Multiple myeloma (MM) is a plasma cell disorder that is on the rise throughout the world, especially in the US, Australia, and Western Europe. In the US, MM accounts for almost 2% of cancer diagnoses and over 2% of cancer deaths (more than double the global proportion). Incidence has risen by 126% globally and over 40% in the US since 1990, while global mortality has risen by 94% and US mortality has fallen by 18%. The 5 year survival in the US has more than doubled over the past decades with the introduction of new targeted therapies and transplant techniques. Risk factors for MM include age (average age of diagnosis is 69), race (African Americans are over double as likely to be diagnosed), sex (men are at a 1.5× risk), and family history. Diagnosis includes serum or urine electrophoresis and free light-chain assay but requires bone marrow biopsy. It is distinguished from smoldering myeloma and monoclonal gammopathy of undetermined significance by a high (>3 g/dL) level of M-protein (monoclonal light chains) and the presence of CRAB (Hypercalcemia, Renal failure, Anemia, Bone pain) symptoms, which include hypercalcemia, renal failure, anemia, and bone pain, suggesting an end-organ damage. International staging system staging involves beta 2 microglobulin and albumin levels, while the revised system considers prognostic factors such as lactate dehydrogenase levels and chromosomal abnormalities. Front-line management includes induction regimen, maintenance therapy and hematopoietic cell transplantation for eligible patients and bisphosphonates or bone-stimulating agents for the prevention of skeletal events. Treatment for relapsed disease includes newly approved monoclonal antibodies like the CD38-targeting daratumumab, proteasome inhibitors, immunomodulating agents, and investigational therapies such as B cell maturation antigen Chimeric antigen receptor T cells.

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IMPORTANCETyrosine kinase inhibitors (TKIs) have been associated with improved survival of patients with chronic myeloid leukemia (CML) but are also associated with adverse effects, especially fatigue and diarrhea. Discontinuation of TKIs is safe and is associated with the successful achievement of treatment-free remission (TFR) for some patients.OBJECTIVE To evaluate molecular recurrence (MRec) and patient-reported outcomes (PROs) after TKI discontinuation for US patients with CML. DESIGN, SETTING, AND PARTICIPANTSThe Life After Stopping TKIs (LAST) study was a prospective single-group nonrandomized clinical trial that enrolled 172 patients from 14 US academic medical centers from December 18, 2014, to December 12, 2016, with a minimum follow-up of 3 years. Participants were adults with chronic-phase CML whose disease was well controlled with imatinib, dasatinib, nilotinib, or bosutinib. Statistical analysis was performed from August 13, 2019, to March 23, 2020. INTERVENTION Discontinuation of TKIs.MAIN OUTCOMES AND MEASURES Molecular recurrence, defined as loss of major molecular response (BCR-ABL1 International Scale ratio >0.1%) by central laboratory testing, and PROs (Patient-Reported Outcomes Measurement Information System computerized adaptive tests) were monitored. Droplet digital polymerase chain reaction (ddPCR) was performed on samples with undetectable BCR-ABL1 by standard real-time quantitative polymerase chain reaction (RQ-PCR). RESULTSOf 172 patients, 89 were women (51.7%), and the median age was 60 years (range, 21-86 years). Of 171 patients evaluable for molecular analysis, 112 (65.5%) stayed in major molecular response, and 104 (60.8%) achieved TFR. Undetectable BCR-ABL1 by either ddPCR or RQ-PCR at the time of TKI discontinuation (hazard ratio, 3.60; 95% CI, 1.99-6.50; P < .001) and at 3 months (hazard ratio, 5.86; 95% CI, 3.07-11.1; P < .001) was independently associated with MRec. Molecular recurrence for patients with detectable BCR-ABL1 by RQ-PCR was 50.0% (14 of 28), undetectable BCR-ABL1 by RQ-PCR but detectable by ddPCR was 64.3% (36 of 56), and undetectable BCR-ABL1 by both ddPCR and RQ-PCR was 10.3% (9 of 87) (P Յ .001). Of the 112 patients in TFR at 12 months, 90 (80.4%) had a clinically meaningful improvement in fatigue, 39 (34.8%) had a clinically meaningful improvement in depression, 98 (87.5%) had a clinically meaningful improvement in diarrhea, 24 (21.4%) had a clinically meaningful improvement in sleep disturbance, and 5 (4.5%) had a clinically meaningful improvement in pain interference. Restarting a TKI resulted in worsening of PROs. CONCLUSIONS AND RELEVANCEIn this study, TKI discontinuation was safe, and 60.8% of patients remained in TFR. Discontinuation of TKIs was associated with improvements in PROs. These findings should assist patients and physicians in their decision-making regarding discontinuation of TKIs. Detectable BCR-ABL1 by RQ-PCR or ddPCR at the time of TKI discontinuation was associated with higher risk of MRec; clinical application of this finding should be c...

Inhibition of the Janus-associated kinases (JAK) with ruxolitinib (RUX) reduces graft-versus-host disease (GVHD) in preclinical and clinical models. In total 19 allograft recipients with moderate/severe steroid-dependent chronic GVHD received RUX as ≥2nd line salvage. RUX was well tolerated, and led to complete/partial resolution of oral (92/7%), cutaneous (82/0%), hepatic (71/28%), gastro-intestinal (75/17%), musculoskeletal (33/67%), pulmonary (0/80%), scleroderma (0/75%), vaginal (0/75%), and ocular (0/100%) chronic GVHD. Overall 18 achieved partial response and 1 complete response according to NIH Consensus Criteria. Responses occurred early and were sustained which enabled discontinuation (68%) or reduction of steroids to physiologic doses (21%). We conclude that RUX is an effective steroid-sparing agent in chronic GVHD.

Bosutinib, a BCR-ABL1 tyrosine kinase inhibitor (TKI), has been available for several years as a treatment for chronic-, accelerated-, and blast-phase chronic myeloid leukemia (CML), for patients with resistance or intolerance to prior therapy. In 2017, the BFORE trial demonstrated efficacy of bosutinib as first-line treatment in adult patients with newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML). The most common adverse events (AEs) of any grade in bosutinib-treated patients in BFORE were diarrhea, nausea, thrombocytopenia, increased alanine aminotransferase, and increased aspartate aminotransferase, consistent with the most commonly reported AEs in earlier studies. To balance the efficacy and tolerability of treatment to optimize patient adherence with medications, treating physicians commonly use various strategies such as initiating treatment at a lower dose, dose reduction, or dose interruption, depending on the type and severity of the AEs and the clinical setting. In light of the recent data from first-line treatment, an expert panel of hematologists reviewed management strategies for the use of bosutinib in treatment of CP-CML and made the recommendations reported here. Although the panel focused on first-line treatment, the principles can be for the most part extended to bosutinib use in later lines of treatment. Recommendations include advice regarding prophylaxis and management for diarrhea. The panel also considered optimum timing for referral to a specialist for specific AEs. Across the commonly occurring AEs, the panel highlighted the importance of education and communication with patients about anticipated AEs.