Managing Complications in Transplant-ineligible Patients with Multiple Myeloma

Value-Based Care in Myeloma - Transplant Considerations, Multiple Myeloma
Kathryn Lilleby, RN

Newly diagnosed patients with multiple myeloma (MM) may present with a complex array of symptoms and laboratory findings, from abnormal blood counts to severe renal impairment. This complexity is often increased in transplant-ineligible patients, who by definition are compromised by age, reduced performance status, and/or comorbidities. In this population, the nurse plays a key role in monitoring and preventing myelosuppression and infection, sustaining appropriate care for renal dysfunction, and assessing the interplay of therapy with chronic comorbid conditions such as diabetes. In this article, Kathryn Lilleby, RN, discusses recent clinical evidence and best practices as they pertain to these critical areas of myeloma care in the nontransplant setting.

What steps can be taken to prevent or minimize infection in transplant-ineligible patients with MM?

Transplant-ineligible patients are typically older and often present with a variety of comorbid conditions, such as diabetes, preexisting renal insufficiency, and/or cardiovascular disease. These complications can reduce performance status and predispose individuals to decreased immune-system function. Evidence suggests that elderly patients with MM may have depressed humoral immunity.1 They are at particular risk for pneumococcal and staphylococcal bacterial infections, and may also have markedly depressed antibody titers against tetanus and diphtheria toxoids and varicella, mumps, and rubella viruses.1 The disease process itself may also affect immune function. Myeloma-related immunodeficiency involves B-cell dysfunction and abnormalities of T cells, dendritic cells, and natural-killer (NK) cells.2 The mechanisms of B-cell dysfunction in MM may predispose patients to Streptococcus pneumoniae and Haemophilus influenzae infections.2

Elevated infection risk arises from the interaction of patient- and treatment-specific factors.2 These include active myeloma, renal insufficiency, and neutropenia produced by antimyeloma therapies. In transplant-ineligible patients, melphalan- based treatments may cause marked myelosuppression and increase the risk of infection; lenalidomide and bortezomib may also cause neutropenia.2 Bortezomib-based therapy may increase the risk of herpes zoster (varicella zoster virus [VZV]) and herpes simplex virus (HSV) infection.2 Although thalidomide is not associated with as great a risk of myelosuppression and infection, and in fact may have some stimulatory effects on T cells and NK cells and other constituents of immunity, 2 it may still induce neutropenia.3 Dexamethasone can diminish cell-mediated immunity and lead to treatment-related hyperglycemia, thus increasing susceptibility to infection.2

In clinical practice, patients with myeloma may present with neutropenia (absolute neutrophil count [ANC] <1.5 ¥ 109/L) as a symptom of their active disease. When they begin treatment with an antimyeloma regimen, their ANC may recover initially, as plasma cells decrease in the bone marrow, making room for new hematopoietic cells. However, as time passes, patients may re-experience neutropenia as an expected side effect of treatment. Thus, regular monitoring of complete blood counts is required to assess and treat neutropenia and evaluate risk of infection.4

Table 1
Best Nonpharmacologic Practices for Prevention of Infection
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Prevention of infection in patients with MM is a vitally important role for the nurse, and indeed for the entire multidisciplinary care team. Simple, nonpharmacologic practices, such as proper hand-washing, are still among the best methods to reduce the risk of infection.2 Patients and their caregivers should wash their hands with soap, warm water, and friction for at least 20 seconds, rinse them under warm water, and dry them thoroughly with a paper or cloth towel. This should be done often during the day as well as before preparing or eating food and after returning from activities that involve contact with crowds of people or touching objects in public (eg, shopping). Table 1 provides a list of best practices for infection control in the setting of MM.

Determining antimicrobial prophylaxis is highly individualized to the patient.2 Trimethoprim-sulfamethoxazole or a fluoroquinolone may be used to provide evidence-based bacterial prophylaxis, but the decision to use this approach is made on a case-by-case basis.2,5 Antifungal prophylaxis is sometimes suggested for patients who are predisposed to mucosal candidiasis.2 Antiviral prophylaxis of VZV and HSV is generally recommended for patients receiving treatment with bortezomib2; a typical regimen is acyclovir 400 mg once daily.6 Despite the fact that MM patients have decreased antibody responses, they should receive pneumococcal and influenza vaccination.4

Signs and symptoms of infection in the neutropenic patient must be assessed and managed promptly. We monitor complete blood counts daily and instruct patients to take their temperature 4 times a day. If febrile neutropenia develops (ie, fever of >38°C in the presence of ANC <0.5 ¥ 109/L), a work-up should be initiated, consisting of blood and urine cultures, chest x-ray, and other radiologic examinations as appropriate.2 Broad-spectrum antibiotics should be started until results of culture and sensitivity are available.2

How does the presence of diabetes affect the selection of therapy in the nontransplant setting?

The presence of diabetes is an important factor when considering myeloma therapy that includes dexamethasone or prednisone. Steroid-induced hyperglycemia can be a serious adverse event, and is associated with marked elevations in blood glucose even in patients without preexisting diabetes.7 Thus, for patients already affected by the endocrine disturbances of diabetes, steroid-based therapy must be used with great caution and close monitoring.

In transplant-ineligible patients, dexamethasone is used in combination with novel agents and as monotherapy.8,9 The decision to use or avoid dexamethasone in the treatment of patients with diabetes is significant. An insulin-dependent patient may benefit from using other treatment modalities first; however, if such treatments produce suboptimal response, dexamethasone may be required to gain control over the disease.8,9

In the phase 3 ECOG E4A03 study, Rajkumar and colleagues reported that lenalidomide given at 25 mg/day on cycle days 1 to 21 plus dexamethasone given at 40 mg on days 1, 8, 15, and 22 of a 28-day cycle (Rd) yielded better overall survival in newly diagnosed MM patients (including elderly patients) than did the same dose of lenalidomide plus dexamethasone given at 40 mg on days 1 to 4, 9 to 12, and 17 to 20 of a 28-day cycle (RD).10 The survival advantage appeared to be related to the decreased toxicity seen with the low-dose dexamethasone regimen, particularly in the first 4 months of treatment and in older patients.10 The rate of hyperglycemia in the low-dose dexamethasone group was numerically lower than in the high-dose group (14 patients [6%] vs 25 patients [11%], respectively), although this difference did not reach statistical significance.10

When treated with steroids, diabetic patients should be reminded of the signs and symptoms of hyperglycemia (serum glucose >160 mg/dL) and hypoglycemia (serum glucose <55 mg/dL).11 They should self-monitor blood glucose more frequently while they are receiving dexamethasone or other steroid medications until it is known how treatment affects glycemic control. They should also consult with a primary care physician regarding any change in their use of oral hypoglycemic agents or insulin and discuss whether diet and exercise can help to control their diabetes.

Both diabetes and MM are disease states associated with renal insufficiency. Thus, comorbid diabetes and the presence of renal impairment demand careful attention regarding the dosing of bisphosphonates used to support bone health. Zoledronic acid is not recommended for patients with severe renal impairment (creatinine clearance [CrCl] <30 mL/min), and dosage reductions are recommended for patients with CrCl 30 to 60 mL/min.12 Pamidronate may be used at unadjusted dose, but some clinicians reduce the dose of this medication as a precautionary measure in patients with renal insufficiency.4,13 Careful monitoring of serum creatinine is necessary prior to each dose of pamidronate; the drug should be withheld in the event of observed deterioration in renal function (serum creatinine >2.0 mg/dL or significant albuminuria) until testing shows a return to baseline.13,14

Finally, MM patients with diabetes are more likely to experience peripheral neuropathy. Therefore, signs and symptoms of this adverse event need careful baseline assessment and frequent monitoring when drugs such as thalidomide and bortezomib are used, since neurotoxicity is associated with these agents.3,15-17

How do you manage renal complications in transplant- ineligible patients with MM?

Renal impairment is a common complication in MM, with up to 50% of newly diagnosed MM patients presenting with renal insufficiency, 20% having severe renal impairment, and 10% requiring hemodialysis.18 As monoclonal light chains (Bence Jones proteins) circulate in the blood through the kidneys, these large molecules can obstruct renal tubules, a condition called “cast nephropathy.” As a result, serum creatinine and blood urea nitrogen (BUN) increase and symptoms of renal failure occur. Hypercalcemia of MM also plays a role in renal dysfunction.4,19

Rapid interventions are needed to reverse renal insufficiency in patients with MM.19 These can range from the very simple— such as increasing hydration—to plasmapheresis in the case of acute renal failure.4 The role of plasma exchange, however, remains controversial for the correction of light-chain cast nephropathy,19,20 and we rarely use it in our practice. Correction of hypercalcemia is essential,4 and nephrotoxic drugs (eg, anti-inflammatory agents) should be avoided.21

Regimens used to treat patients with MM should provide durable support for renal function. Effective antimyeloma therapy, by reducing the production of monoclonal light chains, will ameliorate renal insufficiency. In addition, normalization of serum beta-2-microglobulin, a key marker in MM, is predictive of recovery of acute renal failure.22 Therapeutic doses must be tailored to the individual patient, based on CrCl level. When CrCl improves, the dose of therapy can be in creased for greater efficacy against the disease.

Bortezomib and lenalidomide have been shown to have a favorable impact on renal complications in patients with MM. According to a recent, evidence-based consensus statement from the International Myeloma Working Group (IMWG),19 bortezomib plus high-dose dexamethasone is the treatment of choice to reverse renal insufficiency. The IMWG also considers lenalidomide an effective treatment that can reverse renal insufficiency in a subset of patients. However, dose reductions of this drug are mandatory on the basis of renal function. Specifically, if CrCl is between 30 and 60 mL/min, the recommended dose of lenalidomide is 10 mg/day. If CrCl is <30 mL/min but the patient does not require dialysis, the recommended dose is 15 mg every other day. Finally, if CrCl is <30 mL/min and the patient requires dialysis, the dose is 5 mg /day administered after dialysis only on dialysis days.19

At our institution, managing renal complications begins with monitoring serum creatinine and BUN. The schedule of monitoring depends on the severity of kidney disease and the type of antimyeloma therapy being used. For example, in a patient requiring hemodialysis, we often select bortezomibbased therapy, since this agent can be safely given to these patients.18,23 In these scenarios, we monitor renal function frequently to assess any reversal of renal dysfunction that may permit individuals to become dialysis independent. For all MM patients with renal insufficiency, self-monitoring of fluid intake and output, as well as the use of diuretics, needs to be discussed. Since preexisting hypertension may play a role in renal complications, monitoring blood pressure at each visit and at home is important. Consultation with a nephrologist may be warranted, especially if hemodialysis is a potential need.

Dialysis-dependent, severe renal failure that cannot be reversed is associated with a very poor prognosis in MM, with a median survival of less than 4 months.23-25 Critically ill patients of this type will benefit from quality-of-life and end-of-life conversations relatively soon after diagnosis. They need supportive care in many areas, which may be addressed by palliative care specialists or, if death appears imminent, hospice. MM is a complex disease, and patients with extensive renal complications may also experience a host of other problems, the burden of which may be especially great in the elderly who have underlying comorbidities. Pain, skeletal- related events, infections, anemia, and venous thromboembolism are just some of the conditions these patients may experience.26

How do you assess and treat myelosuppression in elderly patients with MM?

Grade 3/4 hematologic adverse events in a trial of MP vs MPT in elderly MM patients.29
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Several of the regimens used to treat transplant-ineligible myeloma patients are associated with myelosuppression. In the phase 3 VISTA trial, grade 3 hematologic adverse events seen with a regimen of bortezomib/melphalan/prednisone included thrombocytopenia (20%), neutropenia (30%), anemia (16%), leukopenia (20%), and lymphopenia (14%).27 However, these rates were comparable to those seen in patients who received melphalan plus prednisone (MP) alone in this study, attesting to the marked myelosuppressive effect of melphalan. Three-year follow-up data for this trial showed no change in this profile of hematologic toxicities.28 The contribution of melphalan to myelo suppression was also evident in a study by Waage and colleagues,29 which compared MP with melphalan/prednisone/thalidomide (MPT) in newly diagnosed, nontransplant patients with MM. As shown in the Figure, rates of hematologic toxicities for the 2 regimens were comparable. This is not to suggest that thalidomide and bortezomib are without myelosuppressive effects; both drugs can reduce neutrophil counts,3,15 and in a trial of very elderly patients treated with MPT, the addition of thalidomide to MP significantly increased the incidence of neutropenia.30 Neverthe less, the high incidence of melphalan-related toxicity is an explicit rationale for ongoing clinical investigations of novel regimens that do not contain this agent.31

The lenalidomide plus dexamethasone regimen has also been shown to be myelosuppressive. In the phase 3 ECOG E4A03 study, there was no improvement in hematologic toxicity associated with a lower dose of dexamethasone. Instead, it was nonhematologic toxicities such as infection and venous thromboembolism that posed excess risk for patients treated in the high-dose arm, along with a higher incidence of earlyonset toxicity.10

Table 2
Summary of Recommendations for the Management of Hematologic Toxicities3,15,32
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To effectively manage myelosuppression, it is important for elderly myeloma patients to have their blood counts monitored regularly, with the most frequent monitoring performed early in their treatment cycles. We see these patients at least once a week during the first and second cycles to assess how they are responding to treatment and to evaluate the need to make dose or schedule adjustments based on their counts. Patients also need to be evaluated for signs and symptoms of bleeding, bruising, dyspnea, fatigue, and infection. Protocols for managing myelosuppression vary among in - stitutions, but general guidelines for individual agents are shown in Table 2. In an age of multidrug therapy based on novel agents, it is essential that the management of myelosuppression be tailored to the specific drug combination as well as the needs of the individual patient.


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