Citations

SummaryThe optimal duration of induction therapy (IT) in transplant‐eligible multiple myeloma (MM) patients in not well defined, resulting in a wide variation in clinical practice. The objective of our study was to determine whether the duration of IT in patients undergoing upfront autologous stem cell transplantation (ASCT) has an impact on progression‐free survival (PFS) in the era of proteasome inhibitors and immunomodulatory drugs. A total of 596 patients who underwent ASCT at Mayo Clinic between 2007 and 2014 were included. The patients were divided into two cohorts based on the duration of IT: IT ≤ 4 and IT > 4 months. At a median follow‐up of 54·5 months from ASCT, the median PFS in the IT ≤ 4 group was 28 months [95% confidence interval (CI), 25–33], compared to 26 months in the IT > 4 group (95% CI, 24–31) [P = 0·605]. There was no significant difference in overall survival (OS) in the two groups (P = 0·904). The lack of impact of IT duration on PFS and OS was consistent in subgroups with high‐risk features at diagnosis (International Staging System III or high‐risk cytogenetics) and different depths of pre‐transplant response [≥very good partial response (VGPR) and <VGPR]. In conclusion, prolonging the duration of IT beyond 4 months does not impact survival in patients with newly diagnosed MM who complete a single line of IT followed by consolidation with ASCT.

AbstractResponse rates in newly diagnosed multiple myeloma have improved dramatically with the introduction of highly effective novel therapies. However, survival in patients achieving optimal responses to initial treatment can vary significantly, and new prognostic indicators are required to improve risk stratification. We investigated the relationship between time to plateau (TPlat) and survival in 1099 newly diagnosed patients treated with novel agents at our institution from 2005 to 2015.TPlatwas defined as time from initiation of first‐line therapy to best response to first‐line therapy. The medianTPlatwas 4.9 months (0.7‐58.6) and plateau duration was 1.8 years (0.2‐11.0). Patients who required > 120 days to achieve a plateau had longer modified overall survival (mOS) and progression free survival (mPFS) calculated from a landmark of best response (P < .001 for both comparisons). Statistically significant improvement in mOS was retained in subgroup analysis based on age and whether patients received upfront autologous hematopoietic stem cell transplantation (ASCT) (P < .001 for all comparisons). Our results suggest that patients who respond more gradually to initial therapy (TPlat > 120 days) experience longer survival compared to more rapid responders. Patients with a prolongedTPlatcould represent an “ongoing responder” phenotype that portends a survival advantage independent of treatment with upfront ASCT, depth of response, and biologic markers such as ISS stage and cytogenetic risk.

Key Points λ Light chain AL amyloidosis is associated with a shorter PFS and OS compared with κ. Light chain type predicts likelihood of organ involvement in AL amyloidosis.

AbstractAtopic dermatitis is the most common chronic skin disease, and it primarily affects children. Although atopic dermatitis (AD) has the highest effect on burden of skin disease, no high‐level studies have defined optimal therapy for severe disease. Corticosteroids have been used to treat AD since the 1950s and remain the only systemic medication with Food and Drug Administration approval for this indication in children, despite published guidelines of care that recommend against this option. Several clinical trials with level 1 evidence have supported the use of topical treatments for mild to moderate atopic dermatitis in adults and children, but these trials have had little consistency in protocol design. Consensus recommendations will help standardize clinical development and trial design for children. The Food and Drug Administration issues guidance documents for industry as a source for “the Agency's current thinking on a particular subject.” Although they are nonbinding, industry considers these documents to be the standard for clinical development and trial design. Our consensus group is the first to specifically address clinical trial design in this population. We developed a draft guidance document for industry, Developing Drugs for Treatment of Atopic Dermatitis in Children (≥3 months to <18 years of age). This draft guidance has been submitted to the Food and Drug Administration based on a provision in the Federal Register (Good Guidance Practices).

In the absence of suitable oral or intravenous access for medication administration and when the intramuscular medications are undesirable, alternative routes for drug delivery may be considered. Antipsychotics administered via an inhaled, intranasal, rectal, or topical route have been described in the literature. Topically administered antipsychotics have been previously reported to produce negligible systemic absorption despite being used in clinical practice for nausea and behavioral symptoms associated with dementia. Additionally, the American Academy of Hospice and Palliative Medicine recommends against the use of topical medications that lack supporting literature. Three studies have assessed the systemic absorption of different antipsychotics after administration of only a single, topically applied dose. To evaluate whether the repeated administration of a topically applied antipsychotic may result in detectable serum levels in an accumulating fashion, a pharmacokinetic study was conducted. Five healthy, adult participants consented to receive extemporaneously prepared topical quetiapine in Lipoderm every 4 hours for a total of 5 doses. Blood samples were drawn at baseline and hours 2, 4, 8, 12, 16, and 24, and serum quetiapine concentrations were measured using high-performance liquid chromatography. Quetiapine was undetectable in every sample from 3 participants. Two participants had minimally detectable serum quetiapine levels no sooner than hour 12 of the study period. Extemporaneously prepared quetiapine in Lipoderm resulted in nonexistent or minimal serum level following repeated topical administration. The use of topically applied quetiapine should still be questioned.

Dysproteinemia is characterized by the overproduction of an Ig by clonal expansion of cells from the B cell lineage. The resultant monoclonal protein can be composed of the entire Ig or its components. Monoclonal proteins are increasingly recognized as a contributor to kidney disease. They can cause injury in all areas of the kidney, including the glomerular, tubular, and vascular compartments. In the glomerulus, the major mechanism of injury is deposition. Examples of this include Ig amyloidosis, monoclonal Ig deposition disease, immunotactoid glomerulopathy, and cryoglobulinemic GN specifically from types 1 and 2 cryoglobulins. Mechanisms that do not involve Ig deposition include the activation of the complement system, which causes complement deposition in C3 glomerulopathy, and cytokines/growth factors as seen in thrombotic microangiopathy and precipitation, which is involved with cryoglobulinemia. It is important to recognize that nephrotoxic monoclonal proteins can be produced by clones from any of the B cell lineages and that a malignant state is not required for the development of kidney disease. The nephrotoxic clones that do not meet requirement for a malignant condition are now called monoclonal gammopathy of renal significance. Whether it is a malignancy or monoclonal gammopathy of renal significance, preservation of renal function requires substantial reduction of the monoclonal protein. With better understanding of the pathogenesis, clone-directed strategies, such as rituximab against CD20 expressing B cell and bortezomib against plasma cell clones, have been used in the treatment of these diseases. These clone-directed therapies been found to be more effective than immunosuppressive regimens used in nonmonoclonal protein–related kidney diseases.

AbstractWaldenström macroglobulinemia (WM) is an immunoglobulin M‐associated lymphoma, with majority of cases demonstrating MYD88 locus alteration, most commonly, MYD88L265P. Owing to low prevalence of the wild‐type (WT) MYD88 genotype in WM, clinically relevant data in this patient population are sparse, with one study showing nearly a 10‐fold increased risk of mortality in this subgroup compared to patients with MYD88L265P mutation. We studied a large cohort of patients with MYD88L265P and MYD88WT WM, evaluated at Mayo Clinic, Rochester, between 1995 and 2016, to specifically assess the impact of these genotypes on clinical course. Of 557 patients, MYD88L265P mutation status, as determined by allele‐specific polymerase chain reaction, was known in 219, and 174 (79%) of those exhibited MYD88L265P, 157 of 174 patients had active disease. Of 45 (21%) patients with MYD88WT genotype, 44 had active disease. The estimated median follow‐up was 7.0 years; median overall survival was 10.2 years (95% CI: 8.4‐16.5) for MYD88L265P versus 13.9 years (95% CI: 6.4‐29.3) for the MYD88WT (P = 0.86). The time‐to‐next therapy from frontline treatment and the presenting features were similar in the two patient populations. For patients with smoldering WM at diagnosis, the median time‐to‐progression to active disease was 2.8 years (95% CI: 2.2‐3.8) in the MYD88L265P cohort and 1.9 years (95% CI: 0.7‐3.1) in the MYD88WT cohort (P = 0.21). The frequency of transformation to high‐grade lymphoma, or the development of therapy‐elated myelodysplastic syndrome was higher in the MYD88WT cohort (16% versus 4% in the MYD88L265P, P = 0.009). In conclusion, MYD88L265P mutation does not appear to be a determinant of outcome, and its presence may not be a disease‐defining feature in WM. Our findings warrant external validation, preferably through prospective studies.

AbstractExperience with intensive chemotherapy for relapsed/refractory multiple myeloma (RRMM) using VDT PACE regimen and its modifications (VDT PACE‐like regimens: VPLRs) outside TOTAL THERAPY trials is limited. We analyzed the outcomes of 141 patients with RRMM who received VPLRs at our center between 2006 and 2017 in an intent‐to‐treat analysis. Median age was 59.7 years and 66.7% of patients were male. A median of 2.2 years (range 0.02‐11.4) separated diagnosis of myeloma and inititation of VPLR. High‐risk cytogenetics were present in 52.4% patients. Patients received a median of 4 (range 1‐14) prior therapies, including stem cell transplant (SCT) in 66.7% patients. Ninety‐five (67.4%) patients received VDT PACE, 20 (14.2%) patients received VD PACE and 26 (18.4%) patients received other VPLRs. Patients received a median of 1 cycle (range 1‐9) of VPLR. We observed ≥ minimal response in 68.4%, ≥ partial response (PR) in 54.4% and ≥ very good PR in 10.3% patients. Median progression‐free survival was 3.1 months (95% CI, 1.9‐3.9) and median overall survival (OS) was 8.1 months (CI, 6.2‐9.9). One‐hundred and sixteen (82.3%) patients received some therapy after VPLR; 71 (61.2%) received systemic chemotherapy, while 45 (38.8%) underwent SCT. Median OS for those who received SCT after VPLR was 15.1 months (CI, 10.3‐20.8). Age ≥ 60 years (hazard ratio [HR] 2.3 [CI, 1.4‐3.7]; P = 0.0008) and R‐ISS III stage (HR‐ 2.4 [CI, 1.3‐4.0]; P = 0.003) predicted shorter OS in patients receiving VPLR. VPLRs are effective in heavily pre‐treated RRMM. In fit patients, SCT can be used to consolidate the response to VPLR.

Purpose: To describe ophthalmic manifestations of systemic amyloidosis, a group of devastating conditions. Methods: A retrospective chart review including patients who had ocular examinations at Mayo Clinic between January 1, 1985, and April 1, 2014, and a diagnosis of light-chain (AL), secondary (AA), or nontransthyretin familial amyloidosis was undertaken. Sixty-eight patients with AL amyloidosis, eight patients with AA amyloidosis, and five patients with nontransthyretin familial amyloidosis were included. Results: Of 68 patients, 8 patients (14 eyes) with AL amyloidosis had ocular involvement secondary to conjunctiva, temporal artery, extraocular muscle, trabecular meshwork, and cranial nerve deposition. One of the five patients with nontransthyretin familial amyloidosis had gelsolin-related corneal dystrophy. No patients with AA amyloidosis (n = 8) had ophthalmic manifestations. Conclusion: Systemic amyloidosis can lead to ocular morbidity. Patients with AL amyloidosis had involvement of the temporal artery, conjunctiva, extraocular muscles, trabecular meshwork, and cranial nerves. Those with gelsolin nontransthyretin familial amyloidosis were susceptible to corneal dystrophy. Patients with AA amyloidosis did not manifest ophthalmic involvement. Finally, if ocular amyloidosis is detected, patients should be referred for systemic workup.