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INTRODUCTION

Multiple myeloma (MM) continues to be a pervasive disease that is commonly encountered by the oncology care team. The treatment paradigm for this disease continues to evolve, with new treatment schemas and combination regimens continuing to emerge. As such, individuals with MM have more options for treatment of their disease and longevity has increased. Based on the constant evolution in the setting of MM, it’s important for the members of the care team to remain cognizant of their patient’s treatment options and indicated supportive care therapies. This requires an orchestrated back-and-forth between multiple healthcare professionals – including nurses, pharmacists, and physicians – to discuss the patient’s clinical status, goals of therapy, optimal treatment approach, and ability to tolerate therapy. Additionally, the care team should consider the patient from a holistic approach, ensuring they have adequate support not only from a pharmacology perspective, but also from a financial and psychosocial context. Patients may suffer a severe psychological and monetary burden from the treatment of their disease, and so it’s important to gauge these elements to ensure individuals can continue therapy without significantly affecting their quality of life. 

Interprofessional Collaboration WHEN MANAGING PATIENTS WITH MULTIPLE MYELOMA How can the members of the care team work together in the clinical-decision making process to improve outcomes in patients with multiple myeloma? In what ways does the oncology pharmacist’s role complement the oncologist’s and other providers?  Click here to Show/Hide Audio.

SECTION 1: Multiple Myeloma Overview

"Pre-case" Audio

Click here to Show/Hide Audio.

CASE 1 A 61-year-old male with a history of hypertension comes to his physician’s office complaining of fatigue and loss of appetite with multiple recent bouts of upper respiratory infections. Upon routine blood chemistry and CBC, it is noted that he has a decreased hemoglobin at 9 g/dL and elevated calcium at 10 mg/dL with albumin of 3 g/dL. Additionally, his serum creatinine is elevated at 1.8 g/dL (baseline was previously 0.8 g/dL). What details of the patient’s history would be most relevant? What additional testing would you be looking for to determine if multiple myeloma is a concern? What would you want to discuss with the patient regarding the significance of these tests? PAUSE AND REFLECT: Assess this case based on the activity content thus far, then listen to faculty commentary.  Click here to Show/Hide Audio.

Epidemiology and Incidence of MM, Including Change in Prognosis Over Past Several Decades

Multiple myeloma is a hematologic malignancy that accounts for nearly 2% of all cancer diagnoses in the United States (US).[SEER 2019] Approximately 32,110 new cases of MM will occur in 2019, with an estimated 12,960 MM patient deaths expected.[ACS 2019] The median age at diagnosis is 69 years, and MM occurs more commonly in men than in women. While the incidence rate has steadily increased from 1975 through 2015, the median survival rate has also steadily increased, with over 50% of patients reaching 5-year survival in 2010.[Seer 2019]

Pathophysiology, Prognostic Factors, and Potential Risks that Influence Treatment in MM

Multiple myeloma is characterized by a clonal expansion of multiple subsets of abnormal plasma cells in the bone marrow and an intricate interplay between cells in the microenvironment, including bone marrow stromal cells, osteoblasts, and immune cells.[Rollig 2015] The International Myeloma Working Group (IMWG) defines MM as follows: clonal bone marrow plasma cells ≥10% with the presence of the following features or biomarkers: ≥1 osteolytic bone lesions on radiography; ≥2 focal bone lesions ≥5 mm on MRI; serum-free light chain ratio >100; hypercalcemia (>1 mg/dL above upper limit of normal or >11 mg/dL); anemia (hemoglobin >2 g/dL below lower limit of normal or <10 g/dL); or renal insufficiency (CrCl <40 mL/min or serum creatinine >2 mg/dL). The hypercalcemia, renal insufficiency, anemia, and presence of ≥1 osteolytic bone lesions radiographically that are described above are commonly referred to as CRAB symptoms (hyperCalcemia, Renal insufficiency, Anemia, Bone lesions). Additionally, if none of those features are present, but clonal bone marrow plasma cells are ≥60%, then that is sufficient for the diagnosis of MM.[Rajkumar 2016] While some patients may be found asymptomatically, common clinical presentations of patients with MM include anemia, infections, bone disease, or acute renal failure.[Rollig 2015]

The preferred staging system for MM is the revised International Staging System (R-ISS). The original ISS only accounted for a patient’s serum albumin and their serum beta-2 microglobulin levels, which is an indicator of the patient’s burden of disease. The R-ISS still includes these biomarkers, but also considers the patient’s serum lactate dehydrogenase (LDH) level and the presence of standard-risk or high-risk chromosomal abnormalities by fluorescence in situ hybridization (FISH). Based on these parameters, patients are categorized as either having Stage I, II, or III disease (Table 1).[Palumbo 2015]

In addition to MM, there are two precursor conditions to consider: monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) myeloma. MGUS may involve an abnormally high level of immunoglobulin (Ig) M or non-IgM monoclonal protein (<30 g/dL), or an abnormal free light chain (FLC) ratio, which is the ratio of lambda to kappa light chains present in the serum. Additionally, patients with any CRAB symptoms cannot be considered to have MGUS.[Rajkumar 2014] While these patients do not have an active malignancy, the rate of progression from MGUS to MM is estimated at 0.5-1% per year, so patients should be monitored annually by their provider. Smoldering myeloma is defined as a serum M-protein ≥30 g/dL and/or bone marrow clonal plasma cells of 10-59% without the presence of CRAB symptoms or other biomarkers listed above, amyloidosis, or other indicators of active disease (repeated infections, light chain deposition disease, or hyperviscosity). Patients with smoldering myeloma may have indolent disease for several months or years, so the National Comprehensive Cancer Network (NCCN) currently recommends no immediate treatment for these patients and close observation for progression. Alternatively, they recommend that eligible patients be enrolled in clinical trials evaluating the potential benefit of treating smoldering myeloma.[NCCN 2020] Several studies have examined the potential benefit of early treatment for smoldering myeloma with mixed results. A recent meta-analysis by Zhao et al demonstrated that the use of early treatment was associated with significantly decreased risk of progression to active MM, as well as significantly decreased mortality in high-risk smoldering myeloma patients. However, the authors note that only two studies were included in this sub-group analysis of high risk patients, and both studies defined “high risk” differently. Additionally, they also found significantly increased risk of second primary malignancy in smoldering myeloma patients who were treated immediately, as well as significantly increased rates of constipation when treated with immunomodulatory agents.[Zhao 2019] While this evidence seems promising, further randomized controlled trials are necessary to determine the most appropriate patient and regimen to initiate for smoldering myeloma.

CASE 1, CONTINUED As follow-up to the pre-case discussion, the 61-year-old male returns to his physician two weeks later to review his results. His laboratory studies showed a beta-2 microglobulin of 10 mg/dL and LDH of 400 mg/dL. He has a serum monoclonal protein level of 60 g/dL. The patient also has a new complaint of pain in his lumbar region and has noticed a weight loss of 5 lbs due to continued loss of appetite. Whole body low-dose CT showed a 5 mm lesion in the lumber spine, and bone marrow biopsy results showed clonal bone marrow plasma cells of 60% with no high-risk chromosomal abnormalities. CASE QUESTIONS What stage disease of MM would you assign to our patient based on the R-ISS? What psychosocial information would be important to gather from the patient? Assuming the patient is a transplant candidate, what would be the best first-line treatment option for him? What if he was not a transplant candidate? What education would you provide to this patient? PAUSE AND REFLECT: Assess this case based on the activity content thus far, then listen to faculty commentary.  Click here to Show/Hide Audio.

SECTION 2: New Medications and Combinations for Multiple Myeloma

While MM has historically been perceived as an incurable disease without the use of hematopoietic stem cell transplantation (HSCT), great efforts have been made to study both novel drug development and unique combinations of existing agents. Most recently, the US Food and Drug Administration (FDA) approved the use of selinexor in July 2019 for patients with relapsed/refractory multiple myeloma who have failed at least four prior lines of therapy. Prior to this, there were no new FDA-approved medications for the treatment of multiple myeloma since the approval of elotuzumab in November 2015.[FDA 2019] Additionally, emerging research has explored the use of chimeric antigen receptor (CAR)-T cell therapy as a potential cure for patients with refractory disease.[Ghosh 2018]

Initial treatment decisions continue to be based on the patient’s comorbidities, performance status, and potential to undergo autologous stem cell transplant (ASCT). A triplet regimen is generally the standard for all newly diagnosed patients, but those with advanced age or significant comorbidities may be better suited for doublet therapy. In patients who are planned to undergo ASCT, a regimen without a nitrosourea or alkylating agent is preferred so as to not compromise the patient’s stem cells prior to harvesting.[NCCN 2020]

Review of Major Guideline Changes for Initial Treatment

The NCCN separates its treatment recommendations based on whether or not the patient is a transplant candidate.

Transplant-eligible patients

In patients who are eligible for transplantation, providers should avoid agents that could negatively affect harvesting of stem cells, such as nitrosoureas and alkylating agents. For transplant candidates, the NCCN gives a category 1 preferred recommendation for a combination of bortezomib, lenalidomide, and dexamethasone (VRD), as well as a general category 1 recommendation for the combination of bortezomib, thalidomide, and dexamethasone (VTd).[NCCN 2020] Previously, the regimen of bortezomib, cyclophosphamide, and dexamethasone (VCD) was favored, but the aforementioned regimens are now preferred based on results from the IFM2013-04 trial that showed significantly improved overall response rates and near significant improvement in very good partial response (PR) rates using VTd.[Moreau 2016] While thalidomide is not commonly used in the US, it is more widely available and affordable in resource-restricted areas of the world, and the VTd regimen is given the distinction of “useful in certain circumstances” within the guidelines. After primary treatment with one of these regimens, the NCCN provides a category 1 recommendation for maintenance therapy with either lenalidomide or ixazomib.[NCCN 2019]

The Myeloma XI trial was an open-label, randomized trial in the United Kingdom in which the investigators studied the effect of maintenance lenalidomide on progression-free survival (PFS) and overall survival (OS) in patients with newly diagnosed multiple myeloma. The results showed that compared to observation alone, lenalidomide significantly prolonged the median PFS from 20 months to 39 months (HR=0.46; 95% CI 0.41-0.53), although no difference was shown in median OS after 5 years of follow-up. This effect remained consistent across most subgroup analyses, including in patients who were both transplant-eligible and transplant-ineligible. Of note, lenalidomide maintenance was associated with a significantly higher rate of secondary malignancies: 3-year cumulative incidence of secondary malignancies was 5.3% in the lenalidomide group compared to 3.1% in the observation group (HR=1.85; 95% CI 1.18-2.90).[Jackson 2019]

In the TOURMALINE-MM3 trial, patients who had undergone an ASCT were randomized to ixazomib or placebo, with the primary outcome as PFS. After a median follow-up of 31 months, ixazomib significantly increased PFS from 21.3 months to 26.5 months (HR=0.72; 95% CI 0.58-0.89). Unlike the Melanoma XI trial, the cumulative incidence of secondary malignancies between each group was similar at 3%.[Dimopoulos 2019]

Transplant-ineligible patients

In patients who are not candidates for transplant, the NCCN provides multiple category 1 preferred recommendations: VRD; daratumumab, lenalidomide, and dexamethasone; and lenalidomide and low-dose dexamethasone. Daratumumab in combination with lenalidomide and dexamethasone (DRd) is a recent addition to first-line treatment options, and was FDA approved in June 2019 based on data from the MAIA trial. In the MAIA trial, patients were randomized to DRd or lenalidomide with dexamethasone (Rd) until disease progression or unacceptable toxicities. After a median 28 months of follow-up, the addition of daratumumab significantly improved the estimated PFS to 70.6% in the DRd group vs. 55.6% in the Rd group (HR=0.56; 95% CI 0.43 to 0.73). Adverse effects were similar between the two groups, except for a higher incidence of pneumonia and neutropenia in the DRd group.[Facon 2019] Additionally, the NCCN gives a category 1 recommendation for the combination regimen of daratumumab, bortezomib, melphalan, and prednisone.[NCCN 2019] This four-drug regimen was studied in the ALCYONE trial against a triplet regimen of bortezomib, melphalan, and prednisone, and demonstrated significantly improved 18-month PFS, overall response rate (ORR), and complete response (CR) rate.[Mateos 2018] Additionally, lenalidomide has received both an FDA approval and an NCCN category 1 recommendation as maintenance therapy after ASCT based on significantly longer PFS compared to placebo in multiple trials.[FDA 2019][NCCN 2019][Attal 2012][Holstein 2017]

New Treatment Options and Places in Therapy
Daratumumab

Daratumumab is a CD38 monoclonal antibody that was originally FDA approved in 2015 as monotherapy in patients with relapsed or refractory disease who received at least three lines of prior therapy, including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), or who were double-refractory to a PI and an IMiD.[FDA 2016] However, based on data from the POLLUX and CASTOR trials, it gained FDA approval in 2016 for use as part of a combination regimen in patients who had received at least one prior therapy, as well as an NCCN category 1 recommendation for these indications.[FDA 2018][NCCN 2019] In the POLLUX trial, the addition of daratumumab to lenalidomide and dexamethasone compared to lenalidomide and dexamethasone alone (the standard of care at the time in the relapsed setting) significantly improved PFS (HR=0.37; 95% CI: 0.27 to 0.52).[Dimopoulos 2016] In the CASTOR trial, the addition of daratumumab to bortezomib and dexamethasone compared to bortezomib and dexamethasone alone significantly improved PFS (HR=0.39; 95% CI: 0.28 to 0.53).[Palumbo 2016] The next approval was based on the phase I EQUULEUS trial, which studied the combination of daratumumab, pomalidomide, and dexamethasone in 103 patients who received at least two prior therapies. After a median follow-up of 13.3 months, the ORR was 60%, median PFS was 8.8 months, and median OS was 17.5 months.[Chari 2017] Based on these results, daratumumab was approved by the FDA for use in patients who have received at least two prior therapies, including lenalidomide and a PI.[Daratumumab PI]

In September 2019, daratumumab was granted FDA approval in combination with bortezomib, thalidomide, and dexamethasone for newly diagnosed, transplant eligible patients.[Daratumumab PI] This approval was based on results from part 1 of the CASSIOPEIA trial, which is a two-part, open-label, phase III trial in Europe. Part 1 compared daratumumab plus VTd (D-VTd) against VTd alone for four cycles as induction therapy, followed by a standard stem-cell mobilization regimen, conditioning regimen, ASCT, and two cycles of consolidation therapy using the same regimen the patient received for induction. Part 2 randomized patients who has achieved a PR or better at 100 days post-ASCT to either observation or maintenance therapy with daratumumab for up to 2 years. In Part 1, the primary outcome was the proportion of patients who achieved a stringent CR after consolidation therapy, which the IMWG defines as a CR in addition to a normal FLC ratio and absence of clonal myeloma cells on bone marrow biopsy. The reader is encouraged to consult the NCCN guidelines for a more comprehensive review of treatment response definitions.(NCCN 2019) After a median follow-up of 18.8 months, significantly more patients in the D-VTd group achieved a stringent CR than patients in the VTd group (OR=1.6; 95% CI: 1.21 to 2.12). Median PFS and OS had not been reached in either group, but both PFS and OS at the time of data analyses were noted to be significantly longer in the D-VTd group.[Moreau 2019] The NCCN has added this regimen as an option that may be useful in certain situations, likely based on the absence of mature PFS and OS data at this time.[NCCN 2019] As mentioned above, daratumumab is also approved as part of a three-drug and four-drug regimen for primary treatment of non-transplant candidates.

Elotuzumab

Elotuzumab, a SLAMF7 monoclonal antibody that was originally approved in combination with lenalidomide and dexamethasone for patients who received one to three prior lines of therapy, has also been studied more extensively.[FDA 2018] Follow-up results of the ELOQUENT-2 trial, which was the trial that helped it gain its initial FDA approval, have recently been published. The 4-year PFS in patients treated with elotuzumab, lenalidomide, and dexamethasone (ERd) compared to Rd remained significantly higher at 21% vs. 14% (HR=0.71; 95% CI 0.59-0.86).[Dimopoulos 2018a] While still not approved in the first-line setting, it recently received FDA approval in combination with pomalidomide and dexamethasone for the treatment of patients who received at least two prior therapies, including a PI and lenalidomide.[Elotuzumab PI] In the ELOQUENT-3 trial, the triplet regimen of elotuzumab, pomalidomide, and dexamethasone significantly improved PFS compared to the standard-of-care doublet regimen of pomalidomide and dexamethasone (HR=0.54; 95% CI: 0.34 to 0.86).[Dimopoulos 2018b]

Selinexor

Selinexor is an oral inhibitor of exportin 1 (XPO1), which is overexpressed in MM cells and is associated with increased bone disease and decreased survival. Exportin 1 is a nuclear exporter that transports tumor suppressor proteins, glucocorticoid receptor, and oncoprotein messenger ribonucleic acid (mRNA) from the cell nucleus to the cytoplasm. By inhibiting XPO1, selinexor induces apoptosis by trapping tumor suppressor proteins in the nucleus, leading to their functional activation, as well as suppressing nuclear factor kappa-B (NF kappa-B) activity and preventing oncoprotein mRNA translation.[Tai 2014] In the phase II, open-label STORM trial, patients were enrolled if they were refractory to at least one ImiD, one PI, daratumumab, glucocorticoids, and their most recent regimen. Patients received selinexor and dexamethasone twice weekly in 4-week cycles, with the primary outcome of ORR, defined as a PR or better. The ORR was 26% – including a PR in two patients who had failed CAR-T cell therapy – with a median duration of response of 4.4 months. The most common adverse events were thrombocytopenia, fatigue, and nausea, with grade 3 or 4 thrombocytopenia and anemia occurring in 59% and 44% of patients, respectively.[Chari 2019]

Emerging Therapies

Several new agents are under investigation for the treatment of MM. Based on the success of daratumumab, a novel anti-CD38 monoclonal antibody, isatuximab (SAR650984), is among the most promising agents.[Iftikhar 2019] Isatuximab has been studied in multiple phase I and II studies as both monotherapy and combination therapy. In a phase I, dose-finding trial of 84 patients who had received a median of five prior therapies, the ORR in patients who received isatuximab at a dose of 10 mg/kg or 20 mg/kg was 24%. While no maximum tolerated dose was identified, the most common adverse reactions noted were infusion-related reactions upon first infusion in 47.6% of patients.[Martin 2019] These results were replicated in a phase II dose-finding trial in 97 patients who had received at least three prior lines of therapy, with a median duration of response of 6.6 months.[Richter 2016] In a phase Ib trial of isatuximab in combination with pomalidomide and dexamethasone, the ORR was 62% and median PFS was 17.6 months in patients with relapsed/refractory disease who had received a median of three prior lines of therapy.[Mikhael 2019] Based on these results, the ICARIA-MM trial is an ongoing phase III of isatuximab plus pomalidomide and dexamethasone (Pd) compared to Pd alone for patients who received at least two prior lines of therapy. Interim results released this year showed that isatuximab plus Pd significantly improved PFS compared to Pd (HR=0.596; 95% CI: 0.44-0.81), although OS results were not yet finalized.[Richardson 2019] The FDA is currently reviewing a biologics license application (BLA) for the approval of isatuximab for relapsed/refractory MM.[Sanofi 2019]

Many other novel agents have been explored with mixed results; some of the highlights are listed here. Siltuximab (CNTO 328) is an anti-interleukin-6 (anti-IL-6) monoclonal antibody that was studied in combination with RVD in a phase I/II open-label study of 11 newly diagnosed MM patients. After 4 cycles of therapy, one patient achieved a CR and the ORR was 90.9%.[Shah 2016] However, additional phase II studies of siltuximab combination regimens in both the newly-diagnosed and relapsed/refractory settings showed no additional benefit of adding siltuximab.[Orlowski 2015, San-Miguel 2014] Talamumab (LY2127399) is an anti-B-cell activating factor (anti-BAFF) monoclonal antibody that showed an ORR of 56.3% when combined with bortezomib in a phase I study of relapsed/refractory MM patients. However, a phase II study of talamumab in combination with bortezomib and dexamethasone in relapsed/refractory MM patients demonstrated no benefit of talamumab compared to placebo.[Raje 2017] Indatuximab ravtansine is an anti-CD138 antibody-drug conjugate that releases the microtubule inhibitor DM4 once it is internalized in myeloma cells. In a combined report of a one-dose-per-cycle phase I trial and a multiple-dose-per-cycle phase I/IIa trial, patients with relapsed/refractory disease were treated with indatuximab ravtansine monotherapy to establish safety, pharmacokinetics, and efficacy. The patients in the single dose trial had received a median of seven prior therapies, while those in the multiple dose trial had received a median of five prior regimens. The results only showed an ORR of 3.2% in the single dose regimen and 5.9% in the multiple dose regimen, but the authors were encouraged by the rate of stable disease (67.7% and 61.8%, respectively) achieved in each arm.[Jagannath 2019] Oprozomib is an oral PI that is an analog to carfilzomib with similar activity level. In a phase Ib dose escalation trial, oprozomib was studied in combination with pomalidomide and dexamethasone in relapsed/refractory patients, resulting in an ORR of 70.6%. However, there were concerns with bioavailability of the medication in its studied dosage form and a high incidence of gastrointestinal adverse events, including one gastric hemorrhage.[Shah 2019] An additional phase Ib/II trial studied oprozomib with dexamethasone in relapsed/refractory disease, resulting in an ORR rate of 58.7% overall and 46.6% in bortezomib-refractory patients. However, this trial again noted that gastrointestinal events were the most common adverse events and that limitations with the oral dosage form persisted.[Hari 2019] While this is not an exhaustive list, it’s apparent that these agents still need significantly more studies to determine their role, if any, in MM.

Despite the success of programmed death receptor-1 (PD-1) inhibitors in other malignancies, these agents have had less robust results in MM. In 2019, negative results from FDA-requested interim analyses were reported for two phase III, multinational trials of pembrolizumab in combination with other agents for MM. In KEYNOTE-185, pembrolizumab was studied in combination with Rd against Rd alone in newly diagnosed, treatment-naïve MM patients. After a median follow-up of 6.6 months, estimated 6-month PFS between pembrolizumab and control groups were similar at 82% and 85%, but mortality was higher in the pembrolizumab group (13% vs. 6%).[Usmani 2019] KEYNOTE-183 was a phase III, multinational trial that compared pembrolizumab in combination with Pd against Pd alone in patients who had received at least two prior therapies. In an FDA-requested, interim analysis after a median follow-up of 8.1 months, the investigators found that patients in the pembrolizumab group had a median shorter PFS (5.6 months vs. 8.4 months) and shorter estimated 6-month OS (82% vs 90%). Serious adverse events were also more common in the pembrolizumab group, with Grade 5 adverse events occurring in 11% of pembrolizumab patients compared to 2% of control patients. The FDA halted the study early based on these results, and subsequently placed a partial clinical hold on MM trials of another PD-1 inhibitor, nivolumab, that were subsequently lifted after nearly a year of review.[Mateos 2019, BMS 2018] Further research is necessary to determine the utility of this class of agents in MM patients.

CASE 1, CONTINUED As a follow up to Case 1, the patient was started on therapy with bortezomib, lenalidomide, and dexamethasone. After two cycles, he returns to his oncology provider for routine follow-up and evaluation. The patient’s hemoglobin is now 7.8 g/dL and platelets are 70k/mL. He complains of some tingling in his hands and feet that has been interfering with his ability to conduct his activities of daily living. He states that he occasionally forgets to take his lenalidomide (approximately 2 missed doses/week) and notes that he has been taking his dexamethasone in the evening, which has been interfering with his sleep schedule.  CASE QUESTIONS EXAMPLE Which of his agents is most likely causing his peripheral neuropathy? How could we potentially mitigate his symptoms? What further education do we need to provide to the patient? PAUSE AND REFLECT: Assess case based on content thus far, then listen to faculty commentary.  Click here to Show/Hide Audio.

SECTION 3: Adverse Effect Management

Unique Adverse Effects of Newer Agents and Their Management

In addition to the selection of primary treatment regimen, patients with MM require significant supportive care to manage adverse events from their anti-cancer therapy.

Both daratumumab and elotuzumab carry significant risks of infusion-related reactions, and as such have specific recommendations regarding titration of doses and maximum infusion rates. Additionally, prophylactic medication recommendations are available for each agent to reduce the risk of infusion reactions; these recommendations may vary based on the combination regimen in which they are used and the cycle of therapy.[Daratumumab PI][Elotuzumab PI] For daratumumab, all patients should be pre-medicated with an antipyretic and antihistamine agent. Depending on the presence of corticosteroids in the overall treatment plan and whether daratumumab is used as monotherapy or in combination therapy, both pre- and post-treatment corticosteroids may be needed to prevent delayed reactions.[Daratumumab PI] Elotuzumab requires pre-medication with acetaminophen, an H1 blocker (e.g., diphenhydramine), an H2 blocker (ranitidine), and dexamethasone. Of note, on days that patients receive elotuzumab, they will receive dexamethasone 8 mg intravenously prior to therapy, but will also need to take an additional oral dose of dexamethasone at home 3-24 hours prior to treatment.[Elotuzumab PI] Each of these monoclonal antibodies have specific titration instructions, as well as recommendations on how to manage infusion-related reactions should they occur, detailed in their respective package inserts.

Both oncology nursing professionals and pharmacists can play a key role in reviewing a patient’s medication orders to ensure that the appropriate prophylactic medications are ordered. Additionally, nurses can counsel patients about the importance of compliance with oral portions of the patient’s regimen, as several of the other medications given in combination with these agents are taken orally at home.

Daratumumab, based on its binding to CD38 receptors, can interfere with antibody screening and cross- matching of red blood cells for transfusion, as well as serum protein electrophoresis and immunofixation tests.[Daratumumab PI] It’s imperative that providers are aware of this interference so that they can appropriately perform a type and screen prior to beginning therapy with daratumumab and alert the blood bank and laboratory whenever they have a blood sample sent for testing from a patient who is receiving daratumumab. Nurses can play an important role here in reviewing a patient’s medical record to ensure this baseline testing is performed prior to therapy and recommending testing to the provider.

Management of Adverse Effects Caused by Immunomodulatory Drugs (IMiDs)

Stratifying VTE Risk and Appropriate Prophylactic Strategies

As with other malignancies, patients with MM are significantly more likely than the general population to develop a venous thromboembolism (VTE). While the presence of any malignancy increases the risk by 7-10 times the baseline risk, hematologic malignancies may increase this risk by as much as 28-fold.[Palumbo 2008] Additionally, previous studies have shown that the use of an IMiD such as lenalidomide or pomalidomide may increase the risk of VTE in MM patients by 8%-26%.[Anderson 2018] As such, the NCCN has recommended the use of pharmacologic thromboprophylaxis for all MM patients receiving an IMiD, with aspirin as the mainstay of therapy for patients without other significant risk factors (Table 2).[NCCN 2019]

Previous versions of the NCCN guidelines recommended full-dose aspirin (i.e., 325 mg orally once daily) as the prophylactic strategy for patients without other significant risk factors, which providers may not have been comfortable with using due to bleeding concerns. However, the most updated version now provides a range from 81-325 mg, which may ease providers’ concerns enough to improve compliance.[NCCN 2019]

It is often difficult for a community or hospital pharmacist to know when a patient is receiving an IMiD medication, as these each have their own respective Risk Evaluation and Mitigation Strategy (REMS) program that requires dispensing from a specialty pharmacy distributor. However, the pharmacist who works at these specialty pharmacies is responsible for counseling the patient regarding these medications, and part of this review could be to contact the provider regarding appropriate thromboembolic prophylaxis strategies. Infusion center nurses may also play a role in assessing the patient for compliance during their infusion visit and for any signs/symptoms of bleeding.

Alternative Dosing Strategies for PIs

Proteasome inhibitors are notorious for causing peripheral neuropathies, with incidences of bortezomib-induced peripheral neuropathy (BIPN) estimated at up to 80%.[McCullough 2018] While its mechanism is not completely understood, preclinical studies have suggested that proteasome inhibition leads to ubiquitinated aggregate accumulation in the cytoplasm of the dorsal root ganglia in the spinal cord.[Ricahrdson 2012] The symptoms associated with BIPN tend to be paresthesias and numbness in distal areas, as well as sharp, burning pain in the toes and soles of the feet.[Ludwig 2018] While there is little evidence of effective treatment strategies for PI peripheral neuropathy, clinicians often use the same agents used for general chemotherapy-induced peripheral neuropathy, including gabapentin, pregabalin, tricyclic antidepressants, and serotonin and norepinephrine reuptake inhibitors.[McCullough 2018] Richardson et al. published an insightful review article on how to manage patients with BIPN, to which readers are referred for more detailed information. In short, the authors recommend early dose reductions for symptoms of BIPN, as well as the consideration of changing from the package insert-recommended twice weekly dosing to once weekly dosing.[Richardson 2012] Additionally, bortezomib should preferentially be administered subcutaneously, as this has shown noninferior efficacy to the intravenous route while causing significantly less peripheral neuropathy.[Moreau 2011]

CASE 2 A 64-year-old woman is currently being treated for multiple myeloma with daratumumab, lenalidomide, and dexamethasone and reports to her provider’s office for routine follow-up. On her labs today, she is noted to have a serum calcium of 11 g/dL. She was taking aspirin 325 mg daily for VTE prophylaxis, but noted bruising more easily on her upper extremities. However, she has had no bleeding episodes or noted any bleeding in the urine or other excrements. CASE QUESTIONS What additional supportive care should this patient receive along with her myeloma therapy? What key laboratory testing should have been performed prior to her beginning therapy? Which vaccinations should this patient receive? What antimicrobial prophylaxis would this patient require? How could we potentially mitigate her bruising episodes? PAUSE AND REFLECT: Assess case based on content thus far, then listen to faculty commentary.  Click here to Show/Hide Audio.

SECTION 4: Supportive Care

General Supportive Care

As with many cancers, MM and the treatments can cause several different side effects, and also create psychosocial hardships. The primary nurse is instrumental in helping the patient navigate through the treatment and the ensuing hardships.

Educating the patient with respect to maintaining (or starting) healthy eating habits can be essential to decrease side effects of treatment. The patient needs to understand that proper hydration can help to reduce the risk of hypercalcemia as well as help to prevent renal dysfunction. 

It is also imperative that the patient understand the need for follow-up monitoring. Patients will need to have lab values monitored for anemia, thrombocytopenia, neutropenia, hypercalcemia, and renal function, to name a few. Nurses can provide the patient with information related to the importance of lab work. The nurse also needs to verify that the patient understands the need to report any symptoms of pancytopenia, such as easy bruising, bleeding from the gums, fatigue, etc. to their oncology provider.

Fatigue can also be a major side effect of treatment. It is one of the most common symptoms reported by MM patients receiving therapy. Fatigue can have a devastating effect on the patient’s quality of life as well. For the oncology nurse, the NCCN provides guidelines for treating fatigue. There are also easy- to-understand patient education materials available on the NCCN website which the patient can download free of charge. 

Management of Renal Disease

When the nurse is educating the patient regarding maintaining hydration, they also need to explain the preferred amount of urine production to correct renal dysfunction. While medical professionals understand the goal of 100-150 cc per hour to promote urine light chain excretion, the patient will require a tangible example, like needing to urinate at least every 3 hours.

The nurse also needs to educate the patient to avoid nephrotoxic agents like NSAIDs (e.g., ibuprophen). Another good teaching point would be to let the patient know there is a possibility that they will need to undergo plasmapheresis. The patient should be reassured that needing plasmapheresis is not a failure on their part.

Role of Bisphosphonates and Denosumab

In addition to the selection of primary treatment regimen, patients with MM require significant supportive care to manage complications of their disease.

Based on the pathophysiology of the disease, patients are at a significantly higher risk of developing skeletal-related events. As such, the NCCN recommends that all patients receiving primary therapy for their myeloma should receive a bisphosphonate (category I recommendation) or denosumab.[NCCN 2019] However, previous studies have shown significant deviation from this recommendation in clinical practice, with only 58-65% of patients receiving a bisphosphonate within their first year of beginning treatment for their myeloma.[McGrath 2018][Kim 2018]

Zoledronic acid has been shown to significantly prolong OS when used first-line in MM patients compared to clodronic acid, an oral bisphosphonate (HR=0.84; 95% CI: 0.74 to 0.96).[Morgan 2010] Additionally, bisphosphonates as a class have been shown to significantly decrease the rates of pathologic vertebral fractures, skeletal-related events, and pain compared with placebo or no treatment.[Mhaskar 2017] Upon reviewing previous trials, impaired renal function seemed to greatly influence the provider’s decision whether and when to initiate bisphosphonate therapy.[Kim 2018] Denosumab was previously not recommended in patients with MM based on an ad hoc subgroup analysis of a phase III trial that suggested patients who received denosumab had a higher mortality rate compared to those who received zoledronic acid (HR=2.26; 95% CI: 1.13 to 4.50).[Henry 2011] However, a more recent phase III trial specifically comparing these two agents in patients with MM found denosumab to be non-inferior to zoledronic acid in prolonging time to first skeletal-related event (HR=0.98; 95% CI: 0.85-1.14).[Raje 2018] Additionally, denosumab appears to have a slightly lower risk of nephrotoxicity compared to zoledronic acid, and does not need to be dose adjusted based on renal function.[Raje 2018][Xgeva PI 2018] The NCCN considers denosumab the preferred antiresorptive agent in patients with MM and renal insufficiency.[NCCN 2019]

Osteonecrosis could be a concern for patients that require bisphosphonates. Prior to starting treatment, the patient should have a baseline dental exam. The nurse needs to educate the patient that all jaw pain must be reported to the oncology provider immediately. With the use of bisphosphonates, lab work monitoring for renal disease becomes more critical. Serum calcium levels also need to be monitored for hypocalcemia which would require correction. Other concerns for the patient are bony compressions. The oncology provider may decide an orthopedic or radiation oncology consult is warranted. The patient should be instructed to report any new symptoms such as new back pain.

Infection-Related Supportive Care

The NCCN provides several recommendations for prevention of infection based on the agents in a patient’s treatment regimen. Patients receiving a PI, high-dose dexamethasone, elotuzumab, or daratumumab are at an increased risk of disseminated herpes simplex virus infection, and so they should receive prophylaxis with acyclovir, famciclovir, or valacyclovir throughout therapy. Additionally, patients receiving high-dose dexamethasone are at increased risk for Pneumocystis jirovecci pneumonia (PCP) and fungal infections, and so appropriate prophylaxis for these organisms should be used. Prior to daratumumab therapy, patients should also undergo baseline testing for hepatitis B, as it may cause virus reactivation. Short-term antibiotic prophylaxis should be considered for patients at high risk of infection at initiation of therapy.[NCCN 2019]

Patients with MM are at a significantly increased risk of infections due to hypogammaglobulinemia secondary to B-cell dysfunction, as well as abnormalities in T-cell and innate immune system function.[Blimark 2015] Based on this deficiency in B-cell function, the pneumococcal conjugate vaccine (PCV13) is preferred for initial vaccination over the pneumococcal polysaccharide vaccine (PPSV23), followed by the PPSV23 vaccine one year later. Additionally, patients should receive the annual trivalent inactivated influenza vaccine. In patients with recurrent, life-threatening infections, intravenous Ig replacement should be considered to reduce the risk of further infections, particularly if non-myeloma IgG levels are below 500 mg/dL.[NCCN 2019][Sanchez-Ramon 2016] A small study recently demonstrated that the use of subcutaneous Ig replacement could also be effective in reducing the incidence of total infections, as well as the number of days receiving antibiotics or hospitalized throughout the year.[Vacca 2019]

Psychosocial Concerns

Recently, a new article published by All.Can highlighted the need for patients with cancer to receive support beyond medication treatment and education.[All.Can 2019] In the All.Can survey (N=4000), a majority of patients reported that they had several mental health concerns including depression and anxiety. The majority of patients experiencing depression or anxiety stated that they had little or no support from healthcare personnel.[All.Can 2019] It is imperative that patients receive support for mental health issues. The nurse can reassure the patient that depression and anxiety can be normal. The nurse should also tell the patient they should report any feelings of depression or anxiety. Patients who report any mental health issues should be provided with consultations with healthcare providers that specialize in mental health. Peer support groups are also good alternatives for patients. 

Many patients also report that the effects of cancer and the treatment extend beyond the patient themselves. Often, the patient and their family are impacted by an extensive financial burden due to the cost of treatment, cost of travel, or loss of employment. The All.Can article suggested that the oncology nurse should act as a navigator for the patient within an interprofessional team where the oncology nurse is able to advocate for the patient. The nurse can also help to ensure there are consistent messages between all the members of the interprofessional team and the patient. 

Another great supportive measure that oncology nurses can employ is providing the patient with a written treatment schedule and written follow-up schedule for lab work and other tests. Due to the fact that there are several oral medications, the patient needs to understand how to take the medication, and not to skip medications unless directed by their oncology provider. When the patient has a greater understanding, the compliance rate is higher.

Addressing Interprofessional Challenges

While an interprofessional approach is the gold standard to optimize patient care, healthcare professionals may face several changes as they strive to achieve this goal. These may include:

• Time constraints – Throughout a normal day, both inpatient and outpatient nurses are generally providing direct care to multiple patients with different levels of acuity and needs. A pharmacist who may be located remotely won’t be cognizant of urgent situations (e.g., a nurse is providing care to a patient who experiences a rapid decline in clinical status) that preclude the nurse from dedicating as much time to her patient that is to receive chemotherapy. Similarly, pharmacists may have several patients for whom they have to clarify orders (both chemotherapy and non-chemotherapy), which may prevent them from recognizing key omissions in their MM patients’ treatment regimen. Physicians, nurse practitioners, and physician assistants also face organizational pressures to see a certain quota of patients within a day, and thus may not respond in a timely manner to queries about order clarifications or address concerns from other healthcare professionals. As such, it’s important for all members of the team to consider these competing interests when attempting to contact each other and to remain patient when the other may take slightly longer than expected to return a communication. Additionally, each group should develop a standard checklist or other procedure to approach each patient’s treatment plan, to ensure that there are adequate double-checks that may catch an omission or error in the prescribed plan.
• Communication – A lack of communication or miscommunication is usually the root of most issues. For example, at times the physician may be so focused on treating the patient, they may forget to communicate with the primary nurse that they are prescribing a new treatment plan or making significant changes to the patient’s regimen. Additionally, the pharmacist is often not located directly in the patient care area, so they are reliant on the nurse to inform them of the key patient parameters, such as whether or not the patient’s intravenous access site is cleared to administer chemotherapy, if the patient had a reaction to a particular medication, or if their performance status has declined to a state that may be unsuitable for a particular regimen. It’s important for the members of the team to establish a preferred mechanism of communication (e.g., phone call, secure electronic messaging, etc.) and expected response time to prevent delays in therapy. At times, the multiple stressors involved in caring for patients in a timely manner may lead to less than constructive conversations that may breed hostility among clinicians, which can also delay patient care. To prevent this, it’s critical for each individual to remember that they are all part of the same patient care team, and to remain approachable and willing to listen to the concerns of the other members of the team.
• Non-standardized regimens – In 2016, the American Society of Clinical Oncology (ASCO) and Oncology Nursing Society (ONS) released a joint guideline detailing best practices regarding chemotherapy ordering, preparation, and administration. Within this document, the organizations recommend that healthcare institutions should define “standard chemotherapy regimens by diagnosis with references”, as well as to provide a mechanism to handle regimens that may deviate from standard clinical practice or guidelines.[Neuss 2017] While this can largely be mitigated through the use of a comprehensive electronic health record, many institutions may not have access to such technology. Particularly in the latter case, it’s important to have a champion from each of the professions – nursing, pharmacy, and medicine – who can review the evidence and develop a “database” of approved regimens based on guidelines and high-quality research. Even if these regimens are not available electronically, the pharmacy champion could establish a paper version of these regimens with appropriate resources on hand, which can then be disseminated to providers to ensure compliance with available literature. In either case, routine review of these regimens is necessary to ensure that they still reflect the most updated guidelines and evidence-based practices.

Truly the best way to overcome all challenges is to ensure that each member of the team is collegial and collaborative in their dealings with each other. 

SUMMARY SECTION

Closing remarks and key-takeaways

• Interprofessional collaboration is crucial to ensure patients are receiving optimal care, along with involving the patient in all treatment-related decisions.
• Oncology nurses play a key role in patient education, advocacy, and navigating the patient through their oncology treatment plan.
• Pharmacists can make a significant impact on the care provided through their recommendations regarding proper dosing, pre-medications, and supportive care on behalf of the patients.
• Multiple myeloma care extends beyond just the treatment of the disease, from managing adverse reactions to providing a strong support network that can mitigate psychological, financial, and social issues.

Patient Resources

• NCCN Guidelines for Patients®. Available at information.https://www.nccn.org/patients/resources/pdf/NCCN_Guidelines_for_Patients_Informational_Piece.pdf.
• NCCN Guidelines for Patients®: Multiple Myeloma. Available at https://www.nccn.org/patients/guidelines/myeloma/index.html.
• Patient and Caregiver Resources. Fatigue. Available at https://www.nccn.org/patients/resources/life_with_cancer/managing_symptoms/fatigue.aspx.

Post-activity survey via case-study (repeated from initial)

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