Outcomes of patients with multiple myeloma refractory to standard dose vs low dose lenalidomide.

Refractoriness to lenalidomide is an important factor determining the choice of therapy at first relapse in multiple myeloma (MM). It remains debatable if resistance to lenalidomide varies among MM refractory to standard doses vs low dose maintenance doses. In this study, we assessed the outcomes with subsequent therapies in patients with MM refractory to standard dose vs low dose lenalidomide. We retrospectively reviewed all patients with MM at our institution who received first line therapy with lenalidomide containing regimens, and assessed progression free survival (PFS) and overall survival for these patients for second line therapy, and with lenalidomide retreatment. For second line therapy, we found no difference in the PFS between standard dose refractory and low dose refractory groups (median PFS 14 months vs 14 months, p = 0.95), while the PFS for both these groups was inferior to the not refractory group (median PFS 30 months, p < 0.001 for both pairs). Similar trends were seen among these groups on lenalidomide retreatment, and on multivariable analysis. These data suggest that refractoriness to lenalidomide is not dose dependent, and definition of lenalidomide refractoriness should not depend on the dose of lenalidomide to which the disease was considered refractory.

Muscle and fat composition in patients with newly diagnosed multiple myeloma.

Measures of muscle and adipose tissue mass have been associated with outcomes in several malignancies, but studies in multiple myeloma (MM) are inconsistent. The aim of this study was to evaluate the association between muscle and fat areas and radiodensity, and overall survival (OS) in patients with newly diagnosed MM. We included 341 patients diagnosed with MM from 2010-2019 who had an 18F-fluorodeoxyglucose positron emission tomography/computed tomography at diagnosis. A cross-sectional image at the third lumbar vertebrae was segmented into muscle and fat components. Median follow up was 5.7 years. There was no association between sarcopenia and baseline disease characteristics or OS. Low muscle radiodensity was associated with higher disease stage, anemia, and renal failure. OS was 5.6 vs. 9.0 years in patients with muscle radiodensity in the lower vs. middle/upper tertiles, respectively (P = 0.02). High subcutaneous adipose tissue (SAT) radiodensity was associated with higher stage, anemia, thrombocytopenia, hypercalcemia, renal failure, and high LDH. OS was 5.4 years vs. not reached in patients with SAT radiodensity in the upper vs. middle/lower tertiles, respectively (P = 0.001). In conclusion, sarcopenia was not associated with OS in MM patients. High SAT radiodensity and low muscle radiodensity were associated with advanced disease stage and adverse laboratory characteristics.

Outcomes of patients with primary refractory multiple myeloma in the era of triplet and quadruplet induction therapy.

Patients with multiple myeloma (MM) who do not respond to initial therapy have worse outcomes than primary responders, and effective treatments are lacking in this population. However, the outcomes of primary refractory disease in the modern treatment era have not yet been studied. We reviewed patients with MM treated with triplet/quadruplet therapy at our institution to assess the incidence of primary refractory disease and the impact of salvage therapies in this population. We identified 1127 patients, of whom 1086 were evaluated for hematologic responses after 4 to 6 cycles. Of these, 93.3% (1013) had evidence of response, whereas 6.7% (73) had primary refractory disease. With a median overall survival (OS) of 51.3 months, patients with primary refractory disease had an increased risk of shorter survival in univariable and multivariable analyses (hazard ratio [HR], 3.5 [95% confidence interval (CI), 2.5-4.9]; HR, 4.3 [95% CI, 2.6-6.9], respectively). In the subgroup analysis of patients with primary refractory disease, those who received second-line autologous stem cell transplantation (ASCT) had increased second progression-free survival (20.9 vs 8.1 months; P < .01) and second OS (74.7 vs 31.3 months; P = .02) compared with patients who did not. We conclude that early progression remains a significant factor for shorter OS in the current era, and salvage ASCT could be the most beneficial option for this population.

Conditional survival in multiple myeloma and impact of prognostic factors over time.

Overall survival estimates from diagnosis are valuable for guiding treatment, but do not consider the years already survived. Conditional survival (CS) provides dynamic survival predictions over time. This study was conducted to estimate CS at 1-8 years from diagnosis and the impact of baseline prognostic factors on CS in multiple myeloma (MM) patients. This is a retrospective study including 2556 MM patients diagnosed between 2004 and 2019. CS (t | s) was defined as the probability of surviving t years given survival of s years. Median age was 64 years. Median follow-up was 6.2 years and median overall survival from diagnosis was 7.5 years. The 5-year CS estimates at s = 0, 1, 2, 3, and 5 years were 0.64, 0.61, 0.61, 0.61, and 0.58, respectively. On multivariate analysis, age ≥ 65 and proteasome inhibitor+immunomodulatory-based induction were associated with decreased survival and increased survival, respectively, retained at 5 years. The adverse impact of 1q gain/amplification, high-risk IgH translocation, and ISS-3 was significant at 1 and 3 years but not 5 years. Chromosome 17 abnormality was associated with decreased survival only at 1 year. Among MM patients, 5-year CS was stable at 1-5 years from diagnosis. The prognostic impact of high-risk cytogenetic factors decreased with additional years survived.

Thrombosis in multiple myeloma: Risk estimation by induction regimen and association with overall survival.

Lenalidomide-containing (R) triplet and quadruplet regimens are the standard of care for multiple myeloma (MM) and have been shown to increase the risk of thrombosis. The association between thromboembolism (TE) and survival in the novel multidrug era is not yet delineated. In this study, we evaluated the incidence of TE during the first year of MM diagnosis, its association with the type of induction regimen, and its impact on overall survival. We studied 672 newly diagnosed MM (NDMM) patients who received a triplet or quadruplet lenalidomide-based induction at the Mayo Clinic, Rochester. TE was diagnosed in 83 patients (12.4%). Of these, 56 (8.3%) had a deep venous thrombosis (DVT), 23 (3.4%) had a pulmonary embolism (PE) with or without the DVT, and 4 (0.6%) patients had a stroke. Carfilzomib-Rd (KRd) had the highest risk of TE (21.1%, 18/85), followed by quadruplets (11.1%, 5/45), bortezomib-Rd (9.6%, 51/531), and 0/11 (0%), treated with other lenalidomide-containing regimens. The difference in TE risk between KRd and the other regimens was statistically significant (OR = 2.6, p < .01). Nine patients developed a TE before being exposed to any treatment. Survival was significantly lower among patients that developed a TE (66 vs. 133 months, p < .01). The association of TE with reduced survival demonstrated in univariate analysis (HR = 2.2, 95% CI = 1.6-3.3) was maintained in the multivariable analysis adjusted for high-risk interphase fluorescence in situ hybridization (FISH), sex, age, receipt of an upfront transplant, the response at induction, and the International Staging System (ISS) (HR = 2.61, CI = 1.74-3.9). We conclude that TE is an important aspect of MM management, and effective management is especially relevant in the novel treatment era.

Risk factors for severe infection and mortality In patients with COVID-19 in patients with multiple myeloma and AL amyloidosis.

Patients with multiple myeloma (MM) have a lower efficacy from COVID-19 vaccination and a high rate of mortality from COVID-19 in hospitalized patients. However, the overall rate and severity of COVID-19 infection in all settings (including non-hospitalized patients) and the independent impact of plasma cell-directed therapies on outcomes needs further study. We reviewed the medical records of 9225 patients with MM or AL amyloidosis (AL) seen at Mayo Clinic Rochester, Arizona, and Florida between 12/01/2019 and 8/31/2021 and identified 187 patients with a COVID-19 infection (n = 174 MM, n = 13 AL). The infection rate in our cohort was relatively low at 2% but one-fourth of the COVID-19 infections were severe. Nineteen (10%) patients required intensive care unit (ICU) admission and 5 (3%) patients required mechanical ventilation. The mortality rate among hospitalized patients with COVID-19 was 22% (16/72 patients). Among patients that were fully vaccinated at the time of infection (n = 12), two (17%) developed severe COVID-19 infection, without any COVID-related death. On multivariable analysis, treatment with CD38 antibody within 6 months of COVID-19 infection [Risk ratio (RR) 3.6 (95% CI: 1.2, 10.5), p = .02], cardiac [RR 4.1 (95% CI: 1.3, 12.4), p = .014] or pulmonary comorbidities [RR 3.6 (95% CI 1.1, 11.6); p = .029] were independent predictors for ICU admission. Cardiac comorbidity [RR 2.6 (95% CI: 1.1, 6.5), p = .038] was an independent predictor of mortality whereas MM/AL in remission was associated with lower mortality [RR 0.4 (95% CI: 0.2-0.8); p = .008].

The impact of Post-Transplant doxycycline in AL amyloidosis - updated results after Long-Term follow up.

INTRODUCTION: The current treatment paradigm of AL amyloidosis lacks effective fibril-directed therapies. Doxycycline has been shown to have anti-fibril properties in preclinical models. In 2012, we reported that posttransplant prophylaxis with doxycycline was associated with improved survival compared to penicillin in patients with haematologic response. We provide here updated results after long-term follow up. METHODS: We included 553 patients who underwent transplant between July 24th, 1996, and June 24th, 2014. Doxycycline 100 mg daily was used for prophylaxis in patients with penicillin allergy; since 2013, doxycycline was used as the standard for prophylaxis. Prophylaxis was typically continued for a year after transplant. RESULTS: The median follow-up from transplant was 12.7 years. Doxycycline was used for prophylaxis in 33% of patients; the rest received penicillin. The median time to next treatment was 6.0 (95%CI; 4.4-8.8) years and 6.0 (95%CI; 4.9-7.1) years in the doxycycline and penicillin groups, respectively (p = .89). The median overall survival was 12.0 (95%CI: 11.0-19.6) years and 11.0 (95%CI: 9.6-12.7) years in the 2 groups, respectively (p = .17). There was a minimal trend towards improved survival with doxycycline among patients with ≥ very good partial response and among patients with organ response that was not statistically significant. CONCLUSION: After long-term follow-up, there is no clear evidence to support benefit of doxycycline in the post-transplant setting.

A simple additive staging system for newly diagnosed multiple myeloma.

Risk stratification in multiple myeloma is important for prognostication, patient selection for clinical trials, and comparison of treatment approaches. We developed and validated a staging system that incorporates additional FISH abnormalities not included in the R-ISS and reflects the additive effects of co-occurring high-risk disease features. We first evaluated the prognostic value of predefined cytogenetic and laboratory abnormalities in 2556 Mayo Clinic patients diagnosed between February 2004 and June 2019. We then used data from 1327 patients to develop a risk stratification model and validated this in 502 patients enrolled in the MMRF CoMMpass study. On multivariate analysis, high-risk IgH translocations [risk ratio (RR): 1.7], 1q gain/amplification (RR: 1.4), chromosome17 abnormalities (RR: 1.6), ISS III (RR: 1.7), and elevated LDH (RR: 1.3) were independently associated with decreased overall survival (OS). Among 1327 evaluable patients, OS was 11.0 (95% CI: 9.2-12.6), 7.0 (95% CI: 6.3-9.2), and 4.5 (95% CI: 3.7-5.2) years in patients with 0 (stage I), 1 (stage II), and ≥2 (stage III) high-risk factors, respectively. In the MMRF cohort, median OS was 7.8 (95% CI: NR-NR), 6.0 (95% CI: 5.7-NR), and 4.3 (95% CI: 2.7-NR) years in the 3 groups, respectively (P < 0.001). This 5-factor, 3-tier system is easy to implement in practice and improves upon the current R-ISS.

Multicentric Castleman disease: A single center experience of treatment with a focus on autologous stem cell transplantation.

Castleman disease (CD) is a rare lymphoproliferative disease characterized by diverse clinical and pathologic features. Due to its rarity, there are limited studies comparing currently available therapies. The role of autologous stem cell transplantation (ASCT) in CD has not yet been established. In this paper, we describe the clinical characteristics, treatment choices, and outcomes in 34 Mayo Clinic patients diagnosed with multicentric CD from July 1, 2003 to April 30, 2018. Eighteen patients (53%) also met the criteria for POEMS, including 14 with the osteosclerotic variant. The first-line treatments included: steroid monotherapy (4), cytotoxic chemotherapy (6), rituximab alone (8) or with chemotherapy (2), anti-IL6 treatment (3), and ASCT (10). The median follow-up was 4.8 (range: 0.1-15.2) years. The 5- and 10-year overall survival rates were 84% and 71%, respectively. Sixteen patients received high-dose chemotherapy followed by ASCT during their disease course. Among those, 14 had multicentric CD associated with POEMS. There were no transplant-related deaths. All patients had at least a partial response to ASCT, most of whom achieved a complete response. The favorable outcomes seen with ASCT in this cohort suggest that transplantation may have a role in multicentric CD, particularly for patients with multicentric CD associated with POEMS.

Prognostic restaging after treatment initiation in patients with AL amyloidosis.

The utility of systemic light chain (AL) amyloidosis staging systems has been validated for newly diagnosed patients, but their role in restaging after treatment has not been explored. We designed this study to evaluate whether the currently used systems are of prognostic value at 3 and 6 months of starting first-line treatment, and whether stage migration from diagnosis impacts survival. This is a retrospective study including Mayo Clinic patients with AL amyloidosis diagnosed between 1 January 2006 and 30 June 2019; 536 and 204 patients had restaging data for at least 1 system at 3 and 6 months, respectively. Using modified Mayo 2004 staging at 3 months, median overall survival (OSs) were 11.8, 10.8, 4.6, and 1.1 years for stage I, II, IIIa, and IIIb, respectively. Using Mayo 2012, median OSs were 11.8, 9.0, 5.2, and 0.8 years for stage I, II, III, and IV, respectively. Using modified Mayo 2004 staging at 6 months, median OSs were not reached (NR), NR, 5.4, and 0.9 years for stage I, II, IIIa, and IIIb, respectively. Using Mayo 2012, OSs were NR, NR, 4.6, and 0.9 years for stage I, II, III, and IV, respectively. Worsening stage at 3 or 6 months was associated with worse survival than retaining baseline stage. In conclusion, the current staging systems can be used for restaging at 3 and 6 months from treatment initiation. Migration to higher stage predicts poor prognosis.

Comparison of the current renal staging, progression and response criteria to predict renal survival in AL amyloidosis using a Mayo cohort.

Three sets of criteria (International Society of Amyloidosis [ISA], Palladini and Kastritis) were independently developed for staging, progression and response criteria to predict renal survival in patients with AL amyloidosis. We evaluated these criteria using a cohort of 495 newly diagnosed AL amyloidosis patients with renal involvement using time to event competing risk analysis at baseline, 3, 6 and 12 months after treatment. Only Palladini and Kastritis had a staging system and both predicted a higher risk of end stage renal disease (ESRD) in the stage III vs stage I patients but only the Palladini model was predictive for stage II patients. At 3 months, risk of ESRD was significantly higher for Palladini and ISA renal progression (hazard ratio [HR] 2.8 [95% CI: 1.5-5.3, p = .001] and 2.5 [CI: 1.4-4.6, p = .004, respectively]), but renal response was not significantly protective; conversely, the risk of ESRD was not significantly higher for the Kastritis renal progression, but was significantly protective for the Kastritis renal responders (HR 0.38 [95% CI: 0.17-0.84], p = .017). Both progression and response with ISA, Palladini and Kastritis criteria were predictive of ESRD at 6 months and 12 months. While the Palladini staging criteria at baseline, and the ISA and Palladini criteria for progression at 3 months performed better than the Kastritis criteria at baseline and 3 months post-treatment, the Kastritis criteria performed better for response 3 months after treatment. All three sets of criteria performed well at and after 6 months post-treatment. These differences are important when choosing endpoints for clinical trials.

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.

Implications of MYC Rearrangements in Newly Diagnosed Multiple Myeloma.

PURPOSE: Rearrangements involving the MYC protooncogene are common in newly diagnosed multiple myeloma, but their prognostic significance is still unclear. The purpose of this study was to assess the impact of MYC rearrangement on clinical characteristics, treatment response, and survival in patients with newly diagnosed multiple myeloma. EXPERIMENTAL DESIGN: This is a retrospective study including 1,342 patients seen in Mayo Clinic in Rochester, MN, from January 2006 to January 2018, who had cytogenetic testing by FISH at diagnosis, including MYC testing using the break apart FISH probe (8q24.1). RESULTS: A rearrangement involving MYC was found in 8% of patients and was associated with elevated ß2-microglobulin, ≥50% bone marrow plasma cells, IgA multiple myeloma, and the cooccurrence of trisomies. There were no differences in overall response rates between patients with and without MYC rearrangement when induction chemotherapy was proteasome inhibitor (PI)-based, immunomodulatory drug (IMiD)-based or PI + IMiD-based. Overall survival was shorter in patients with MYC rearrangement compared with patients without MYC rearrangement (5.3 vs. 8.0 years, P < 0.001). MYC rearrangement was associated with increased risk of death on multivariate analysis when high-risk cytogenetic abnormalities, ISS stage III, and ≥70 years of age were included (risk ratio: 1.5; P = 0.007). CONCLUSIONS: MYC rearrangement is associated with high disease burden and is an independent adverse prognostic factor in patients with newly diagnosed multiple myeloma.

The why and how of maintaining hydration during cancer therapy.

PURPOSE OF REVIEW: To provide an overview of the role hydration plays in the oncology population while providing a synopsis of recent scientifically relevant published practice advancements. RECENT FINDINGS: Dehydration causes substantial symptom burden in cancer patients, secondary to both disease process and treatment complications. Maintaining fluid and electrolytes balance is the key to hydration therapy. When oral intake is diminished, artificial hydration can be delivered via enteral, intravenous and subcutaneous routes. Use of artificial hydration in end-of-life care for cancer patients remains a highly debated topic with unclear benefits and lack of established standards. A holistic approach is required in the decision-making process. SUMMARY: Maintaining adequate hydration is important in patients receiving cancer therapy. Challenges exist, secondary to limited clinical guidelines of hydration in patients with advanced cancer. Artificial hydration may be indicated for selected patients at the end of life if used on an individualized basis as medical treatment.

Cytogenetic abnormalities in multiple myeloma: association with disease characteristics and treatment response.

Cytogenetic abnormalities are found in most multiple myeloma (MM) patients. Although their prognostic value has been well studied, there are limited data on the association of primary cytogenetic abnormalities with disease characteristics and treatment response. This study was designed to evaluate these associations. This is a retrospective study including 2027 Mayo Clinic patients diagnosed with MM between February 2004 and February 2018 who had cytogenetic testing by FISH at diagnosis. Translocations t(4;14), t(14;16), t(6;14), and t(14;20) were associated with anemia, beta2microglobulin >5.5 µg/ml and ≥50% bone marrow plasma cells; t(4;14) was associated with higher serum monoclonal protein and plasma cell proliferation. Overall response rate to proteasome inhibitor (PI)-based treatment was higher for IgH translocations compared to trisomies (83% vs. 71%, P = 0.002), but was higher for trisomies with immunomodulatory drug (IMiD)-based treatment (87% vs. 75%, P < 0.001). Time to next treatment was longer with trisomies than IgH translocation with IMiD-based (32.1 vs. 18.4 months, P < 0.001) and PI + IMiD-based (44.0 vs. 27.4 months, P = 0.003) treatments. Outcomes were superior with PI + IMiD combinations in all groups. Our results show that t(4;14), t(14;16), t(6;14), and t(14;20) are associated with high-risk disease characteristics, and IgH translocations and trisomies may be associated with better responses to PIs and IMiDs, respectively.