Assessment and monitoring of patients receiving chemotherapy for multiple myeloma: strategies to improve outcomes

Figures & data

Table 1 Diagnostic criteria for multiple myeloma and differential diagnosis

Condition	MGUS	SMM	Active multiple myeloma
% of clonal plasma cells in bone marrow	<10%	10%–60%	≥10%
Myeloma-defining events: hypercalcemia, anemia <10 g/dL or 2 g below normal, renal insufficiency with creatinine >2 g/dL, bone disease (more than one focal lesion on MRI or widespread lytic lesions)	None	None; however, patients are at a high risk for progression if diffuse abnormalities or one focal lesion on MRI	Yes, or any one: 1) clonal BMPCs ≥60%, or 2) serum FLC ratio ≥100 (plus measurable involved FLC level ≥100 mg/L), or 3) more than one focal lesion on MRI scan
Likelihood of progression	∼1% per year	∼10% per year; higher if serum involved/uninvolved FLC ratio ≥8 (but <100), IgA isotype and immunoparesis	Not applicable
Treatment	No, watchful waiting	Yes for high risk (especially in the context of clinical trial) No for others	Yes

Note: Data from Durie et al,¹⁶ Rajkumar et al.⁴

Abbreviations: BMPC, bone marrow plasma cell percentage; FLC, free light chain; IgA, immunoglobulin A; MGUS, monoclonal gammopathy of undetermined significance; MRI, magnetic resonance imaging; SMM, smoldering multiple myeloma.

Table 2 Common adverse events and survivorship considerations in patients with MM

Toxicity	Signs and symptoms	Associated drugs	Patient education/intervention
Cardiovascular
Bradycardia	Fatigue, low heart rate	Thalidomide	• Educate patient as to the risk of fatigue and importance of managing activities •Evaluate for hypothyroidism, ECG if moderate to severe, or if patient is symptomatic
Deep vein thrombosis, pulmonary embolism	Pain in leg or arm, unilateral swelling of extremity; shortness of breath and/or tachycardia	IMiDs High-dose carfilzomib Erythropoietin Dexamethasone	• Patients with MM are at increased risk for VTEs. All patients must be screened for the risk and educated on the signs and symptoms of VTE. Daily ASA 81–325 mg PO. Anticoagulation with LMWH, direct thrombin inhibitor, or therapeutic warfarin is recommended if more than two risk factors are present Educate patients regarding signs, symptoms, and prophylactic strategies (such as ambulation)
Heart failure	Shortness of breath, edema	Proteosome inhibitors (bortezomib, carfilzomib) Alkylating agents (melphalan, cyclophosphamide) Anthracyclines (adriamycin, doxorubicin) corticosteroids (especially if severe low left ventricular ejection fraction)	•Evaluate for swelling of extremities •Titrate diuretics according to chemotherapy •Minimize the use of pre-/posthydration for proteasome inhibitors
Hypertension	Headache	Dexamethasone, carfilzomib	Educate patient as to the risk of increased blood pressure and to report prolonged headaches
Hypotension	Dizziness, fatigue	Bortezomib (more common with IV than SC)	•Educate patient on adequate hydration, careful position changes, and to report worsening of the symptom
Prolonged QT-c interval	Palpitations; or may be asymptomatic	HDAC-I panobinostat, vorinostat	• Avoid medications (such as levofloxacin, ondansetron) that prolong QT-c interval
Endocrine
Diabetes	Polyuria, polydipsia, polyphagia	Dexamethasone, prednisone	• Patients may develop steroid-induced hyperglycemia or diabetes; glucose monitoring, insulin-sensitizing agents, or insulin may be necessary • Educate patients on the increased risk of diabetes with steroids. Exercise and low-carbohydrate diet, especially around the dates of steroids, can decrease the risk of high blood sugars
Hypothyroidism	Anemia, fatigue	Immunomodulatory drugs	• Hypothyroidism can occur with lenalidomide or thalidomide Routine screening of TSH levels should be conducted, especially if there is anemia, fatigue
Gastrointestinal
Constipation	Abdominal pain, bloating, lack of bowel movements	Immunomodulatory drugs, anthracyclines, bortezomib, and corticosteroids	• Inquire about bowel habits at each visit • Educate patients on the benefits of increased fluid and dietary fiber intake, and encourage exercise Initiate a bowel regimen: Stool softeners are indicated for patients taking opiate analgesic agents. Laxatives should be prescribed if no bowel movement within 24 hours
Diarrhea	Increase in loose or watery stools, or ostomy output from baseline	Lenalidomide (long term) Bortezomib	• First institute dietary modifications (avoid bulk fiber, spicy, fried, salty foods) and increase fluid intake Recommend loperamide if associated with chemotherapy for mild-to-moderate diarrhea. Hospitalization will be required for severe diarrhea. A stool sample may be indicated to rule out Clostridium difficile or other infection, if change in character of diarrhea, abdominal cramping, fever, or chills
Myelosuppression
Anemia	Fatigue and shortness of breath which can be mild to severe, depending on the degree of anemia	Most chemotherapy agents can cause mild-to-moderate anemia	• Encourage adequate rest and hydration • Treat anemia with RBC transfusion or ESAs. ESAs must be used with caution as can increase the risk of VTE • Ensure patients are not bleeding Check intermittently for secondary causes of anemia (such as vitamin B12 or iron deficiency, or progressive MM disease)
Neutropenia, infection risk	Fever >100.4°F (38°C), chills, sweats (signs of infection) Neutropenia may not have associated signs or symptoms	Most agents can cause, specifically chemotherapy	• Avoid patient contact with individuals with known infection. • Administer hematopoietic growth factors, if indicated • Administer antibiotic prophylaxis if at high risk for neutropenic fever • Administer acyclovir for HSV prophylaxis (if on proteasome inhibitor, posttransplant) • Give influenza vaccine yearly • Give pneumonia vaccine (PCV-13 and PPSV23) every 5 years • Wash hands and avoid people with colds Patients must seek emergent care if fever is present with ANC <500 mm/mL
Neurologic
Peripheral neuropathy (sensory or motor)	Numbness or pain, dysesthesia, hyperesthesia, ataxia, and imbalance if severe	Common drugs: proteosome inhibitors thalidomide, vincristine, and cisplatin	• Monitor for symptoms of sensory or motor neuropathy. Educate the patient to report promptly as dose reductions may be necessary, especially with proteasome inhibitors • Follow safety precautions due to decreased sensation and/or muscle strength • For mild neuropathy, no adjustment to the chemotherapy agents is necessary For moderate loss of sensation, weakness, or pain, chemotherapy must be held and decreased once acute symptoms resolve • Secondary causes of neuropathy, such as vitamin B deficiency, are common and must be ruled out Pain medications, anticonvulsive agents (gabapentin, pregabalin), antidepressants (duloxetine), and vitamins (B vitamins, alpha-lipoic acid) can mitigate symptoms in some patients. For severe neuropathy, a neurology referral may be necessary
Disease-related considerations
Disease monitoring	–	–	• Obtain SPEP, UPEP, 24-hour urine, and serum free light chains (if indicated) monthly during treatment Obtain skeletal survey every year or when there is new-onset bone pain or suspicion for relapse
Fatigue	Lack of energy, excessive sleep (or too little)	Many drugs to treat MM cause fatigue Additional agents such as gabapentin and opioids may worsen fatigue Insomnia may result from steroids	• Encourage patient to remain active and balance activities • Educate patient about the need for adequate rest, nutrition, and hydration • Review medication list to see if any can be eliminated if contributing to fatigue • Consider the timing of when the patient takes medications. For example, immunomodulatory drugs should be taken at bedtime
Osteoporosis, weakened bone structure, lytic lesions, or plasmacytoma	Pain	Pamidronate 90 mg IVPB or zoledronic acid 4 mg intravenously should be given monthly to prevent skeletal-related events	• Administer bisphosphonates to all with MM diagnosis for at least 12–24 months, then intermittently or stop, according to disease status and extent of bone damage • All patients should maintain some form of exercise with weight/lifting restrictions Surveillance skeletal imaging with skeletal survey should be performed at least annually. Orthopedic intervention may be warranted (prophylactic rodding or pinning of extremity), with or without radiotherapy, if large lesions and cortical disruption are present
Renal	Low urinary output, dysuria, or none	Dose reduction with lenalidomide, melphalan, ixazomib, and cisplatin. Refer to package insert for dosing instructions for patients on dialysis	• Patients can develop renal insufficiency at diagnosis or throughout • Avoid NSAIDs, IV contrast dyes, and aminoglycoside antibiotics • Encourage hydration • Monitor serum creatinine at least monthly during active treatment and every 3 months when in remission • Work with the patient and primary care provider to ensure adequate blood pressure control if hypertensive and control of diabetes if diabetic Dose adjustment of antibiotics, antiviral agents, or chemotherapy may be necessary
Survivorship
Psychosocial			• Screen patients for depression or anxiety Refer to support groups and counselors when necessary
Safety			• Watch for risk of falls if older age or on multiple medications or mood altering drugs • Instruct patients to remove throw rugs, increase physical activity, and use assistive devices
Financial			Refer to physical therapy for balance, gait training Evaluate financial and social support available
Health maintenance, disease monitoring			• Emphasize the importance of maintaining a well-balanced diet, mild-to- moderate exercise (based on the level of physical fitness) • Routine health screening for hypertension, hyperlipidemia, correct modifiable risk factors (obesity, smoking, excessive alcohol intake) Disease monitoring for MM, surveillance of secondary cancers

Notes: Based on information from: Faiman et al;¹²³ Bilotti et al;⁹⁸ Faiman et al;⁹⁹ Miceli et al;⁹⁶ Rome et al;¹²⁴ Rome et al;⁹⁷ Colson;⁷³ Richards and Brigle;¹²⁵ and product prescribing information.

Abbreviations: ANC, absolute neutrophil count; ASA, acetylsalacytic acid; ECG, electrocardiogram; ESAs, erythropoiesis stimulating agents; HDAC-I, histone deacetylase inhibitor; HSV, herpes shingles virus; IMiDs, immunomodulatory drugs; IV, intravenous; LMWH, low-molecular-weight heparin; MM, multiple myeloma; NSAIDs, non-steroidal anti-inflammatory drugs; PCV, pneumococal polyvalent vaccine; PPSV, pneumococcal polysaccharide vaccine; RBC, red blood cell; SC, subcutaneous; SPEP, serum protein electrophoresis; TSH, thyroid stimulating hormone; UPEP, urine protein electrophoresis; VTE, venous thromboembolic events.

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