A phase 2 trial of lenalidomide, bortezomib, and dexamethasone in patients with relapsed and relapsed/refractory myeloma.

In this prospective, multicenter, phase 2 study, 64 patients with relapsed or relapsed and refractory multiple myeloma (MM) received up to 8 21-day cycles of bortezomib 1.0 mg/m(2) (days 1, 4, 8, and 11), lenalidomide 15 mg/day (days 1-14), and dexamethasone 40/20 mg/day (cycles 1-4) and 20/10 mg/day (cycles 5-8) (days of/after bortezomib dosing). Responding patients could receive maintenance therapy. Median age was 65 years; 66% were male, 58% had relapsed and 42% had relapsed and refractory MM, and 53%, 75%, and 6% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Forty-eight of 64 patients (75%; 90% confidence interval, 65-84) were alive without progressive disease at 6 months (primary end point). The rate of partial response or better was 64%; median duration of response was 8.7 months. Median progression-free and overall survivals were 9.5 and 30 months, respectively (median follow-up: 44 months). Common treatment-related toxicities included sensory neuropathy (53%), fatigue (50%), and neutropenia (42%); common grade 3/4 treatment-related toxicities included neutropenia (30%), thrombocytopenia (22%), and lymphopenia (11%). Grade 3 motor neuropathy was reported in 2 patients. Lenalidomide-bortezomib-dexamethasone appears effective and tolerable in patients with relapsed or relapsed and refractory MM, demonstrating substantial activity among patients with diverse prior therapies and adverse prognostic characteristics. This trial is registered with www.clinicaltrials.gov as #NCT00378209.

Treatment-related symptom management in patients with multiple myeloma: a review.

PURPOSE: Recent therapeutic advancements have significantly improved overall survival of patients with multiple myeloma (MM). As a result, the impact of disease- and treatment-related symptoms must be managed effectively to improve patient quality of life, given prolonged survival after diagnosis. This review discusses current MM treatment options, effective symptom management approaches, and practical strategies for supportive care. METHODS: A literature search was performed using MEDLINE/PubMed and scientific congress databases, focusing on clinical trials, review articles, clinical practice guidelines, and other guidance documents on treatment paradigms and supportive care strategies in MM. Additionally, clinical practice worksheets were developed from published sources, and nursing "pearls of wisdom" were gathered from practical experience in the clinic. RESULTS: Current therapeutic regimens for relapsed/refractory MM include proteasome inhibitors (i.e., bortezomib, carfilzomib) and immunomodulatory agents (i.e., thalidomide, lenalidomide, pomalidomide), alone or in combination with chemotherapy or corticosteroids. Toxicities associated with agents and combination regimens used in the treatment of MM include myelosuppression, venous thromboembolism, peripheral neuropathy, infections, fatigue, gastrointestinal disorders, and/or cardiac events. Treatment-specific tools and clinical assessments can be useful for optimizing dosing and schedule adjustments to increase therapy duration, and implementing supportive care strategies (e.g., growth factors, transfusional support, intravenous hydration, bisphosphonates, antiviral therapies) to manage treatment-related symptoms. CONCLUSIONS: Improved survival after MM diagnosis has led to increased patient susceptibility to other diseases and comorbidities due to advanced age. In addition to appropriate drug dosing and administration, effective supportive care and health maintenance are crucial for maximizing quality of life and disease control.

The potential benefits of participating in early-phase clinical trials in multiple myeloma: long-term remission in a patient with relapsed multiple myeloma treated with 90 cycles of lenalidomide and bortezomib.

We present the case of a woman with relapsed multiple myeloma (MM) who received combination lenalidomide and bortezomib therapy for 90 cycles followed by continuous lenalidomide monotherapy and has completed over 100 cycles of treatment to date. The patient was diagnosed with advanced-stage, symptomatic MM in 2001. Following a partial response (PR) to dexamethasone in combination with pamidronate and thalidomide, the patient underwent protocol-directed non-myeloablative allogeneic bone marrow transplantation from her matched sibling donor the following year. In 2004, the patient relapsed and was enrolled in a phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and refractory MM. After eight cycles of study treatment, the patient achieved a minimal response. The patient received a total of 90 cycles of treatment with lenalidomide 5 mg given for 14 d every 21 d, and 1 mg/m(2) of bortezomib initially given on days 1, 4, 8, and 11 for the first 20 cycles, and then weekly thereafter on days 1 and 8. Bortezomib was discontinued after 90 cycles, and the patient continued to receive lenalidomide monotherapy. As of cycle 100, the patient achieved a PR. Currently, she is clinically stable with response sustained for over 7 yrs. Therapy has been well tolerated with no significant long-term toxicity; no dose reductions of lenalidomide and bortezomib were required. The excellent tolerability of this steroid-free approach and the durable response seen underscore the potential benefits of participating in early-phase clinical trials evaluating novel therapies and new drug combinations. This case further supports that combination treatment with lenalidomide and bortezomib is an effective therapy in the management of patients with relapsed and refractory MM.

A Focus on Special Populations in Relapsed Multiple Myeloma.

The overall care of patients with multiple myeloma can present similar challenges. However, disparities in health care require that providers consider each individual's unique circumstances. Disparities based on ethnic/racial group, religion, socioeconomic status, age, sexual orientation or gender identity, or other characteristics can lead to patients receiving less than optimal care and therefore poorer outcomes. Patients who have received more than two lines of therapy can acquire new genetic changes, accelerated cadence of relapse, and suffer from disease sequelae such as pain from prior or ongoing skeletal fractures, recurrent infections, and progressive decline in organ function. Numerous treatment options remain for patients in their first three relapses. Well-designed clinical trials with newer drugs are preferred. Clinicians should discuss clinical trial options and availability with all patients in spite of disparities that may exist. Patients facing disparities are at risk for suboptimal care and should be closely monitored and provided appropriate resources. Continued attention to disease and organ surveillance are critical throughout the course of the disease.

Isatuximab: Nursing Considerations for Use in the Treatment of Multiple Myeloma.

BACKGROUND: Isatuximab is a CD38 monoclonal antibody approved for use in combination with pomalidomide plus dexamethasone to treat adults with relapsed/refractory multiple myeloma who have received at least two prior therapies. Because isatuximab is a relatively new treatment option, published guidelines for oncology nurses are limited. OBJECTIVES: This article provides nurses with guidance on all aspects of isatuximab administration and patient management to better support those receiving this treatment. METHODS: Data from the ICARIA-MM (NCT02990338) clinical trial and additional nursing resources were collected and condensed into concise treatment and management recommendations for the care of patients with multiple myeloma undergoing treatment with isatuximab. FINDINGS: Nursing care of patients prescribed isatuximab includes monitoring of clinical and laboratory parameters and requires knowledge and management of associated adverse events, including infusion reactions and neutropenia. This information could aid oncology nurses in providing optimal, treatment-specific education to patients and caregivers.

Phase 1 open-label study of panobinostat, lenalidomide, bortezomib + dexamethasone in relapsed and relapsed/refractory multiple myeloma.

Additional therapeutic options are needed for relapsed and refractory multiple myeloma (RRMM). We present data from a phase 1b, open-label, dose-escalation study (NCT01965353) of 20 patients with RRMM (median age: 63 years [range: 50-77]) and a median of four prior regimens (range: 2-14); 85% had refractory disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib [50%]). Patients received a median of six cycles (range: 1-74) of panobinostat (10 or 15 mg), lenalidomide 15 mg, bortezomib 1 mg/m2, and dexamethasone 20 mg (pano-RVd). Median follow-up was ~14 months. Six dose-limiting toxicities were reported (mostly hematological); maximum tolerated dose of panobinostat (primary endpoint) was 10 mg. Most common adverse events (AEs) were diarrhea (60%) and peripheral neuropathy (60%); all grade 1/2. Grade 3/4 AEs occurred in 80% of patients and included decreased neutrophil (45%), platelet (25%) and white blood cell (25%) counts, anemia (25%) and hypophosphatemia (25%). No treatment-related discontinuations or mortality occurred. In evaluable patients (n = 18), overall response rate was 44%, and clinical benefit rate was 61%. Median duration of response was 9.2 months; progression-free survival was 7.4 months; overall survival was not reached. Pano-RVd proved generally well-tolerated and demonstrated potential to overcome lenalidomide and/or bortezomib resistance.

Tailoring treatment for multiple myeloma patients with relapsed and refractory disease.

Responses to treatment of relapsed and refractory multiple myeloma are characteristically short, and median survival is as brief as 6 months. Although prognostic factors in the context of relapsed and refractory disease require further characterization, high-risk patients include those with certain cytogenetic abnormalities, high beta2-microglobulin, and low serum albumin. The development of novel therapies targeting disease biology and tumor microenvironment has significantly improved the outlook for patients with relapsed and refractory disease, with bortezomib (Velcade), a first-in-class proteasome inhibitor, and the immunomodulatory agents thalidomide (Thalomid) and lenalidomide (Revlimid) constituting "backbone"agents in this setting. More recent approaches for treating relapsed and refractory myeloma that are recommended by the National Comprehensive Cancer Network include single-agent bortezomib, single-agent lenalidomide, bortezomib/dexamethasone, bortezomib plus pegylated liposomal doxorubicin, lenalidomide/dexamethasone, and lenalidomide/bortezomib/dexamethasone. Individualized treatment of progressive myeloma should take into account the time to progression and/or the type of prior therapy. Additional clinical challenges discussed in this article are renal dysfunction, extramedullary disease, and advanced bone disease. Finally, participation in clinical trials is especially encouraged in this patient population.

Randomized, placebo-controlled, phase 3 study of perifosine combined with bortezomib and dexamethasone in patients with relapsed, refractory multiple myeloma previously treated with bortezomib.

Perifosine, an investigational, oral, synthetic alkylphospholipid, inhibits signal transduction pathways of relevance in multiple myeloma (MM) including PI3K/Akt. Perifosine demonstrated anti-MM activity in preclinical studies and encouraging early-phase clinical activity in combination with bortezomib. A randomized, double-blind, placebo-controlled phase 3 study was conducted to evaluate addition of perifosine to bortezomib-dexamethasone in MM patients with one to four prior therapies who had relapsed following previous bortezomib-based therapy. The primary endpoint was progression-free survival (PFS). The study was discontinued at planned interim analysis, with 135 patients enrolled. Median PFS was 22.7 weeks (95% confidence interval 16·0-45·4) in the perifosine arm and 39.0 weeks (18.3-50.1) in the placebo arm (hazard ratio 1.269 [0.817-1.969]; P = .287); overall response rates were 20% and 27%, respectively. Conversely, median overall survival (OS) was 141.9 weeks and 83.3 weeks (hazard ratio 0.734 [0.380-1.419]; P = .356). Overall, 61% and 55% of patients in the perifosine and placebo arms reported grade 3/4 adverse events, including thrombocytopenia (26% vs 14%), anemia (7% vs 8%), hyponatremia (6% vs 8%), and pneumonia (9% vs 3%). These findings demonstrate no PFS benefit from the addition of perifosine to bortezomib-dexamethasone in this study of relapsed/refractory MM, but comparable safety and OS.

Myelosuppression associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board.

Novel therapies for multiple myeloma include the immunomodulatory drugs lenalidomide and thalidomide and the proteasome inhibitor bortezomib, which have increased response rates and survival times. However, the agents can cause myelosuppression, which, if not managed effectively, can be life threatening and interfere with optimal therapy and quality of life. The International Myeloma Foundation's Nurse Leadership Board developed a consensus statement that includes toxicity grading, strategies for monitoring and managing myelosuppression associated with novel therapies, and educational recommendations for patients and their caregivers. Although anemia, neutropenia, and thrombocytopenia are expected side effects of novel therapies for multiple myeloma, they are manageable with appropriate interventions and education.

Management of side effects of novel therapies for multiple myeloma: consensus statements developed by the International Myeloma Foundation's Nurse Leadership Board.

Nurses play an essential role in managing the care of patients with multiple myeloma, who require education and support to receive and adhere to optimal therapy. The International Myeloma Foundation created a Nurse Leadership Board comprised of oncology nurses from leading cancer centers and community practices. An assessment survey identified the need for specific recommendations for managing key side effects of novel antimyeloma agents. Myelosuppression, thromboembolic events, peripheral neuropathy, steroid toxicities, and gastrointestinal side effects were selected for the first consensus statements. The board developed recommendations for healthcare providers in any medical setting, including grading of side-effect toxicity and strategies for managing the side effects in general, with specific recommendations pertaining to the novel agents.

Immunomodulatory Agents and Proteasome Inhibitors in the Treatment of Multiple Myeloma.

OBJECTIVE: To review the current evidence on the use of immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) in the treatment of multiple myeloma (MM). DATA SOURCES: Journal articles, research reports, state of the science papers, and clinical guidelines. CONCLUSION: There has been a tremendous increase of new agents to treat multiple myeloma in the last 15 years. The IMiDs and PIs remain essential components of many anti-myeloma regimens. IMPLICATIONS FOR NURSING PRACTICE: With these advances in the therapeutic landscape, knowledge of these drugs, side effects and nursing implications are essential to improve outcomes. Patient education is also of vital importance in achieving optimal responses to treatment.

Renal, GI, and Peripheral Nerves: Evidence-Based Recommendations for the Management of Symptoms and Care for Patients With Multiple Myeloma

BACKGROUND: A majority of patients with multiple myeloma experience damage to the kidneys and peripheral nerves either at diagnosis or throughout the disease. Symptoms of diarrhea, nausea, vomiting, or constipation can also occur. Prevention and management of disease- and treatment-related side effects are essential to treatment adherence.
. OBJECTIVES: This article aims to provide insight into prevention and management of organ health-related toxicities and give best practice recommendations for optimal nursing care.
. METHODS: The authors performed a literature search, and articles were reviewed for relevance to each organ-related topic. FINDINGS: Prevention and management strategies include close monitoring and prompt intervention when organ damage develops to reverse impairment and maintain adherence to therapy when indicated.

Optimizing the efficacy and safety of bortezomib in relapsed multiple myeloma.

Bortezomib (Velcade, Millennium) is the first proteasome inhibitor to be used in clinical practice and is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy. Bortezomib inhibits the intracellular degradation of proteins necessary for normal cell cycling and function. This, in turn, results in cell-cycle arrest and apoptosis. Bortezomib has shown significant activity in trials of patients with relapsed or refractory multiple myeloma; approximately one third of patients have shown significant improvement with bortezomib monotherapy in phase II and III clinical trials. Early phase trials are also evaluating bortezomib in combination with other agents used in the treatment of multiple myeloma, including melphalan, prednisone, thalidomide, and lenalidomide. Preliminary data suggest that bortezomib may act synergistically with some agents, and improves response rates. Bortezomib is generally well tolerated, but common side effects include peripheral neuropathy and thrombocytopenia. Studies are underway to explore different dosing strategies as well as ways to maximize patient benefit while reducing toxicity. This review will discuss what is known thus far about the efficacy and safety profile of bortezomib, ways for optimizing treatment with bortezomib, and strategies for managing side effects and enhancing quality of life.

Bortezomib, a newly approved proteasome inhibitor for the treatment of multiple myeloma: nursing implications.

Multiple myeloma (MM), a malignancy of the plasma cells, accounts for an estimated 14% of all newly diagnosed hematologic malignancies. Advances in chemotherapy and stem cell transplantation have improved survival rates, but MM remains incurable. Bortezomib (Velcade, Millennium Pharmaceuticals, Inc., Cambridge, MA), a first-in-class proteasome inhibitor, has been approved for patients with MM who have received at least two prior treatments and have demonstrated disease progression on the most recent one. During clinical trials, most side effects were manageable with standard interventions. The most common toxicities were asthenic conditions (fatigue, malaise, and weakness), gastrointestinal disturbances (nausea, vomiting, diarrhea, and constipation), thrombocytopenia, peripheral neuropathy, pyrexia, and anemia. Supportive therapies and strategies for side-effect management can prevent worsening of these symptoms, thereby avoiding dose reductions and treatment delays. Oncology nurses play a key role in ensuring the proper and safe administration of bortezomib and often are the first to identify the signs of side effects. Patient education about anticipated side effects and close monitoring of patients can lead to symptom management interventions that are essential to patient comfort and safety.

Maintaining bone health in patients with multiple myeloma: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board.

About 90% of individuals with multiple myeloma will develop osteolytic bone lesions from increased osteoclastic and decreased osteoblastic activity. Severe morbidities from pathologic fractures and other skeletal events can lead to poor circulation, blood clots, muscle wasting, compromised performance status, and overall poor survival. Supportive care targeting bone disease is an essential adjunct to antimyeloma therapy. In addition, the maintenance of bone health in patients with multiple myeloma can significantly improve quality of life. Oncology nurses and other healthcare providers play a central role in the management of bone disease and maintenance throughout the course of treatment. Safe administration of bisphosphonates, promotion of exercise, maintenance of adequate nutrition, vitamin and mineral supplementation, scheduled radiographic examinations, and monitoring of bone complications are among the important functions that oncology nurses and healthcare providers perform in clinical practice.

Perifosine plus bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma previously treated with bortezomib: results of a multicenter phase I/II trial.

PURPOSE: Novel agents have improved patient outcome in relapsed or relapsed/refractory multiple myeloma (MM). Preclinical data show that the novel signal transduction modulator, perifosine, enhances the cytotoxicity of dexamethasone and bortezomib. Clinical data suggest that perifosine in combination with dexamethasone has activity in relapsed or relapsed/refractory MM. PATIENTS AND METHODS: In a phase I/II study, perifosine in combination with bortezomib with or without dexamethasone was prospectively evaluated in 84 patients with relapsed or relapsed/refractory MM. All were heavily pretreated and bortezomib exposed; 73% were refractory to bortezomib, and 51% were refractory to bortezomib and dexamethasone. The dose selected for the phase II study was perifosine 50 mg/d plus bortezomib 1.3 mg/m(2), with the addition of low-dose dexamethasone at 20 mg if progression occurred on perifosine plus bortezomib alone. RESULTS: An overall response rate (ORR; defined as minimal response or better) of 41% was demonstrated with this combination in 73 evaluable patients, including an ORR of 65% in bortezomib-relapsed patients and 32% in bortezomib-refractory patients. Therapy was generally well tolerated; toxicities, including gastrointestinal adverse effects and fatigue, proved manageable. No treatment-related mortality was seen. Median progression-free survival was 6.4 months, with a median overall survival of 25 months (22.5 months in bortezomib-refractory patients). CONCLUSION: Perifosine-bortezomib ± dexamethasone demonstrated encouraging activity in heavily pretreated bortezomib-exposed patients with advanced MM. A phase III trial is underway comparing perifosine-bortezomib plus dexamethasone with bortezomib-dexamethasone in patients with relapsed/refractory MM previously treated with bortezomib.

Expanding role of bortezomib in multiple myeloma: nursing implications.

Multiple myeloma is the second most common hematologic malignancy and remains incurable, despite advances in chemotherapy and stem cell transplantation. Bortezomib, a novel proteasome inhibitor, is approved for the treatment of patients with multiple myeloma who have received at least 1 prior therapy. In the assessment of proteasome inhibition for extending remissions phase III trial of bortezomib versus high-dose dexamethasone, bortezomib led to significantly longer survival and time to progression and higher response rate in patients with relapsed multiple myeloma. The principal adverse events were gastrointestinal effects, fatigue, transient thrombocytopenia, and reversible peripheral neuropathy. The side effect profile of bortezomib is extensively characterized, predictable, and generally manageable; retreatment or extended bortezomib therapy seems well tolerated. Nurses play a unique role in bortezomib treatment: they are often closest to the patients and are most able to educate patients about side effects and, if necessary, take appropriate action, independently or collaboratively with healthcare team members. In this review, we present the latest efficacy and safety data for bortezomib in relapsed multiple myeloma and characterize common side effects associated with bortezomib and the implications for nursing. We also highlight practical strategies for preventing and managing side effects, thereby enhancing the clinical benefit of bortezomib-based therapies to patients.

Phase I trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced multiple myeloma.

A Phase I trial (NCT00109109) of oral vorinostat 200, 250 or 300 mg twice daily for 5 days/week/4-week cycle or 200, 300, or 400 mg twice daily for 14 days/3-week cycle until progressive disease or intolerable toxicity was conducted. Patients with measurable, relapsed/refractory multiple myeloma were eligible. The objectives were to determine maximum tolerated doses (MTDs) and assess activity and safety. Thirteen patients (median age, 63 years; median prior therapies, 3) were enrolled. MTDs were not determined due to early study termination by sponsor decision. One patient (250 mg twice daily 5 days/week) developed dose-limiting toxicity (DLT; grade 3 fatigue). There were no other DLTs and the maximum administered doses were 250 mg twice daily for 5 days/week/4-week cycle and 200 mg twice daily for 14 days/3-week cycle. Drug-related adverse experiences included fatigue, anorexia, dehydration, diarrhea, and nausea and were mostly grade

A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma.

This multicenter, open-label, randomized phase 2 study evaluated 2 dose regimens of lenalidomide for relapsed, refractory myeloma. Seventy patients were randomized to receive either 30 mg once-daily or 15 mg twice-daily oral lenalidomide for 21 days of every 28-day cycle. Patients with progressive or stable disease after 2 cycles received dexamethasone. Analysis of the first 70 patients showed increased grade 3/4 myelo-suppression in patients receiving 15 mg twice daily (41% versus 13%, P = .03). An additional 32 patients received 30 mg once daily. Responses were evaluated according to European Group for Blood and Marrow Transplantation (EBMT) criteria. Overall response rate (complete, partial, or minor) to lenalidomide alone was 25% (24% for once-daily and 29% for twice-daily lenalidomide). Median overall survival in 30-mg once-daily and twice-daily groups was 28 and 27 months, respectively. Median progression-free survival was 7.7 months on once-daily versus 3.9 months on twice-daily lenalidomide (P = .2). Dexamethasone was added in 68 patients and 29% responded. Time to first occurrence of clinically significant grade 3/4 myelosuppression was shorter in the twice-daily group (1.8 vs 5.5 months, P = .05). Significant peripheral neuropathy and deep vein thrombosis each occurred in only 3%. Lenalidomide is active and well tolerated in relapsed, refractory myeloma, with the 30-mg once-daily regimen providing the basis for future studies as monotherapy and with dexamethasone.