Approach

Patients with smouldering (asymptomatic) MM (SMM) do not require immediate therapy; the initiation of treatment in these patients can be deferred until the appearance of active disease.[45][78]​ Patients with SMM should be closely monitored or enrolled in a clinical trial if available/eligible, particularly those with high-risk SMM.[45][78]​ See Criteria for risk stratification.​​

Patient with active MM should begin treatment at the time of diagnosis. The goal of treatment is to induce remission, prolong survival, alleviate symptoms, and preserve quality of life, while minimising toxicity.

All patients requiring treatment should undergo induction therapy. Treatment is guided by eligibility for stem cell transplant (SCT) and risk stratification. Performance status, age, and comorbidities dictate whether a patient is a candidate for high-dose therapy and SCT.[79][80][81][82]​​ Frailty assessment (e.g., using the International Myeloma Working Group frailty score; UK Myeloma Research Alliance risk profile score) should be considered in older patients to further tailor therapy selection and drug dosing.[83][84][85]​​​​​ Patients eligible for SCT should be referred to a stem cell centre.

Maintenance therapy should follow SCT, or follow induction therapy in non-transplant candidates.

Transplant candidates: induction therapy

Induction therapy regimens use a combination of three (triplet) or four (quadruplet) drugs, including:

  • Proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib)

  • Immunomodulatory drug (e.g., lenalidomide, thalidomide)

  • CD38-directed monoclonal antibody (e.g., daratumumab, isatuximab)

  • Corticosteroid (e.g., dexamethasone)

  • Chemotherapy (e.g., cyclophosphamide, doxorubicin, cisplatin, etoposide), in some cases

In many institutions, use of non-chemotherapy regimens (comprising only targeted agents and a corticosteroid) has replaced chemotherapy-based regimens due to their improved efficacy and tolerability.[86][87]

Recommended induction regimens for transplant candidates include:[45]​​

  • Bortezomib plus lenalidomide plus dexamethasone (VRD)

  • Carfilzomib plus lenalidomide plus dexamethasone (KRD)

  • Daratumumab plus bortezomib plus lenalidomide plus dexamethasone (Dara-VRD)

Alternative induction regimens that may be considered for transplant candidates include:[45]

  • Ixazomib plus lenalidomide plus dexamethasone (IRD)

  • Bortezomib plus cyclophosphamide plus dexamethasone (VCD)

  • Bortezomib plus doxorubicin plus dexamethasone (PAD)

  • Carfilzomib plus cyclophosphamide plus dexamethasone (KCD)

  • Ixazomib plus cyclophosphamide plus dexamethasone (ICD)

  • Daratumumab plus bortezomib plus thalidomide plus dexamethasone (Dara-VTD)

  • Daratumumab plus bortezomib plus cyclophosphamide plus dexamethasone (Dara-VCD)

  • Daratumumab plus carfilzomib plus lenalidomide plus dexamethasone (Dara-KRD)

  • Daratumumab plus ixazomib plus lenalidomide plus dexamethasone (Dara-IRD)

  • Bortezomib plus thalidomide plus dexamethasone plus cisplatin plus doxorubicin plus cyclophosphamide plus etoposide (VTD-PACE; option for high-risk or aggressive disease)

  • Isatuximab plus bortezomib plus lenalidomide plus dexamethasone (Isa-VRD)

All transplant-eligible patients should be treated with a quadruplet or triplet regimen, if tolerated.[44][45]​​​​ Quadruplet non-chemotherapy regimens offer improved response rates compared to triplet non-chemotherapy regimens, while triplet non-chemotherapy regimens offer improved response rates compared with two-drug (doublet) non-chemotherapy regimens.[88][89][90][91]

A doublet regimen (e.g., lenalidomide plus dexamethasone [RD], bortezomib plus dexamethasone [VD], or thalidomide plus dexamethasone [TD]) can be considered for initial treatment in those unsuitable for quadruplet or triplet regimens (e.g., due to poor performance status), with a third agent added if performance status improves.[45]

If patients do not respond to the initial induction therapy regimen, a different induction regimen should be tried.

Transplant candidates should receive no more than 4-6 cycles of induction therapy before stem cell harvesting in order to minimise stem cell toxicity and maximise stem cell yield.[44][45]

Daratumumab is available as an intravenous formulation, or a subcutaneous formulation (daratumumab/hyaluronidase).[92][93] Dosing and administration are different for each formulation, but either of the formulations can be considered in daratumumab-containing regimens (including those used in the relapse and refractory setting).[45]

Stem cell transplant (SCT)

Options include single or double (tandem) autologous SCT or allogeneic SCT. The collection of a sufficient number of haematopoietic stem cells after induction therapy is essential for autologous SCT.

Autologous SCT

Single autologous SCT is the standard approach for transplant-eligible patients.[45] This achieves 40% complete remission rates, but the median duration of response is only 2-3 years.[94] Double autologous SCT (i.e., a second SCT performed within 3-6 months of the first SCT) may be considered if patients have high-risk disease and/or if a complete response or a very good partial response is not achieved after the first SCT.[45] Double autologous SCT increases response rate and duration of response in these patients.[94][95]​​​​ Treatment-related mortality is higher with double autologous SCT (approximately 5%) compared with single autologous SCT (approximately 3%).[96]

Timing of autologous SCT

Up-front autologous SCT (i.e., after 3-6 cycles of induction therapy) is recommended, but delaying autologous SCT until progression may be considered for select patients (i.e., those who do not have high-risk disease and are responding well to systemic treatment).[45][89]

Up-front autologous SCT is associated with higher rates of complete response, minimal residual disease negativity, and improved progression-free survival, compared with delaying autologous SCT until progression.[97][98][99]​​​​ However, an overall survival benefit has not been shown.[97]

Allogeneic SCT

Allogeneic SCT is not routinely recommended for transplant-eligible patients, but may be considered in select patients (e.g., those with high-risk disease) if a matched-related donor is available.[45][81]​ It should only be conducted in a specialist centre or in a clinical trial setting.[81][100]​

Allogeneic SCT provides long-term disease-free survival in some patients, but transplant-related mortality is high. Acute and chronic graft-versus-host disease may complicate allogeneic SCT strategies.

Conditioning regimens for SCT

Patients should receive conditioning with high-dose therapy before undergoing SCT (e.g., high-dose melphalan for autologous SCT; fludarabine plus melphalan, or total body irradiation, for allogeneic SCT).[101][102][103][104]

Non-transplant candidates: induction therapy

Patients who are older (age >65-70 years), frail, and/or with certain comorbidities, disabilities, or organ dysfunction (e.g., cardiac, pulmonary, hepatic, gastrointestinal, renal) are generally unsuitable for transplant.[105] 

Recommended induction regimens for ​non-transplant candidates include:[45][106][107]

  • Bortezomib plus lenalidomide plus dexamethasone (VRD)

  • Daratumumab plus lenalidomide plus dexamethasone (Dara-RD)

  • Isatuximab plus bortezomib plus lenalidomide plus dexamethasone (Isa-VRD)

  • Daratumumab plus bortezomib plus melphalan plus prednisolone (Dara-VMP)

  • Carfilzomib plus lenalidomide plus dexamethasone (KRD)

  • Daratumumab plus bortezomib plus cyclophosphamide plus dexamethasone (Dara-VCD)

Alternative induction regimens that may be considered for non-transplant candidates include:[45]

  • Ixazomib plus lenalidomide plus dexamethasone (IRD)

  • Lenalidomide plus dexamethasone (RD)

  • Bortezomib plus cyclophosphamide plus dexamethasone (VCD)

  • Bortezomib plus dexamethasone (VD)

  • Bortezomib plus lenalidomide plus dexamethasone (dose-adjusted VRD [VRD-lite]; for frail patients)

  • Carfilzomib plus cyclophosphamide plus dexamethasone (KCD)

  • Ixazomib plus cyclophosphamide plus dexamethasone (ICD)

  • Lenalidomide plus cyclophosphamide plus dexamethasone (RCD)

The choice of induction therapy for non-transplant candidates should take into consideration patient age, performance status, and the risks associated with each regimen.[105]​ Dose modification is often necessary for frail patients.

Triplet and quadruplet regimens are favoured over doublet regimens due to improved survival outcomes and response rates.[89][108] However, doublet regimens may be appropriate for older and/or frail non-transplant candidates with specific comorbidities and poor performance status.[45]

Maintenance therapy

Maintenance therapy after SCT, or after induction therapy in non-transplant candidates, is required to maintain remission and prolong survival.[45][81][109] The choice of maintenance therapy can be guided by risk stratification and the choice of induction therapy.

Maintenance therapy with lenalidomide (preferred) or bortezomib is recommended for patients who do not have high-risk disease.[45][81][110][111][112][113][114]

For patients with high-risk disease, the following maintenance regimens can be considered:[45][115][116][117]​​​​[118][119]

  • Bortezomib plus lenalidomide

  • Carfilzomib plus lenalidomide (after autologous or allogeneic SCT)

  • Daratumumab with or without lenalidomide (after autologous SCT)

Maintenance therapy with ixazomib improves progression-free survival in transplant-eligible and transplant-ineligible patients.[120][121]​ However, interim analyses of two randomised controlled trials reported no statistically significant difference in overall survival between ixazomib and placebo.[122]

Maintenance therapy should be continued until disease progression or unacceptable toxicity.

Relapse or refractory disease

Almost all patients who initially respond to treatment will eventually relapse.

Salvage therapy for patients with relapsed or refractory MM (RRMM) should take into account prior treatment and duration of response, aggressiveness of relapse, and patient factors (e.g., performance status, frailty). A clinical trial should be considered for all patients with RRMM.

Patients relapsing >6 months after completing initial treatment may be retreated with the same regimen.[45]

Patients relapsing ≤6 months after completing initial treatment may be switched to a different regimen containing a newer-generation targeted agent, or a different type of targeted agent.[45] For example, patients who relapse on or following a bortezomib-containing regimen (i.e., bortezomib-refractory) may be switched to a regimen containing carfilzomib (a second-generation proteasome inhibitor), and patients who are lenalidomide-refractory may be switched to a regimen containing pomalidomide (a second-generation immunomodulatory agent).

If tolerated, triplet regimens are preferred over doublet regimens due to improved response rate and survival.[123] However, the risk of grade 3 and 4 adverse events is higher with triplet regimens.[123] Patients unable to tolerate triplet regimens should receive a doublet regimen (e.g., dexamethasone combined with lenalidomide, pomalidomide, bortezomib, or carfilzomib).[45][124][125][126][127][128]​​​​

Targeted agents and regimens for relapse or refractory disease

Carfilzomib: used in combination with lenalidomide and dexamethasone; dexamethasone; daratumumab and dexamethasone; or isatuximab and dexamethasone, in those who have received one to three prior therapies.[128][129]​​[130][131][132][133]​​ 

Pomalidomide: used in combination with carfilzomib or bortezomib and dexamethasone in patients who have received one to three prior therapies, or in combination with dexamethasone (with or without cyclophosphamide) in those who have received at least two prior therapies (including lenalidomide and a proteasome inhibitor) and have disease progression on or within 60 days of completion of the last therapy.[45][126][134][135][136][137][138]​​​​​​​ In the US, pomalidomide is available only through a Risk Evaluation and Mitigation Strategy (REMS) programme.

Daratumumab: used in combination with pomalidomide and dexamethasone in those who have received at least one prior line of therapy (including lenalidomide and a proteasome inhibitor); or in combination with lenalidomide or bortezomib plus dexamethasone in those who have received at least one prior therapy; or in combination with carfilzomib plus dexamethasone in those who have received one to three prior therapies; or as monotherapy in those who have received at least three prior therapies (including a proteasome inhibitor and an immunomodulatory agent), or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent.​[131][132][139][140][141][142][143][144][145][146][147]

Isatuximab: an anti-CD38 monoclonal antibody, used in combination with carfilzomib and dexamethasone in those who have received one to three prior therapies, or in combination with pomalidomide and dexamethasone for those who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.[133][148]​​

Selinexor: a selective inhibitor of nuclear export (SINE), used in combination with bortezomib and dexamethasone in those who have received at least one prior therapy, and in combination with dexamethasone in those who have received at least four prior therapies, with disease refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.[149][150]

Elotuzumab: a SLAMF7-targeted monoclonal antibody, used in combination with lenalidomide plus dexamethasone in patients who have received at least one prior therapy, or in combination with pomalidomide plus dexamethasone in those relapsed or refractory to lenalidomide and a proteasome inhibitor.[151][152][153]

Ixazomib: an oral proteasome inhibitor, used in combination with lenalidomide plus dexamethasone in those who have received at least one prior therapy.[154][155]

Panobinostat: a pan-histone deacetylase (HDAC) inhibitor, used in combination with bortezomib plus dexamethasone in those who have received at least two prior therapies.[156][157]​​​ Panobinostat is not available in the US (accelerated approval was withdrawn in 2022 due to lack of post-approval confirmatory trials), but is available elsewhere, including Europe.

Idecabtagene vicleucel (ide-cel): a chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA), used in those who have received two or more prior therapies including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.[158][159]

Ciltacabtagene autoleucel (cilta-cel): a CAR T-cell therapy targeting BCMA, used in those who have received at least one prior therapy including an immunomodulatory agent and a proteasome inhibitor, and are refractory to lenalidomide.[160][161]​​

Bispecific monoclonal antibodies: elranatamab (targeting BCMA), talquetamab (targeting GPRC5D), or teclistamab (targeting BCMA) can be used in those who have received at least four prior therapies, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody.[162][163][164] 

Belantamab mafodotin (belamaf): an antibody-drug conjugate targeting BCMA, has been withdrawn from the US and Europe. In a confirmatory phase 3 trial, belantamab did not significantly improve progression-free survival (primary endpoint) compared with pomalidomide plus dexamethasone in patients with relapsed or refractory MM.[165] Median progression-free survival with belantamab mafodotin was longer than for pomalidomide plus dexamethasone (11.2 vs. 7.0 months), but the difference was not statistically significant. Patients in the US receiving belantamab mafodotin and enrolled in the REMS programme will be able to continue treatment by enrolling into a compassionate use programme (this may also apply in other countries). Studies of belantamab mafodotin combined with other agents in the relapsed or refractory setting are ongoing.

Stem cell transplant (SCT) for relapse or refractory disease

Autologous SCT should be considered for patients with RRMM who are eligible and have not previously received an autologous SCT.[45]

Patients who have received a single autologous SCT and achieved a durable response (e.g., ≥36 months) or stable disease before relapsing may be considered for high-dose chemotherapy plus salvage autologous SCT, if eligible.[45][89][166]​​

Treatment toxicity

Major toxic complications of therapies for MM include recurrent infection; sepsis (rare); venous thromboembolic events (associated with immunomodulatory drugs); neuropathy; and cardiac failure (associated with carfilzomib). See Complication.

CAR T-cell and bispecific antibody therapy

CAR T-cell therapy (idecabtagene vicleucel, ciltacabtagene autoleucel) and bispecific antibody therapy (elranatamab, talquetamab, teclistamab) may lead to cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and non-ICANS neurological toxicities (e.g., Guillain-Barre syndrome, parkinsonism [with CAR T-cell therapy]), all of which can be fatal or life-threatening.

CAR T-cell therapy may also lead to haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), prolonged cytopenias, and secondary haematological malignancies (including T-cell malignancies), all of which can be fatal or life-threatening.

Patients receiving CAR T-cell or bispecific antibody therapy require close monitoring for immune-related adverse effects (e.g., CRS and ICANS).[167][168]​​​​​ Management of immune-related adverse effects includes supportive care, use of anti-cytokine therapy (e.g., tocilizumab, anakinra), and use of dexamethasone.[167][169][170]​ The risk for severe infection related to CAR T-cell and bispecific antibody therapy warrant considerations for infection monitoring, prophylaxis, and treatment.​[169][170][171]​​ Notably, BCMA-targeting bispecific antibodies are associated with pneumocystis jiroveci pneumonia and cytomegalovirus infection/reactivation.[172][173]​ Intravenous immunoglobulin (IVIG) should be considered for patients with IgG levels <400 mg/dL.[45]

Patients receiving CAR T-cell therapy require life-long monitoring for secondary haematological malignancies.[174]​ 

In the US, CAR T-cell therapy and bispecific antibody therapy are available only through a REMS programme.

Supportive care

Use supportive care measures to prevent and manage complications of MM (e.g., renal failure, bone disease) and treatment (e.g., infection, venous thromboembolic events, neuropathy, cardiac failure). See Complication.

Hydration is important to prevent renal failure in MM.[175]​ If there is high tumour burden, hydration should be provided intravenously during treatment.

A systematic approach to pain relief must be integrated into the management plan of all patients.

Bone-targeting treatment

Bone pain and osteolytic bone disease can be treated with bisphosphonates (e.g., zoledronic acid, pamidronate).[176][177] [ Cochrane Clinical Answers logo ] ​ Denosumab (a monoclonal antibody that targets the receptor activator of nuclear factor-kappaB ligand [RANKL]) may be used instead of bisphosphonates, particularly in patients with renal impairment.[176][177][178]​ In June 2018, the UK Medicines and Healthcare products Regulatory Agency issued a safety alert following a pooled analysis of four phase 3 studies of denosumab in patients with advanced malignancies involving bone.[179] New primary malignancies were reported more frequently among patients receiving denosumab than those receiving zoledronic acid (cumulative incidence of new primary malignancy at 1 year was 1.1% for denosumab and 0.6% for zoledronic acid). No treatment-related pattern for individual cancers or cancer groupings was identified.

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