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This Policy Review presents the International Myeloma Working Group's clinical practice recommendations for the treatment of relapsed and refractory multiple myeloma. Based on the results of phase 2 and phase 3 trials, these recommendations are proposed for the treatment of patients with relapsed and refractory disease who have received one previous line of therapy, and for patients with relapsed and refractory multiple myeloma who have received two or more previous lines of therapy. These recommendations integrate the issue of drug access in both low-income and middle-income countries and in high-income countries to help guide real-world practice and thus improve patient outcomes. © 2021 Elsevier Ltd

A comprehensive understanding of the effects of agricultural management on climate–crop interactions has yet to emerge. Using a novel wavelet–statistics conjunction approach, we analysed the synchronisation amongst fluxes (net ecosystem exchange NEE, evapotranspiration and sensible heat flux) and seven environmental factors (e.g., air temperature, soil water content) on 19 farm sites across Australia and New Zealand. Irrigation and fertilisation practices improved positive coupling between net ecosystem productivity (NEP = −NEE) and evapotranspiration, as hypothesised. Highly intense management tended to protect against heat stress, especially for irrigated crops in dry climates. By contrast, stress avoidance in the vegetation of tropical and hot desert climates was identified by reverse coupling between NEP and sensible heat flux (i.e., increases in NEP were synchronised with decreases in sensible heat flux). Some environmental factors were found to be under management control, whereas others were fixed as constraints at a given location. Irrigated crops in dry climates (e.g., maize, almonds) showed high predictability of fluxes given only knowledge of fluctuations in climate (R2 > 0.78), and fluxes were nearly as predictable across strongly energy- or water-limited environments (0.60 < R2 < 0.89). However, wavelet regression of environmental conditions on fluxes showed much smaller predictability in response to precipitation pulses (0.15 < R2 < 0.55), where mowing or grazing affected crop phenology (0.28 < R2 < 0.59), and where water and energy limitations were balanced (0.7 < net radiation ∕ precipitation < 1.3; 0.27 < R2 < 0.36). By incorporating a temporal component to regression, wavelet–statistics conjunction provides an important step forward for understanding direct ecosystem responses to environmental change, for modelling that understanding, and for quantifying nonstationary, nonlinear processes such as precipitation pulses, which have previously defied quantitative analysis.

In this proof-of-concept, open-label, phase 2 study, patients with relapsed/refractory multiple myeloma (RRMM) received elotuzumab with bortezomib and dexamethasone (EBd) or bortezomib and dexamethasone (Bd) until disease progression/unacceptable toxicity. Primary endpoint was progression-free survival (PFS); secondary/exploratory endpoints included overall response rate (ORR) and overall survival (OS). Two-sided 0.30 significance level was specified (80% power, 103 events) to detect hazard ratio (HR) of 0.69. Efficacy and safety analyses were performed on all randomized patients and all treated patients, respectively. Of 152 randomized patients (77 EBd, 75 Bd), 150 were treated (75 EBd, 75 Bd). PFS was greater with EBd vs Bd (HR, 0.72; 70% confidence interval [CI], 0.59-0.88; stratified log-rank P = .09); median PFS was longer with EBd (9.7 months) vs Bd (6.9 months). In an updated analysis, EBd-treated patients homozygous for the high-affinity Fc?RIIIa allele had median PFS of 22.3 months vs 9.8 months in EBd-treated patients homozygous for the low-affinity allele. ORR was 66% (EBd) vs 63% (Bd). Very good partial response or better occurred in 36% of patients (EBd) vs 27% (Bd). Early OS results, based on 40 deaths, revealed an HR of 0.61 (70% CI, 0.43-0.85). To date, 60 deaths have occurred (28 EBd, 32 Bd). No additional clinically significant adverse events occurred with EBd vs Bd. Grade 1/2 infusion reaction rate was low (5% EBd) and mitigated with premedication. In patients with RRMM, elotuzumab, an immunostimulatory antibody, appears to provide clinical benefit without added clinically significant toxicity when combined with Bd vs Bd alone. Registered to ClinicalTrials.gov as NCT01478048.

The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM. © 2016 Macmillan Publishers Limited.

Purpose: The aim of the International Myeloma Working Group was to develop practical recommendations for the diagnosis and management of multiple myeloma–related renal impairment (RI). Methods: Recommendations were based on published data through December 2015, and were developed using the system developed by the Grading of Recommendation, Assessment, Development, and Evaluation Working Group. Recommendations: All patients with myeloma at diagnosis and at disease assessment should have serum creatinine, estimated glomerular filtration rate, and electrolytes measurements as well as free light chain, if available, and urine electrophoresis of a sample from a 24-hour urine collection (grade A). The Chronic Kidney Disease Epidemiology Collaboration, preferably, or the Modification of Diet in Renal Disease formula should be used for the evaluation of estimated glomerular filtration rate in patients with stabilized serum creatinine (grade A). International Myeloma Working Group criteria for renal reversibility should be used (grade B). For the management of RI in patients with multiple myeloma, high fluid intake is indicated along with antimyeloma therapy (grade B). The use of high-cutoff hemodialysis membranes in combination with antimyeloma therapy can be considered (grade B). Bortezomib-based regimens remain the cornerstone of the management of myeloma-related RI (grade A). High-dose dexamethasone should be administered at least for the first month of therapy (grade B). Thalidomide is effective in patients with myeloma with RI, and no dose modifications are needed (grade B). Lenalidomide is effective and safe, mainly in patients with mild to moderate RI (grade B); for patients with severe RI or on dialysis, lena-lidomide should be given with close monitoring for hematologic toxicity (grade B) with dose reduction as needed. High-dose therapy with autologous stem cell transplantation (with melphalan 100 mg/m2 to 140 mg/m2) is feasible in patients with RI (grade C). Carfilzomib can be safely administered to patients with creatinine clearance > 15 mL/min, whereas ixazomib in combination with lenalidomide and dex-amethasone can be safely administered to patients with creatinine clearance > 30 mL/min (grade A). © 2016 by American Society of Clinical Oncology.

Embedded Image Introduction: Daratumumab (DARA) is a human anti-CD38 IgG1kappa monoclonal antibody that showed synergistic anti-tumor activity in combination with lenalidomide (LEN) in in vitro preclinical studies (van der Veer M. Haematologica 2011;96(2):284-90). DARA has shown favorable safety and robust efficacy as a single agent in patients with relapsed and refractory (RR) multiple myeloma (MM) (Lokhorst HM. J Clin Oncol 2014;32 Suppl:abstr 8513. Lonial S. J Clin Oncol 2015;33 Suppl:abstr LBA8512) and in combination with LEN/Dexamethasone (DEX) in patients with relapsed or RR MM (Plesner T. Blood 2014;124(21):84). This study assessed the updated safety and efficacy of DARA in combination with LEN/DEX following more than 12 months of exposure in patients with relapsed or RR MM. Methods: The study design of this ongoing, open-label phase 1/2 study of DARA in combination with LEN/DEX has been presented previously (Plesner T. Blood 2014;124(21):84). Briefly, the study comprised a 3 + 3 design dose escalation study (DARA 2-16 mg/kg + LEN/DEX; Part 1) and a cohort expansion study using the recommended phase 2 dose (DARA 16 mg/kg + LEN/DEX; Part 2). In Part 2, patients refractory to LEN were excluded and patients with >1 prior line of therapy were included. In Part 2, DARA 16 mg/kg was administered weekly during the first two 28-day cycles, every other week during Cycles 3 through 6, and monthly in Cycle 7 and beyond until disease progression or unacceptable toxicity. LEN 25 mg was administered orally on Days 1 through 21 of each cycle, and DEX 40 mg was given weekly. The primary objective was safety. Efficacy was evaluated per the International Myeloma Working Group criteria. The last patient was enrolled in August 2014. Results: Updated safety and efficacy results (data cut January 9, 2015) of DARA 16 mg/kg plus LEN/DEX in the expansion cohort (n = 32) are presented. The median (range) number of prior lines of therapy was 2 (1-3) and the median (range) duration of follow up was 7.8 (3.0-10.4) months. Eleven (34%) patients received prior LEN treatment. Six (19%) patients discontinued treatment due to either disease progression (n = 3), treatment-emergent adverse events (TEAE; 1 patient with gastric adenocarcinoma and 1 patient with laryngeal edema that was a grade 3 infusion-related reaction [IRR]), or physician decision (n = 1). The most common (>25%) TEAEs included neutropenia (81%), muscle spasms (44%), cough (38%), diarrhea (34%), fatigue and hypertension (28% each). Only 1 (3%) patient experienced febrile neutropenia (grade 1). Neutropenia was the most frequently (>25%) reported grade 3 or 4 TEAE (75%). Eighteen (56%) patients had IRRs and these were generally mild to moderate and occurred mostly during the first cycle. IRRs included cough (25%), allergic rhinitis, nausea, and vomiting (9% each), as well as dyspnea, nasal congestion, and hypertension (6% each). Two (6%) patients had grade 3 IRRs (laryngeal edema and hypertension). All patients with IRRs recovered and continued to receive treatment, with the exception of the patient with grade 3 laryngeal edema, who recovered but was discontinued from treatment per protocol. The overall response rate (Rajkumar SV. Blood. 2011;117:4691-5) was 88%, with 11 (34%) partial responses and 17 (53%) >very good partial responses (VGPRs) that included 7 (22%) stringent complete responses, 1 (3%) complete response, and 9 (28%) VGPRs. The median time to first and best response was 1 (95% confidence interval [CI], 0.9-1.9) month and 4.5 (95% CI, 1.9-5.6) months, respectively. The median duration of response was not reached, as 26 (93%) of 28 responders had not progressed or relapsed at the time of this analysis and remained on treatment at data cutoff. Importantly, responses deepened over time in 17 (61%) of 28 responders. The 12-month duration of response will be updated at the time of ASH. Conclusions: In the expansion cohort, the combination of DARA and LEN/DEX continues to be associated with a remarkably favorable benefit/risk profile for treatment of relapsed or RR MM. D ep and durable responses were maintained throughout the study. Additional updates on the safety and efficacy results of the expansion cohort with over 12 months of exposure will be presented at the time of the meeting.

Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive, an IMiD (immunomodulatory drug), had measurable disease, and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T-0). The median age at diagnosis was 58 years, and time from diagnosis to T-0 was 3.3 years. Following T-0, 213 (74%) patients had a treatment recorded with one or more regimens (median = 1; range 0-8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T0 in 94 patients (44%) including >= partial response in 69 (32%). The median overall survival and event-free survival from T-0 were 9 and 5 months, respectively. This study confirms the poor outcome, once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs. Leukemia (2012) 26, 149-157; doi:10.1038/leu.2011.196; published online 29 July 2011

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