Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

newly diagnosed transplant candidates

1st line – induction therapy

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ACUTE
|
newly diagnosed transplant candidates
1st line – 

induction therapy

Patients should be treated under specialist care.

Patients with active MM should begin treatment at the time of diagnosis. Patients with smoldering (asymptomatic) MM do not require immediate therapy; the initiation of treatment in these patients can be deferred until the appearance of active disease.[44][79]

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.[80][81][82][83]​​​ 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.[84][85][86]​ Patients eligible for SCT should be referred to a stem cell center.

Induction therapy regimens use a combination of three (triplet) or four (quadruplet) drugs, including: proteasome inhibitor; immunomodulatory drug; CD38-directed monoclonal antibody; corticosteroid; and chemotherapy, in certain cases. In many institutions, use of nonchemotherapy regimens (comprising only targeted agents and a corticosteroid) has replaced chemotherapy-based regimens due to their improved efficacy and tolerability.[87][88]

Recommended induction regimens for transplant candidates include: bortezomib plus lenalidomide plus dexamethasone (VRD); carfilzomib plus lenalidomide plus dexamethasone (KRD); and daratumumab plus bortezomib plus lenalidomide plus dexamethasone (Dara-VRD).[44]

Alternative induction regimens that may be considered for transplant candidates include: 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); and isatuximab plus bortezomib plus lenalidomide plus dexamethasone (Isa-VRD).[44]

All transplant-eligible patients should be treated with a quadruplet or triplet regimen, if tolerated.[43][44]​​ Quadruplet nonchemotherapy regimens offer improved response rates compared to triplet nonchemotherapy regimens, while triplet nonchemotherapy regimens offer improved response rates compared with two-drug (doublet) nonchemotherapy regimens.[89][90][91][92]

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.[44]

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 minimize stem cell toxicity and maximize stem cell yield.[43]

Daratumumab is available as an intravenous formulation, or a subcutaneous formulation (daratumumab/hyaluronidase).[93][94]​ 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).[44]

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.

See local specialist protocol for dosing guidelines. Patients may be treated with combinations of novel agents as part of clinical trials.

Primary options

bortezomib

and

lenalidomide

and

dexamethasone

OR

carfilzomib

and

lenalidomide

and

dexamethasone

OR

daratumumab

or

daratumumab/hyaluronidase

-- AND --

bortezomib

-- AND --

lenalidomide

-- AND --

dexamethasone

Secondary options

ixazomib

and

lenalidomide

and

dexamethasone

OR

bortezomib

and

cyclophosphamide

and

dexamethasone

OR

bortezomib

and

doxorubicin

and

dexamethasone

OR

carfilzomib

and

cyclophosphamide

and

dexamethasone

OR

ixazomib

and

cyclophosphamide

and

dexamethasone

OR

daratumumab

or

daratumumab/hyaluronidase

-- AND --

bortezomib

-- AND --

thalidomide

-- AND --

dexamethasone

OR

daratumumab

or

daratumumab/hyaluronidase

-- AND --

bortezomib

-- AND --

cyclophosphamide

-- AND --

dexamethasone

OR

daratumumab

or

daratumumab/hyaluronidase

-- AND --

carfilzomib

-- AND --

lenalidomide

-- AND --

dexamethasone

OR

daratumumab

or

daratumumab/hyaluronidase

-- AND --

ixazomib

-- AND --

lenalidomide

-- AND --

dexamethasone

OR

bortezomib

and

thalidomide

and

dexamethasone

and

cisplatin

and

doxorubicin

and

cyclophosphamide

and

etoposide

OR

isatuximab

and

bortezomib

and

lenalidomide

and

dexamethasone

Plus – stem cell transplant

Back
ACUTE
|
newly diagnosed transplant candidates
Plus – 

stem cell transplant

Treatment recommended for ALL patients in selected patient group

Options for stem cell transplant (SCT) include single or double (tandem) autologous SCT or allogeneic SCT.

The collection of a sufficient number of hematopoietic stem cells after induction therapy is essential for autologous SCT.

Single autologous SCT is the standard approach for transplant-eligible patients.[44] This achieves 40% complete remission rates, but the median duration of response is only 2-3 years.[95]

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.[44] Double autologous SCT increases response rate and duration of response in these patients.[95][96]​​​​​ Treatment-related mortality is higher with double autologous SCT (approximately 5%) compared with single autologous SCT (approximately 3%).[97]

Upfront 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).[44][90]​​​

Upfront 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.[98][99][100]​ However, an overall survival benefit has not been shown​.

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.[44][82]​​​ ​It should only be conducted in a specialist center or in a clinical trial setting.[82][101]​​​ 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.

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).[102][103][104][105]

Consider – supportive care

Back
ACUTE
|
newly diagnosed transplant candidates
Consider – 

supportive care

Treatment recommended for SOME patients in selected patient group

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.[174] If there is high tumor burden, hydration should be provided intravenously during treatment.​

Plus – bisphosphonates or denosumab

Back
ACUTE
|
newly diagnosed transplant candidates
|
bone disease
Plus – 

bisphosphonates or denosumab

Treatment recommended for ALL patients in selected patient group

Bisphosphonates (e.g., zoledronic acid, pamidronate) are the standard therapy for MM-related bone disease.[175][176] [ 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 for patients with renal impairment.[175][176][177]

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.[178] 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.

Primary options

zoledronic acid 4 mg injection: 4 mg intravenously every 3-4 weeks

OR

pamidronate: 90 mg intravenously every 4 weeks

OR

denosumab: 120 mg subcutaneously every 4 weeks

Consider – analgesics

Back
ACUTE
|
newly diagnosed transplant candidates
|
bone disease
Consider – 

analgesics

Treatment recommended for SOME patients in selected patient group

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

Bone pain is a common feature in MM, occurring in 60% to 70% of patients.[5][6]

Treatment of the underlying disease and use of bisphosphonates are usually sufficient to reduce the pain.

Some patients may require additional pain medication. Avoiding nonsteroidal anti-inflammatory drugs is recommended.

Primary options

acetaminophen: 500-1000 mg orally every 4-6 hours when required, maximum 4000 mg/day

OR

codeine sulfate: 15-60 mg orally every 4-6 hours when required, maximum 360 mg/day

OR

morphine sulfate: 5-10 mg orally (immediate-release) every 4 hours when required

newly diagnosed nontransplant candidates

1st line – induction therapy

Back
ACUTE
|
newly diagnosed nontransplant candidates
1st line – 

induction therapy

Patients should be treated under specialist care.

Patients with active MM should begin treatment at the time of diagnosis. Patients with smoldering (asymptomatic) MM do not require immediate therapy; the initiation of treatment in these patients can be deferred until the appearance of active disease.[44][79]

All patients requiring treatment should undergo induction therapy.

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.[84][85][86]

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.[106]

Recommended induction regimens for nontransplant candidates include: 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 prednisone (Dara-VMP); carfilzomib plus lenalidomide plus dexamethasone (KRD); and daratumumab plus bortezomib plus cyclophosphamide plus dexamethasone (Dara-VCD).[44][107][108]

Alternative induction regimens that may be considered for nontransplant candidates include: ixazomib plus lenalidomide plus dexamethasone (IRD); lenalidomide plus dexamethasone (RD); bortezomib plus cyclophosphamide plus dexamethasone (VCD); bortezomib plus dexamethasone (VD); dose-adjusted VRD (VRD-lite; for frail patients); carfilzomib plus cyclophosphamide plus dexamethasone (KCD); ixazomib plus cyclophosphamide plus dexamethasone (ICD); and lenalidomide plus cyclophosphamide plus dexamethasone (RCD).[44]

The choice of induction therapy for nontransplant candidates should take into consideration patient age, performance status, and the risks associated with each regimen.[106] Dose modification is often necessary for frail patients.

Triplet and quadruplet regimens are favored over doublet regimens due to improved survival outcomes and response rates.[90][109] However, doublet regimens may be appropriate for older and/or frail nontransplant candidates with specific comorbidities and poor performance status.[44]

​Daratumumab is available as an intravenous formulation, or subcutaneous formulation (daratumumab/hyaluronidase).[93][94]​ 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).[44]

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.

See local specialist protocol for dosing guidelines. Patients may be treated with combinations of novel agents as part of clinical trials.

Primary options

bortezomib

and

lenalidomide

and

dexamethasone

OR

daratumumab

or

daratumumab/hyaluronidase

-- AND --

lenalidomide

-- AND --

dexamethasone

OR

isatuximab

and

bortezomib

and

lenalidomide

and

dexamethasone

OR

daratumumab

or

daratumumab/hyaluronidase

-- AND --

bortezomib

-- AND --

melphalan

-- AND --

prednisone

OR

carfilzomib

and

lenalidomide

and

dexamethasone

OR

daratumumab

or

daratumumab/hyaluronidase

-- AND --

bortezomib

-- AND --

cyclophosphamide

-- AND --

dexamethasone

Secondary options

ixazomib

and

lenalidomide

and

dexamethasone

OR

lenalidomide

and

dexamethasone

OR

bortezomib

and

cyclophosphamide

and

dexamethasone

OR

bortezomib

and

dexamethasone

OR

Dose-adjusted VRD (VRD-lite)

bortezomib

and

lenalidomide

and

dexamethasone

OR

carfilzomib

and

cyclophosphamide

and

dexamethasone

OR

ixazomib

and

cyclophosphamide

and

dexamethasone

OR

lenalidomide

and

cyclophosphamide

and

dexamethasone

Consider – supportive care

Back
ACUTE
|
newly diagnosed nontransplant candidates
Consider – 

supportive care

Treatment recommended for SOME patients in selected patient group

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.[174] If there is high tumor burden, hydration should be provided intravenously during treatment.​

Plus – bisphosphonates or denosumab

Back
ACUTE
|
newly diagnosed nontransplant candidates
|
bone disease
Plus – 

bisphosphonates or denosumab

Treatment recommended for ALL patients in selected patient group

Bisphosphonates (e.g., zoledronic acid, pamidronate) are the standard therapy for MM-related bone disease.[175][176] [ 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 for patients with renal impairment.[175][176][177]

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.[178] 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.

Primary options

zoledronic acid 4 mg injection: 4 mg intravenously every 3-4 weeks

OR

pamidronate: 90 mg intravenously every 4 weeks

OR

denosumab: 120 mg subcutaneously every 4 weeks

Consider – analgesics

Back
ACUTE
|
newly diagnosed nontransplant candidates
|
bone disease
Consider – 

analgesics

Treatment recommended for SOME patients in selected patient group

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

Bone pain is a common feature in MM, occurring in 60% to 70% of patients.[5][6]

Treatment of the underlying disease and use of bisphosphonates are usually sufficient to reduce the pain.

Some patients may require additional pain medication. Avoiding nonsteroidal anti-inflammatory drugs is recommended.

Primary options

acetaminophen: 500-1000 mg orally every 4-6 hours when required, maximum 4000 mg/day

OR

codeine sulfate: 15-60 mg orally every 4-6 hours when required, maximum 360 mg/day

OR

morphine sulfate: 5-10 mg orally (immediate-release) every 4 hours when required

ONGOING

patients responding to initial treatment

1st line – maintenance therapy

Back
ONGOING
|
patients responding to initial treatment
1st line – 

maintenance therapy

Patients should be treated under specialist care.

Maintenance therapy after stem cell transplant (SCT), or after induction therapy in nontransplant candidates, is required to maintain remission and prolong survival.[44][82][110]

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.[44][82]​​[111][112]​​​[113][114]​​​​[115]

For patients with high-risk disease, the following maintenance regimens can be considered: bortezomib plus lenalidomide; carfilzomib plus lenalidomide (after autologous or allogeneic SCT); or daratumumab with or without lenalidomide (after autologous SCT).[44][116][117][118]​​​​​[119][120]

Maintenance therapy with ixazomib improves progression-free survival in transplant-eligible and transplant-ineligible patients.[121][122]​ However, interim analyses of two randomized controlled trials reported no statistically significant difference in overall survival between ixazomib and placebo.[123]

Maintenance therapy should be continued until disease progression or unacceptable 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.

See local specialist protocol for dosing guidelines.

Primary options

lenalidomide

OR

bortezomib

OR

bortezomib

and

lenalidomide

OR

carfilzomib

and

lenalidomide

OR

daratumumab

or

daratumumab/hyaluronidase

-- AND --

lenalidomide

OR

daratumumab

OR

daratumumab/hyaluronidase

Secondary options

ixazomib

Consider – supportive care

Back
ONGOING
|
patients responding to initial treatment
Consider – 

supportive care

Treatment recommended for SOME patients in selected patient group

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.[174] If there is high tumor burden, hydration should be provided intravenously during treatment.​

Plus – bisphosphonates or denosumab

Back
ONGOING
|
patients responding to initial treatment
|
bone disease
Plus – 

bisphosphonates or denosumab

Treatment recommended for ALL patients in selected patient group

Bisphosphonates (e.g., zoledronic acid, pamidronate) are the standard therapy for MM-related bone disease.[175][176] [ 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 for patients with renal impairment.[175][176][177]

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.[178] 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.

Primary options

zoledronic acid 4 mg injection: 4 mg intravenously every 3-4 weeks

OR

pamidronate: 90 mg intravenously every 4 weeks

OR

denosumab: 120 mg subcutaneously every 4 weeks

Consider – analgesics

Back
ONGOING
|
patients responding to initial treatment
|
bone disease
Consider – 

analgesics

Treatment recommended for SOME patients in selected patient group

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

Bone pain is a common feature in MM, occurring in 60% to 70% of patients.[5][6]

Treatment of the underlying disease and use of bisphosphonates are usually sufficient to reduce the pain.

Some patients may require additional pain medication. Avoiding nonsteroidal anti-inflammatory drugs is recommended.

Primary options

acetaminophen: 500-1000 mg orally every 4-6 hours when required, maximum 4000 mg/day

OR

codeine sulfate: 15-60 mg orally every 4-6 hours when required, maximum 360 mg/day

OR

morphine sulfate: 5-10 mg orally (immediate-release) every 4 hours when required

relapsing or refractory disease

1st line – salvage therapy

Back
ONGOING
|
relapsing or refractory disease
1st line – 

salvage therapy

Patients should be treated under specialist care.

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.[44]

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.[44] 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.[124] However, the risk of grade 3 and 4 adverse events is higher with triplet regimens.[124] Patients unable to tolerate triplet regimens should receive a doublet regimen (e.g., dexamethasone combined with lenalidomide, pomalidomide, bortezomib, or carfilzomib).[44][125][126][127][128][129]

The following targeted agents can be considered for patients with RRMM: carfilzomib, pomalidomide, daratumumab, isatuximab, selinexor, elotuzumab, ixazomib, idecabtagene vicleucel, ciltacabtagene autoleucel, elranatamab, talquetamab, and teclistamab.

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.[129][130]​​​​[131][132][133][134]

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.[44][127]​​​[135][136][137][138][139]​ In the US, pomalidomide is available only through a Risk Evaluation and Mitigation Strategy (REMS) program.

Daratumumab: an anti-CD38 monoclonal antibody, 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.​[132][133][140][141][142][143][144][145][146][147][148]​ ​Daratumumab is available as an intravenous formulation, or subcutaneous formulation (daratumumab/hyaluronidase).[93][94]​​ 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).[44]

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.[134][149]​​

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.[150][151]

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.[152][153][154]

Ixazomib: an oral proteasome inhibitor, used in combination with lenalidomide plus dexamethasone in those who have received at least one prior therapy.[155][156]

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.[157][158] 

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.[159][160]

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.[161][162][163]

​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 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 neurologic 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 hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), prolonged cytopenias, and secondary hematologic 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).[166][167]​​​​​ Management of immune-related adverse effects includes supportive care, use of anticytokine therapy (e.g., tocilizumab, anakinra), and use of dexamethasone.​[168][169]​​​ The risk for severe infection related to CAR T-cell and bispecific antibody therapy warrant considerations for infection monitoring, prophylaxis, and treatment.[168][169][170]​​ Notably, BCMA-targeting bispecific antibodies are associated with pneumocystis jiroveci pneumonia and cytomegalovirus infection/reactivation.[171][172]​ Intravenous immune globulin (IVIG) should be considered for patients with IgG levels <400 mg/dL.[44]​ 

Patients receiving CAR T-cell therapy require life-long monitoring for secondary hematologic malignancies.[173]

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

Autologous stem cell transplant (SCT) should be considered for patients with RRMM who are eligible and have not previously received an autologous SCT.[44]

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.[44][90][165]

See local specialist protocol for dosing guidelines. Patients may be treated with combinations of novel agents as part of clinical trials.

Primary options

carfilzomib

and

lenalidomide

and

dexamethasone

OR

carfilzomib

and

pomalidomide

and

dexamethasone

OR

bortezomib

and

pomalidomide

and

dexamethasone

OR

daratumumab

or

daratumumab/hyaluronidase

-- AND --

carfilzomib

-- AND --

dexamethasone

OR

daratumumab

or

daratumumab/hyaluronidase

-- AND --

pomalidomide

-- AND --

dexamethasone

OR

isatuximab

and

carfilzomib

and

dexamethasone

OR

isatuximab

and

pomalidomide

and

dexamethasone

OR

lenalidomide

and

dexamethasone

OR

bortezomib

and

dexamethasone

OR

carfilzomib

and

dexamethasone

Secondary options

pomalidomide

and

dexamethasone

OR

pomalidomide

and

cyclophosphamide

and

dexamethasone

OR

carfilzomib

Tertiary options

daratumumab

OR

daratumumab/hyaluronidase

OR

daratumumab

or

daratumumab/hyaluronidase

-- AND --

lenalidomide

-- AND --

dexamethasone

OR

daratumumab

or

daratumumab/hyaluronidase

-- AND --

bortezomib

-- AND --

dexamethasone

OR

selinexor

and

bortezomib

and

dexamethasone

OR

selinexor

and

dexamethasone

OR

elotuzumab

and

lenalidomide

and

dexamethasone

OR

elotuzumab

and

pomalidomide

and

dexamethasone

OR

ixazomib

and

lenalidomide

and

dexamethasone

OR

idecabtagene vicleucel

OR

ciltacabtagene autoleucel

OR

elranatamab

OR

talquetamab

OR

teclistamab

Consider – supportive care

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ONGOING
|
relapsing or refractory disease
Consider – 

supportive care

Treatment recommended for SOME patients in selected patient group

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.[174] If there is high tumor burden, hydration should be provided intravenously during treatment.​

Plus – bisphosphonates or denosumab

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ONGOING
|
relapsing or refractory disease
|
bone disease
Plus – 

bisphosphonates or denosumab

Treatment recommended for ALL patients in selected patient group

Bisphosphonates (e.g., zoledronic acid, pamidronate) are the standard therapy for MM-related bone disease.[175][176] [ 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 for patients with renal impairment.[175][176][177]

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.[178] 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.

Primary options

zoledronic acid 4 mg injection: 4 mg intravenously every 3-4 weeks

OR

pamidronate: 90 mg intravenously every 4 weeks

OR

denosumab: 120 mg subcutaneously every 4 weeks

Consider – analgesics

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ONGOING
|
relapsing or refractory disease
|
bone disease
Consider – 

analgesics

Treatment recommended for SOME patients in selected patient group

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

Bone pain is a common feature in MM, occurring in 60% to 70% of patients.[5][6]

Treatment of the underlying disease and use of bisphosphonates are usually sufficient to reduce the pain.

Some patients may require additional pain medication. Avoiding nonsteroidal anti-inflammatory drugs is recommended.

Primary options

acetaminophen: 500-1000 mg orally every 4-6 hours when required, maximum 4000 mg/day

OR

codeine sulfate: 15-60 mg orally every 4-6 hours when required, maximum 360 mg/day

OR

morphine sulfate: 5-10 mg orally (immediate-release) every 4 hours when required

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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