Updates in Supportive Care in Multiple Myeloma

Caitlin Costello, MDAssociate Clinical Professor of MedicineDivision of Blood and Marrow TransplantMoores Cancer CenterUniversity of California, San Diego

• Management of drug-related toxicities• Review key prophylactic interventions• Management of infections• Improvement of bone health

Learning Objectives

Peripheral Neuropathy

• Causes:– Effects of the monoclonal protein – amyloid, IgM-ab– Results of radiculopathy from direct compression– Therapy-related

Peripheral Neuropathy

Drug Any grade Grade ≳ 3

Bortezomib 24% (SC); 39% (IV) 6% (SC); 15% (IV)Carfilzomib 11% 2%Ixazomib 28% 2%

Lenalidomide/Pomalidomide

10-15% 1-3%

Thalidomide 54% 4%

Drug Toxicity – Peripheral Neuropathy

Patient communication is keyCan you

button your shirt?

Can you use your phone?

Do you feel tingling or

burning in your fingers and

toes?

Do you avoid walking

barefoot?

Does it feel like something is in

your shoes when you

walk?

Do you have reduced

sensation in your hands or

feet?

Optimizing communication with patients

Treat patients as partners;

communicate openly

Improved adherence

ImprovedQoL

Longer survival

Basch E, et al. JAMA. 2017;318:197-198.

PreventionAssess baseline neuropathy

Dosing route (Use SC weekly bortezomib)

CommunicationEducate patients about potential symptoms and encourage them

to report symptoms ASAP

Adjustments Consider reducing dose or frequency

Stop/SwitchIf symptoms persist, to avoid irreversible

neuropathy

Management of Peripheral Neuropathy

Bortezomib modificationSeverity Modification of bortezomib

Grade 1 (paresthesias, weakness), no pain

Reduce by one level

Grade 1 with pain, or Grade 2 (interferes with function, not ADL)

Reduce by one level; once-weekly OR temporary discontinuation

Grade 2 with pain or Grade 3 (interfering with ADLs) or Grade 4

Discontinue

Pharmaceutical intervention:• Anticonvulsants: Gabapentin, pregabalin• Tricyclic anti-depressants: Nortriptyline, Amitriptyline• Selective serotonin reuptake inhibitors: Duloxetine, Venlafaxine

Non-pharmaceutical intervention• Emollients: cocoa butter, menthol-based cream• Therapeutic massage or acupuncture• Alpha Lipoic Acid, L-Carnitine • Topical Agents: Lidocaine, capsaicin

Management options

Ø Vitamin supplements: B complex, folic acid, Vitamin E

Ø Dose reduction

Ø Careful communication with patient

Prevention of Peripheral Neuropathy?

Cardiopulmonary Concerns

Ø Cardiac signals with all proteasome inhibitors• Most pronounced with carfilzomib

Ø Patients may have predisposing factors• Older age or comorbidities• Prior treatment history

Ø Identify patients with uncontrolled BP or CHF• Attain control of BP, CHF in advance

Ø History, examination are the most important screening toolsØ Myeloma is usually the most pressing health concern

Cardiopulmonary concerns

Mikhael J. Clin Lymphoma Myeloma Leuk. 2016;16:241-245.

Dimopoulos MA, et al. Lancet Oncol. 2016;17:27-38; Stewart AK, et al. N Engl J Med. 2015;372:142-152.

0% 2% 4% 6% 8% 10%

Cardiac failure

Dyspnea

Hypertension

Kd vs Vd

Vd Kd

0% 2% 4% 6% 8% 10%

Dyspnea

Cardiac Failure

Ischemic heart disease

Hypertension

KRd vs Rd

KRd Rd

Endeavor Trial Aspire Trial

Incidence of ≳grade 3 cardiotoxicity

Prevent Carfilzomib-induced cardiotoxicity

Mikhael J. Clin Lymphoma Myeloma Leuk. 2016;16:241-245.

Medical history

Baseline studies

Alternative drugs?

Manage comorbidities

Cardiac evaluation

• Fluid management– Minimize IVF: pre-hydration 250cc NS sufficient only with 1st cycle– Monitor home weights, report rapid weight gain– Diuretics, close monitoring of renal function/electrolytes– Decrease dex if fluid retention persists

• Infusion time– 30-minute infusions if dose is >27 mg/m2 (or all doses?)

• Assess for heart failure symptoms• Assess for ischemia development• Hold drug, reinstitute at lower dose, discontinue

Tips for carfilzomib administration

Palumbo A, et al. Leukemia. 2008;22:414-423; NCCN website. Cancer-Associated VTE Disease. v1.2017; De Stefano V, et al. Sem Thromb Hemost. 2014;40:338-347.

Risk of thromboembolism in MM

Disease-Related

• Biology of the disease

• Hyperviscosity

Therapy-Related

• High-dose steroids• Thalidomide• Lenalidomide• Pomalidomide• Erythropoietin• Anthracyclines• Multiagent

chemotherapy– Car/Len/Dex

Patient-Related

• Surgery/trauma• Acute infection• Obesity• Orthopedic

procedures• Diabetes/renal

disease• Hypertension• CVAD/pacemaker• History of

thromboembolism

Palumbo A, et al. Leukemia. 2008;22:414-423. International Myeloma Working Group (IMWG) website.

Prevention of Thromboembolism

• Limited data on use of direct oral anticoagulants• OK to resume immunomodulatory agents after thromboembolic event if fully

anticoagulated

Thromboprophylaxis Risk Factors

Daily aspirin (81 mg to 325 mg) 0-1 individual or disease-related

LMWH or therapeutic warfarin ≥ 2 individual or disease-related OR≥ 1 therapy-related

Monoclonal Antibody Based Therapies

Infusion-related

reactions

• Daratumumab: 50% risk 1st infusion – add montelukast

• Elotuzumab: 10% risk 1st infusion

False positive IAT

• Inform local blood bank prior to starting• RBC antigen phenotyping• Inform patients of false positive

IInterference

on SPEPIgGk

• Ensure residual M-protein is not Mab

• Severe hypogammaglobulinemia– Recurrent sinopulmonary infections and IgG < 400mg/dL àIVIG

• Antibacterial prophylaxis– Be aware of side effects of drugs

• Vaccinations– No live vaccines– Should receive annual influenza and be vaccinated against pneumonia– Recombinant Zoster vaccine- phase 3 ZOE-HSCT trial reduced risk by 68.2%

Managing Infections

de la Serna J, et al. BMT Tandem 2018. LBA2.

ProphylaxisAnti-viral agents VZV risk while on proteasome inhibitors (15-20%!)Acyclovir: reduces risk to 1-2%1

Risk of VZV reactivation increases withProteasome inhibitor treatment2Post-ASCT3

Monoclonal antibody treatment4

Infections - Viral

1 Fukushima T, et al. Anticancer Res. 2012;32:5437-54402 Chanan-Khan A, et al. J Clin Oncol. 2008;26:4784-47903 Kamber C, et al. Bone Marrow Transplant. 2015;50:573-5784 NCCN Guidelines for Prevention and Treatment of Cancer-Related Infection v1.2020

• TEAMM trial – phase 3– Primary endpoint: Reduce rate of

febrile episodes and/or death– Improve QOL, OS– Levofloxacin 500mg PO QD x

12w vs placebo

Time to first febrile episode

Infections - Bacterial

Drayson, et al. Lancet Oncol. 2019;20(12):1760-1772.

Bone Health

1Mhaskar, et al. Cochrane Database Syst Rev. 2017;12(12).

• Bisphosphonates vs placebo – meta-analysis1 of 24 studies• No difference in OS or PFS• No significant difference between bisphosphonates• Prevention of pathological vertebral events and skeletal related events

• RR 0.74• Increased ONJ overall – no difference between bisphosphonates

• 1/1000 incidence / RR 4.61

Management of Skeletal Events

ØFor lytic disease on plain radiographs or other imaging • IV pamidronate or zoledronic acid• Every 4 weeks for up to 2 years• Consider a 3-month interval during maintenance or inactive

disease periods• Resume treatment with relapse

ØBisphosphonates in patients with MGUS, solitary plasmacytoma, SMM are not recommended

ØTo prevent ONJ• Dental exam prior to starting; withhold for major dental procedures

ØRenal disease• Monitor calcium and replete calcium and vitamin D• Dose reduce pamidronate and zoledronic acid• Consider denosumab

Bone modifying agents

Denosumab

- Phase 3 RCT- Denosumab vs

zoledronic acid in NDMM

- Primary endpoint: non-inferiority of denosumab to ZA

- Time to first skeletal event

- Consider use in patients with CKD

Raje, N, Terpos E, Willenbacher W, et al. Lancet Oncol. 2018;19(3):370-381.

Frequency of zoledronic acid?

Himelstein AL, Foster JC, Khatcheressian JL, et al. JAMA. 2017;317(1):48–58.Anderson, J, Ismaila N, Flynn PJ, et al. J Clin Oncol. 2018;26(8):812-818

• Vertebral augmentation – vertebroplasty or kyphoplasty– Decrease in pain, noted early after treatment, sustained1

– Equally effective in reducing pain scores• Hypocalcemia

– Grade 1 – 48%, Grade 2 39%, G3 in 10%2

– Within 2 months of starting bisphosphonate• Palliative radiation to symptomatic lesions• Calcium, vitamin D supplementation

Bone Health

1Khan OA, Brinjikji W, Kallmes DF. AJNR Am J Neuroradiol. 2014;35(1):207-210.2Zuradelli M, Masci G, Biancofiore G, et al. Oncologist. 2009;14(5):548-556.