocortisone. They are considered part of multimodal therapy. Concurrent intrathecal Methotrexate and radiotherapy increases myelopathy risk and therefore should be spaced >2 weeks. 

Systemic Chemotherapy  

Systemic chemotherapy used for multiple myeloma with CNS disease include Bendamustine, Cytarabine, and high-dose Methotrexate. They are used as part of multimodal therapy and can be considered in combination with IMiD if there are no alternatives.  

Novel Agents  

Novel agents that can be used in multiple myeloma patients with CNS disease include IMiD (eg Lenalidomide, Pomalidomide), and immunotherapy (eg CAR T-cell therapy, bispecific antibody engager therapy). Incorporation of IMiD into multiple myeloma management has shown improved outcomes in retrospective studies. Additionally, immunotherapy may be used as consolidative therapy to treat extra-CNS disease in patients receiving multimodality CNS-directed therapy. Monoclonal antibody therapy may also be considered in patients who can tolerate systemic therapy. Other novel agents that can be considered include proteosome inhibitors, Selinexor, and Venetoclax. However, it must be noted that proteosome inhibitors possess limited penetrative properties of the blood-brain barrier. Selinexor can penetrate the blood-brain barrier, but further studies are needed. Lastly, Venetoclax is used as a last-line option in patients with t(11;14) mutation if no other options are available.

Relapsed or Progressive or Refractory Multiple Myeloma After 1-3 Previous Therapies  

Preferred Regimens

Repeat administration of primary induction regimens may be considered if relapse occurs >6 months after completion of initial therapy.  

Preferred regimens for anti-CD38-refractory multiple myeloma include:

• Carfilzomib/Lenalidomide/Dexamethasone (KRd)
• Carfilzomib/Pomalidomide/Dexamethasone (KPd)

Preferred regimens Bortezomib-refractory multiple myeloma include:

• Carfilzomib/Dexamethasone plus Isatuximab-irfc
• Carfilzomib/Dexamethasone (DKd) plus Daratumumab¹
• Carfilzomib/Lenalidomide/Dexamethasone (KRd)
• Carfilzomib/Pomalidomide/Dexamethasone
• Lenalidomide/Dexamethasone plus Daratumumab¹
• Lenalidomide/Dexamethasone plus isatuximab-irfc
• Pomalidomide/Dexamethasone (DPd) plus Daratumumab¹: Treatment option for multiple myeloma patients previously treated with at least 2 regimens which include Lenalidomide and a PI
• Pomalidomide/Dexamethasone plus Isatuximab-irfc: Indicated for patients with relapsed or refractory multiple myeloma who received ≥2 prior regimens including Lenalidomide and a PI

Preferred regimens for Lenalidomide-refractory multiple myeloma:

• Bortezomib/Dexamethasone plus Belantamab mafodotin
• Carfilzomib/Pomalidomide/Dexamethasone
• Bortezomib/Dexamethasone (DVd) plus Daratumumab¹
• Carfilzomib/Dexamethasone (DKd) plus Daratumumab¹
• Pomalidomide/Dexamethasone plus Daratumumab¹: Treatment option of patients with relapsed or refractory multiple myeloma after 1 previous therapy including Lenalidomide and a PI
• Carfilzomib/Dexamethasone plus Isatuximab-irfc
• Pomalidomide/Dexamethasone plus Isatuximab-irfc: Treatment option for patients with relapsed or refractory multiple myeloma after 2 previous therapies including Lenalidomide and a PI
  
  

Other preferred regimens for refractory or relapsed multiple myeloma involve the use of CAR T-cell therapy including:

• Anti-B-cell maturation antigen (BCMA) therapy
  • Teclistamab-cqyv ± Daratumab
• Chimeric antigen receptor (CAR) T-cell therapy
  • Ciltacabtagene autoleucel: Treatment option for patients after 1 previous therapy including IMiD and a PI refractory to Lenalidomide

Multiple Myeloma_Management

• Belantamab mafodotin-blmf/Bortezomib/Dexamethasone: Treatment option for patients after 2 previous therapies including an IMiD and a PI
• Bortezomib/Cyclophosphamide/Dexamethasone (VCd)
• Bortezomib/Cyclophosphamide/Dexamethasone plus Daratumumab
• Bortezomib/Dexamethasone plus Elotuzumab
• Bortezomib/Lenalidomide/Dexamethasone (VRD)
  • Studies showed that this combination was well-tolerated even by patients who received continuous high-dose treatments and hematopoietic cell transplantation
  • May be given with or without pegylated Doxorubicin
• Bortezomib/Pomalidomide/Dexamethasone
• Bortezomib/Selinexor/Dexamethasone
• Carfilzomib/Cyclophosphamide/Dexamethasone
• Carfilzomib/Pomalidomide/Dexamethasone plus Daratumumab
• Cyclophosphamide/Lenalidomide/Dexamethasone
• Daratumumab plus Talquetamab-tgvs/Dexamethasone
• Iberdomide/Dexamethasone plus Daratumumab
• Idecabtagene vicleucel
• Ixazomib/Cyclophosphamide/Dexamethasone
• Ixazomib/Lenalidomide/Dexamethasone
• Ixazomib/Pomalidomide/Dexamethasone
• Lenalidomide/Dexamethasone plus Elotuzumab
• Pomalidomide/Dexamethasone plus Daratumumab plus Talquetamab-tgvs
• Pomalidomide/Dexamethasone plus Elotuzumab

Pomalidomide/Dexamethasone with Cyclophosphamide is a treatment option for multiple myeloma patients previously treated with at least 2 regimens which include an IMiD and a PI 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 or refractory disease include the following:

• Bortezomib/Dexamethasone with or without liposomal Doxorubicin
• Carfilzomib/Dexamethasone
• Carfilzomib/Cyclophosphamide/Thalidomide/Dexamethasone
• Carfilzomib/Selinexor/Dexamethasone
• Dexamethasone/Cyclophosphamide/Etoposide/Cisplatin (DCEP): Treatment option for aggressive multiple myeloma
• Dexamethasone/Thalidomide/Cisplatin/Doxorubicin/Cyclophosphamide/Etoposide (DT-PACE) with or without Bortezomib (VTD-PACE): Treatment option for aggressive multiple myeloma
• Lenalidomide/Dexamethasone  
• Pomalidomide/Dexamethasone: A treatment option for multiple myeloma patients previously treated with at least 2 regimens which include an IMiD and a PI, with disease progression on or within 60 days after completion of the last therapy
• Pomalidomide/Dexamethasone plus Belantamab mafoditin-blmf
• Pomalidomide/Selinexor/Dexamethasone: A treatment option for multiple myeloma patients previously treated with at least 2 regimens which include an IMiD and a PI, with disease progression on or within 60 days after completion of the last therapy
• Selinexor/Dexamethasone plus Daratumumab
• Talquetamab-tgvs plus Teclistamab-cqyv: Treatment option for aggressive multiple myeloma
• Venetoclax/Dexamethasone with or without Daratumumab or PI only: Indicated for patients with relapsed or refractory multiple myeloma with t(11;14) translocation 

Monotherapy with Daratumumab¹ may be considered for multiple myeloma patients with at least 3 previously taken anti-cancer regimens which include a PI and an IMiD agent, or who are double refractory to a PI and an IMiD agent. Lenalidomide or Pomalidomide monotherapy may be given to steroid-intolerant patients.  

Relapsed or Refractory Multiple Myeloma After ≥3 Previous Therapies

Preferred Regimens  

The therapies for patients with more than 3 prior therapies include CAR T-cell therapy (preferred) (eg Ciltacabtagene autoleucel, Idecabtagene vicleucel).

The regimens indicated for patients who have received ≥4 prior regimens including an anti-CD38 monoclonal antibody, a PI and an IMiD include:

• Bispecific antibodies (preferred):
  • BCMA-targeted therapy: Elranatamab-bcmm, Linvoseltamab-gcpt, Teclistamab-cqyv
  • GPRC5D-Targeted therapy: Talquetamab-tgvs  

Conditional Regimens  

Conditional regimens that can be used for relapsed or refractory multiple myeloma after 3 previous therapies include Belantamab mafodotin-blmf, Bendamustine, and Bendamustine/Dexamethasone with either Lenalidomide, Carfilzomib or Bortezomib. Talquetamab-tgvs plus Teclistamab-cqyv may be an option in certain circumstances such as in patients previously treated with 3 regimens.

Other conditial regimens include Bortezomib/Liposomal Doxorubicin/Dexamethasone, Daratumumab plus Talquetamab-tgvs, high-dose or fractionated Cyclophosphamide, Pomalidomide plus Talquetamab-tgvs, Selinexor/Dexamethasone, Talquetamab-tgvs plus Teclistamab-cqyv, and Venetoclax/Dexamethasone with or without Daratumumab or PI only (for t[11;14] patients only)

Regimens After BCMA Therapy  

Regimens after BCMA therapy include T-cell redirecting therapies (Talquetamab-tgvs, Talquetamab-tgvs plus Teclistamab-cgyv, Teclistamab-cqyv, and second BCMA CAR-T therapy) and standard chemotherapy (Bortezomib/Selinexor/Dexamethasone, Belantamab-containing combinations, Carfilzomib-containing regimens, Venetoclax/Dexamethasone with or without Daratumumab or PI only (for t[11;14] patients only).

¹Daratumumab is given with Hyaluronidase-fihj when administered subcutaneously.      

Palliative Therapy  

Palliative therapy should be considered for all patients, regardless if the patient is eligible for hematopoietic cell transplantation or not.  

Bone Disease

Give bone-targeting therapy to all patients receiving primary myeloma therapy (eg bisphosphonate category 1 or Denosumab), for up to 2 years. MGUS and osteoporosis should follow osteoporosis-dose regimens. Pamidronate and Zoledronic acid are recommended for patients with bone disease secondary to multiple myeloma (eg osteopenia, osteolytic lesions). Denosumab may be considered as an alternative to bisphosphonates for the prevention of bone disease in multiple myeloma and is preferred in patients with renal disease. Dental clearance should be obtained prior to initiation of bisphosphonate therapy. Assessment of vitamin D status is also essential. Monitoring of renal function and symptoms of osteonecrosis of the jaw is recommended during bisphosphonate therapy.  

Patients with intolerable pain due to pathologic fracture or cord compression may opt to undergo low-dose radiation therapy (8 Gy x 1 fraction or 20-30 Gy in 5-15 total fractions). For patients with severe symptoms, moderately fractionated courses (20-25 Gy in 8-10 fractions) are preferred over higher doses (30 Gy) for lesser adverse effects. Surgical management via kyphoplasty or vertebroplasty may also be considered for symptomatic vertebral compression fractures. 

Anemia or Granulocytopenia  

Decreased Hgb levels of <10 g/dL may be treated with recombinant human erythropoietin and Darbepoietin alfa. Red blood cell transfusion may also be considered in patients with an abrupt need for increased Hgb levels. Patients who develop severe granulocytopenia after chemotherapy may be considered for granulocyte-stimulating factor (G-CSF) therapy.  

Hypercalcemia  

Adequate hydration, bisphosphonates (eg Zoledronic acid, Pamidronate, Ibandronate), Denosumab, corticosteroids, and/or Calcitonin may be given to patients with increased bone resorption secondary to bone disease in multiple myeloma.  

Venous Thromboembolism (VTE)  

Hyperviscosity and hypercoagulability due to multiple myeloma may lead to increased risk for thrombosis formation which is highest within the first 6 months after new diagnosis of multiple myeloma. Multiple myeloma patients are at increased risk for thrombotic events especially during chemotherapy with Doxorubicin and IMiDs (eg Lenalidomide, Pomalidomide, Thalidomide) with Dexamethasone. 

The IMPEDE (IMiD, body mass index [BMI], pathologic fracture, erythropoiesis-stimulating agent [ESA], Dexamethasone/Doxorubicin, ethnicity) score or the SAVED (surgery within 90 days, Asian race, VTE history, age ≥80, Dexamethasone) score may be used for risk stratification. 

Individual risk factors with assigned scores under the IMPEDE scoring include:

Multiple myeloma risk factors with assigned scores under the IMPEDE scoring include:

Negative risk factors under the IMPEDE scoring include:

SAVED score variable with assigned points include:

Aspirin is recommended for patients with low risk for venous thromboembolism (IMPEDE score ≤3 points or SAVED score <2 points). Apixaban, Fondaparinux, LMWH, Rivaroxaban or Warfarin is recommended for patients at increased risk for thrombosis (IMPEDE score ≥4 points or SAVED score of ≥2 points). Plasmapheresis may be used as adjunctive therapy for symptomatic hyperviscosity. Duration of the VTE prophylaxis is indefinite while on multiple myeloma therapy or 3-6 months followed by Aspirin.

Renal Impairment  

Pulse Dexamethasone, Bortezomib-based regimens (eg Bortezomib plus Dexamethasone with or without Thalidomide, Doxorubicin, or Cyclophosphamide) and/or Daratumumab are recommended for patients with renal failure; may switch to other regimens once the renal function has stabilized or improved.  

Infection or Reactivation  

The prevention of infectious complications by administration of intravenous immunoglobulin (IVIg), anti-infective prophylaxis, and vaccinations are recommended. Vaccination for influenza, SARS-CoV-2, respiratory syncytial virus, and Streptococcus pneumoniae is recommended. Consider 2 doses of high-dose inactivated quadrivalent influenza vaccine. Revaccination with pneumococcal vaccine after CAR-T therapy or autologous hematopoietic cell transplantation may be done 3-6 months after treatment. Vaccination status should be checked prior to initiation bispecific antibody T-cell engager therapy. 

IVIg replacement therapy may be considered for patients with recurrent, severe infection despite prophylactic antibiotic therapy and/or hypogammaglobulinemia (IgG <400 mg/dL). IVIg with CAR-T and bispecific antibodies irrespective of IgG level are started. Prophylaxis against Pneumocystis jirovecii pneumonia (PJP) should be considered in patients being given steroids. Patients being treated with PI, especially Bortezomib, Carfilzomib, Isatuximab-irfc, Ixazomib, Daratumumab, and Elotuzumab or undergoing autologous hematopoietic cell transplantation or allo-hematopoietic cell transplantation should receive prophylaxis for herpes zoster (eg Acyclovir, Valaciclovir). Consider Levofloxacin for 12 weeks at the time of initial multiple myeloma diagnosis.

Antibacterial agents that may be considered include Levofloxacin (preferred), Cefdinir or Amoxicillin/clavulanic acid. Antibacterial agents are started when absolute neutrophil count (ANC) is <500 or depending on clinician discretion and continue until neutrophil recovery. Levofloxacin is considered for 12 weeks at the time of initial multiple myeloma diagnosis.  

Antifungal and antiviral agents that may be considered, depending on the etiologic agent, include Acyclovir, Valacyclovir, Trimethoprim-sulfamethoxazole, and Fluconazole. 

Nonpharmacological

Observation and Follow-Up  

Smoldering (Asymptomatic) Multiple Myeloma

Initiation of treatment in early-stage disease is not recommended. Re-evaluation every 3-6 months is advised. Repeat 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, whole-body FDG PET-CT) are recommended annually or as needed. Bone marrow aspirate and biopsy with FISH, SNP array, NGS panel, or multiparameter flow cytometry may be requested as needed. Multiparameter flow cytometry may effectively predict the risk of disease progression in patients with confirmed monoclonal gammopathy of undetermined significance or smoldering myeloma.

Hematopoietic Cell Transplantation

Autologous Hematopoietic Cell Transplant

Autologous hematopoietic cell transplant is the preferred management strategy for younger patients with newly diagnosed multiple myeloma, combined with systemic therapy. Early front-line treatment with autologous hematopoietic cell transplant is preferred and showed improved PFS compared with performing autologous hematopoietic cell transplant at disease relapse. Transplantation 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 autologous hematopoietic cell transplant in multiple myeloma patients over systemic therapy.  

Tandem Autologous Hematopoietic Cell Transplant  

Tandem autologous hematopoietic cell transplant is defined as undergoing repeat hematopoietic cell transplant with high-dose chemotherapy within 6 months after the first course. A second autologous hematopoietic cell transplant may be considered in patients who did not achieve a very good partial response or better following their first autologous hematopoietic cell transplant, with high-risk features and during disease relapse.  

Allogeneic Hematopoietic Cell Transplant

Allogeneic hematopoietic cell transplants include myeloablative and non-myeloablative transplant. Myeloablative allo-hematopoietic cell transplant may be considered in multiple myeloma patients whose disease is responsive to primary therapy, with primary disease progression, or with disease progression after initial autologous hematopoietic cell transplant. Non-myeloablative is preferred over myeloablative allo-hematopoietic cell transplant due to the lesser adverse effects from the high-dose chemotherapeutic regimen. It avoids the contamination of reinfused autologous tumor cells and is associated with reduced disease relapse brought about by its graft-versus-myeloma effect.  

Allogeneic hematopoietic cell transplant is limited by the scarcity of compatible donors and increased morbidity. It is not recommended for patients with newly diagnosed disease outside of a clinical trial, with the exception of young patients with high-risk prognostic factors. 

Radiation Therapy

Radiation therapy is part of a multimodal therapy in patients with multiple myeloma with CNS disease. Focal radiation therapy may help rapidly reverse or prevent progression of focal neurologic deficits from localized disease within the brain, spine or cranial nerves while awaiting further workup or if alternative therapies are not immediately available. Whole brain radiation therapy can be considered for patients with poorly localized or cranial nerve disease. The recommended dose is ≤23.4 Gy in 13 fractions. Craniospinal irradiation may be used for patients with negative or otherwise well-controlled extra-CNS involvement. It is an effective bridge to consolidation therapy like CAR T-cell therapy or autologous hematopoietic cell transplantation.