Rajshekhar Chakraborty

Autologous stem cell transplant for multiple myeloma patients 70 years or older

Autologous stem cell transplant (Auto-SCT) is increasingly used in older patients with multiple myeloma (MM), despite lack of phase 3 trials in this age-defined population. For 207 consecutive MM patients who underwent Auto-SCT and were 70 years or older at transplant (study cohort), data were analyzed and compared with a younger cohort (1764 Auto-SCT patients <70 years old). The proportion of Auto-SCT in the older patients increased from 7.8% of all transplants in 1998–2006 to 12.9% in 2007–2015. Sixty percent of patients required stem cell mobilization with chemotherapy or plerixafor. Full-dose melphalan conditioning was given to 55% of the older patients compared with 93% of the younger patients (P<0.001). Older patients were more likely to be hospitalized (64% vs 55%; P=0.01), but hospitalization duration was comparable. For newly diagnosed patients, median PFS was 33.5 months for the older cohort and 33.8 months for the younger cohort (P=0.91), and median overall survival was 6.1 and 7.8 years, respectively (P=0.11). Presumably, a smaller fraction of patients, age 70–76, is selected for Auto-SCT, but the benefits are comparable to those seen for younger patients. Reduced-dose melphalan was given to approximately half the patients to avoid excessive toxicity.

Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category

The significance of interphase fluorescence in situ hybridization (iFISH) by regimen type was assessed in 692 immunoglobulin light-chain (AL) amyloidosis patients with iFISH at diagnosis. First-line treatment was categorized as stem cell transplant and three non-transplant regimens. The most common abnormality was t(11;14) (49% of patients) followed by monosomy 13/del(13q) (36%) and trisomies (26%). A lower rate of very good partial response (VGPR) or better was observed in patients with t(11;14) treated with bortezomib-based (52% vs 77%; P=0.004) and IMiD-based regimens (13% vs 54%; P=0.04) compared with those lacking t(11;14). This corresponded to an inferior overall survival (OS) in t(11;14)-positive bortezomib-treated (median 15 vs 27 months; P=0.05) and IMiD-treated patients (median 12 vs 32 months; P=0.05). The inferior OS associated with t(11;14) bortezomib-treated patients was restricted to patients with favorable disease. Trisomies were associated with a shorter OS (median 29 vs 69 months; P=0.001), reaching statistical significance only for melphalan (median 15 vs 32 months; P=0.02). Multivariate analysis confirmed an independent survival impact for trisomies in the entire cohort and for t(11;14) among bortezomib-treated patients. iFISH is prognostic in untreated AL amyloidosis and may influence treatment selection. Patients with t(11;14) should be considered for ASCT or standard-dose melphalan at diagnosis because the survival disadvantage may be abrogated.

Ibrutinib for the treatment of Waldenström macroglobulinemia

Waldenström macroglobulinemia (WM) is a B-cell non-Hodgkin lymphoma (NHL) characterized by IgM monoclonal gammopathy and bone marrow infiltration by lymphoplasmacytic cells. Until recently, there was no drug specifically approved for WM by the US FDA, leading to wide variations in therapeutic strategies across the globe. Ibrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor, is the first drug approved specifically for WM by the FDA after a clinical trial showed impressive response in previously treated WM. Ibrutinib is a non-stem cell toxic and non-neurotoxic option and suitable for long-term oral maintenance therapy, with the potential of improving survival in WM. With identification of novel genetic mutations impacting response to ibrutinib, it would be possible to individualize therapy based on MYD88 and CXCR4 genotypes. However, long-term safety and efficacy data are required, and cost-effectiveness needs to be addressed before ibrutinib can gain widespread acceptance for front-line therapy of WM.

Immunoparesis in newly diagnosed AL amyloidosis is a marker for response and survival

Immunoparesis is an adverse prognostic marker in plasma cell proliferative disorders. Its impact in AL amyloidosis has not been explored in depth. Newly diagnosed AL amyloidosis patients (n=998) were evaluated for immunoparesis by two methods. The first method was qualitative, considering the number of suppressed uninvolved immunoglobulins below the lower limit of normal (LLN) (none, partial, all). The second method was quantitative, assessing the average relative difference (ARD) of the uninvolved immunoglobulins from the LLN. Patients with suppression of all the uninvolved immunoglobulins were less likely to achieve very good partial response (VGPR) or better to first-line treatment (44%) compared with patients with partial suppression (68%) or preserved uninvolved immunoglobulins (64%; P<0.0001). In addition, patients with suppression of all the uninvolved immunoglobulins had a shorter survival compared with the respective comparators (median 18 vs 54 vs 52 months; P<0.0001). In the quantitative method, patients with a negative ARD were less likely to achieve VGPR or better (48%) and had a shorter survival (median 24 months) compared with patients with a positive ARD (69%, 57 months, respectively; P<0.0001). In a multivariate analysis for survival, both assessment methods retained an independent impact. Significant immunoparesis has a negative impact on response and survival in newly diagnosed AL amyloidosis.

Prevalence and predictors of thyroid functional abnormalities in newly diagnosed AL amyloidosis

Data on the effect of systemic immunoglobulin light chain amyloidosis (AL amyloidosis) on thyroid function are limited.

Revisiting conditioning dose in newly diagnosed light chain amyloidosis undergoing frontline autologous stem cell transplant: impact on response and survival

Autologous stem cell transplantation (ASCT) is an important treatment modality in light chain (AL) amyloidosis. Use of reduced-dose melphalan conditioning is common, given the associated organ and functional decline. The impact of full-intensity melphalan conditioning (n=314) was compared to reduced-dose conditioning (n=143). Patients in the full-intensity group were younger, with better performance status, fewer involved organs, lower tumor burden and lower Mayo stage. Full-dose conditioning was associated with higher rate of very good partial response or better (79% vs 62%; P<0.001), complete response rate (53% vs 37%; P=0.003) and organ response rate (74% vs 59%; P=0.002) as compared to reduced-dose conditioning. PFS was superior in the full-intensity group compared to the reduced-dose group (4-year PFS 55% vs 31%; P<0.001) as well as a longer overall survival (OS) 4-year OS (86% vs 54%; P<0.001). In addition, the OS and PFS were significantly lower in the reduced-dose group compared to the full-intensity group in Mayo stage III/IV as well as stage I/II. A multivariate analysis confirmed an independent impact for conditioning dose on PFS/OS. This study calls for re-assessment of the use of reduced-dose conditioning in ASCT for AL amyloidosis.

Newer Therapies for Amyloid Cardiomyopathy

The heart and the kidneys are the most commonly involved organs in systemic amyloidosis. Cardiac involvement is associated with an increased morbidity, treatment intolerance, and poorer overall survival. The most common types of amyloidosis that are associated with cardiac involvement include light chain (AL) amyloidosis and transthyretin (TTR) amyloidosis (both mutant and wild type). The traditional first-line treatment for AL amyloidosis includes alkylator-based chemotherapy or high-dose melphalan followed by autologous stem cell transplantation (ASCT). Novel agents, including proteasome inhibitors, immunomodulators, and monoclonal antibodies, have shown promising activity in both frontline and relapsed settings. Orthotopic heart transplantation (OHT) followed by ASCT has led to superior outcomes compared to OHT alone. Orthotopic liver transplantation (OLT) is the first-line treatment for TTR amyloidosis. However, progression of cardiac amyloidosis after OLT is often noted due to deposition of wild TTR. Combined OLT and OHT also has a role in treatment and leads to superior outcomes in carefully selected candidates. Pharmacologic agents, including diflunisal, tafamidis, small interfering ribonucleic acid, and doxycycline, have shown promising activity in stabilizing TTR from misfolding into fibrils and are being actively investigated. Best supportive care and management of heart failure symptoms with diuretics are a mainstay of treatment in all cardiac amyloidosis subtypes. Robust data on the benefit of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or beta blockers in amyloid cardiomyopathy is lacking.

A systematic review of religious beliefs about major end-of-life issues in the five major world religions.

OBJECTIVE The objective of this study was to examine the religious/spiritual beliefs of followers of the five major world religions about frequently encountered medical situations at the end of life (EoL). METHOD This was a systematic review of observational studies on the religious aspects of commonly encountered EoL situations. The databases used for retrieving studies were: Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid PsycINFO, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. Observational studies, including surveys from healthcare providers or the general population, and case studies were included for review. Articles written from a purely theoretical or philosophical perspective were excluded. RESULTS Our search strategy generated 968 references, 40 of which were included for review, while 5 studies were added from reference lists. Whenever possible, we organized the results into five categories that would be clinically meaningful for palliative care practices at the EoL: advanced directives, euthanasia and physician-assisted suicide, physical requirements (artificial nutrition, hydration, and pain management), autopsy practices, and other EoL religious considerations. A wide degree of heterogeneity was observed within religions, depending on the country of origin, level of education, and degree of intrinsic religiosity. SIGNIFICANCE OF RESULTS Our review describes the religious practices pertaining to major EoL issues and explains the variations in EoL decision making by clinicians and patients based on their religious teachings and beliefs. Prospective studies with validated tools for religiosity should be performed in the future to assess the impact of religion on EoL care.

Impact of Post-Transplant Response and Minimal Residual Disease on Survival in Myeloma with High-Risk Cytogenetics

The impact of depth of response and minimal residual disease (MRD) status on survival is not well defined in multiple myeloma (MM) with high-risk (HR) cytogenetics because of the low representation of such patients in clinical trials. We have evaluated the impact of post-transplant stringent complete response (sCR) and MRD status on progression-free survival (PFS) and overall survival (OS) in 185 consecutive MM patients with HR fluorescence in situ hybridization cytogenetics undergoing upfront autologous stem cell transplantation between 2007 and 2015 in our institution. The median age at transplant was 61 years. Post-transplant sCR was achieved by 42 patients (23%). Patients achieving sCR had a superior PFS (median, 38 versus 21 months) compared with those who did not (P = .002). One hundred three patients (56%) were MRD negative on day 100 by 6- or 7-color flow cytometry. Patients achieving MRD negativity had a superior PFS (median, 26 versus 17 months; P < .001) and superior OS (5-year OS rate, 64% versus 41%; P = .023) compared with MRD-positive patients. In the subgroups with deletion(17p) (n = 84) and those with ≥2 HR cytogenetic abnormalities (n = 32), sCR and MRD negativity did not translate into a superior PFS or OS. In patients with t(4;14) (n = 65), sCR post-transplant led to a trend toward superior PFS and MRD negativity translated into significantly superior PFS and OS. Depth of response and MRD status are important surrogate markers for survival in patients with HR cytogenetics, except in the subgroups with deletion(17p) and ≥2 HR abnormalities, where sCR and MRD negativity post-transplant did not translate into a superior survival.

First report of MYD88 L265P somatic mutation in IgM-associated light-chain amyloidosis

To the editor: A mutation in myeloid differentiation factor gene, MYD88 , leading to constitutive activation of the nuclear factor κB pathway was shown to be oncogenically active in 29% of patients with activated B-cell type diffuse large B-cell lymphoma.[1][1] The most common somatic variant of