Antibiotic Exposure Concurrently with Anti-PD1 Blockade Therapy Reduces Overall Survival in Patients with Child-Pugh Class A Advanced Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide with a poor prognosis. Treatment with immune checkpoint inhibitors (ICIs) has improved overall survival in patients with HCC. However, not all patients benefit from the treatment. In this study, 59 patients with HCC were enrolled from two medical centers in Saudi Arabia, with 34% using antibiotics concurrently with their Nivolumab (anti-PD1 blockade). The impact of antibiotic use on the clinical outcomes of patients with HCC undergoing treatment with anti-PD1 blockade was examined. The patients' overall survival (OS) was 5 months (95% CI: 3.2, 6.7) compared to 10 months (95% CI: 0, 22.2) (p = 0.08). Notably, patients with Child-Pugh A cirrhosis receiving anti-PD1 blockade treatment without concurrent antibiotic use showed a significantly longer median OS reaching 22 months (95% CI: 6.5, 37.4) compared to those who were given antibiotics with a median OS of 6 months (95% CI: 2.7, 9.2) (p = 0.02). This difference in overall survival was particularly found in Child-Pugh class A patients receiving anti-PD1 blockade. These findings suggest that antibiotic use may negatively affect survival outcomes in HCC patients undergoing anti-PD1 blockade, potentially due to antibiotic-induced alterations to the gut microbiome impacting the anti-PD1 blockade response. This study suggests the need for careful consideration when prescribing antibiotics to patients with HCC receiving anti-PD1 blockade.

Treatment and outcomes of patients with light chain amyloidosis who received a second line of therapy post autologous stem cell transplantation.

We retrospectively reviewed 292 patients who received a second line of therapy post ASCT for their light chain amyloidosis. Most patients (40%) were treated with an alkylator + PI ± dex or PI ± dex followed by an alkylator + 2nd-gen IMiD ± dex or 2nd-gen IMiD ± dex (26%), an alkylator ± steroid or steroid monotherapy (19%), a 2nd-gen IMiD + PI ± dex (6%), an alkylator + thalidomide ± dex (5%), or daratumumab-based therapy (4%). The rate of CR or VGPR was 70% among the daratumumab-based group, 62% in the alkylator + PI ± dex or PI ± dex group, 55% in the alkylator + 2nd-gen IMiD ± dex or 2nd-gen IMiD ± dex group, 47% in the 2nd-gen IMiD + PI ± dex group, 24% in the alkylator ± steroid or steroid monotherapy group, and 18% in the alkylator + thalidomide ± dex group. The median OS was NR for the 2nd-gen IMiD + PI ± dex group and the daratumumab group, 130.4 months in the alkylator + 2nd-gen IMiD ± dex or 2nd-gen IMiD ± dex group, 100 months for the alkylator + PI ± dex or PI ± dex group, 36 months for the alkylator ± steroid or steroid monotherapy group, and 21 months for the alkylator + thalidomide ± dex group (P < 0.0001). The median OS was 100 months in patients who received melphalan 200 mg/m2 compared to 41 months in the 140 mg/m2 group (P < 0.0001). In conclusion, patients receiving novel therapy post ASCT and melphalan conditioning dosing at 200 mg/m2 at diagnosis had better outcomes.

Treatment and outcome of newly diagnosed multiple myeloma patients > 75 years old: a retrospective analysis.

This is a retrospective study of patients with multiple myeloma (MM) who were >75 years old. We identified 394 patients and for non-trial patients (n = 350), immunomodulatory drug (IMiD)+dex (32%) was the most commonly used regimen followed by alkylator with steroids or other therapy (21%), alkylator + proteasome inhibitor (PI)+steroid (18%), and IMiD + PI + dex (13%). Overall, achieving ≥ very good partial response was more in patients receiving a triplet compared to other therapies (46% vs. 21%, p < 0.0001). Also, the median overall survival (OS) was significantly longer in patients who were treated with a triplet (median OS: 50.2 vs. 32.8 months, p = 0.0006). In a multivariate for OS, receiving a triplet (HR: 0.65, p = 0.02), not having an R-ISS stage 3 (HR: 0.36, p = 0.0003), and bone marrow plasma cell percentage <60% (HR: 0.69, p = 0.03) were predictive. In conclusion, being able to receive triplet therapy was associated with better survival in our MM patients >75 years old.

Venetoclax for the treatment of multiple myeloma: Outcomes outside of clinical trials.

Multiple myeloma (MM) remains an incurable disease despite incorporation of novel agents. Venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor is approved for some hematologic malignancies but not yet for MM, although clinical trials have shown efficacy in patients with MM, particularly those harboring t(11;14). We reviewed the medical records of relapsed and/or refractory MM patients to study the efficacy and safety of venetoclax used outside of clinical trials at Mayo Clinic between December, 2016 and March, 2019. The data cut-off date was August 06, 2020. We identified 56 patients of whom 42 (75%) harbored t(11;14). The median number of prior therapies was six (range 1-15) and 14% of patients had received ≥10 prior lines of therapy. Fifty-three (95%) patients were refractory to an immunomodulatory drug and proteasome inhibitor. Venetoclax was used as monotherapy or doublet, in combination with dexamethasone in 55% (n = 31) and a triplet or quadruplet in 45% of patients. No patient experienced tumor lysis syndrome. Overall response rate in 52 evaluable patients was 44%. The median time to best response was 2 months and median duration of response was 13.6 months. The median PFS for the entire cohort was 5.8 (95% CI 4.9-10.3) months and median OS was 28.4 (95% CI 14.6-not reached) months. The presence of t(11;14) was associated with improved PFS (median 9.7 months vs. 4.2 months, p = 0.019) and OS (median not reached vs. 10.8 9 months, p = 0.015). Venetoclax demonstrates encouraging activity in heavily-treated patients with relapsed/refractory MM, particularly the t(11;14) patient-population.

Prognostic Implications of Rising Serum Monoclonal Protein and Free Light Chains after Autologous Stem Cell Transplantation in Patients with Multiple Myeloma.

Patients who undergo autologous stem cell transplantation (ASCT) for multiple myeloma (MM) are routinely assessed at day +100 using serum and urine protein electrophoresis/immunofixation and the serum free light chain (sFLC) assay. We evaluated whether an increase in M-spike or FLC from immediately before ASCT to day +100 post-ASCT has any prognostic impact. We retrospectively reviewed 1218 patients with MM at the Mayo Clinic who underwent their first ASCT between 2000 and 2016. We stratified patients into those with a rise in M-spike by at least 0.1 g/dL from immediately before ASCT to day +100 post-ASCT (M-spike cohort 1) and those who did not (M-spike cohort 2). We also stratified patients into those with a rise in the involved FLC by at least 5 mg/dL (FLC cohort 1) and those who did not (FLC cohort 2). Survival analysis for progression-free survival (PFS) and overall survival (OS) was performed using the Kaplan-Meier method. A rise in M-spike by at least 0.1 g/dL from pre-ASCT to day +100 was seen in 53 patients (4.3%). The median PFS and OS were found to be significantly shorter in M-spike cohort 1 compared with their counterparts (median PFS, 10 months versus 26 months [P < .0001]; median OS, 35 months versus 79 months [P < .0001]). An increase in involved FLC by at least 5 mg/dL was observed in 25 patients (2.3%). Similarly, the median PFS and OS were found to be inferior in FLC cohort 1 compared with FLC cohort 2 (median PFS, 4 months versus 28 months [P < .0001]; median OS, 11 months versus 82 months [P < .0001]). An increase of M-spike by at least 0.1 g/dL and an increase in involved FLC by at least 5 mg/dL from pre-ASCT to day +100 increases the likelihood of an early relapse after ASCT, and these patients may benefit from closer surveillance after day +100.

Depth of response prior to autologous stem cell transplantation predicts survival in light chain amyloidosis.

The goal of therapy in AL amyloidosis is to inhibit further production of the amyloidogenic light chains, thereby allowing organ recovery and improving survival. We aimed to assess the impact of depth of hematologic response prior to ASCT on survival. We conducted a retrospective study of 128 newly diagnosed AL amyloidosis patients who received induction prior to ASCT between January 2007 and August 2017 at Mayo Clinic. The overall response rate to induction was 86% (CR 18%, VGPR 31% and PR 38%). With a median follow up of 52 months, the median PFS and OS was 48.5 months and not reached, respectively. Response depth to induction therapy was associated with improved PFS and OS. The median PFS was not reached for patients achieving ≥VGPR prior to ASCT and 34.1 months for patients achieving PR or less (P = 0.0009). The median OS was longer in patients with deeper responses (not reached for ≥VGPR vs. 128 months for PR or less (P = 0.02)). On multivariable analysis, independent predictors of OS were melphalan conditioning dose (RR = 0.42; P = 0.036) and depth of response prior to transplant (RR 0.37; P = 0.0295). Hematologic response prior to transplant predicts improved post transplant outcomes in AL amyloidosis.

Correlation between urine ACR and 24-h proteinuria in a real-world cohort of systemic AL amyloidosis patients.

A 24-h urine protein collection (24hUP), the gold standard for measuring albuminuria in systemic AL amyloidosis, is cumbersome and inaccurate. We retrospectively reviewed 575 patients with systemic AL amyloidosis to assess the correlation between a urine albumin to creatinine ratio (uACR) and the 24hUP. The uACR correlated strongly with 24hUP at diagnosis (Pearson's r = 0.87, 95% CI 0.83-0.90) and during the disease course (Pearson's r = 0.88, 95% CI 0.86-0.90). A uACR ≥300 mg/g estimated a 24hUP ≥ 500 mg with a sensitivity of 92% and specificity of 97% (area under the receiver operating curve = 0.938, 95% CI 0.919-0.957). A uACR cutoff of 3600 mg/g best predicted a 24hUP > 5000 g (sensitivity 93%, specificity 94%), and renal stage at diagnosis was strongly concordant using either 24hUP or uACR as the proteinuria measure (k = 0.823, 95% CI 0.728-0.919). In patients with serial urine collections, a > 30% decrease in uACR predicted a > 30% decrease in 24hUP with a sensitivity of 94%. In conclusion, the uACR is a reliable and convenient method for ruling out proteinuria >500 mg per day, prognosticating renal outcomes, and assessing renal response to therapy. Further studies are needed to validate the uACR cutoffs proposed in this study.

Colon perforation in multiple myeloma patients - A complication of high-dose steroid treatment.

Gastrointestinal complications of multiple myeloma (MM) treatment are common and include nausea, constipation, and diarrhea. However, acute gastrointestinal events like perforations are rare. We aimed to describe the characteristics and outcomes of patients with MM that had colonic perforations during their treatment. This is a retrospective study that included patients from all three Mayo Clinic sites who had MM and developed a colonic perforation. All patients were diagnosed with colonic perforations based on CT scans and were surgically treated. Patients diagnosed with AL amyloidosis, a perforated colon complicating neutropenic colitis during ASCT and those with perforation due to colonic cancer were excluded. A high dose of dexamethasone was defined as ≥40 mg dexamethasone once a week. Thirty patients met inclusion criteria. All patients received steroids at doses ≥10 mg once weekly prior to the perforation, while four (11%) were on high-dose dexamethasone without chemotherapy. Fourteen patients were given high doses of dexamethasone. Twenty-five patients required ostomies with all surviving surgery. Twenty-four perforations (80%) were associated with diverticulitis. Treatment with steroids was resumed in 23 patients with no further gastrointestinal complications. The median OS was 20 months following perforation (IQR 8-59). Within the same timeframe 5854 patients were treated at Mayo Clinic for MM, making the risk of bowel perforation 0.5%. Intestinal perforations in MM are rare and, in our series, always occurred with dexamethasone ≥10 mg per week. Urgent surgery is lifesaving and resumption of anti-myeloma treatment appears to be safe.

Differences in engraftment with day-1 compared with day-2 melphalan prior to stem cell infusion in myeloma patients receiving autologous stem cell transplant.

We conducted a retrospective study comparing posttransplant outcomes between myeloma patients receiving conditioning melphalan on day-2 vs day-1 for autologous stem cell transplant. Between January 2017 and December 2018, 201 patients received melphalan on day-2 and 166 on day-1 prior to stem cell infusion. Baseline disease and clinical characteristics between the two groups were similar. Although rates of hospitalization were similar between the cohorts, duration of hospital admission was longer for day-1 (median 7 days for day-1 vs 5 days for day-2, p = 0.003). Rates of fever were higher in the day-1 cohort (69% vs 49%, p = 0.0002). Time to platelet and neutrophil engraftment was significantly longer in the day-1 cohort (platelet engraftment median days 17 for day-1 vs 15 for day-2, p < 0.0001, neutrophil engraftment median days 16 for day-1 vs 16 for day-2, p = 0.025). Overall response rate was similar between the cohorts (99% for day-1, vs 100% for day-2). Day-2 melphalan infusions should be considered in preference for day-1 protocols, given the clinically significant delay in platelet and neutrophil engraftment and longer duration of hospitalization with day-1 infusions.

Increased Bone Marrow Plasma-Cell Percentage Predicts Outcomes in Newly Diagnosed Multiple Myeloma Patients.

BACKGROUND: Previous reports have suggested that a higher bone marrow plasma-cell percentage (BMPC%) is associated with worse outcomes. However, it is unknown whether BMPC% is an independent predictor because genetic information was not available at that time. Currently the impact of BMPC% at diagnosis of multiple myeloma (MM) is not well described. PATIENTS AND METHODS: We evaluated the prognostic impact of BMPC% ≥ 60% versus < 60% in 1426 newly diagnosed MM patients. All patients had an estimation of their BMPC% at diagnosis, and the highest percentage was used. Progression-free survival (PFS) and overall survival (OS) analyses were performed by the Kaplan-Meier method. Univariate and multivariate analyses for PFS and OS using the Cox proportional hazards model were performed for age, Revised International Staging System (R-ISS) score, creatinine level, and BMPC%. RESULTS: BMPC% ≥ 60% was found in 562 patients (39%), and the median PFS was shorter for these patients compared to BMPC% < 60% (22.6 vs. 32.1 months; P < .0001). Also, for OS, the median was shorter for the higher BMPC% group (53.4 vs. 75.4 months; P < .0001). On the multivariate analysis for PFS, age ≥ 65 years (hazard ratio [HR], 1.46; P < .0001), R-ISS (1-2 vs. 3) (HR, 0.49; P < .0001), and BMPC% ≥ 60% (HR, 1.23; P = .015) were predictive. On the multivariate analysis for OS, age ≥ 65 years (HR, 2.23; P < .001), R-ISS (1-2 vs. 3) (HR, 0.41; P < .0001), and BMPC% ≥ 60% (HR, 1.24; P = .02) were also predictive. CONCLUSION: BMPC% ≥ 60% at diagnosis is predictive for PFS and OS, even in a multivariate analysis that included known prognostic factors for MM.

Prognostic Role of Beta-2 Microglobulin in Patients with Light Chain Amyloidosis Treated with Autologous Stem Cell Transplantation.

The prognostic impact of increased beta-2 microglobulin (B2M) in patients with light chain (AL) amyloidosis undergoing autologous stem cell transplantation (ASCT) is unknown. The Mayo 2012 stage and increased bone marrow plasma cell (BMPC) percentage are known predictors for survival. Increased B2M is predictive of survival in patients with multiple myeloma. We evaluated the prognostic role of B2M in patients with newly diagnosed AL undergoing ASCT. We retrospectively reviewed patients with a diagnosis of AL amyloidosis who were treated with ASCT between July 1996 and September 2017. Patients with a creatinine level >1.2 mg/dL were excluded, because that affects B2M levels. The receiver operator characteristic curve was used to determine the best cutoff for B2M before ASCT in predicting survival, which was 2.5 µg/mL, which was also the upper limit of normal in our laboratory. Baseline characteristics were compared between patients with B2M >2.5 µg/mL and ≤2.5 µg/mL. Progression-free survival (PFS) was defined as the time from ASCT to relapse or death, whichever occurred first. Overall survival (OS) was calculated from the time of ASCT to death of any cause. Univariate and multivariate analyses were done for OS. Five hundred and ten patients were identified, 222 of whom (44%) had a B2M >2.5 µg/mL. These patients were more likely to be older (median age, 61 versus 57 years; P = .0002), to have Mayo 2012 stage III/IV disease (33% versus 8%; P < .0001), to have more than 2 organs involved (25% versus 14%; P = .001), and to have ≥10% BMPCs (56% versus 40%; P = .0002) compared with patients with B2M ≤2.5 µg/mL. The median PFS and OS were shorter in patients with B2M >2.5 µg/mL (median PFS, 64 months versus 80 months [P = .03]; median OS, 104.9 months versus 175.5 months [P < .0001]). On univariate analysis, predictors for OS included age >60 years (hazard ratio [HR], 1.61; P = .001), Mayo 2012 stage III/IV (HR, 3.36; P < .0001), more than 2 organs involved (HR, 1.36; P = .07), ≥10% BMPCs (HR, 1.5; P = .005), melphalan conditioning with 200 mg/m2 (HR, .29; P < .0001), B2M >2.5 µg/mL (HR, 1.82; P < .0001), and transplantation during or after 2010 (HR, .4; P = .0006). On multivariate analysis, only Mayo 2012 stage III/IV (HR, 1.89; P = .005), melphalan conditioning with 200 mg/m2 (HR, .39; P < .0001), B2M >2.5 µg/mL (HR, 1.84; P = .003), and transplantation performed during or after 2010 (HR, .58; P = .03) remained independent predictors of OS. Our findings identify B2M >2.5 µg/dL before ASCT as an independent predictor for OS in patients with AL amyloidosis and normal kidney function and should be routinely measured.

Multiple Myeloma in the Time of COVID-19.

We provide our recommendations (not evidence based) for managing multiple myeloma patients during the pandemic of COVID-19. We do not recommend therapy for smoldering myeloma patients (standard or high risk). Screening for COVID-19 should be done in all patients before therapy. For standard-risk patients, we recommend the following: ixazomib, lenalidomide, and dexamethasone (IRd) (preferred), cyclophosphamide lenalidomide and dexamethasone (CRd), daratumumab lenalidomide and dexamethasone (DRd), lenalidomide, bortezomib, and dexamethasone (RVd), or cyclophosphamide, bortezomib, and dexamethasone (CyBorD). For high-risk patients we recommend carfilzomib, lenalidomide, and dexamethasone (KRd) (preferred) or RVd. Decreasing the dose of dexamethasone to 20 mg and giving bortezomib subcutaneously once a week is recommended. We recommend delaying autologous stem cell transplant (ASCT), unless the patient has high-risk disease that is not responding well, or if the patient has plasma cell leukemia (PCL). Testing for COVID-19 should be done before ASCT. If a patient achieves a very good partial response or better, doses and frequency of drug administration can be modified. After 10-12 cycles, lenalidomide maintenance is recommended for standard-risk patients and bortezomib or ixazomib are recommended for high-risk patients. Daratumumab-based regimens are recommended for relapsed patients. Routine ASCT is not recommended for relapse during the epidemic unless the patient has an aggressive relapse or secondary PCL. Patients on current maintenance should continue their therapy.

Recurrent and refractory corneal perforation secondary to rheumatoid arthritis treated with infliximab.

Rheumatoid arthritis (RA) can affects many organs including the eyes. Corneal perforation in the form of peripheral ulcerative keratopathy can be debilitating and difficult to manage. A 48-year-old female with known RA presented with sudden loss of vision in her left eye, she was diagnosed with left corneal perforation secondary to severe dry eye. Penetrating keratoplasty (PKP) and punctum occlusion were done. Amniotic membrane transplant (AMT) was done 1 month later due to nonhealing epithelial defect. Her RA was clinically inactive, and no changes in her current medications were made. However, 4 months later, she presented with a second corneal perforation with melting. She had another PKP and AMT with permanent temporal tarsorrhaphy. Cyclosporine 100 mg P. O. twice daily was added, but after 5 months, she presented again with a third left corneal perforation with melting. Again, PKP and AMT with tarsorrhaphy were done, and she was started on infliximab. Since then, she had a stable graft with no further corneal perforations. In summary, patients with RA can have corneal perforations even if other signs of RA are absent. If the systemic treatment that is used to treat RA fails, one should consider using other classes of drugs, such as monoclonal antibodies (e.g., rituximab), tumor necrosis factor alpha blockers (such as infliximab or adalimumab), interleukin (IL)-1 receptor antagonists (e.g., anakinra), or IL-6 receptor antagonist (e.g., tocilizumab).