Phase 1 Trial Evaluating Vorinostat Plus Bortezomib, Lenalidomide, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma.

INTRODUCTION: Bortezomib plus lenalidomide and dexamethasone (VRD) is a standard induction therapy for newly diagnosed multiple myeloma (NDMM) patients. Given preclinical and clinical data suggesting the synergistic activity of the histone deacetylase inhibitor vorinostat with both bortezomib and lenalidomide for the treatment of multiple myeloma, we hypothesized that adding vorinostat to VRD (R2V2) would increase the rate and the quality of responses to induction treatment. Here we report the results of a phase 1 trial (NCT01038388) evaluating R2V2 as up-front treatment for NDMM patients. PATIENTS AND METHODS: R2V2 was tested as induction therapy in a dose-escalation phase 1 study in 30 NDMM patients deemed eligible for autologous stem-cell transplantation. Treatment consisted of 4 induction cycles with R2V2, followed by either autologous stem-cell transplantation or 4 additional R2V2 cycles and lenalidomide maintenance therapy. RESULTS: The maximum tolerated dose of vorinostat was 200 mg daily. The most common adverse events were gastrointestinal (87%), fatigue and peripheral neuropathy (60%), and thrombocytopenia (33%). R2V2 induced an objective response in 96% of patients, with 48% obtaining at least a complete remission. Median progression-free survival was 52 months, with 77% of patients alive at 5 years. CONCLUSION: R2V2 as induction treatment for NDMM patients resulted in remarkable response rates at the cost of increased toxicity.

Clinical efficacy of daratumumab, pomalidomide, and dexamethasone in patients with relapsed or refractory myeloma: Utility of re-treatment with daratumumab among refractory patients.

BACKGROUND: The efficacy of daratumumab (DARA) both as a monotherapy and in combination with standard-of-care regimens in multiple myeloma (MM) has been established in clinical trials. This article presents a retrospective analysis of the safety and efficacy of DARA in combination with pomalidomide (POM) and dexamethasone (ie, daratumumab, pomalidomide, and dexamethasone [DARA-POM-D]) and, more importantly, the long-term follow-up of a cohort that was naive to DARA and POM as well as a cohort in which the utility of re-treatment was evaluated among patients who were DARA- and/or POM-refractory. METHODS: Thirty-four consecutive patients with relapsed and/or refractory MM treated with DARA-POM-D at the Winship Cancer Institute of Emory University from January 2015 through July 2016 were included in the analysis. The study was approved by Emory University's institutional review board. All received prior proteasome inhibitors and immunomodulatory drugs (IMiDs) and were refractory to their last line of therapy. RESULTS: All patients were lenalidomide-refractory, and 91% were bortezomib-refractory. Two cohorts were identified on the basis of prior exposure to DARA and/or POM. Cohort 1 (12 patients) was DARA- and POM-naive, and cohort 2 (22 patients) was DARA- and/or POM-refractory. A subgroup of 12 patients in cohort 2 (cohort 3) was DARA- and POM-refractory. The combination's tolerability was consistent with the results of the published phase 1b study (EQUULES) that evaluated the combination and no new safety signals were observed. The overall response rates (ORRs) were 91.7%, 40.9%, and 33.3% in cohorts 1, 2, and 3, respectively. Deep responses, including 4 stringent complete responses, were observed in cohort 1. In cohort 2, the ORR comprised 8 partial responses (PRs) and 1 very good PR. The median progression-free survival (PFS) was not reached in cohort 1 at a median follow-up of 41 months, and it was 3.2 months in cohort 2. DARA-POM-D not only was effective in DARA- and POM-naive patients but also produced clinical responses in a third of patients re-treated with these drugs. CONCLUSIONS: A better than quadrupled PFS benefit observed in cohort 1 in comparison with the previously reported benefit in the EQUULEUS trial (which led to US Food and Drug Administration approval of the DARA-POM-D combination) highlights the fact that the introduction of monoclonal antibody combination strategies and IMiDs as earlier lines of therapeutic options potentially could deliver better clinical outcomes. One-third of patients refractory to separate lines of DARA and/or POM responded when they were re-treated with a combination, and this resulted in survival benefits equivalent to those of other antimyeloma agents/combinations available for DARA-refractory patients.

Combining carfilzomib and panobinostat to treat relapsed/refractory multiple myeloma: results of a Multiple Myeloma Research Consortium Phase I Study.

Proteasome (PIs) and hystone deacetylase inhibitors (HDACis) have previously shown synergistic activity in the treatment of relapesed/refractory multiple myeloma (RRMM) patients. In this phase 1 study, we combined carfilzomib, a second generation PI, with panobinostat, a HDACi, to determine the maximum tolerated dose (MTD) of the combination (CarPan) and assess safety and efficacy among RRMM patients. Thirty-two patients (median of 4 prior lines of therapy) were enrolled. The MTD was carfilzomib 36 mg/m2 (on days 1, 2, 8, 9, 15, and 16) and panobinostat 20 mg (TIW, 3 weeks on/1 week off, every 28 days), administered until progression. At the MTD, the most common grade 3/4, treatment-related adverse events were thrombocytopenia (41%), fatigue (17%), and nausea/vomiting (12%). The objective response rate (ORR) and clinical benefit rate were 63% and 68%, respectively. Median progression-free survival (PFS) and overall survival (OS) for the entire population were 8 and 23 months, respectively. No differences in terms of ORR (55% vs. 57%), median PFS (months 8 vs. 7 months) and OS (24 vs. 22 months) were observed between bortezomib-sensitive and -refractory patients. CarPan proved to be a safe and effective steroid-sparing regimen in a heavily pre-treated population of MM patients. (Trial registered at ClinicalTrial.gov: NCT01549431).

Survival outcomes of patients with primary plasma cell leukemia (pPCL) treated with novel agents.

BACKGROUND: Primary plasma cell leukemia (pPCL) is an aggressive plasma cell disorder characterized by circulating plasma cells and a poor prognosis. Although patients who have pPCL benefit from the use of stem cell transplantation (SCT) and novel agents, their prognosis remains inferior to that of patients who have myeloma. METHODS: This was a retrospective analysis of 38 consecutive patients with pPCL who were diagnosed between October 2005 and July 2016 and were registered in the Winship Cancer Institute of Emory University database. Baseline characteristics as well as data about treatment and survival outcomes were collected. RESULTS: The median patient age at diagnosis was 58 years. All patients received a bortezomib-based induction regimen, and 92% received both bortezomib and an immunomodulatory drug (thalidomide or lenalidomide); in addition, 74% of patients underwent autologous SCT (ASCT), and 61% received maintenance therapy. The best response to first-line therapy was a partial response or better in 87% of patients, and 45% had a complete response (CR). The achievement of ≥CR was a predictor for prolonged progression-free survival (PFS) and overall survival (OS). The median PFS was 20 months, and the median OS was 33 months. PFS was prolonged in patients who underwent ASCT compared with those who did not undergo ASCT (25 vs 6 months; P = .004), and patients who received maintenance therapy after ASCT had prolonged median PFS (27 vs 11 months; P = .03) and a trend toward prolonged OS (median, 38 vs 22 months; P = .06) compared with those who did not receive maintenance therapy. CONCLUSIONS: The current data support the use of regimens combining novel agents in the upfront treatment of patients with pPCL as well as the role of ASCT and maintenance therapy for long-term disease control.

Antimicrobial Prophylaxis for Adult Patients With Cancer-Related Immunosuppression: ASCO and IDSA Clinical Practice Guideline Update.

PURPOSE: To provide an updated joint ASCO/Infectious Diseases Society of America (IDSA) guideline on antimicrobial prophylaxis for adult patients with immunosuppression associated with cancer and its treatment. METHODS: ASCO and IDSA convened an update Expert Panel and conducted a systematic review of relevant studies from May 2011 to November 2016. The guideline recommendations were based on the review of evidence by the Expert Panel. RESULTS: Six new or updated meta-analyses and six new primary studies were added to the updated systematic review. RECOMMENDATIONS: Antibacterial and antifungal prophylaxis is recommended for patients who are at high risk of infection, including patients who are expected to have profound, protracted neutropenia, which is defined as < 100 neutrophils/µL for > 7 days or other risk factors. Herpes simplex virus-seropositive patients undergoing allogeneic hematopoietic stem-cell transplantation or leukemia induction therapy should receive nucleoside analog-based antiviral prophylaxis, such as acyclovir. Pneumocystis jirovecii prophylaxis is recommended for patients receiving chemotherapy regimens that are associated with a > 3.5% risk for pneumonia as a result of this organism (eg, those with ≥ 20 mg prednisone equivalents daily for ≥ 1 month or on the basis of purine analog usage). Treatment with a nucleoside reverse transcription inhibitor (eg, entecavir or tenofovir) is recommended for patients at high risk of hepatitis B virus reactivation. Recommendations for vaccination and avoidance of prolonged contact with environments that have high concentrations of airborne fungal spores are also provided within the updated guideline. Additional information is available at www.asco.org/supportive-care-guidelines .

Daratumumab and its use in the treatment of relapsed and/or refractory multiple myeloma.

Daratumumab gained initial US FDA approval as fourth-line therapy among relapsed and/or refractory multiple myeloma (RRMM) patients who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), or who are double refractory to a PI and an IMiD. Further combination trials of daratumumab led to FDA approvals in combination with bortezomib and dexamethasone or lenalidomide and dexamethasone for multiple myeloma patients who have received at least one prior therapy. The most recent expansion of the FDA approval of daratumumab comes in combination with pomalidomide and dexamethasone for patients with multiple myeloma that have received ≥2 prior lines of therapy including lenalidomide and a PI. The current manuscript reviews data supporting the efficacy and safety of daratumumab in RRMM.

Managing Infusion Reactions to New Monoclonal Antibodies in Multiple Myeloma: Daratumumab and Elotuzumab.

Monoclonal antibodies (elotuzumab and daratumumab) are the newest class of drugs that have proven to be efficacious antimyeloma agents. Although daratumumab, a CD38 monoclonal antibody, has established its efficacy as a single agent and in combination with immunomodulatory agents and proteasome inhibitors, elotuzumab (signaling lymphocytic activation molecule F7 monoclonal antibody) has proven activity in combination with lenalidomide and dexamethasone. Infusion-related reactions (respiratory and nonrespiratory) seem to be a common theme of adverse events with monoclonal antibodies, although the relative incidence differs across these two agents. Identifying the appropriate pre- and postinfusion medication strategies can help lower the rates of infusion-related reactions and facilitate reduction in infusion times. In this article, we review the incidence of the infusion-related reactions with elotuzumab and daratumumab and their clinical activity in myeloma, review our institutional experience of management of infusion-related reactions, and provide some practical mitigation strategies to reduce their incidence.

Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America Clinical Practice Guideline Update.

Purpose To provide an updated joint ASCO/Infectious Diseases Society of American (IDSA) guideline on outpatient management of fever and neutropenia in patients with cancer. Methods ASCO and IDSA convened an Update Expert Panel and conducted a systematic review of relevant studies. The guideline recommendations were based on the review of evidence by the Expert Panel. Results Six new or updated meta-analyses and six new primary studies were added to the updated systematic review. Recommendation Clinical judgment is recommended when determining which patients are candidates for outpatient management, using clinical criteria or a validated tool such as the Multinational Association of Support Care in Cancer risk index. In addition, psychosocial and logistic considerations are outlined within the guideline. The panel continued to endorse consensus recommendations from the previous version of this guideline that patients with febrile neutropenia receive initial doses of empirical antibacterial therapy within 1 hour of triage and be monitored for ≥ 4 hours before discharge. An oral fluoroquinolone plus amoxicillin/clavulanate (or clindamycin, if penicillin allergic) is recommended as empirical outpatient therapy, unless fluoroquinolone prophylaxis was used before fever developed. Patients who do not defervesce after 2 to 3 days of an initial, empirical, broad-spectrum antibiotic regimen should be re-evaluated and considered as candidates for inpatient treatment. Additional information is available at www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki .

Distress, Fatigue, and Sexuality: Understanding and Treating Concerns and Symptoms in Patients With Multiple Myeloma 
.

BACKGROUND: The psychological needs of patients and caregivers may be inadvertently overlooked, contributing to the patient's distress and possibly compromising outcomes. Untreated, these psychological needs may impair the patient's ability to make decisions and adhere to treatment. 
. OBJECTIVES: This article aims to present consensus statements to guide oncology nurses in the recognition and management of distress, fatigue, and sexual dysfunction in patients with multiple myeloma (MM). 
. METHODS: Members of the International Myeloma Foundation Nursing Leadership Board reviewed the current literature and clinical experience regarding interventions related to distress, fatigue, and sexual dysfunction in patients with MM.
. FINDINGS: Ongoing patient education and attention to medical and psychological care is important to assess and address patients' needs, such as cancer-related fatigue, sexual dysfunction, and distress.

Immunotherapy in Multiple Myeloma.

OBJECTIVES: To review the use of monoclonal antibodies (mAbs) in the treatment of multiple myeloma (MM) and the management of most common side effects. DATA SOURCES: Review of journal articles related to mAbs in MM. CONCLUSION: The therapeutic options for MM have improved dramatically and the development of mAbs has been associated with improvement in clinical outcomes and favorable toxicity profiles. IMPLICATIONS FOR NURSING PRACTICE: With appropriate pre-medications and nursing management, mAbs are a well-tolerated treatment option for myeloma patients.

New Treatment Strategies Making an Impact in Multiple Myeloma.

Even though multiple myeloma remains incurable, mean overall survival has improved dramatically as newer game-changing therapies enter the scene. At the same time, treatment decisions and the management of toxicities related to newer drug regimens are becoming more complex.

Lack of health maintenance examinations and risk in myeloma patients.

Health maintenance (HM) practices are essential to prevent illness, promote well-being, and maximize health. Patients with multiple myeloma (MM) are at increased risk for cardiovascular disease and cancers, yet, research on HM practices and preventative care of MM survivors has limited report. The study comprised a descriptive, correlational, and cross-sectional online survey design. Survey of patients with MM was carried out through the International Myeloma Foundation (IMF) and the Association of Cancer Online Resources (ACOR) e-mail list services. The members of the IMF and ACOR e-mail list services were surveyed, of which 237 patients responded. The modified Medical Expenditure Preventive Survey-Preventive Care questionnaire was used; it included items that ask patients regarding their healthcare practices that relate to dental care, cancer prevention, addiction, lifestyles, sensory screening, immunizations, cardiovascular, endocrine, psychosocial, and bone health. Descriptive statistics, Pearson's chi-square, and Spearman's rho correlation coefficient were obtained. In this study, men had statistically significant inferior global health maintenance scores than women (P = 0.002). Being employed (P = 0.054) and married or partnered (P = 0.017) were significantly correlated with better health maintenance patterns among male respondents. In contrast, no statistically significant correlations between sociodemographic factors and health maintenance patterns were found in women. Patients with MM, particularly men, require continued education and close monitoring of health maintenance practices. These findings are consistent with publications looking at gender disparities in healthcare utilization in the United States. Studies show that men, in general, are less likely to seek preventative healthcare screenings. Healthcare providers must incorporate health maintenance promotion during clinic visits.

Down to the bitter end.

"The daintiest last, to make the end most sweet," comes to us from Shakespeare's Richard II, but in the most recent edition of Blood, the paper from Martinez-Lopez et al suggests that by using minimal residual disease (MRD) testing by sequencing, we may be nearing the "end most sweet" or, in 21st century vernacular, the cure of myeloma.

Autologous hematopoietic stem cell transplantation for multiple myeloma: frequently asked questions.

When caring for patients with multiple myeloma, questions often arise about the role and timing of autologous hematopoietic stem cell transplantation. As a complement to the other articles in this supplement, as well as to ensure that readers are provided with the insight needed to feel comfortable speaking to patients and other practitioners about this topic, the authors address eight frequently asked questions about common decision points in the process of autologous hematopoietic stem cell transplantation as a treatment for patients with multiple myeloma.

Bortezomib-containing induction regimens in transplant-eligible myeloma patients: a meta-analysis of phase 3 randomized clinical trials.

BACKGROUND: The objective of this meta-analysis in patients with myeloma was to test the hypothesis that the addition of bortezomib to induction therapy not only improves the depth of response but also improves post-transplant progression-free survival (PFS) and overall survival (OS) outcomes. METHODS: Phase 3 trials that randomized newly diagnosed, transplant-eligible patients with myeloma to receive either a bortezomib-containing induction regimen (BCIR) or a nonbortezomib-containing induction regimen (NBCIR) were identified. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were adapted for data synthesis, and comprehensive meta-analysis software was used to report pooled data as hazard ratios or odds ratios under a random-effects model. RESULTS: Four published phase 3 trials that included 2169 patients were analyzed. The postinduction and post-transplant pooled odds ratio for achieving a complete response/near complete response or a very good partial response or better and the overall response rate were higher with BCIR. The pooled hazard ratios for 3-year PFS and OS were 0.71 (95% confidence interval, 0.60-0.83; P < .00,001) and 0.79 (95% confidence interval, 0.66-0.96; P = .014), respectively, favoring BCIR. The odds of developing selected grade ≥ 3 toxicities (peripheral neuropathy and varicella-zoster virus reactivation) also were higher with BCIR. CONCLUSIONS: The current meta-analysis demonstrated that BCIR results in an improved depth of response, which translates into improved post-transplant PFS and OS outcomes despite a higher incidence of toxicity. This analysis supports the concept that the choice of induction regimen can influence post-transplant outcomes such as PFS and OS.

Relapsed and refractory lymphoid neoplasms and multiple myeloma with a focus on carfilzomib.

Proteasomal inhibition revolutionized myeloma therapies in this decade of novel agents. The only US Food and Drug Administration approved proteasome inhibitor so far, bortezomib effectively targets the constitutive proteasome subunit ß5 of the 26S proteasome. Bortezomib induces high and quality response rates that are durable. However, myeloma cells acquire resistance to bortezomib through various mechanisms. Further, grade 3/4 peripheral neuropathy is seen in up to a quarter of patients treated with bortezomib. While the recent change in the mode of administration via the subcutaneous route is associated with a lower incidence of grade 3/4 peripheral neuropathy, it remains a major concern. The second generation proteasome inhibitors are promising, with increased preclinical efficacy and a better administration schedule. The current review spotlights the second generation proteasome inhibitors with special focus on the safety and efficacy of carfilzomib, an epoxyketone with lesser peripheral neuropathy, which exhibits irreversible proteasome inhibition. In this article, we review the pharmacology and preclinical and clinical efficacy and safety of carfilzomib alone and in combination with other chemotherapeutic agents in the various lymphoid neoplasms and multiple myeloma as well as ongoing clinical trials.

Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline.

PURPOSE: To provide guidelines on antimicrobial prophylaxis for adult neutropenic oncology outpatients and on selection and treatment as outpatients of those with fever and neutropenia. METHODS: A literature search identified relevant studies published in English. Primary outcomes included: development of fever and/or infections in afebrile neutropenic outpatients and recovery without complications and overall mortality in febrile neutropenic outpatients. Secondary outcomes included: in afebrile neutropenic outpatients, infection-related mortality; in outpatients with fever and neutropenia, defervescence without regimen change, time to defervescence, infectious complications, and recurrent fever; and in both groups, hospital admissions, duration, and adverse effects of antimicrobials. An Expert Panel developed guidelines based on extracted data and informal consensus. RESULTS: Forty-seven articles from 43 studies met selection criteria. RECOMMENDATIONS: Antibacterial and antifungal prophylaxis are only recommended for patients expected to have < 100 neutrophils/µL for > 7 days, unless other factors increase risks for complications or mortality to similar levels. Inpatient treatment is standard to manage febrile neutropenic episodes, although carefully selected patients may be managed as outpatients after systematic assessment beginning with a validated risk index (eg, Multinational Association for Supportive Care in Cancer [MASCC] score or Talcott's rules). Patients with MASCC scores ≥ 21 or in Talcott group 4, and without other risk factors, can be managed safely as outpatients. Febrile neutropenic patients should receive initial doses of empirical antibacterial therapy within an hour of triage and should either be monitored for at least 4 hours to determine suitability for outpatient management or be admitted to the hospital. An oral fluoroquinolone plus amoxicillin/clavulanate (or plus clindamycin if penicillin allergic) is recommended as empiric therapy, unless fluoroquinolone prophylaxis was used before fever developed.

Routine health maintenance in patients living with multiple myeloma: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board.

Patients diagnosed with multiple myeloma are living longer because of new therapeutic options. Helping patients with multiple myeloma maintain a good state of health from the time of diagnosis and throughout their therapy leads to better quality of life. However, patients with multiple myeloma are at risk for illnesses experienced by the general population and at additional risk for illnesses related to multiple myeloma and its treatment. Therefore, the International Myeloma Foundation Nurse Leadership Board (NLB) has developed practice recommendations to meet the particular needs of adult patients with multiple myeloma using evidence-based recommendations for screening and disease prevention, as well as nursing experience. The NLB recommendations are designed to address and overcome barriers to health maintenance by educating and empowering nurses and their patients.

Treatment of severe neutropenia with high-dose pyridoxine in a patient with chronic graft versus host disease and squamous cell carcinoma: a case report.

INTRODUCTION: The differential diagnosis of neutropenia includes medications, infections, autoimmune diseases, and deficiencies of Vitamin B12 and folate. The association of Vitamin B6 deficiency with severe neutropenia is a rare finding. CASE PRESENTATION: A 51-year-old Caucasian woman presented with fever and profound neutropenia (48 neutrophils/uL). Her clinical history included non-Hodgkin lymphoma, in remission following treatment with allogeneic bone marrow transplantation, quiescent chronic graft-versus-host disease, and squamous cell carcinoma of the skin metastatic to cervical lymph nodes. Medications included atenolol, topical clobetasol, Ditropan (oxybutynin), prophylactic voriconazole, prophylactic valganciclovir, Soriatane (acitretin), and Carac (fluorouracil) cream. The bone marrow was hypocellular without metastatic cancer or myelodysplasia. Neutropenia did not respond to stopping medications that have been associated with neutropenia (valganciclovir, voriconazole and Soriatane) or treatment with antibiotics or granulocyte colony stimulating factor. Blood tests revealed absence of antineutrophil antibodies, normal folate and B12 levels, moderate zinc deficiency and severe Vitamin B6 deficiency. Replacement therapy with oral Vitamin B6 restored blood vitamin levels to the normal range and corrected the neutropenia. Her cervical adenopathy regressed clinically and became negative on scintography following Vitamin B6 therapy and normalization of the blood neutrophil count. CONCLUSION: Severe pyridoxine deficiency can lead to neutropenia. Screening for Vitamin B6 deficiency, along with folate and Vitamin B12 levels, is recommended in patients with refractory neutropenia, especially those with possible malabsorption syndromes, or a history of chronic-graft-versus host disease. Severe neutropenia may facilitate progression of squamous cell carcinoma.