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Received: 26 November 2019 Revised: 11 February 2020 Accepted: 18 February 2020
DOI: 10.1002/ajh.25764

CRITICAL REVIEW

Treatment and disease-related complications in multiple

myeloma: Implications for survivorship

Rajshekhar Chakraborty | Navneet S. Majhail

Taussig Cancer Center, Cleveland Clinic,

Cleveland, Ohio Abstract
New treatments have transformed multiple myeloma into a chronic disease. Hence,
Correspondence
Navneet S. Majhail, Blood and Marrow optimal management of treatment and disease-related complications remains a criti-
Transplant Program Cleveland Clinic, cal component of survivorship care. Survivorship care model in cancers requiring a
Cleveland, Ohio
Email: majhain@ccf.org fixed-duration therapy may not be applicable to myeloma, since patients are exposed
to multiple lines of continuous therapy along the disease trajectory. The two most
common therapy-related causes of death, which require special consideration, are
infection and second cancers. Identifying patients at a high risk of toxicities will facili-
tate individualized treatment selection and designing clinical trials for protective
strategies targeting those patients. For example, prophylactic antibiotic or immuno-
globulin replacement can be tested for primary prevention of infections in high-risk
patients. Long-term follow up of ongoing trials and epidemiologic data will help iden-
tify the nature and trajectory of rare toxicities with a long latency, such as secondary
cancers. Patients who are frail, have persistent renal insufficiency, and refractory to
multiple lines of therapy need special attention regarding treatment toxicity and qual-
ity of life. In this review, we discuss the incidence, risk-factors, and management of
treatment and disease-related complications in myeloma, discuss knowledge gaps
and research priorities in this area, and propose a survivorship care model to improve
health-care delivery to a growing pool of myeloma survivors.

1 | I N T RO DU CT I O N will lead to re-classification of some patients with high-risk smoldering

Multiple Myeloma is a clonal plasma cell neoplasm, characterized by
anemia, renal insufficiency, hypercalcemia, and bone destruction. The
incidence of myeloma has increased globally by 126% between 1990
and 2016.1 Furthermore, the age-standardized mortality rate has been
steadily declining,1 likely due to new therapies including proteasome
inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal anti-
bodies (mAbs) as well as upfront autologous hematopoietic cell trans-
plantation (AHCT). Although myeloma is predominantly a disease of
older adults with a median age at diagnosis of 69 years, incidence in
younger adults aged 20-49 years is steadily rising in the United States.2
Recent data from the Swedish national registry showed a roughly
3
3-fold increase in myeloma prevalence from 1980 to 2014. Further-
more, modification of the International Myeloma Working Group
(IMWG) diagnostic criteria by addition of disease-defining biomarkers4
myeloma to newly diagnosed myeloma, further increasing the pool of
myeloma survivors on active treatment.
New treatments have converted myeloma into a chronic disease,
with the treatment goal being to prevent end-organ damage, improve
or maintain quality of life (QoL), and achieve long-term disease free sur-
vival. Notably, most patients remain on continuous treatment for
extended time-periods. Hence, management of immediate and late
complications from disease and treatment is a critical component of
survivorship care in myeloma. In this review, we summarize the inci-
dence, risk-factors, and management of common treatment and
disease-related complications (Figure 1) and discuss implications for
survivorship care in this population. Since transplant-related late effects
have been well-described in literature,5 we will focus mainly on compli-
cations from non-transplant therapies. However, we acknowledge that
exposures and risk factors of systemic complications in myeloma are

672 © 2020 Wiley Periodicals, Inc. wileyonlinelibrary.com/journal/ajh Am J Hematol. 2020;95:672–690.


CHAKRABORTY AND MAJHAIL
F I G U R E 1 Major treatment-related toxicities in multiple myeloma. Abbreviations: BCMA, B-cell maturation antigen; ADC, Antibody-drug
conjugate; IMiDs, Immunomodulatory drugs; PIs, Proteasome inhibitors; CAR T, Chimeric Antigen Receptor T-cell therapy [Color figure can be
viewed at wileyonlinelibrary.com]
often difficult to separate and must be considered collectively. The inci-
dence and risk factors of major complications is summarized in Table 1.
Strategies for prevention and management is summarized in Table 2.
2 | NEUROLOGIC COMPLICATIONS
2.1 | Peripheral neuropathy
Treatment-induced Peripheral Neuropathy (PN) is a common and a
potentially debilitating toxicity in myeloma. Apart from pre-existing
PN,68 which is an established risk-factor for severe treatment-induced
PN in myeloma, literature on risk-factors is mostly borrowed from tradi-
tional cytotoxic chemotherapies.20 The incidence of PN with commonly
used agents and risk factors has been summarized in Table 1.6-18
PIs and IMiDs are the major drug classes that cause PN in myeloma.
Among PIs, bortezomib has the highest incidence of PN, with approxi-
mately one-third of patients developing this toxicity. Notably, subcutane-
ous9 and once-weekly administration21 of bortezomib leads to a lower
incidence of severe PN without compromising efficacy. The time-to-onset
of bortezomib-induced PN is around 2 months, with a plateau
68
in incidence after 5-6 months. With optimal dose modification,
bortezomib-induced PN is completely reversible in 60% of patients at a
median of 6 months, with initial improvement seen at a median of
68
2 months. The primary target of bortezomib is small nerve fibers and
dorsal root ganglion, leading to sensory polyneuropathy.22 Involvement of
large fibers and motor neurons causing areflexia, proprioception loss, and
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673
muscle weakness is rare and typically happens in the backdrop of severe
sensory PN. Among second generation PIs, carfilzomib is associated with
a significantly lower incidence of PN compared to bortezomib.10,11 Nota-
bly, there is a lack of longitudinal toxicity data with newer PIs. The inci-
dence of PN with the first-generation IMiD thalidomide is higher, seen in
up to two-thirds of patients.14,15 An increased incidence is noted beyond
a daily dose of 200 mg and with a longer treatment duration.22 Further-
more, motor and autonomic neuropathy is more common with thalido-
mide than with bortezomib. Thalidomide-induced PN is reversible in only
one-fourth of patients and takes around 4-6 years.22 Controlled studies
of newer IMiDs (lenalidomide and pomalidomide) did not demonstrate an
increased signal of PN.13,16-18 In the first-in-human study of bispecific
T-cell engager (BiTE) targeting B-cell maturation antigen (BCMA), two out
of 42 patients developed grade 3 polyneuropathy, with both resolving by
2-3 months after treatment discontinuation.69
2.2 | Management
The first step in management of PN is severity assessment and dose
modification of the offending agent.22 Other causes like metabolic or
inflammatory neuropathy should be considered in the differential
diagnosis, especially if the clinical course is atypical for treatment
induced PN. Neurophysiologic studies are not sensitive to small-fiber
involvement and may not mirror symptoms. However, they are helpful
when other causes [eg, demyelinating neuropathy related to underly-
ing monoclonal gammopathy] are in the differential diagnosis.
 TABLE 1 Incidence and risk-factors for common treatment-related toxicities in MM
674

Risk Factors

Toxicities/Late effects Incidence Patient-related Disease-related Treatment-related

19
peripheral neuropathy • Bortezomib [IV]: All-grade: 31–44% • Pre-exiting PN • Concomitant Monoclonal gammopathy- • Use of PIs or IMiDs [specifically,
[≥grade 3:8–13%]6-8 • Comorbidities [Diabetes Mellitus, associated PN, AL Amyloidosis, or bortezomib or thalidomide]
• Bortezomib [SC]: All-grade: 35% Nutritional deficiencies, Alcohol abuse, POEMS syndrome • Intravenous9 or twice-weekly21
[≥grade 3:5%]9 and Hypothyroidism] administration of bortezomib
• Carfilzomib: All-grade: 5-15% [≥ grade • Age/Sex20 • Thalidomide daily dose>200 mg or
3:0.2-1.5%]10,11 treatment duration>6-12 mo.22
• Ixazomib: All-grade: 19-27% [≥grade • Previous treatment with potentially
3:1-2%]12,13 neurotoxic drugs [eg, vincristine or
• Thalidomide: All-grade: Up to 70% thalidomide]
[≥grade 3:7-11%, with ≥grade 3 motor
neuropathy in 3%]14,15
• Lenalidomide: All-grade: 22% [≥grade
3:0.75-2%]13,16
• Pomalidomide: All-grade: 4-15% [≥Grade
3:0-1%]17,18
secondary malignancy • Actuarial incidence of secondary • Older Age29,30 • Underlying Plasma Cell Disorder • Treatment with alkylating agents
hematologic malignancies: 0.4-9.8%23-28 • Germline predisposition [including precursor conditions [especially oral melphalan]23,29
• Standardized Incidence Ratio [Observed: • Prior malignancies26 like MGUS] • Duration of therapy [oral melphalan].23
Expected] for secondary hematologic • Obesity30 • Immunophenotypic abnormalities Risk: 3% with each year of melphalan
malignancies: 2.2-8.225,27 • Male sex30 characteristic of MDS in the bone marrow therapy
• Actuarial incidence of secondary solid at diagnosis of plasma cell disorder31 • Treatment with lenalidomide29,32
tumors: 3.5-5.3%24,27 • Combined treatment with lenalidomide
• Standardized Incidence Ratio and oral melphalan29
[Observed: Expected] for • HDM-ASCT30,33
secondary solid tumors: 0.75-1.0924,27
venous thrombo- • Lenalidomide-based combination • Personal or family history of VTE37 • Diagnosis of MM per se41 • Concomitant use of IMiDs with high-dose
embolism regimens in Newly Diagnosed MM: Rd- • Known hypercoagulable state37 • Hyperviscosity42 dexamethasone, anthracycline, or multi-
7-13.5%16,34; VRd- 13%34 • Central venous catheter or agent cytotoxic chemotherapy42,43
• Thalidomide-based combination regimens pacemaker38,39 • Use of erythropoietin stimulating
in Newly Diagnosed • Neurologic disease with extremity agents42
MM: VTd [Newly diagnosed]: 3% paresis38 • Carfilzomib-based combination regimens
grade 3-435 • Immobilization38 [with lenalidomide or
• Carfilzomib-based combination • Surgery38 dexamethasone]10,36
regimens: 1.7-10.2%10,11,36 • Trauma38
• Superficial vein thrombosis38
• Obesity39
• Asian race, Alaskan native or Native
American [Low risk]39,40
• Cardiac disease
• Chronic kidney disease
• Acute infection
• Diabetes mellitus
CHAKRABORTY AND MAJHAIL

(Continues)

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 TABLE 1 (Continued)

Risk Factors

Toxicities/Late effects Incidence Patient-related Disease-related Treatment-related

therapy-related
cardiac toxicities
• Carfilzomib-based combination regimens: • Chronic Kidney Disease • Underlying AL amyloidosis or cardiac light • Carfilzomib-based regimens46
All-grade: 18-51%; ≥Grade 3:8%44,45 • Anemia chain deposition disease • Carfilzomib dose ≥45 mg/m270
• Traditional cardiac risk-factors: Family • Underlying hypercalcemia [Risk of • High-dose Dexamethasone47
44
history, HTN, HLD, DM, Tobacco use arrhythmias]
CHAKRABORTY AND MAJHAIL

• Elevated baseline BNP or NT-pro-BNP44

infections • Bortezomib-based combination regimens: • Male sex52
All-grade 28-48% and ≥ grade
34,48,49
3 6-15%
• Carfilzomib-based combination regimens:
All-grade 28-29% and ≥ grade
3 9-13%*8,17
• Lenalidomide-based combination
regimens: All-grade 27-34% and ≥ grade
3 14-25%16,34,50
• Daratumumab-based combination
regimens: All-grade 46-86% and ≥ grade-
3 23-32%48,50,51
therapy-related renal • Carfilzomib-All-grade: 14-37%
toxicities and ≥ grade 3:4-19%
• Zoledronic Acid-All-grade: 5-6%
and ≥ grade 3:3% for AKI55,56
bone health • Incidence of SREs after treatment
initiation for newly diagnosed MM in the
setting of BMA use: 27–45%
• Normal baseline BNP/NT-Pro-BNP that
becomes elevated mid-first cycle of
treatment44
• Baseline serum β-2 microglobulin53 • Treatment with anti-CD-38 monoclonal
• Older age52 • Baseline LDH53 antibody48,50
53
• ECOG PS53 • Baseline hemoglobin • Treatment with PIs [Increased risk of VZV
• Extramedullary disease and low ALC [Risk infections]
factors for CMV infection]54
• Suppression of polyclonal
immunoglobulins [Immunoparesis]
• CrCl 30-60 mL/min for patients receiving • Baseline renal dysfunction • Use of carfilzomib-based combination
Zoledronic Acid55 regimens
• Use of zoledronic acid as bone modifying
therapy
• Baseline SRE57 • Diagnosis of MM per se • Prolonged use of corticosteroids58

Abbreviations: IV: Intravenous; AKI, Acute Kidney Injury; BMA, Bone-modifying Agent.; BNP, Brain Natriuretic Peptide; DM, Diabetes Mellitus; ECOG, Eastern Co-operative Oncology group; HDM-ASCT, High
Dose Melphalan-Autologous Stem Cell Transplantation; HLD, Hyperlipidemia; HTN, Hypertension; HZV, Herpes Zoster Virus; IMiDs, Immunomodulatory Drugs; LDH, Lactate Dehydrogenase; MDS,
Myelodysplastic Syndrome; MGUS, Monoclonal Gammopathy of Undetermined Significance; ND, Newly Diagnosed; NT-pro-BNP, N-Terminal Pro-Brain Natriuretic Peptide; POEMS, Polyneuropathy,
Organomegaly, Endocrinopathy, Monoclonal plasma proliferative disorder, and Skin changes, PN, peripheral Neuropathy, PIs, Proteasome Inhibitors, IMiDs, Immunomodulatory drugs; PS, Performance Status;
Rd, Lenalidomide-dexamethasone; SC, Subcutaneous; SREs, Skeletal-Related Events [Typically defined as a composite of pathologic fractures, spinal cord compression, and need for surgery or palliative
radiotherapy to the affected bone]; VRd, Bortezomib-Lenalidomide-Dexamethasone; VTd, Bortezomib-Thalidomide-Dexamethasone; VTE, Venous Thromboembolism.
Estimates of pulmonary infection only [including upper respiratory tract infection, pneumonia, and lung infection in primary publication].
675

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676 CHAKRABORTY AND MAJHAIL

TABLE 2 Prevention and management of common toxicities and complications in MM

Toxicity/Late effects Prevention Management

peripheral neuropathy • Active management of common • Assessment of severity
comorbidities like DM, nutritional • Dose modification of the offending
deficiencies, hypothyroidism, and alcohol agent
abuse • Pharmacotherapy: Duloxetine,59
• Choice of optimal treatment regimen Venlafaxine60 [Supported by RCT data].
considering baseline risk-factors for PN Others used off-label: Gabapentin,
[eg, considering DRd for induction pregabalin, tramadol, opiate analgesics.
instead of D-VMP or VRd in a • Assessment of fall risk and frailty in older
transplant-ineligible patient with pre- adults.
existing PN] • Physical therapy
secondary malignancy • Avoid using oral alkylating agents for a • Management according to underlying
prolonged duration [>1 y] tumor type
• Avoid using alkylating agent-based
induction therapy prior to ASCT, if PIs,
IMiDs, and mAbs are available33
• Avoid using lenalidomide and oral
melphalan combinations [eg, MPR]
• If alkylating agent required for disease
control, consider cyclophosphamide over
melphalan31
• Risk assessment for development of
secondary malignancies prior to
choosing a treatment regimen
• Baseline bone marrow examination prior
to initiating lenalidomide maintenance61
• Consider age-appropriate cancer
screening for patients, especially for
those in MRD-negative remission who
are expected to have prolonged survival
• Consider therapy-related myeloid
neoplasm in differential diagnosis for
patients with persistent unexplained
cytopenias
venous thrombo-embolism • Avoid using high-dose dexamethasone • Therapeutic anticoagulation with
with IMiD-based regimens [except in LMWH, warfarin, or DOACs [Lack of
rare circumstances like cast studies comparing above agents in the
nephropathy, when benefit might context of myeloma]
outweigh risk] • Avoid treatment regimens with a high
• Avoid using doxorubicin or multi-agent VTE risk in subsequent lines of therapy
cytotoxic chemotherapy [except for patients with prior VTE unless
bortezomib] with IMiD-based regimens benefits outweigh risk
• Meticulous assessment of patient- • Address modifiable risk factors like
related, disease-related, and treatment- obesity
related risk factors as well as bleeding
risk prior to choosing the optimal
treatment regimen and
thromboprophylaxis strategy
cardiac complications • Pre-treatment cardiovascular • Hold offending agent if patient develops
assessment for addressing traditional signs and symptoms of CHF until initial
risk-factors like HTN, HLD, tobacco evaluation is completed
abuse, and DM. • Consider evaluation and co-management
• Pre-treatment BNP or NT-Pro-BNP to by cardio-oncology clinic
assess the risk of subsequent cardiac • If patient is re-challenged with
toxicities with PIs44 carfilzomib, consider lower dose and
• Consider cardiology evaluation and co- lower IV fluid volume
management for high-risk patients • Aggressive risk factor modification
• Careful consideration of CV risk factors • Optimization of blood pressure control
prior to choosing a treatment regimen
(Continues)

CHAKRABORTY AND MAJHAIL
TABLE 2 (Continued)
Toxicity/Late effects
infections and immunity
renal complications
skeletal-related events and bone health
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677
Prevention Management
• Careful assessment of frailty status at • Treatment according to the site of
baseline and critical decision points infection and/or causative organism
[eg, initiation of subsequent lines of
treatment] to anticipate severe
treatment-related toxicities including
infection
• Ensuring that patients are up-to-date
with recommended vaccinations,
especially, annual inactivated influenza
and pneumococcal polysaccharide
vaccine [PCV13àPPV23]62
• Infectious disease consultation to
complete specific vaccination schedules
after hematopoietic cell transplantation
• Consider daily oral levofloxacin in the
first 12 weeks of induction therapy63
• Consider IVIG in patients with recurrent
infections or secondary
hypogammaglobulinemia62,64,65
• HZV prophylaxis for patients receiving
PIs [until at least 2 mo post-treatment],
anti-CD38 MoABs, high-dose
dexamethasone, and post hematopoietic
cell transplantation62
• Consider PJP and anti-fungal prophylaxis
in patients receiving high-dose
dexamethasone62
• Careful assessment of baseline renal • Follow general dose modification
function, comorbidities and risk of renal guidelines if renal toxicity develops with
toxicity with the treatment regimen treatment
• Consider using denosumab instead of • Consider alternative causes like disease
zoledronic acid for bone-modifying progression, renal amyloidosis, MGRS, or
therapy if CrCl<60 mL/min TMA if renal function does not improve
• Monitoring of serum calcium, vitamin D, after holding the offending agent [kidney
parathyroid hormone, and iron level [for biopsy should be considered in selected
anemic patients] in patients with CKD cases after consultation with
• Follow dose modification guidelines for nephrologist]
chemotherapeutic agents in patients
with baseline renal dysfunction
• Initiation of BMAs [Bisphosphonates or • Consider balloon kyphoplasty over
RANKL inhibitors] at diagnosis and vertebroplasty for vertebral compression
relapse in MM irrespective of the fractures in MM
presence of baseline bone disease • Consider orthopedics, radiation
• Advantage of zoledronic acid over oncology, and pain management or
denosumab: treatment can be de- palliative care evaluation in patients
escalated to every 3 mo, data on overall with SREs
survival benefit over clodronic acid,
lower cost, and no signal for rebound
fracture after discontinuation
• Advantage of denosumab over
zoledronic acid: Subcutaneous route of
administration and lower risk of AKI,
especially in patients with baseline renal
impairment
• High index of suspicion for spinal cord
compression in patients with concerning
signs and symptoms
• Strategies to prevent ONJ in patients on
BMAs: Comprehensive dental evaluation
at baseline [including treatment of active
(Continues)
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678 CHAKRABORTY AND MAJHAIL

TABLE 2 (Continued)

Toxicity/Late effects Prevention Management

dental infection and eliminating sites at a
high risk of infection]; Avoiding invasive
dental procedures and maintaining
excellent oral hygiene while on BMAs;
Holding bisphosphonates 90 d before
and after invasive dental procedures [eg,
tooth extraction, dental implants, and
surgery to the jaw but not root canals];
Limiting cumulative duration of BMAs
[eg, discontinuing zoledronic acid after
2 y from diagnosis if patient is in a deep
hematologic remission]
• Lifestyle modifications: Weight loss,
exercise, smoking cessation, and
limitation of alcohol consumption
• Consider strategic discontinuation of
corticosteroids from the treatment
backbone once a deep hematologic
remission [≥VGPR] has been achieved.
Do not administer corticosteroids with
lenalidomide in the maintenance
setting66
hematologic complications • Consider G-CSF for secondary • Consider ESAs if hemoglobin
prophylaxis in patients with febrile persistently <10 g/dL after treatment
neutropenia on prior chemotherapy with anti-MM agent(s), with the goal of
cycle at physician's discretion reducing transfusion needs
• No role of prophylactic growth factors
for red blood cells and platelets
endocrine complications • Consider baseline thyroid function • Obtain thyroid function panel and
assessment prior to initiating IMiDs initiate appropriate treatment if
• Consider strategic discontinuation of symptoms of hypo or hyperthyroidism
dexamethasone from treatment develop during therapy
backbone once deep hematologic • Co-management with endocrinology in
remission is achieved patients with adrenal insufficiency from
• Avoid high-dose dexamethasone except long-term steroid use
in special circumstances like myeloma
cast nephropathy
• Consider assessment for hypogonadism
in males and pre-menopausal females
ocular complications • Ocular hygiene and patient education • Bortezomib-induced eyelid
regarding potential ocular complications complications [Chalazia or Blepharitis]:
with therapy Ocular therapy [first line]:Warm
• Consider annual ophthalmologic compresses, topical antibiotic
evaluation to assess for toxicities from [+/− steroids], or oral antibiotic
long-term corticosteroid use for [Doxycycline]67
example, cataract Dose modification of offending agent
[second line]

Abbreviation: ASCT, autologous stem cell transplantation; BMA, bone modifying agent; CKD, chronic kidney disease; CrCl, creatinine clearance; CV,
cardiovascular; DM, diabetes mellitus; DM, diabetes mellitus; DOACs, direct oral anti-coagulants; DRd, daratumumab-lenalidomide-dexamethasone; D-
VMP, daratumumab-bortezomib-melphalan-Prednisone; G-CSF, granulocyte colony stimulating factor; HLD, hyperlipidemia; HTN, hypertension; HZV,
herpes zoster virus; IV, intravenous; LMWH, low molecular weight heparin; MGRS, monoclonal gammopathy of renal significance; MoABs, monoclonal
antibodies; mpr, melphalan-prednisone-lenalidomide; ONJ, osteonecrosis of jaw; PCV, pneumococcal conjugate vaccine; PI, proteasome inhibitors; PIs,
proteasome inhibitors; PJP, pneumocystis jiroveci pneumonia; PN, peripheral neuropathy; PPV, pneumococcal polysaccharide vaccine; RANKL, receptor
activator of nuclear factor-κb ligand; RCT, randomized controlled trial; SRE, skeletal-related events; TMA, thrombotic microangiopathy; VGPR, very good
partial response.

Regarding pharmacotherapy, high-level evidence based on random- not included, neurotoxic targets of bortezomib are similar to taxanes
ized controlled trial (RCT) exists for duloxetine in chemotherapy- and platinum.20 Venlafaxine is also effective for neuropathic pain,
59
induced PN. Although patients with bortezomib-induced PN were demonstrated in a small RCT in the context of oxaliplatin-induced

CHAKRABORTY AND MAJHAIL
PN.60 Drugs like gabapentin, pregabalin, and tricyclic antidepressants
are commonly used off-label.70 For poorly controlled neuropathic
pain, opiates, tramadol, or inhaled cannabis could be considered, how-
ever, robust efficacy data are lacking.
2.3 | Future directions
Studies on predictive biomarkers for development of treatment
induced-PN with PIs and IMiDs are urgently needed. Since PN is a
symptomatic adverse event which is prone to under-reporting by
71
clinicians, incorporating patient-reported outcomes (PROs) in clinical
trials and practice can help identify symptoms early. Quantifying the
burden of PN using toxicity over time (ToxT) framework72 in clinical tri-
als will help better estimate the toxicity burden with individual thera-
pies. RCTs of non-pharmacological measures (eg, acupuncture) should
be conducted to mitigate symptoms and improve physical functioning.
3 | COGNITIVE IMPAIRMENT
Cognitive impairment has been reported with the use of IMiDs in
73,74
myeloma. In the phase III TOURMALINE-MM1 trial comparing
ixazomib-lenalidomide-dexamethasone to lenalidomide-dexamethasone
in relapsed/refractory myeloma, a decline in cognitive functioning from
baseline was noted in both arms.73 AHCT can also lead to short-term
deterioration in cognitive functioning, which resolves by 6-month
75
follow-up. Cognitive impairment caused by IMiDs is mostly reversible
within days to weeks after dose discontinuation.74 High-dose dexa-
methasone can also lead to mood changes and cognitive impairment.
Selinexor, which has received accelerated approval by the FDA for
triple-class refractory myeloma, causes mental status changes in 17%
of patients (6% being grade 3).76
3.1 | Management
Risk factors such as prior dementia, cognitive impairment, frailty, cere-
brovascular disease, and polypharmacy should be meticulously
assessed before initiating a new treatment regimen. Once cognitive
impairment is detected on anti-myeloma therapy, search for alternate
etiologies like hypothyroidism, vitamin B12 deficiency, and vascular
dementia should be considered. For patients with persistent cognitive
impairment, central nervous system stimulants like methylphenidate,
anti-dementia drugs like donepezil, memantine, and gingko biloba, and
bone marrow stimulants like erythropoietin have been used,77
although robust evidence-base is lacking in this population.
3.2 | Future directions
Cognitive behavioral therapy is effective in cancer survivors with cog-
nitive impairment,78 and further studies are warranted in myeloma
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679
survivors. Incorporating frailty assessment tools like the one devel-
oped by the IMWG79 or Revised Myeloma Comorbidity Assessment80
at critical time-points (eg, diagnosis, relapse or initiating a new line of
therapy) should be prospectively studied.
4 | SECOND CANCERS
The association between myeloma and therapy-related myeloid
neoplasms (t-MN) was initially described in the era of alkylating agent-
based therapies.23 Notably, there is marked heterogeneity in estimates
of cumulative incidence across databases,23-27,81 likely due to variable
follow-up durations and ascertainment of myelodysplastic syndrome
(MDS). Prior to the era of PIs and IMiDs (1958-1996), the Swedish
group showed a standardized incidence ratio (SIR) of 8.2 for secondary
acute myeloid leukemia (AML) in patients with myeloma.25 Another
study on Finnish patients treated with alkylating agents with a median
follow-up of 16 years revealed a cumulative risk of acute leukemia of
approximately 10% at 9 years, with the risk being 45-fold compared to
the general population.24 Data from the SEER registry showed an
increase in cumulative incidence of secondary malignancies from 4.7%
in the 1995-99 to 6.3% in the 2005-09 cohort (p < .001), with a pro-
gressive increase in the risk of secondary hematologic malignancies.
Studies have also demonstrated an increased risk of acute lymphoblastic
leukemia (ALL) in myeloma survivors, with SIR of 5.48.82 A recent study
on therapy-related ALL (t-ALL) identified myeloma as the second most
common cancer preceding t-ALL, after breast cancer.83 The median time
to development of secondary malignancies from myeloma diagnosis is
around 3-5 years.24,28 Most population studies do not demonstrate an
increase in the risk of therapy-related solid tumors in myeloma.24,27
Among currently used anti-myeloma therapies, there is robust evi-
dence on increased risk of secondary malignancy with oral melphalan
and lenalidomide. In a British RCT, duration of melphalan but not cyclo-
phosphamide was associated with an increased risk of t-MN.23 Post-
transplant maintenance with lenalidomide increases the risk of both
secondary hematologic (6% vs 3%) and solid neoplasms (7% vs 4%) com-
pared to controls.32 Furthermore, combined exposure to lenalidomide
and oral melphalan (but not lenalidomide with cyclophosphamide) is
associated with a 5-fold higher risk of secondary hematologic malignan-
cies compared to melphalan alone.29 The incremental risk of developing
secondary malignancies with AHCT in the era of PIs and IMIDs is
unclear. A CIBMTR study on patients undergoing AHCT between 1990
and 2010 did not find an increased risk of second malignancies in gen-
eral. However, subgroup analysis showed increased risk of AML (SIR 5.2)
and melanoma (SIR 3.6) compared to demographically matched healthy
controls.30 Risk factors for t-MN risk after AHCT are older age,30 male
sex,30 obesity,30 and duration of pre-transplant alkylator therapy.33
4.1 | Management
Careful consideration of risk-factors for development of secondary
malignances is warranted prior to initiating treatment in myeloma.

680
Age-appropriate cancer screening per guidelines should be consid-
ered, since an increasing proportion of standard-risk myeloma patients
may achieve long-term survival. Combined exposure to lenalidomide
31
and oral melphalan should be avoided. The duration of alkylator-
based therapy, if used, should not exceed 6-12 months. The IMWG
guidelines recommend performing a baseline bone marrow examina-
tion to rule out overt dysplasia or clonal cytogenetic abnormalities at
initiation of lenalidomide maintenance.61 Since transplant-eligible
myeloma patients are known to have a high incidence of CHIP (Clonal
Hematopoiesis of Indeterminate Potential) at approximately 30%,84
long-term follow-up is needed to assess whether CHIP can be a pre-
dictor of subsequent t-MN. Survival in patients developing t-MN after
myeloma is similar to those with secondary AML/MDS28 and alloge-
neic HCT is the only curative option in this setting.
4.2 | Future directions
Most of the data on characterization of secondary cancers in myeloma
survivors include patients treated prior to the novel agent era. Hence,
more data is needed on incidence and timeline for development of
secondary cancers exclusively in the era of PIs and IMiDs with long
follow-up. Research on genetic determinants of second cancers like
damage in DNA repair genes and CHIP will help individualize therapy
and surveillance. The impact of AHCT on development of second can-
cers in the current era also needs to be clarified.
5 | CARDIOVASCULAR AND THROMBOTIC
C O M P L I CA T I O N S
5.1 | Venous thromboembolism
The diagnosis of MM per se is associated with a high risk of venous
thromboembolism (VTE), with a relative risk of 9.2 (95% CI, 7.9-10.8)
compared to the matched general population.41 A signal for increased
VTE risk was identified with both thalidomide and lenalidomide,43,85
which led to the initiation of routine risk-stratified thromboprophylaxis
with IMiDs.42
The incidence of VTE with currently used IMiD-based combination
16,34,35,37,38,40-43
regimens and risk factors are summarized in Table 1.
The strongest patient-specific risk-factors of VTE include previous VTE,
presence of central venous catheter, and prior surgery or immobiliza-
tion.38-40,42 Treatment-related risk factors include use of IMiDs with
high-dose dexamethasone, doxorubicin, or multi-agent chemother-
apy.42,43,47 The incidence of VTE with IMiDs is highest in the first
6 months of therapy and higher in newly diagnosed compared to
relapsed/refractory setting.42 The risk of VTE with IMiD maintenance is
extremely low and routine thromboprophylaxis is not recommended in
this setting.42 Notably, two RCTs of carfilzomib have demonstrated a sig-
nal for higher VTE risk with carfilzomib-based combination regimens
compared to control.10,36 Hence, the FDA label recommends throm-
boprophylaxis with carfilzomib-based regimens. A new risk model called
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CHAKRABORTY AND MAJHAIL
“SAVED” score has been developed and validated, which has the follow-
ing variables: Surgery within 90 days, Asian race, VTE history,
age ≥ 80 years, and dexamethasone dose (c-index of 0.61).86 This model
could be considered for identifying high-risk patients in clinical practice
and designing thromboprophylaxis trials targeting such patients.
5.2 | Management
As per IMWG consensus guidelines, patients with one or no risk fac-
tor should take aspirin 81-325 mg daily and those with more than one
risk-factor should take low molecular weight heparin or therapeutic
dose warfarin.42 Treatment should follow American Society of Clinical
Oncology (ASCO) guidelines for cancer-related VTE.87
5.3 | Future directions
The incidence of VTE with contemporary IMiD-based regimens despite
thromboprophylaxis is 6-7%.88,89 Around 70% of VTE events happen on
ASA.88 Hence, well-designed clinical trials on thromboprophylaxis strate-
gies targeting patients at a high risk of VTE are urgently needed. Cur-
rently, efforts are underway to test direct oral anticoagulants like
apixaban for thromboprophylaxis in myeloma (NCT02066454). Identify-
ing novel biomarkers like differentially expressed genes or pathways for
myeloma-associated VTE will also facilitate risk stratification and
treatment.
6 | T H E R A P Y - R E L A T E D CA R D I A C
TOXICITIES
Patients with myeloma have a high incidence of baseline cardiovascu-
lar co-morbidities.90 Furthermore, 10%-20% of patients also have
concomitant light-chain amyloidosis which requires a high index of
suspicion during diagnostic workup.
Carfilzomib has demonstrated a signal for increased cardiac toxic-
ities, with the incidence of all-grade and ≥ grade 3 toxicities being
18.1% and 8.2% respectively and the risk ratio for high-grade cardiac
toxicities being 2.2.46 Potential mechanisms include endothelial toxic-
ity, inhibition of the ubiquitin proteasome system in cardiac myocytes,
and cardiorenal syndrome.44,45 The most common cardiac toxicities
with carfilzomib are heart failure (systolic or diastolic), cardiac chest
pain, hypertension, arrhythmia, acute coronary syndrome, and pulmo-
nary hypertension.44,46 Approximately 90% of cardiac toxicities hap-
pen in the first 3 months of treatment, with the median time to first
event being 31 days and a plateau in the incidence curve beyond
5 months.44 Elevated natriuretic peptide at baseline but not echocar-
diogram or electrocardiography findings are predictive for develop-
ment of subsequent cardiac toxicities with PIs. Furthermore, normal
baseline natriuretic peptide level which becomes elevated mid-first
cycle is also an independent predictor of cardiotoxicity.44 Although
cardio-toxicity is considered to be a class effect of PIs, the incidence

CHAKRABORTY AND MAJHAIL
is lower with bortezomib, as shown in the ENDEAVOR trial, where
the incidence of grade 3 hypertension and dyspnea was 9% and 5% in
10
carfilzomib arm vs 3% and 2% in bortezomib arm respectively.
6.1 | Management
Management of therapy-related cardiotoxicity depends on the type of
event and severity. In patients who develop signs and symptoms of
congestive heart failure on carfilzomib-based regimens, initial evalua-
tion should include an echocardiogram and cardio-oncology consulta-
tion. Carfilzomib should be held at this time until evaluation is
completed. After signs and symptoms subside, re-challenge with
carfilzomib at a lower dose and lower fluid volume could be consid-
ered after risk-benefit assessment. Notably, majority of cardiac toxic-
ities are transient, with natriuretic peptide levels returning to
near-baseline value at a median of 3.5 weeks after the event.44 Tran-
sient dyspnea after carfilzomib administration has been well-described
and is usually self-limiting, however, pulmonary hypertension, infec-
tion, and pulmonary embolism should be in the differential diagnosis.
6.2 | Future directions
Prospective studies with cardio-toxic agents to identify the trajectory
and predictive biomarkers for specific cardiac events are needed to
inform clinical practice and surveillance. Pre-clinical studies show that
carfilzomib has off-target effects on the AMPKα/mTORC1 pathway
and metformin can be potentially cardio-protective by restoring the
AMPKα phosphorylation in mouse models, leading to reduced frac-
91
tional shortening of ventricles. This lays the groundwork for a clini-
cal trial of metformin in patients at a high risk of cardiotoxicity with
carfilzomib.
7 | INFECTIONS AND IMMUNITY
Myeloma is associated with a high risk of infections, both due to the
underlying disease and treatment-induced immunosuppression. A Swed-
ish study of 9253 patients treated prior to the novel agent-era showed a
cumulative incidence of any infection of 41% at 2.6 years median follow-
up, with the risk being 7-fold compared to controls.52 Around 90% of
patients had bacterial, and 15% had viral infections. The most commonly
reported bacterial infections were pneumonia, septicemia, cellulitis,
pyelonephritis, meningitis, osteomyelitis, and endocarditis, in decreasing
order of incidence. Herpes zoster and influenza were the most com-
monly reported viral infections. Notably, the risk of infection was highest
in the first year following diagnosis. Furthermore, the risk ratio of infec-
tion increased progressively from 6-fold in the 1988-1993 cohort, to
12-fold in the 2000-2004 cohort, compared to matched controls. A ret-
rospective study has shown higher risk of cytomegalovirus infection in
patients with extramedullary disease and low absolute neutrophil
54
count. Treatment with daratumumab is also a risk factor for Listeria
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681
infection, likely due to CD38 expression on activated macrophages,
which play a role in Listeria defense.92 The cumulative incidence of hepa-
titis B virus (HBV) reactivation, as described in a Japanese study, is 8%
and 14% at 2 and 5 years respectively, among which, 17% developed
clinical hepatitis.93 On multivariable analysis, receipt of AHCT was asso-
ciated with a significantly higher odds of HBV reactivation. The incidence
of infections with currently used anti-myeloma agents are summarized in
Table 1.10,11,16,34,48-54
A validated predictive model for early ≥grade 3 infections has
been developed in the context of treatment with IMiDs.53 The scoring
system includes four variables: ECOG Performance Status, β-2 micro-
globulin, hemoglobin, and lactate dehydrogenase. The model divided
patients into high and low risk groups, with the risk of early serious
infection being 24% vs 7% respectively (P < .0001; c-index, 0.66).
Notably, an initial grade ≥ 3 infection in the first 4 months of treat-
ment was associated with a worse OS.
7.1 | Management
One of the key clinical questions in this area is the optimal strategy
for infection prevention. An RCT on patients receiving induction ther-
apy prior to the novel agent-era did not demonstrate risk reduction of
serious bacterial infections with prophylactic ciprofloxacin or
trimethoprim-sulfamethoxazole (TMP-SMZ) over placebo.94 However,
another trial from the United Kingdom demonstrated a significant
reduction in the risk of febrile episode or death (primary endpoint) in
the first 12 weeks with daily oral levofloxacin compared to placebo
(27% vs 19% respectively; P = .002),95 in the context of cyclophos-
phamide and PI/IMiD-based therapy. Notably, levofloxacin signifi-
cantly reduced the incidence of invasive gram-negative but not gram-
positive infections. Based on available data, levofloxacin prophylaxis
in the first 12 weeks can be considered in newly diagnosed patients.
A small RCT in the 1990s had demonstrated a decrease in the risk of
pneumonia or septicemia with use of intravenous immunoglobulin
(IVIG) in the plateau phase (0% vs 24% with and without IVIG respec-
tively).64 The maximal benefit from IVIG was derived by those who
had a suboptimal IgG antibody response to pneumococcal polysaccha-
ride vaccine before therapy. Another small Italian RCT in the era of
PIs and IMiDs has also shown that monthly subcutaneous immuno-
globulin replacement in myeloma patients with secondary hyp-
ogammaglobulinemia leads to a lower infection rate and superior
QoL.65 However, given the cost and potential toxicities of IVIG, it is
not used routinely for primary prophylaxis in newly diagnosed
patients. Of note, IVIG should be considered in patients with recur-
rent infections and IgG level persistently below 400 mg/dL. Vaccina-
tions including inactivated influenza and pneumococcal
polysaccharide should be administered to all patients. For those
receiving PIs, anti-CD-38 mAbs, or high-dose dexamethasone, herpes
zoster virus prophylaxis is mandatory. Pneumocystis jiroveci pneumonia
and anti-fungal prophylaxis should be considered in patients on high-
dose dexamethasone.62 Screening and prophylaxis for HBV reac-
tivation should follow general ASCO guidelines, which recommends

682
starting antiviral therapy in patients who are HBsAg-positive/anti-
HBc-positive before or during anti-cancer treatment.
7.2 | Future directions
Whether all newly diagnosed myeloma patients treated with combinations
of PIs, IMiDs, mAbs, and low-dose dexamethasone need infection prophy-
laxis still remains an open question. Furthermore, whether antibiotics (levo-
floxacin and/or TMP-SMZ) or immunoglobulin replacement is better for
primary prophylaxis also needs to be tested in well-designed RCTs in the
context of current treatment landscape. Designing these studies as a com-
panion to therapeutic trials run by cooperative groups might be feasible
and facilitate faster accrual. The validated tool for infection prediction, as
mentioned earlier,53 can be used to target high-risk patients for such trials.
8 | RENAL COMPLICATIONS
Renal health is an important survivorship issue in patients with mye-
loma. Approximately one in five patients with myeloma present with
renal impairment at diagnosis.96 Complete renal response can be seen
in 40% of these patients treated in the era of PIs and IMiDs, which
leads to a superior OS compared to non-responders.96 In patients with
cast nephropathy, instituting prompt bortezomib-based systemic ther-
apy along with intravenous hydration, and treating hypercalcemia
aggressively are key to renal recovery.97 Management of myeloma-
related renal dysfunction in the novel agent-era is beyond the scope
of this review and has been described elsewhere.98
Among current treatments, signal for therapy-related renal toxicity
has been seen with the second generation PI carfilzomib and with
bisphosphonates.10,11,55,56 RCTs have shown a higher rate of all-grade
and ≥ grade 3 renal toxicities in carfilzomib arms compared to con-
trols.10,11,36,99 The majority of renal toxicities were classified as acute
kidney injury (AKI). However, there is a lack of prospective data on risk
factors and trajectory of renal toxicities with carfilzomib. A study on real-
world experience with carfilzomib-based regimens has shown the risk of
all-grade AKI and creatinine increase to be 28% and 37% respectively,
with majority being grade 1-2. Most toxicities were transient, similar to
100
cardiac toxicities. The incidence of renal toxicity is higher in patients
10,99
with eGFR<50. Endothelial toxicity, cardiorenal syndrome, and
thrombotic microangiopathy (TMA) are some of the proposed mecha-
45
nism for renal adverse events with carfilzomib. Zoledronic acid also
increases the risk of AKI compared to denosumab, with the risk being
more in patients with eGFR<60 mL/min55. Notably, zoledronic acid
should be avoided in patients with eGFR<30 mL/min. The incidence and
risk-factors of therapy-related renal toxicities is summarized in Table 1.
8.1 | Management
There is a lack of data on risk factors and dose modification strategy
specifically for renal toxicities. Hence, general dose modification
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CHAKRABORTY AND MAJHAIL
guidelines should be followed. Notably, lenalidomide can be adminis-
tered safely in a once-daily dosing regimen in patients with creatinine
clearance <30 mL/min at doses of at least 15 mg, whether or not on
dialysis.101 For patients on bisphosphonates, a spot urine sample
should be checked every 3-6 months, and if positive, should be
followed by 24-hour urine protein analysis to look for the presence
and degree of albuminuria.102 If patients develop AKI on anti-
myeloma therapy, causes such as progression of underlying disease,
hypercalcemia, development of renal amyloidosis, and sepsis should
be ruled out. Supportive care should be initiated, including adequate
hydration, avoidance of nephrotoxic agents, and optimal blood pres-
sure control. TMA should be in the differential diagnosis if AKI
develops on carfilzomib. Case reports have suggested that
carfilzomib-induced TMA is associated with heterozygous deletion of
complement pathway genes CFHR3-CFHR1, and eculizumab may be
effective in this setting.103
8.2 | Future directions
Prospective studies are needed to identify the nature, trajectory, and
risk factors of renal toxicity with carfilzomib, especially with wide-
spread use in frontline setting. Pre-clinical studies to identify the
molecular mechanism of renal toxicity may help devise preventative
strategies.
9 | M U S C U L O S K E L E T A L CO M P L I C A T I O N S
(BONE HEALTH)
Patients with myeloma are at risk of skeletal-related events (SREs), either
as an end-organ damage from underlying disease or from prolonged
administration of corticosteroids. In clinical trials, SREs are typically
defined as a composite of pathologic fracture, spinal cord compression,
and need for surgery or palliative radiotherapy to the affected bone.
Even with routine use of bone-modifying agents (BMAs), the incidence
of SREs after treatment initiation in newly diagnosed myeloma remains
substantial at 27-45% in recent clinical trials (Table 1).55,56 Approxi-
mately 80% of SREs happen in the first 6 months after diagnosis.55 Base-
line SRE at diagnosis is a risk-factor for subsequent SREs within 1 year.57
Corticosteroids form the backbone of most combination regimens used
in newly diagnosed and relapsed/refractory MM. A prednisolone equiva-
lent of more than 30 mg per day or a cumulative dose of more than 5 g is
associated with 14-fold increase in the risk of vertebral fracture and a
3-fold increase in the risk of hip fracture.104 However, the fracture risk
decreases dramatically after discontinuation of corticosteroids.58
9.1 | Management
All patients with MM should be initiated on BMAs, either
bisphosphonates or denosumab, at diagnosis irrespective of the pres-
ence of baseline bone disease.102,105 BMAs may be discontinued after

CHAKRABORTY AND MAJHAIL
2 years at at physician's discretion if a patient is in deep hematologic
remission. However, denosumab has a reversible mechanism of action,
with reports of rebound fractures after discontinuation in the setting of
osteoporosis.106 Hence, patients should be switched to bisphosphonates
in case denosumab is discontinued. In patients with renal impairment at
baseline, denosumab should be preferred over zoledronic acid due to a
lower incidence of AKI. 102
Furthermore, denosumab can be adminis-
tered subcutaneously unlike bisphosphonates, which are administered
intravenously. For patients on zoledronic acid, treatment burden can be
reduced by de-escalating frequency from every 4-week to every
107
12-week without compromising efficacy. Both bisphosphonates and
denosumab leads to comparable rates of jaw osteonecrosis (≈4%).55
Strategies to prevent ONJ are summarized in Table 2. In the mainte-
nance setting, adding corticosteroids to lenalidomide does not improve
PFS or OS, both in transplant-eligible and ineligible patients.66 Hence,
corticosteroid should be strategically discontinued once a deep hemato-
logic remission is achieved to avoid toxicities. If BMAs are discontinued
in first remission after 2 years of treatment, they should be resumed at
102
subsequent relapse.
9.2 | Future directions
Further investigation on serum and urinary biomarkers of bone
resorption in myeloma survivors can be potentially used to personal-
ize the intensity and duration of BMAs. Long-term follow up data
from clinical trials on denosumab should be investigated to identify
the incidence of rebound fractures, if any, after dose discontinuation.
Clinical trials on novel BMAs like romosozumab (monoclonal antibody
targeting sclerostin) and sotatercept (a fusion protein of the extracel-
lular domain of high affinity activin receptor IIA and human immuno-
globulin G Fc domain) should be conducted in patients developing
SREs on currently used BMAs.
10 | HEMATOLOGIC COMPLICATIONS
Anemia is one of the most common hematologic toxicities in myeloma
and can be a result of anti-myeloma therapy or poorly controlled dis-
ease. A Cochrane review of more than 20 000 cancer patients
enrolled in RCTs of erythropoietin stimulating agents (ESAs) showed
significantly lower transfusion requirement but higher risk of throm-
108
boembolic events and death in patients receiving ESAs. In non-
myeloid hematologic malignancies like myeloma, current ASCO/ASH
guidelines recommend waiting for hematologic response of treat-
ments prior to initiating ESAs.109 Red blood cell transfusions can be
considered in the interim. If hemoglobin is persistently <10 g/dL, ESAs
can be administered after considering alternate causes of anemia, like
nutritional deficiency or therapy-related myeloid neoplasm. The target
hemoglobin should be individualized to the lowest level needed to
decrease transfusion requirements and should not exceed 12 g/dL. In
patients who do not respond within 6 to 8 weeks, ESAs should be
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683
discontinued. Iron supplementation should be considered in patients
receiving ESAs both with and without iron deficiency.
Neutropenia has been reported with several combination regimens
in myeloma, especially those including traditional cytotoxic agents and
newer IMiDs.110 ASCO recommends using granulocyte-colony stimulat-
ing factor (G-CSF) as primary prophylaxis with chemotherapy regimens
having a febrile neutropenia risk of ≥20%.111 Secondary G-CSF prophy-
laxis can be considered if dose modification is thought to compromise
treatment outcome. G-CSF should be administered after AHCT to
reduce the duration and severity of neutropenia.111
11 | E N D O C RI NE C O M P L I C A T I O N S
Thyroid function abnormalities have been reported with the use of
IMiDs. The incidence of new thyroid dysfunction after lenalidomide initi-
ation is 6%.112 A prospective study revealed grade 2 thyroid abnormality
in 10% of patients, with the median time to thyroid dysfunction being
4 months (range, 2-8).113 Hypothyroidism is also a late effect of
AHCT.114 Patients should be assessed for baseline thyroid dysfunction
prior to initiating IMiDs and a high index of suspicion for hypo- and
hyperthyroidism should be maintained during the treatment course.
Prolonged administration of corticosteroids, which forms the
backbone of most combination regimens in myeloma, can lead to
adrenal insufficiency (AI). A retrospective study showed a cumulative
median dexamethasone dose of 960 mg prior to developing AI in
myeloma patients.115 Patients experiencing signs and symptoms of AI
(eg, hypotension, weight loss, diarrhea, and fatigue) should have a
serum cortisol level and ACTH stimulation test done to establish diag-
nosis. Co-management with endocrinologist should be considered.
12 | O CU L A R C O M P L I C A T I O N S
Eyelid complications, including chalazia and blepharitis, has been reported
with bortezomib.67 Time-to-ocular complication from first bortezomib
exposure is around 3 months. Rare cases of eyelid complications have
been reported after carfilzomib as well.67 Treatment includes ocular ther-
apy or dose modification/omission of the offending agent. Average time
to resolution with ocular therapy alone is around 2 months. Ocular ther-
apy consists of warm compresses, topical antibiotics (+/− steroids), and
oral antibiotic. Prolonged oral doxycycline can be used to treat severe
bortezomib-induced blepharitis.116 Combination of ocular therapy and
discontinuation of the offending agent leads to a higher rate of resolution
than ocular therapy alone.67
A novel antibody-drug conjugate targeting B-cell maturation antigen
(Belantamab mafadotin; GSK2857916), which has a high single-agent
activity (60%) in relapsed MM, leads to ocular toxicity in the form of cor-
neal events.117 Corneal toxicity was noted in 63% of patients with 9%
being grade 3 or higher. The most common finding on ophthalmologic
examination was superficial punctate keratitis, with decrease in visual acu-
ity by Snellen method noted in most patients during treatment. Around
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684 CHAKRABORTY AND MAJHAIL

one-third of patients had complete resolution, with the median duration 14 | S UR V I V O R S H I P C A R E I N M U L T I P L E

of toxicity being 30 days. Management included dose modification or
omission, and supportive care with artificial tears and steroid eye drops.
Further data on long-term follow up and phase 3 trials will establish the
trajectory and late effects of corneal toxicities with GSK2857916.
1 3 | F R A I LT Y , SYM P TOM A TI C A D V ER SE
E V E NT S , A N D Q U A L I T Y OF L I F E
Myeloma is a disease of older adults, with approximately one-third of
patients more than 75 years of age. The IMWG frailty index incorporates
age, activities of daily living (ADL), instrumental ADLs, and Charlson
Comorbidity Index to identify three categories of patients: fit, intermediate
fit, and frail. Baseline frailty status is predictive of treatment discontinuation
rate, severe non-hematologic toxicities, and overall survival.79 Gait speed
and grip strength, which can be easily assessed in the clinic, also identifies
frail patients and predicts for higher mortality, unplanned hospitalization,
118
and emergency department visits. Assessment of frailty status at base-
line and decision points (eg, initiation of subsequent lines of therapy) is
important for treatment decision-making and supportive care delivery.
Several symptoms including pain, fatigue, anxiety, depression, and
decreased mobility are independently associated with global QoL in
patients with myeloma.119 A systematic review of QoL findings from mye-
loma clinical trials showed clinically meaningful QoL improvements with
effective first-line therapy.120 However, in relapsed myeloma, no clinically
meaningful improvement or deterioration was observed, with mainte-
nance of QoL on treatment in most studies. Gastrointestinal symptomatic
adverse events including nausea, vomiting, diarrhea, or constipation can
be seen with several oral agents including thalidomide, lenalidomide,
pomalidomide, ixazomib, and panobinostat. Diarrhea can happen in up to
44% of patients receiving lenalidomide maintenance.121 Further studies
are needed on the value of assessing PROs in clinical practice and develop-
ing survivorship care plans in this patient population.
MYELOMA
In cancer survivorship, the term “survivor” applies to individuals with
cancer, anywhere along the disease trajectory from diagnosis till end-
of-life.122 Much of the work in cancer survivorship has focused on
curable cancers for example, early stage breast cancer, Hodgkin's lym-
phoma, and survivors of allogeneic HCT. However, the survivorship
care needs of patients with myeloma is unique due to several factors.
First, myeloma remains an incurable disease despite advances in ther-
apy and marked improvement in overall survival. Second, the treat-
ment paradigm has shifted from a fixed duration-therapy to
continuous therapy until disease progression or unacceptable toxicity.
Hence, implementation of survivorship care plan (SCP) at a single
time-point may not be meaningful since the exposure profile changes
along the disease trajectory. Third, despite myeloma being an incur-
able disease, around one-tenth of transplant-eligible patients are able
to achieve an overall survival comparable to demographically matched
healthy population.123 The proportion of patients achieving long-term
survival will likely increase due to current advances in therapy.
Hence, further research on non-cancer comorbidities, QoL, and
myeloma- or therapy-related late adverse effects in this population
will be needed to optimize survivorship care. Fourth, fear of relapse
and prognostic uncertainty remains a challenge for patients and care-
givers, given the rapidly changing treatment landscape and new
insights into biology and risk stratification. Longitudinal conversations
with patients regarding their prognosis, treatment options, and goals
of care are important to facilitate informed treatment decisions.
Finally, patients with myeloma can experience financial burden due
to high drug costs,124 missed work, and difficulty obtaining or
maintaining health insurance. Further research on the prevalence of
financial toxicity, impact on QoL, and identifying opportunities for
intervention (eg, financial navigator programs) is urgently needed in this
population.

F I G U R E 2 Survivorship care model for patients living with multiple myeloma. Primary responsibility for cancer-related care and complications from
treatment or underlying cancer. Primary responsibility for managing non-cancer co-morbidities. Co-management with multiple myeloma specialist or
primary care physician on special situations for example, co-management with cardiooncology for carfilzomib-induced cardiotoxicity. Communication time-
points between multiple myeloma specialist, primary care physician, and other subspecialists: A, Discuss multiple myeloma diagnosis, planned induction and
consolidation therapy, and anticipated adverse events. B, Discuss maintenance strategy, adverse effects of maintenance therapy, and plan for post-
transplant immunization in transplant-eligible patients. C, Discuss disease relapse, treatment strategy, and anticipated adverse events of treatment.
D, Communication between multiple myeloma specialist, primary care physician, and subspecialist during periods of active subspecialty care needs [Color
figure can be viewed at wileyonlinelibrary.com]
 10968652, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.25764 by CAPES, Wiley Online Library on [14/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
CHAKRABORTY AND MAJHAIL 685

TABLE 3 Overview of knowledge gaps and research agenda for management of toxicities in MM

Toxicity/Late effects Knowledge gaps and research priorities

peripheral neuropathy • Identify risk-factors and predictive biomarkers [including pharmacogenomic markers] for development of PN with PIs and
IMiDs
• Assessment of longitudinal persistence of PN-related symptoms using Toxicity over Time [ToxT] models72
• Implementation of PRO instruments in clinical trials and practice to quantify symptom burden and potential early
intervention
• Conduct RCTs on pharmacological as well as non-pharmacological interventions for management of therapy related PN
in MM
secondary malignancy • Conduct population studies using large databases to estimate the risk of secondary hematologic and solid malignancies
exclusively in the era of PIs and IMiDs
• Long-term follow up of ongoing RCTs in MM [Median time to development of secondary malignancies from MM
diagnosis is around 3-5 y24,28], with incorporation of secondary malignancies as an additional endpoint
• Investigate the trajectory of incidence, genetic makeup, and treatment outcomes of secondary malignancies after MM
diagnosis
• Identify predictive biomarkers [eg, CHIP or inherited damage in DNA-damage repair genes] to ascertain the risk of
developing subsequent secondary malignancies
• Investigate the impact of duration of lenalidomide maintenance on risk of secondary malignancies
• Long-term follow up of patients undergoing HDM-ASCT without exposure to alkylating agents or anthracycline during
induction therapy to ascertain the risk of second malignancies with auto-transplant in the context of novel-agent based
induction and subsequent therapies
venous thrombo- • Develop and validate risk -stratification models for predicting VTE with contemporary combination regimens
embolism • Externally validate SAVED and IMPEDE-VTE scores in datasets with contemporary IMiD-based combination regimens [eg,
IMiDs in combination with PIs, MoABs, or both]
• Conduct RCTs of novel oral anticoagulants for thromboprophylaxis in MM
• Secondary analysis of clinical trials to identify the cumulative incidence and trajectory of VTE events with new IMiD-
based combination regimens
therapy-related cardiac • Conduct prospective multi-center studies on CVAEs with specific agents of interest like carfilzomib
toxicity • Secondary analysis of individual patient-level clinical trial data to identify predictors of cardiac toxicities
• Preclinical studies to identify the mechanistic basis of cardiotoxicity with proteasome inhibitors
• Perform RCTs of cardio-protective strategies [eg, using ACEi or beta-blockers] in high-risk patients
• Clinical trial of metformin to prevent carfilzomib-induced cardiotoxicity based on promising pre-clinical data
infections and immunity • Develop a validated predictive model for severe infections in the context of treatment with combination of novel agents
[PIs, IMiDs, and mAbs]
• Perform RCTs on prophylactic antibiotics in patients at a high risk of severe infections and infection-related mortality
• Perform RCTs on IVIG in the context of currently used mAb-based combination regimens
• Periodic investigation of population-based registries and databases to identify risk and epidemiology of infections with
changing treatment patterns
• Translational studies on immune reconstitution in MM upon treatment with different combination regimens
therapy-related renal • Conduct prospective multi-center studies to assess the nature and trajectory of renal toxicities with carfilzomib-based
toxicity combination regimens
• Develop and validate predictive model for identifying patients at a high risk of therapy-related renal toxicity
bone health • Incorporation and reporting of PROs in clinical trials of bone-modifying agents in MM
• Conduct correlative studies to identify biomarkers for bone resorption which can be potentially used to tailor therapy
• Conduct clinical trials on novel bone modifying agents like romosozumab [monoclonal antibody targeting sclerostin] and
sotatercept [a fusion protein of the extracellular domain of high affinity activin receptor IIA and human immunoglobulin G
Fc domain] in MM
• Conduct randomized trials on structured physical activity and impact on bone health in MM survivors
• Identify patient-related, disease-related, and treatment-related risk factors of SREs in MM
survivorship care • Conduct quantitative and qualitative research on financial toxicity with anti-cancer therapy in MM
• Conduct RCTs on palliative care intervention to optimize symptom management

Abbreviations: ACEi, angiotensin converting enzyme inhibitors; ASCT, autologous stem cell transplantation; CHIP, clonal hematopoiesis of undetermined
significance; CVAE, cardiovascular adverse events; HDACi, histone deacetylase inhibitors; HRQoL, health-related quality of life; IMiDs, immunomodulatory
drugs; IVIG, intravenous immunoglobulins; MM, multiple myeloma; MoABs, monoclonal antibodies; PI, proteasome inhibitors; PN, peripheral neuropathy;
PN, peripheral neuropathy; PRO, patient-reported outcome; PROs, patient-reported outcomes.; RCT, randomized controlled trial; t-MN, therapy-related
myeloid neoplasm; ToxT, toxicity over time.

Survivorship care is best delivered under the framework of patient-level factors include distance from myeloma treatment center,
patient-centric care models. There are several patient, provider, and disease biology, complexity of ongoing therapy, and depth of disease
system level factors that are important in this context. Important control. Provider-level factors include expertise and comfort in

686
providing survivorship care, knowledge of survivorship care needs,
and relationship with patient. System-level concerns include payer
requirements and access to subspecialties for multidisciplinary care.
Since myeloma patients are on continuous therapy, the treating hema-
tologist/oncologist is often the primary clinician driving survivorship
care with the assistance of primary care providers (PCP) and other
subspecialties depending on patients' unique needs (Figure 2). PCPs
should be educated about common side-effects of medications (eg,
hypertension with carfilzomib) and roles of different members in the
care team should be clearly defined. Co-management with sub-
specialty teams may be needed in patients developing specific toxic-
ities (eg, endocrinology consultation for management of adrenal
insufficiency or uncontrolled diabetes exacerbated by corticosteroids).
Ancillary services like physical therapy, social workers, financial navi-
gator, clinical psychologist, and dietician should be utilized as needed.
The role of SCPs in myeloma is not well-defined. In patients
remaining in a stable remission post-transplant, individualized SCP has
been shown to reduce distress and improve mental QoL in an RCT.125
However, due to constantly changing exposure profile in most
patients, SCPs at several time-points along the disease trajectory (eg,
Figure 2; time-points a, b, c, and d) may facilitate better care-
coordination and further studies on the utility of SCPs are warranted.
15 | CONCLUSION AND FUTURE
DIRECTIONS
With transformation of myeloma into a chronic disease, focus on
immediate and late complications from treatment and underlying dis-
ease is critical to deliver optimal survivorship care. The knowledge gap
and agenda for future research is summarized in Table 3. Long-term
follow-up data from clinical trials is needed to assess the incidence of
late complications like secondary malignancies and major adverse car-
diovascular events. Large databases or tumor registries can also be
helpful in identifying rare adverse events. In a study from the UK with
1843 myeloma patients who have survived 1 year after diagnosis, the
incidence of coronary artery disease, arrhythmia, heart failure, valvular
heart disease, pericarditis, and stroke was higher compared to demo-
graphically matched-controls.126 Since infection-related morbidity and
mortality is one of the major non-malignant late effect in myeloma sur-
vivors, further research is needed to identify patients at high risk of
infection and design evidence-based strategies to mitigate risk. Reduc-
tion of SREs along the disease trajectory is another area of unmet
need in this population as the risk remains substantial (27-45%)
despite currently available agents. With an increasing prevalence of
myeloma survivors, the community is responsible for appropriately
monitoring and managing both early and late complications. Further
research to investigate the biology and management of treatment-
related complications alongside drug development will continue to
improve the quantity and quality of life in patients with myeloma.
CONFLIC T OF INT ER ES T
No relevant financial conflicts of interest.
10968652, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.25764 by CAPES, Wiley Online Library on [14/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
CHAKRABORTY AND MAJHAIL
AUTHOR CONTRIBU TIONS
R.C. reviewed the literature, wrote the first draft of the manuscript, and
edited the final version of the manuscript. N.S.M. critically reviewed the
first draft of the manuscript, provided substantial critique and assistance in
writing the revised versions, and approved the final draft of the manuscript.
FUNDING SOU RCE
Dr. Navneet S. Majhail is supported by the NCI grant
R01-CA215134.
ET HICS COMMITTEE APPROVAL
Not Applicable.
OR CID
Rajshekhar Chakraborty https://orcid.org/0000-0001-7336-3003
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