Multiple myeloma: Administration considerations for common therapies

INTRODUCTION — There are many treatment regimens for multiple myeloma (MM), often representing a combination of drugs from different drug classes (table 1A-B). Dosing and administration of these regimens is complicated, often requiring dose adjustments and adjunctive therapies.

Administration considerations for common therapies used in MM will be discussed here. The choice of regimen for initial and subsequent therapy is discussed separately.

●(See "Multiple myeloma: Overview of management".)

●(See "Multiple myeloma: Initial treatment".)

●(See "Multiple myeloma: Treatment of first or second relapse".)

●(See "Multiple myeloma: Treatment of third or later relapse".)

GENERAL PRINCIPLES

Assess for drug interactions — Some medications used for MM have drug interactions that may necessitate dose adjustments. Consultation with a clinical pharmacist may help with identifying and managing interactions.

For more detailed information on potential drug-drug interactions, refer to the drug interactions program within UpToDate.

Maximize communication and support — Open and regular communication is key to setting expectations for the prevention and management of adverse effects of MM treatment. Drug intolerance leads to treatment discontinuation for some patients. General guidance for drug holidays and dose reductions is provided in the drug package inserts and, together with adjuvant supportive therapies, can be used to maximize drug benefit.

While there are general principles described for all patients, application should be patient-centered, guided by the patient's prioritization of which symptoms and side effects affect them most.

IMMUNOMODULATORY DRUGS — In the United States, immunomodulatory drugs are prescribed through a restricted "risk evaluation and mitigation strategy (REMS)" program.

●Teratogenicity – Immunomodulatory drugs are teratogenic and absolutely contraindicated in pregnant and nursing females. These agents are also found in the semen of men receiving treatment, and thus appropriate precautions are necessary as outlined in the REMS program. All patients must take precautions to avoid pregnancy.

●Anti-thrombotic prophylaxis – Regimens that incorporate immunomodulatory drugs require prophylaxis against thromboembolism (algorithm 1). Details regarding risk of thrombosis and options for prophylaxis are discussed separately. (See "Multiple myeloma: Prevention of venous thromboembolism".)

●Dose adjustments for special populations

•Kidney impairment – Patients with kidney impairment experience more neutropenia and thrombocytopenia with the use of lenalidomide [1]. Lenalidomide is dose adjusted for patients with creatinine clearance (CrCl) <60 mL/min. Pomalidomide dose adjustments are recommended for patients with severe kidney impairment requiring dialysis. Dose adjustments for kidney impairment are not necessary for patients treated with thalidomide. (See "Nephrotoxicity of chemotherapy and other cytotoxic agents", section on 'Immunomodulatory drugs'.)

•Liver dysfunction – Studies of lenalidomide have not been conducted in patients with hepatic impairment. Pomalidomide dose adjustments are recommended for patients with mild to moderate hepatic impairment. Dose adjustments for liver impairment are not necessary for patients treated with thalidomide.

•Frail adults – Frail adults may not tolerate full doses of immunomodulatory agents. There are limited data regarding dose reductions in this population. We often use a lower initial dose of these agents in frail adults:

-Lenalidomide 15 mg (instead of 25 mg) (see "Multiple myeloma: Initial treatment", section on 'Frail adults')

-Pomalidomide 2 or 3 mg (instead of 4 mg)

-Thalidomide 50 to 100 mg (instead of 200 mg)

●Monitoring parameters – Assess complete blood count with differential, electrolytes, renal function, and liver function prior to starting each cycle. Monitor for the development of peripheral neuropathy, which is more common with thalidomide than with lenalidomide or pomalidomide. Long-term use of lenalidomide as maintenance therapy can be associated with the development of diarrhea.

●Stem cell collection – Lenalidomide is myelosuppressive and generally should not be given for more than six cycles before stem cell collection in transplant-eligible patients. Longer-term treatment with lenalidomide has been associated with inadequate peripheral blood stem cells in some patients when mobilization is attempted using growth factor alone. Stem cells in such patients can usually be harvested using growth factors plus stimulating agents such as plerixafor. (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)

●Second primary malignancies (SPM) – There is an increased risk of SPM among patients treated with lenalidomide maintenance following autologous hematopoietic cell transplantation (HCT) therapy. Controlled trials reported an increased rate of SPM among patients treated with lenalidomide following autologous HCT [2], but not in those who were ineligible for HCT [3], or for those treated in the relapsed setting [4]. A retrospective pooled analysis of 11 clinical trials of lenalidomide-based therapy that included data from 3848 patients with relapsed or refractory myeloma reported an overall incidence rate of SPM of 3.62 events per 100 patient-years [4]. The rate of invasive second primary cancers was similar to that expected in older adults according to the Surveillance, Epidemiology, and End Results (SEER) database. However, this study's ability to report the long-term risk of SPMs was limited, because reliable reporting of SPMs was restricted to the duration of lenalidomide treatment (median five months).

PROTEASOME INHIBITORS

Risks with all proteasome inhibitors

●Teratogenicity – Proteasome inhibitors (eg, bortezomib, carfilzomib, ixazomib) can cause fetal harm and should be avoided in pregnancy. All patients must take precautions to avoid pregnancy.

●Antimicrobial prophylaxis – Proteasome inhibitors may be associated with an increased risk of herpes zoster reactivation and infections not related to neutropenia. As such, regimens that contain a proteasome inhibitor are administered with antiviral prophylaxis (table 2). Some clinicians also administer prophylaxis for prevention of Pneumocystis infection. (See "Infections in patients with multiple myeloma", section on 'Proteasome inhibitors'.)

●Adjustments to minimize neuropathy – Bortezomib-induced peripheral neuropathy can be curtailed with adjustments in the route (subcutaneous rather than intravenous) and scheduling (weekly versus more frequent) of administration. Peripheral neuropathy is less common and less severe with carfilzomib and ixazomib. (See 'Specific recommendations for bortezomib' below and "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Proteasome inhibitors'.)

●Dose adjustments for special populations

•Liver dysfunction

-Bortezomib – Dose reductions are indicated for moderate (bilirubin >1.5 to 3 times upper limit of normal [ULN] and any AST and any ALT) and severe impairment (bilirubin >3 times ULN and any AST and any ALT).

-Carfilzomib – Dose reductions are indicated for mild (total bilirubin 1 to 1.5 times ULN and any AST and any ALT or total bilirubin ≤ULN and AST or ALT >ULN) or moderate impairment. Carfilzomib pharmacokinetics have not been evaluated for patients with a bilirubin more than three times the ULN.

-Ixazomib – Dose reductions are indicated for moderate or severe impairment.

•Kidney impairment – Dose adjustments of bortezomib and carfilzomib are not necessary for baseline kidney impairment. Dose reductions of ixazomib are needed for patients with creatinine clearance (CrCl) <30 mL/minute or kidney disease requiring dialysis.

●Monitoring parameters – Assess complete blood count with differential, electrolytes, renal function, and liver function prior to starting each cycle. Some patients may also require intra-cycle laboratory assessments, particularly those with renal impairment or significant cytopenias. Monitor for the development of peripheral neuropathy, which is more common with bortezomib than with carfilzomib or ixazomib. Monitor for development of cardiotoxicity, which is more common with carfilzomib than with bortezomib or ixazomib.

●Cardiovascular events – There is increasing awareness of cardiovascular adverse events (CVAE; eg, heart failure, hypertension, ischemia, arrhythmia) with proteasome inhibitors, particularly carfilzomib. A prospective cohort that used intensive screening reported CVAE in 51 percent of those treated with carfilzomib and 17 percent of those treated with bortezomib [5]. Most CVAE occurred during the first three months of therapy and CVAE were more common among patients with elevated baseline levels of brain natriuretic peptide (BNP) or NT-proBNP. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines", section on 'Proteasome inhibitors'.)

●Thrombotic microangiopathy – Rarely, proteasome inhibitors have been associated with thrombotic microangiopathy (TMA), which can present with Coombs-negative hemolysis, thrombocytopenia, kidney failure, and/or neurologic findings. If TMA is suspected, stop the proteasome inhibitor and evaluate. (See "Drug-induced thrombotic microangiopathy (DITMA)".)

●Reversible posterior leukoencephalopathy syndrome (RPLS) – Rare cases of RPLS have been reported with proteasome inhibitors. RPLS can present with seizures, hypertension, headache, lethargy, confusion, blindness, or as other visual or neurological disturbances. The proteasome inhibitor should be discontinued if the diagnosis of RPLS is confirmed on brain magnetic resonance imaging (MRI). (See "Reversible posterior leukoencephalopathy syndrome".)

●Progressive multifocal leukoencephalopathy (PML) – Rare cases of PML caused by reactivation of the polyomavirus JC (JCV) have also been reported [6]. PML can present with subacute neurologic deficits including altered mental status, motor deficits (hemiparesis or monoparesis), limb ataxia, gait ataxia, and visual symptoms such as hemianopia and diplopia. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)

Specific recommendations for bortezomib — The following are important considerations for patients taking bortezomib and should be considered in addition to the general risks for proteasome inhibitors described above. (See 'Risks with all proteasome inhibitors' above.)

●Peripheral neuropathy – Peripheral neuropathy, often painful, develops in 40 to 50 percent of patients who receive bortezomib 1.3 mg/m² twice weekly [7-9] and in 20 to 30 percent of patients who receive bortezomib 1.3 mg/m² once weekly [9,10]. Neuropathy is more frequent and severe in those who have previously received neurotoxic therapy and those with pre-existing neuropathy [11]. Older patients with subclinical, asymptomatic peripheral neuropathy are also likely to develop sensorimotor peripheral neuropathy after only a few injections of bortezomib. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Proteasome inhibitors'.)

●Once versus twice weekly administration – Nearly all of the major randomized trials that have evaluated the use of bortezomib in combination therapy have used twice-weekly administration. Some experts advocate for the use of twice-weekly bortezomib to mimic that used in the trials [12]. We often administer bortezomib once weekly rather than twice weekly, an approach taken in one major randomized trial and nonrandomized studies that have demonstrated dramatically lower rates of peripheral neuropathy without compromising efficacy [9,10]. Once-weekly administration of bortezomib is particularly advantageous in elderly, transplant-ineligible patients, who often have comorbid conditions that accentuate the morbidity associated with peripheral neuropathy [13].

If a rapid response to initial treatment is needed, we administer one or two cycles of bortezomib 1.3 mg/m² twice weekly (days 1, 4, 8, 11) before transitioning to the once-weekly schedule. Candidates for this more aggressive approach include patients with acute renal failure from light chain cast nephropathy or patients with an aggressive disease presentation.

●Subcutaneous administration preferred – Bortezomib can be administered intravenously or subcutaneously; in general, subcutaneous administration is preferred due to a lower risk of neuropathy [14-16], including asymptomatic nerve damage which may impact the rates of neuropathy with subsequent regimens [17].

●Dose adjustment for neuropathy – Dose modification schema have been suggested by the manufacturer [18] and a group of European myeloma experts [19]. One approach is provided in the table (table 3). Further details are discussed separately. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Proteasome inhibitors'.)

Specific recommendations for carfilzomib — The following are important considerations for patients taking carfilzomib and should be considered in addition to the general risks for proteasome inhibitors described above. (See 'Risks with all proteasome inhibitors' above.)

●Dosing

•Weekly 20/70 dosing – Carfilzomib is most often administered once weekly on days 1, 8, and 15 of a 28-day cycle. While most of the initial randomized trials that evaluated carfilzomib used twice-weekly administration, once-weekly dosing is more convenient, well tolerated, and appears to be at least as effective as twice-weekly dosing. Once-weekly dosing uses an initial dose of 20 mg/m² for cycle 1 day 1, followed by 70 mg/m²/dose weekly for subsequent doses. In a randomized trial that compared this once-weekly dosing schedule versus the 20/27 twice-weekly dosing schedule in 478 patients with relapsed or refractory MM, once-weekly dosing was well tolerated and prolonged progression-free survival (PFS; median 11 versus 8 months) [20,21]. Further support comes from phase 1b trials that used once-weekly carfilzomib in combination with daratumumab and dexamethasone (EQUULEUS, NCT01998971) and in combination with lenalidomide and dexamethasone (NCT 02335983) that showed good safety, tolerability, and efficacy [22-24]. When used in triplet or quadruplet combinations, depending on the age and performance status of the patient, the once-weekly carfilzomib dose can be reduced to 56 mg/m².

•Twice-weekly 20/27 and 20/56 dosing – While once-weekly administration is generally preferred, carfilzomib can be administered twice weekly using one of two approved dosing schema (20/27 and 20/56). Of these, we prefer the 20/27 dosing given its similar efficacy and potentially less toxicity and lower cost.

-Carfilzomib 20/27 dosing – When given in combination with lenalidomide and dexamethasone, carfilzomib is administered on two consecutive days weekly for three weeks (ie, days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (ie, days 17 to 28). The dose for days 1 and 2 of cycle 1 is 20 mg/m²/day, followed by 27 mg/m²/day for subsequent doses, if tolerated. Carfilzomib is not given on days 8 and 9 of cycles 13 to 18 and is not given on any days of subsequent cycles.

-Carfilzomib 20/56 dosing – Carfilzomib is administered at 20 mg/m²/day for cycle 1 days 1 and 2, followed by 56 mg/m²/day for subsequent doses.

A randomized trial comparing the 20/27 dosing versus the 20/56 dosing was unable to demonstrate a significant difference in response rates or PFS with the two dosing regimens [25]. The 20/27 dosing resulted in less fatigue, thrombocytopenia, and peripheral neuropathy than 20/56 dosing; cardiopulmonary adverse events were similar between the two arms. Crossover was allowed. Among the 16 patients assigned to the 20/27 dosing who received the 20/56 dosing at the time of progression, median second PFS was three months.

●Prophylaxis for infusion reactions – At a minimum, premedicate prior to all doses in the first cycle, and in patients with prior infusion reactions. Infusion can be associated with a hypersensitivity reaction immediately following or up to 24 hours after the administration. (See "Infusion reactions to systemic chemotherapy", section on 'Carfilzomib'.)

●Cardiovascular toxicity – Initial studies reported cardiovascular toxicity (eg, heart failure, hypertension, ischemia, arrhythmia) in up to 18 percent [26-28]. However, the true rate may be significantly higher. A prospective cohort that used intensive screening for cardiovascular toxicity reported signs of cardiovascular toxicity in approximately half of patients receiving carfilzomib [5]. Expert groups have published management recommendations for hypertension and cardiac events in patients receiving carfilzomib [29,30]. Monitor for signs and symptoms of cardiac failure or ischemia and monitor blood pressure regularly. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines", section on 'Proteasome inhibitors'.)

●Thromboprophylaxis – Thromboprophylaxis is advised when carfilzomib is administered in combination with lenalidomide and dexamethasone, in combination with daratumumab and dexamethasone, or with dexamethasone alone [31]. In randomized trials, an increase in venous thromboembolism (VTE) was seen when carfilzomib was added to lenalidomide plus dexamethasone and when carfilzomib was substituted for bortezomib [32-36].

MONOCLONAL ANTIBODIES

Anti-CD38 monoclonal antibodies — The following administration considerations apply to patients receiving the anti-CD38 monoclonal antibodies, daratumumab and isatuximab.

●Teratogenicity – Daratumumab and isatuximab can cause fetal harm and should be avoided in pregnancy. All patients must take precautions to avoid pregnancy [37,38].

●Infusion-related reactions – Patients receiving daratumumab or isatuximab are premedicated to minimize infusion-related reactions. In addition, those receiving intravenous daratumumab are given post-infusion corticosteroids to reduce the risk of delayed infusion reactions. Additional prophylactic measures (eg, bronchodilators, inhaled corticosteroids) may be needed for patients with a history of an obstructive pulmonary disorder. The infusion should be interrupted immediately for infusion reactions of any severity. Prophylaxis for infusion-related reactions is discussed in more detail separately. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Daratumumab'.)

If available, we suggest the use of fixed-dose, subcutaneously administered daratumumab in combination with hyaluronidase (daratumumab-hyaluronidase) rather than intravenous daratumumab. While the initial trials evaluating the efficacy of daratumumab alone and in combination regimens used the intravenous formulation, the subcutaneous formulation appears to have similar efficacy with lower rates of infusion-related reactions, a faster administration time, similar drug cost, and lower total administration cost [39-41]. A randomized trial comparing these two formulations as monotherapy reported similar overall response rate (41 percent with subcutaneous versus 37 percent with intravenous), progression-free survival (median 5.6 with subcutaneous versus 6.1 months with intravenous, HR 0.99, 95% CI 0.78-1.26), and safety profiles among those receiving subcutaneous and intravenous daratumumab, respectively [40]. Fewer patients receiving daratumumab-hyaluronidase developed an infusion-related reaction (13 versus 34 percent) and the rate of grade 3 reactions was also lower (2 versus 5 percent).

We monitor patients receiving subcutaneous daratumumab on site for infusion reactions for four to six hours following the first dose. For subsequent doses, patients can be monitored for shorter durations depending on the severity of the initial infusion reaction. We expect that most patients will not need on-site monitoring beyond the first two to three doses. Patients should be instructed to use acetaminophen and/or diphenhydramine should they develop mild signs or symptoms of an infusion reaction at home. Patients should contact their health care provider if any fever or shortness of breath occurs after reaching home following subcutaneous daratumumab. Pre- and post-infusion medications to minimize infusion reactions are described separately. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Subcutaneous daratumumab'.)

●Antimicrobial prophylaxis – Patients receiving daratumumab or isatuximab are at high risk for bacterial infections and reactivation of varicella-zoster virus and/or herpes simplex virus (table 2). The prescribing information recommends antiviral prophylaxis to prevent herpes zoster reactivation with both of these agents. The indications for and choice of antimicrobial prophylaxis are discussed separately. (See "Infections in patients with multiple myeloma".)

Patients with serologic evidence of hepatis B virus (HBV) infection (HBsAg-positive or anti-HBc-positive) are at risk for HBV reactivation. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

●Cytopenias – Complete blood cell counts (CBC) should be monitored before each treatment cycle, and a CBC is typically obtained on all days of treatment with these agents. Dose delays are occasionally required for neutropenia and/or thrombocytopenia.

●Blood bank issues – Daratumumab and isatuximab can interfere with cross-matching and red blood cell antibody screening. Patients should have a type and screen performed prior to receiving these drugs to inform future matching. If the patient requires a transfusion, the blood bank should be notified of prior exposure to these agents. (See "Red blood cell (RBC) transfusion in individuals with serologic complexity", section on 'Anti-CD38 (daratumumab, isatuximab)'.)

●Interference with disease monitoring – Daratumumab and isatuximab are immunoglobulin G (IgG) kappa monoclonal antibodies and thus can be detected on serum protein electrophoresis (SPEP) and immunofixation (IFE) assays. As such, they may obfuscate the response assessment in patients with IgG kappa myeloma protein. Interference assays are available, but they are typically used only in the setting of clinical research protocols. (See "Multiple myeloma: Evaluating response to treatment", section on 'Serum and urine tests'.)

●Second primary malignancies (SPM) – Higher incidences of SPM are observed among patients receiving isatuximab [38]. The US Food and Drug Administration (FDA) advises monitoring patients for the development of SPM.

Anti-CS1 antibody therapy (elotuzumab)

●Infusion-related reactions – Patients receiving elotuzumab are premedicated to minimize infusion-related reactions. The infusion should be interrupted immediately for infusion reactions of any severity. Prophylaxis for infusion-related reactions is discussed in more detail separately. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Daratumumab'.)

●Antimicrobial prophylaxis – Patients receiving elotuzumab are at high risk for bacterial infections and reactivation of varicella-zoster virus and/or herpes simplex virus (table 2). The indications for and choice of antimicrobial prophylaxis are discussed separately. (See "Infections in patients with multiple myeloma".)

●Monitoring parameters – CBCs should be monitored before each treatment cycle and are often obtained with intra-cycle dosing of the agent as well. Dose delays may be required for neutropenia and/or thrombocytopenia. Liver enzymes are monitored routinely and elotuzumab is held for grade 3 or higher elevation in liver enzymes. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Molecularly targeted agents", section on 'Elotuzumab'.)

●Interference with disease monitoring – Elotuzumab is an IgG kappa monoclonal antibody and can be detected on SPEP and IFE assays. As such, it may obfuscate the response assessment in patients with IgG kappa myeloma protein. (See "Multiple myeloma: Evaluating response to treatment", section on 'Serum and urine tests'.)

●Second primary malignancies (SPM) – Higher incidences of SPM were observed among patients receiving elotuzumab in a randomized controlled trial [42]. The US FDA advises monitoring patients for the development of SPM.

CHIMERIC ANTIGEN RECEPTOR (CAR)-T CELLS — In the United States, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel are prescribed through restricted "risk evaluation and mitigation strategy" (REMS) programs. Facilities that dispense these agents require special certification, and staff must be trained to recognize and manage these adverse events. Consensus-based guidance on the prevention and management of adverse events are also available from the European Myeloma Network [43]. Detailed description of administration considerations is beyond the scope of this topic. (See "Multiple myeloma: Treatment of third or later relapse", section on 'Chimeric antigen receptor T cells'.)

●Manufacturing and preparation – Chimeric antigen receptor (CAR)-T cells are generated from the patient's own T lymphocytes, which are genetically modified (transfected) with a gene that encodes a CAR to direct the patient's T cells against the MM cells. The T cells are genetically modified ex vivo, expanded in a production facility, and then infused back into the patient as therapy. Prior to reinfusion, patients receive a lymphodepleting chemotherapy preparative/conditioning regimen (ie, cyclophosphamide plus fludarabine).

●Cytokine release syndrome (CRS) – CRS is a severe systemic response (eg, high fever, flu-like symptoms, hypotension, mental status changes) to the activation and proliferation of CAR-T cells. CRS is common and may be life-threatening, but it typically responds to treatment with aggressive supportive care that includes tocilizumab and corticosteroids. Evaluation and management of CRS is discussed separately. (See "Cytokine release syndrome (CRS)".)

●Other toxicities – Other important, potentially life-threatening toxicities include:

•Hypersensitivity reactions

•Neurologic toxicities, including immune effector cell-associated neurotoxicity syndrome (ICANS) (see "Immune effector cell-associated neurotoxicity syndrome (ICANS)")

•Hemophagocytic lymphohistiocytosis/macrophage activation syndrome

•Prolonged cytopenia with bleeding and infection

•Hypogammaglobulinemia

•Second primary malignancies

●Antimicrobial prophylaxis – Patients treated with CAR-T cells may have prolonged cytopenias and are at increased risk for infections. Antiviral and pneumocystis prophylaxis are standard following B cell maturation antigen (BCMA) CAR-T therapy. (See "Infections in patients with multiple myeloma", section on 'Chimeric antigen receptor-T cell therapy'.)

BISPECIFIC ANTIBODIES — Three bispecific antibodies are approved for use in multiple myeloma: teclistamab (B cell maturation antigen [BCMA]/CD3 antibody [44]), elranatamab (BCMA/CD3 antibody [45]), and talquetamab (G protein-coupled receptor, class C, group 5, member D [GPRC5D]/CD3 antibody [46]). (See "Multiple myeloma: Treatment of third or later relapse", section on 'Bispecific antibodies' and "Multiple myeloma: Treatment of third or later relapse", section on 'Talquetamab'.)

In the United States, these bispecific antibodies are prescribed through restricted "risk evaluation and mitigation strategy" (REMS) programs. They are administered subcutaneously in gradually increasing doses over the first week, followed by weekly or every other week dosing thereafter. Patients are closely monitored for at least 48 hours after each dose escalation. Consensus-based guidance on the prevention and management of adverse events are available from the European Myeloma Network [43]. Detailed description of administration considerations is beyond the scope of this topic.

●Teratogenicity – Bispecific antibodies may cause fetal harm and should be avoided in pregnancy and in those who are breastfeeding. All patients must take precautions to avoid pregnancy.

●Cytokine release syndrome (CRS) – CRS is a severe systemic response (eg, high fever, flu-like symptoms, hypotension, mental status changes) to bispecific antibodies. CRS is common and may be life-threatening, but it typically responds to treatment with aggressive supportive care that includes tocilizumab and corticosteroids [47]. The prescribing information provides detailed information about recommended pretreatment medications to minimize the risk of CRS, including a corticosteroid, histamine-1 receptor antagonism, and antipyretics. Evaluation and management of CRS is discussed separately. (See "Cytokine release syndrome (CRS)".)

●Neurologic toxicities – Neurologic toxicities, including immune effector cell-associated neurotoxicity syndrome (ICANS), are an uncommon but serious complication of bispecific antibodies. ICANS should be suspected in patients with neurologic changes, including alterations in level of consciousness, confusion, behavioral changes, and speech and language abnormalities. It is discussed in detail separately, and dose adjustments are provided in the prescribing information. (See "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)

●Hepatotoxicity – Bispecific antibodies can cause hepatotoxicity. Measure baseline liver enzymes and bilirubin and repeat these studies during treatment as clinically indicated.

●Antimicrobial prophylaxis – Severe, life-threatening, and fatal infections have occurred with bispecific antibodies. Do not start treatment in patients with an active infection. Antiviral prophylaxis for herpes zoster reactivation should be offered according to local guidelines (table 2).

●Local injection site reactions – Local injection site reactions are seen in approximately one-quarter of patients [47,48].

●Skin and nail toxicity – Talquetamab is associated with skin reactions and nail changes in most patients, which are most frequently grade 1 or 2, but may be severe. Skin reactions include maculopapular rash, erythematous rash, xerosis, and pruritus.

●Oral toxicity and weight loss – Talquetamab is associated with oral toxicity and weight loss in most patients. Patients should be advised to monitor for oral toxicity and/or weight loss and seek care early as these toxicities may not be reversible.

SELINEXOR

●Teratogenicity – Selinexor can cause fetal harm and should be avoided in pregnancy. All patients must take precautions to avoid pregnancy.

●Antiemetic prophylaxis – Selinexor is moderately to highly emetogenic (emetogenic risk ≥30 percent) and antiemetic prophylaxis should be routine. In the clinical trials evaluating selinexor, all patients received antiemetic prophylaxis with a 5-HT3 receptor antagonist. In clinical practice, patients receiving selinexor often require multiple antiemetics, which in addition to a 5-HT3 receptor antagonist may include prochlorperazine or olanzapine. Special attention should be made to maintaining adequate fluid and caloric intake throughout treatment. (See "Prevention of chemotherapy-induced nausea and vomiting in adults".)

●Monitoring parameters – Assess complete blood count with differential, electrolytes, kidney function, and liver function prior to starting each cycle. Patients may develop hyponatremia. Patients may develop severe thrombocytopenia and neutropenia.

●Neurologic toxicity – Monitor for dizziness and confusion. Patients taking selinexor should avoid taking other medications that might cause dizziness or confusion. Patients with neurologic toxicity should refrain from driving and other potentially hazardous activities.

●Cataracts – Patients taking selinexor can develop ocular side effects including blurred vision, dry eyes, and cataracts, and/or have progression of pre-existing cataracts [49]. Ophthalmology should be involved in the care of patients who develop these symptoms.

CORTICOSTEROIDS

●Once-weekly dosing preferred – When used in combination therapy for MM, we usually administer dexamethasone once weekly rather than more frequently. For younger, healthy patients we use dexamethasone 40 mg by mouth on days 1, 8, 15, and 22 of each 28-day cycle. For older and/or frail patients, we use dexamethasone 20 mg weekly.

In some clinical situations, pulsed dosing of dexamethasone (20 or 40 mg days 1 through 4, 9 to 12, and 17 to 20) can be administered to induce an initial treatment response as a patient is being prepared to receive definitive, multiagent chemotherapy. This type of approach may be utilized, for example, in a patient who requires radiation therapy to a plasmacytoma prior to initiating systemic therapy. It can also be employed in patients with acute renal failure from light chain cast nephropathy or patients with other aggressive disease features. (See "Multiple myeloma: Initial treatment", section on 'Acute kidney failure'.)

Potential harm from higher dose dexamethasone was illustrated in a phase 3 trial (ECOG E4A03) in which 445 patients with previously untreated MM receiving lenalidomide plus dexamethasone were randomly assigned to higher dose dexamethasone (40 mg/day by mouth on days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle) versus lower dose dexamethasone (40 mg by mouth on days 1, 8, 15, and 22 of each cycle) [50]. The trial was stopped prematurely by the data safety monitoring committee because mortality was increased in the higher dose dexamethasone arm. When compared with higher dose dexamethasone, lower dose dexamethasone resulted in higher rates of overall survival at both one and two years (96 versus 87 percent and 87 versus 75 percent, respectively) and less toxicity. There was a lower rate of deep vein thrombosis or pulmonary embolus (12 versus 26 percent) and a lower incidence of infection or pneumonia (9 versus 16 percent).

Corticosteroid dosing around the administration of bortezomib may decrease peripheral neuropathy. This was suggested by a retrospective study that administered dexamethasone on the day of and the day following bortezomib administration and demonstrated a lower than expected burden of neuropathy [51].

●Hyperglycemia – Monitor for the development or worsening of hyperglycemia.

●Hypothalamic-pituitary-adrenal (HPA) axis suppression – Patients taking dexamethasone doses over 2 mg/day for more than three weeks likely have functional suppression of HPA function. Replacement glucocorticoids may be necessary for illness or surgery. (See "Treatment of adrenal insufficiency in adults".)

●Psychiatric/behavioral/central nervous system effects – Monitor for the development of apathy, depression, and psychiatric disturbances (including agitation, anxiety, distractibility, fear, hypomania, insomnia, irritability, lethargy, labile mood, pressured speech, restlessness, and tearfulness).

●Antimicrobial prophylaxis – The risk of infection increases with higher cumulative doses of corticosteroids. Regimens that use high-dose corticosteroids are administered with antiviral and Pneumocystis prophylaxis (table 2). (See "Infections in patients with multiple myeloma", section on 'Dexamethasone'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple myeloma".)

SUMMARY AND RECOMMENDATIONS

●General principles – Treatment of multiple myeloma (MM) often employs a combination of drugs from different drug classes (table 1A-B). Dosing and administration of these regimens is complicated, often requiring dose adjustments and adjunctive therapies.

Drug interactions can occur, and the involvement of a clinical pharmacist may help identify and manage potential interactions. For detailed information, refer to the Lexicomp drug interactions program within UpToDate.

Open and regular communication with patients is key to setting expectations about toxicity. General guidance for drug holidays and dose reductions is provided in the drug package inserts and, together with adjuvant supportive therapies, can be used to maximize drug benefit. (See 'General principles' above.)

●Immunomodulatory agents – Prophylaxis against thromboembolism is used with regimens that incorporate immunomodulatory agents (algorithm 1), as discussed in detail separately. (See "Multiple myeloma: Prevention of venous thromboembolism".)

Use of lenalidomide as maintenance therapy after autologous hematopoietic cell transplant is associated with an increased risk of second primary malignancies. (See 'Immunomodulatory drugs' above.)

●Proteasome inhibitors – Proteasome inhibitors are associated with an increased risk of herpes zoster reactivation. Antiviral prophylaxis is discussed separately (table 2). (See 'Risks with all proteasome inhibitors' above and "Infections in patients with multiple myeloma", section on 'Varicella-zoster virus and herpes simplex virus prophylaxis'.)

Bortezomib-induced peripheral neuropathy can be minimized with adjustments in the route (subcutaneous rather than intravenous) and scheduling (weekly versus more frequent) of administration. Peripheral neuropathy is less common and less severe with carfilzomib and ixazomib. (See 'Specific recommendations for bortezomib' above.)

Proteasome inhibitors, particularly carfilzomib, are associated with an increased risk of cardiovascular adverse events (eg, heart failure, hypertension, ischemia, arrhythmia). Monitor for signs and symptoms of cardiac failure or ischemia and monitor blood pressure regularly. (See 'Specific recommendations for carfilzomib' above.)

●Monoclonal antibodies – Patients receiving daratumumab, isatuximab, or elotuzumab are premedicated with corticosteroids to minimize infusion-related reactions. (See 'Anti-CD38 monoclonal antibodies' above and 'Anti-CS1 antibody therapy (elotuzumab)' above.)

We suggest the use of fixed-dose, subcutaneously administered daratumumab in combination with hyaluronidase (daratumumab-hyaluronidase) rather than intravenous daratumumab (Grade 2B). The subcutaneous formulation has similar efficacy with lower rates of infusion-related reactions, a faster administration time, similar drug cost, and lower total administration cost. (See 'Anti-CD38 monoclonal antibodies' above.)

Patients receiving daratumumab, isatuximab, or elotuzumab are at risk for bacterial infections such as pneumonia and reactivation of varicella-zoster virus and/or herpes simplex virus (table 2). Patients with serologic evidence of hepatis B virus (HBV) infection (HBsAg-positive or anti-HBc-positive) are at risk for HBV reactivation. Antiviral prophylaxis is discussed separately. (See "Infections in patients with multiple myeloma", section on 'Varicella-zoster virus and herpes simplex virus prophylaxis'.)

●CAR-T cells and bispecific antibodies – Chimeric antigen receptor (CAR)-T cell therapies and bispecific antibodies are immunotherapies that require careful monitoring for potentially severe toxicities, including hypersensitivity reactions, cytokine release syndrome, neurologic toxicities, and infections. (See 'Chimeric antigen receptor (CAR)-T cells' above and 'Bispecific antibodies' above.)

●Selinexor – Administration of selinexor requires careful management of gastrointestinal toxicity. All patients should receive antiemetic prophylaxis and be encouraged to maintain adequate fluid and caloric intake. (See 'Selinexor' above.)

●Corticosteroids – When used in combination therapy for MM, we suggest dexamethasone once weekly rather than more frequently (Grade 2B). If an urgent response is needed, we use more intensive dexamethasone for one cycle before starting the once-weekly schedule. (See 'Corticosteroids' above.)