Last updated March 14, 2022

Immunotherapy for the Treatment of Multiple Myeloma

Panel recommendations

Daratumumab

Frontline daratumumab

Dara is FDA-approved and the panel recommends its use in the following settings:

  • In combination with lenalidomide and dexamethasone (D-Rd)in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with RRMM who have received at least one prior therapy.

  • In combination with bortezomib, melphalan, and prednisone (D-VMP) in newly diagnosed patients who are ineligible for autologous stem cell transplant.

  • In combination with bortezomib, thalidomide, and dexamethasone (D-VTD) in newly diagnosed patients who are eligible for autologous stem cell transplant.

  • In combination with bortezomib and dexamethasone (D-Vd) in patients who have received at least one prior therapy.

  • In combination with pomalidomide and dexamethasone (D-Pd)in patients who have received at least two prior therapies including lenalidomide and a PI.

  • As monotherapy, in patients who have received at least three prior lines of therapy including a PI and an IMiD or who are double-refractory to a PI and an IMiD.

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Other combinations in newly diagnosed patients:

  • Based on emerging data (e.g. from the Griffin trial37), the panel was comfortable recommending D-VRd as one possible induction regimen option in newly diagnosed patients who are eligible for autologous stem cell transplant.

  • A consensus could not be reached regarding the use of dara in combination with carfilzomib, lenalidomide and dexamethasone (D-KRd) in newly diagnosed patients who are eligible for autologous stem cell transplant.

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Other combinations in RRMM:

  • KdD is recommended for patients with RRMM in the USA that are refractory to immunomodulatory drugs and bortezomib, based on emerging data from the CANDOR trial.

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Cytogenetic risk status

Until further phase III data become available, a consensus could not be reached to recommend that dara is the definitive choice for patients with high-risk cytogenetics, particularly in the frontline setting.
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Dosing and administration

Standard premedications as suggested below may be used to mitigate IRRs:

  • Dexamethasone, 20 mg intravenous (IV) (for dara monotherapy methylprednisolone, 100 mg is preferred).

  • Acetaminophen, 650–1000 mg oral.

  • Diphenhydramine, 25–50 mg oral or intravenous.

  • Montelukast, 10 mg, orally dissolving tablet (ODT) preferred, prior to first infusion.

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After cycle 2, steroids may be omitted if the patient has tolerated dara without IRRs.
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For patients with severe IRRs during dose or a history of respiratory comorbidities, oral corticosteroids (≤20 mg methylprednisolone or equivalent intermediate-acting or long-acting corticosteroid) should be administered per the prescribing label on each of the 2 days following dara infusions.
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Short-acting and long-acting bronchodilators and inhaled corticosteroids may be considered for patients with a long history of chronic obstructive pulmonary disease (COPD).
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Subcutaneous dosing
The panel felt that the new subcutaneous formulation will provide a convenient option for patients.
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Split dosing
For infusion centers with limited hours of operation, the first dose of dara can be split as 8 mg/kg across 2 days, which has a median infusion time of approximately 4 hours on each day. Nearly all IRRs occur on the first dose.
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For dose 4 and beyond, dara can be given safely over 90 min.
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Once subcutaneous dara is commercially available, the need to split dose will diminish.
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Special considerations

Although patients with renal failure, patients with COPD and patients with plasma cell leukemia are commonly excluded from clinical trials, the panel felt that these populations may safely be treated with dara.
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Before administering dara, patients should be tested for hepatitis B, given the potential risk of viral reactivation.
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For patients with no known hepatitis B exposure history, serum tests should be performed for HepBcAb, HepBsAb, and HepBsAg. In cases with evidence of hepatitis B exposure, a PCR test for hepatitis B genomes is recommended. For patients with positive serum tests for HepBcAb, entacavir should be considered.
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Prophylactic acyclovir should be administered to patients receiving dara.
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Response evaluation, treatment duration

Response to dara should be monitored according to institutional protocols, most of which assay MM labs monthly. In patients with IgG kappa myeloma, serologic determination of CR can be confounded by the presence of dara.
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In the presence of a measurable M-spike, dara will have a minimal effect on disease measurement. When patients reach undetectable levels, however, mass spectrometry or other antibody interference testing methods should be considered.
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A consensus could not be reached to recommend retreatment with dara in patients relapsing on monthly dosing.
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Patients on dara should receive seasonal influenza vaccines.
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To manage infections following treatment, intravenous IgG (IVIG) should be administered according to established institutional criteria, which are not specific to dara.
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Elotuzumab

Patient selection

E-Rd is approved in patients who have received one to three prior therapies.
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E-Pd is approved in patients who have received at least two prior therapies.
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Patients with high-risk cytogenetics may benefit from elotuzumab.
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At present, there is no approved indication for the use of elotuzumab in the initial management of myeloma.
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By consensus, elotuzumab-containing regimens may be considered for patients who have progressed on dara-containing regimens.
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Elotuzumab should not be used as a single agent.
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Prior treatment with elotuzumab is not a contraindication for treatment with anti-CD38 antibodies.
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By consensus, elotuzumab-containing regimens are not recommended for patients with a rapidly growing disease burden.
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Administration, dosing, and monitoring

In published trials, infusion-related reactions (IRRs) have been most prevalent with the first infusion.
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The first dose of elotuzumab should start at 0.5 mL/min for the first 30 min, then 1 mL/min. The second dose should start at 3 mL/min for 30 min, then 4 mL/min and from the third dose on, the infusion can be given at 5 mL/min.
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Per prescribing information, patients should be premedicated 45–90 min prior to infusion with dexamethasone 8 mg, an H1 and H2 blocker and acetaminophen (650–1000 mg orally).
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For the most part, myeloma-specific immune responses should be measured with each cycle as per normal practice.
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In patients with IgG kappa myeloma, determination of CR can be confounded by elotuzumab.
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In the presence of a measurable M-spike, elotuzumab will have a minimal effect on disease measurement. When patients reach undetectable levels, however, mass spectrometry or other antibody-interference testing methods should be considered.
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Other considerations

Although patients with renal impairment were excluded from clinical trials, the panel felt that elotuzumab may be used in patients with severe renal insufficiency (CrCL <30 mL/min).
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A consensus could not be reached to recommend using elotuzumab in patients with hepatic impairment or plasma cell leukemia.
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Antiviral prophylaxis is recommended for patients receiving elotuzumab.
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To manage infections following treatment, IVIG should be administered according to established institutional criteria, which are not specific to elotuzumab.
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At this time, no biomarkers of response or resistance to elotuzumab are known.
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Isatuximab

I-Pd is approved and recommended by the panel for patients with RRMM who have received more than two prior lines of therapy.
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Although patients with renal failure, patients with COPD and patients with plasma cell leukemia were excluded from initial clinical trials, these populations may safely be treated with isatuximab.
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Administration and dosing

In accordance with published protocols, isatuximab should be started at 175 mg/hour initial infusion rate with a duration range of 2–7 hours.
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Standard premedications are recommended up to 60 min prior to infusion to mitigate IRRs. Recommendations should be guided by label once approved by regulatory agencies. A suggested example is as follows:

  • Dexamethasone 40 mg IV or methylprednisolone 100 mg IV.

  • Diphenhydramine 50 mg IV or equivalent.

  • Ranitidine 50 mg intravenous or equivalent.

  • Acetaminophen 650–1000 mg oral administration.

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In patients with respiratory disease (eg, asthma or reduced forced expiratory volume in 1 s), consider adding an adrenergic bronchodilator (albuterol inhaler/nebulizer) as premedication.
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Special considerations

Prior exposure to mAb therapies

No consensus could be reached on using isatuximab in patients who had progressed on a dara-containing regimen.
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Antibody interference in serum protein electrophoresis

For most patients, the panel recommends antibody interference testing by mass spectrometry for patients treated with isatuximab.
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Infection care

Patients should receive seasonal influenza vaccines while on isatuximab.
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To manage infections following treatment, IVIG should be administered according to established institutional criteria, which are not specific to isatuximab.
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Emerging therapies

CAR T cells

Patient selection

The decision of suitability for CAR T cell therapy is often based on the potential for toxicity. Thus, baseline bone marrow function, cardiopulmonary, hepatic and renal function as well as performance status and organ status with respect to ability to tolerate CRS should be evaluated and toxicities should be considered, especially prolonged cytopenias.

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Registration trial results and FDA labels should guide disease-specific characteristics such as number of prior antimyeloma therapies.
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For patients earlier in their disease course, the presence of high-risk disease is an unmet medical need, and may shift the benefit/risk calculation in support of enrollment on cellular therapy trials.
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Heavily pretreated patients, including those who have undergone allo-HSCT may be considered for CAR T cell therapy.
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No data have been reported indicating that prior bispecific antibody or ADC therapy impacts the potential efficacy of future CAR T cell therapy or vice versa, and the panel agreed that there is not enough data to report on a consensus. Future trials should seek to address this question.
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Myeloma disease progression kinetics and likelihood of control should be weighed against the manufacturing time when considering patient eligibility for collection and likelihood to be clinically stable for CAR T cell administration.

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Administration, dosing and monitoring

Patients should be re-evaluated including disease restaging prior to lymphodepletion if they received cytotoxic bridging therapy or >30 days have passed since apheresis.

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Registration trial results and FDA labels should guide lymphodepletion regimens.
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The dose of fludarabine used for lymphodepletion in patients with renal insufficiency should be reduced per FDA prescribing guidelines.
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Evidence of adequate blood counts based on complete blood count should be present prior to lymphodepletion, unless impaired by disease burden.
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If bridging therapy induces a CR, while data are limited, the panel feels that the benefits of proceeding with planned CAR T cell therapy in the heavily pretreated RRMM setting regardless of CR outweighs the risk of lower disease burden limiting CAR T cell expansion.
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Patients may consider receiving CAR T cell therapy as outpatient provided all the following criteria are met:

  • Patient has appropriate caretaker who can provide 24/7 support when the patient is away from the outpatient facility.

  • Patient is compliant with medical management instructions.

  • Patient meets clinical criteria for outpatient monitoring including stable vital signs, maintaining oral intake and no impending clinical deterioration from myeloma.

  • Patient has no active infection, increased risk for CRS or neurotoxicity and no other clinical conditions requiring inpatient care.

  • Treatment center has appropriate infrastructure to expedite care to inpatient if clinically indicated 24/7.

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Toxicities

The ASTCT consensus guideline grading system for CRS and ICANS should be used to assess CAR T cell toxicities in patients with myeloma.
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To treat patients with CRS who do not respond to tocilizumab and steroids, the panel could not reach a consensus as to whether anakinra or siltuximab is preferred.
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For grade 1 CRS, tocilizumab may be considered, especially in cases of patients with prolonged high fevers, elderly patients or patients with significant comorbidities.
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Grade 2 or higher CRS should be managed with prompt tocilizumab administration.
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All patients should undergo comprehensive baseline neurological assessment prior to CAR T cell dosing to enable assessment for neurotoxicity signs and symptoms after infusion.
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Initial management of neurotoxicity should be based on experience and guidelines from registration trials, with escalation from supportive management to steroids, based on severity of signs and symptoms.
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Levetiracetam should be administered if seizures or other evidence of severe neurotoxicity develop in the context of CAR T cell therapy. Although no consensus could be reached to recommend antiseizure medicines prophylactically, the panel was unanimous in the opinion that there are few downsides to treating with levetiracetam.
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Patients may have had a high number of prior therapies before receiving CAR T cells, therefore, for patients who have persistent cytopenia beyond 3 months, evaluation for other causes are recommended including infections such as CMV and parvovirus B19, and bone marrow examination to rule out myelodysplastic syndrome (MDS).
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If patients develop neutropenia during CAR T cell therapy, filgrastim can be considered.
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Patients should be monitored for blood count and IgG levels regularly post-CAR T cell infusion until recovery.
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IVIG supplementation should be considered for patients with severe hypogammaglobulinemia (IgG <400 mg/dL).
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Macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH)-like toxicity is potentially fatal, and for patients who do not respond to tocilizumab and steroids, anakinra can be considered.
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Other considerations

CAR T cell safety when CrCl is <20 mL/min has not been assessed and the majority of the panel would not feel comfortable recommending CAR T therapy for patients with renal failure or significant hepatic impairment.
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Viral prophylaxis should be administered during CAR T cell therapy, and maintained through the treatment period and the neutropenic period.
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Pneumocystis jirovecii pneumonia prophylaxis should be administered during CAR T cell therapy, although a consensus could not be reached on the optimal length of administration.
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A consensus could not be reached to recommend antifungal prophylaxis during CAR T cell therapy, however, as more data accumulate this may require further study.
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A consensus could not be reached to recommend antibacterial prophylaxis during CAR T cell therapy.
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During influenza season, all patients should receive the influenza vaccine prior to leukapheresis (if not already administered in the current season) and if lymphodepletion is not scheduled to start within 14 days. Influenza vaccines should be given with each influenza season thereafter.
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Bispecific T-cell engagers

Patient selection

To date, there is no consensus on the optimal indications for bispecific cell engager therapy. These agents have been studied in patients who have relapsed/progressed after standard treatments and were refractory to the last line of therapy, including PIs, IMiDs and CD38 antibodies.
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Administration, dosing and monitoring

The ASTCT consensus grading system for CRS and ICANS should be used to evaluate toxicities associated with bispecific cell engager therapy.
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Toxicities should be managed as per established or mandated investigational protocols.
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As these therapies may eventually be administered in the outpatient setting, it is important to recognize that time to onset of CRS is typically within the first 2 days of beginning treatment, but may be delayed.
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Atypical infections reported in one phase I trial of AMG 420 suggest that attention should be paid to monitoring for infectious sequelae.
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A consensus could not be reached regarding how to interpret MRD status as opposed to traditional IMWG response criteria in both CAR T cell therapy and bispecific antibody patients. However, there was general consensus that MRD status can be a useful tool for predicting favorable outcomes.
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Antibody-drug conjugates

Patient selection

To date, there is no consensus on the optimal indications for ADC therapy. The agents have been studied in patients who have relapsed/progressed after standard treatments and were refractory to the last line of therapy, including PIs, IMiDs and CD38 antibodies.
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Patients with severe cytopenias (especially thrombocytopenia) or pre-existing corneal disease may be unsuitable for ADC therapy with belantamab mafodotin.
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Although patients with prior allo-HSCT were excluded from the DREAMM-1 and DREAMM-2 trials, based on the known mechanisms of action for ADCs, patients with prior allo-HSCT can be considered for treatment.
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Administration, dosing and monitoring

Prior to receiving belantamab mafodotin the patient should receive a complete ophthalmological examination.
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Monitoring in the initial studies included weekly complete blood counts and complete metabolic panels. After the first few cycles or after blood counts normalize, testing can be reduced to occur every treatment cycle.
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Management of corneal toxicity includes use of preservative-free lubricant eye drops as needed for symptoms of dryness, blurry vision or photophobia.
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Management of moderate-to-severe corneal toxicity includes holding therapy until improvement of symptoms to grade 1 or less and improvement of corneal changes is confirmed by ophthalmological examination, then restarting with a one level dose reduction.
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During belantamab mafodotin treatment specifically, therapy can be restarted once keratopathy or other AEs (such as cytopenias) have resolved to grade 1 or less. Dose reduction from 3.4 to 2.5 mg/kg may be considered. Further dose reductions to 1.9 mg/kg may be done if significant toxicity recurs.
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Since a proportion of patients may have delayed responses, it is recommended that ADC therapy be continued as long as patients exhibit stable disease or better responses and are tolerating therapy.
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Vaccines

The panel did not make any recommendations regarding the use of vaccines in myeloma. Participation in well-designed clinical trials is encouraged.
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Quality of life and patient engagement

Education must prepare the patient and caregivers for the timeline of expected side effects. It is critical to educate patients and caretakers about the signs and symptoms of immune-related side effects because early recognition is essential to effective treatment.
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Caregiver education is paramount as neurological toxic effects may impair a patient’s ability to recognize symptoms.
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It is crucially important to also coordinate education with the interdisciplinary care team. This may include provider, advanced practice provider, nurse, coordinator (research or non-research), social worker and pharmacist.
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Quality of life considerations for administration, dosing and monitoring during immunotherapy

Patient monitoring and management depends on the immunotherapy agent.
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All patients receiving immunotherapies should be given detailed call parameters specific to their treatment so patients can promptly communicate with their cancer care providers for direction.
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Special considerations for quality of life

Patients should be referred for a social work evaluation to assess needs and connect to available resources.
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It is especially important to provide whole-person care. Patients should be connected to other patients, survivors, support groups and online forums, and referrals should be made to social workers, chaplains and psycho-oncologists.
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Recommended advocacy groups include the International Myeloma Foundation (www.myeloma.org), Multiple Myeloma Research Foundation (www.themmrf.org), Leukemia & Lymphoma Society (www.lls.org), Myeloma Crowd (www.myelomacrowd.org) and the SITC (sitc.org).
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Ideally, immunotherapy-specific survivorship programs should be developed or patients receiving immunotherapy should be included in existing programs.
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Immunotherapy-specific quality of life 

Validated tools, including EORTC QLQ-C30 and PROMIS, should be considered in evaluation of effects of immune therapies on QoL.
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Immune-related side effects and quality of life

Patients should be educated on the potential need for prophylactic antimicrobials, IVIG and/or growth factor and transfusion support to manage cytopenias and immunodeficiency.
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Patients should also be educated that they may experience fatigue as a sequelae of cellular and immunotherapy. Pharmacological and non-pharmacological interventions may be used to address fatigue, although it is important to avoid steroids as treatment because of the concern of T cell suppression.
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Recommendation Grading

Overview

Title

Immunotherapy for the Treatment of Multiple Myeloma

Authoring Organization

Publication Month/Year

July 12, 2020

Document Type

Consensus

External Publication Status

Published

Country of Publication

US

Inclusion Criteria

Male, Female, Adult, Older adult

Health Care Settings

Ambulatory, Hospital, Outpatient

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Treatment, Management

Diseases/Conditions (MeSH)

D009101 - Multiple Myeloma

Keywords

multiple myeloma, Cancer immunotherapy

Source Citation

Shah N, Aiello J, Avigan DE, et al The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of multiple myeloma Journal for ImmunoTherapy of Cancer 2020;8:e000734. doi: 10.1136/jitc-2020-000734