Impact of acquired del(17p) in multiple myeloma.

The high-risk abnormality del(17p) can be detected by fluorescence in situ hybridization on malignant plasma cells (PCs) and has an adverse prognostic impact in patients with multiple myeloma (MM). Patients with del(17p) have reduced overall survival (OS). Patients who acquire del(17p) later during the disease course are not well described. The disease characteristics at diagnosis predicting for acquired del(17p) and its overall impact on patient survival is not known. We compared 76 patients with MM who were negative for del(17p) at diagnosis and acquired it later with 152 control MM patients who did not acquire del(17p) at a comparable time point. Patients acquired del(17p) at a median of 35.6 months (range, 4.6-116.1 months) from diagnosis of MM after a median of 2 lines of therapy (range, 1-10 lines of therapy). When compared with controls, patients with acquired del(17p) had shorter median progression-free survival (PFS) (30.1 vs 23.0 months; P = .032) and OS (106.1 vs 68.2 months; P < .001) from diagnosis. After the detection of del(17p), the median PFS was 5.4 months and the median OS was 18.1 months. High lactate dehydrogenase level (odds ratio [OR], 3.69; 95% confidence interval [CI], 1.11-12.24) and presence of t(4;14) (OR, 2.66; 95% CI, 1.09-6.48) or any high-risk translocation (OR, 2.23; 95% CI, 1.00-4.95) at diagnosis predicted acquisition of del(17p). High PC proliferative rate predicted shorter OS from detection of del(17p) (hazard ratio, 2.28; 95% CI, 1.31-3.96; P = .004). Our study shows that acquisition of del(17p) is an important molecular event associated with reduction in OS in MM. Certain baseline factors may predict acquisition of del(17p). This needs validation in prospective data sets.

Development of thrombocytopenia during first-line treatment and survival outcomes in newly diagnosed multiple myeloma.

The prognostic significance of novel agent-induced thrombocytopenia in newly diagnosed multiple myeloma (MM) is unknown. We identified 665 newly diagnosed patients receiving proteasome inhibitors and/or immunomodulators with pretreatment platelet counts ≥100,000/µL. Median progression-free survival (PFS) was 1.88 years (95% CI 1.48-2.38) for patients who developed treatment-related thrombocytopenia (<100,000/µL) within sixty days of initiation of first-line therapy, compared to 2.64 years (95% CI 2.39-2.78) in patients who did not (p = .042), while median overall survival (OS) was 5.70 years (95% CI 3.02-9.00) and 8.43 years (95% CI 6.62-9.17), respectively (p = .030). Platelet count reduction >70% from pretreatment baseline was similarly predictive of inferior PFS and OS. This is the first study to demonstrate the predictive and prognostic value of treatment-related thrombocytopenia in newly diagnosed MM.

Prognostic value of minimal residual disease and polyclonal plasma cells in myeloma patients achieving a complete response to therapy.

Achievement of a complete response has been associated with improved outcomes in patients with multiple myeloma. Recently, increasing application of minimal residual disease (MRD) assessment has shown that MRD negativity is a powerful prognostic factor for survival outcomes. We wanted to examine the impact of the polyclonal plasma cell (pPC) compartment among patients in complete response (CR) but are MRD positive. This is a retrospective cohort study where 460 myeloma patients were identified who met criteria for CR and had multicolor flow cytometry performed on the bone marrow (BM). Monoclonal and pPCs were estimated during MRD testing. Final outcomes including overall survival (OS) and time to next treatment (TTNT) were compared among the groups. The median OS for the entire cohort was not reached (95% CI; 63 mos, NR) and the median TTNT was 31 months (95% CI; 27,36). Among the MRDneg group, median TTNT was 37.6 months vs 23 months for MRDpos patients (P < .001); the median OS was not reached for either group, but there was a trend toward better survival for MRDneg patients. Among the MRDpos group, median percentage of pPCs was 65% (2.5-98.5), and those with >95% pPCs had a significantly better TTNT (NR vs 23 months; P = .02) and a trend toward better OS. We conclude that achievement of MRD negativity predicts for better response durability and trend toward improved OS and an increased proportion of pPC predicts for better outcomes within those who have residual tumor cells highlighting the importance of marrow normalization.

Natural history of multiple myeloma with de novo del(17p).

We compared the outcomes of 310 patients with newly diagnosed multiple myeloma with del(17p) detected by FISH to patients with high-risk translocations (HRT) (n = 79) and standard-risk (SR) cytogenetics (n = 541). The median progression-free survival (PFS) following initial therapy for the three groups was 21.1, 22, and 30.1 months, respectively (P = 0.437- del(17p) vs. HRT); the median overall survival (OS) was 47.3, 79.1, and 109.8 months, respectively, (P = 0.007- del(17p) vs. HRT). PFS and OS for patients with relative loss of 17p (n = 21) were comparable to other patients with del(17p). The PFS was similar between the del(17p) and HRT groups when stratified for age, ISS stage or treatment. The OS of del(17p) and HRT groups were similar in presence of advanced age, ISS III stage or if patients did not receive a proteasome-inhibitor containing induction. ISS III stage, high LDH and HRT, but not the percentage of cells with del(17p) predicted shorter OS in patients with del(17p). The median OS for low (ISS I, normal LDH and no HRT), intermediate (neither low nor high-risk) and high-risk (ISS III and either elevated LDH or coexistent HRT) groups among del(17p) patients were 96.2, 45.4, and 22.8 months, respectively, allowing further risk stratification.

Impact of prior diagnosis of monoclonal gammopathy on outcomes in newly diagnosed multiple myeloma.

Multiple myeloma (MM) is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma (SMM), or solitary plasmacytoma (SPC). There is a lack of data regarding impact of these pre-existing monoclonal gammopathies (MGs) on MM outcomes. Patients with prior diagnosis of MGUS, SMM, or PC from 1973 to 2015 (cases) were identified from our institution's database and compared to those without a known MG (controls). The primary outcome of interest was overall survival (OS). Multivariate analysis was performed to ascertain factors impacting all-cause mortality. We identified 774 patients with a prior diagnosis of MGUS, SMM or SPC (cases) and a control population (1:2) matched for the year of diagnosis (n = 1548). After a median follow-up of 81 months, the cases showed a longer median OS than the controls (71 months vs. 56 months). The improved OS was limited to those with a known prior diagnosis of SMM (80 months) and SPC (95 months), compared to MGUS (60 months). Multivariable analysis revealed that MM patients with known prior MG had less overall mortality than those without, and this was limited to prior SMM/SPC group (HR 0.68, 95% CI: 0.50-0.93), as compared to the MGUS group (HR 0.83, 95% CI: 0.66-1.05).

Substratification of patients with newly diagnosed standard-risk multiple myeloma.

Despite the absence of high-risk cytogenetics and lower International Staging System (ISS) stages, a subset of patients with multiple myeloma (MM) experience poor overall survival (OS). We studied 1461 patients with newly diagnosed MM to identify patient and disease characteristics that predict a high-risk phenotype among standard-risk patients. Fifty-six percent of all patients presented with standard-risk disease. Among them, advanced age, extremes of body mass index, non-hyperdiploid karyotype and abnormal lymphocyte counts were associated with worse OS. Standard-risk patients with 0-1 of these adverse factors (hazard ratio [HR] 0·32, 95% confidence interval [CI] 0·24-0·43, P < 0·001) and 2 adverse factors (HR 0·54, 95% CI 0·41-0·72, P < 0·001) experienced better OS than high-risk patients. Two or more adverse factors were present in 17% of standard-risk patients and were associated with OS comparable to high-risk patients (HR 0·91, 95% CI 0·67-1·24, P = 0·548). Predictive power among standard-risk patients was improved using score groups compared to ISS stages. Patients with standard-risk MM are a heterogeneous group with one in six patients experiencing OS comparable to high-risk disease. Patients at risk can be identified using readily available patient and disease characteristics. These findings emphasize the importance of accurate risk stratification and help explain part of the heterogeneity observed in clinical practice.

Peripheral blood biomarkers of early immune reconstitution in newly diagnosed multiple myeloma.

Peripheral blood biomarkers of tumor microenvironment and immune surveillance are independent prognostic factors in multiple myeloma. The timing and prognostic impact of immune reconstitution has been studied after autologous hematopoietic stem cell transplantation, less is known about its significance in newly diagnosed multiple myeloma. We studied absolute lymphocyte (ALC) and absolute monocyte (AMC) counts at the time of treatment initiation and 1 month thereafter in 771 newly diagnosed patients. Two hundred and thirty-four patients (31%) had evidence of immune dysregulation at baseline (abnormal biomarkers). Eighty-seven of these patients (37%) recovered normal biomarkers at 1 month (early immune reconstitution). The absence of immune dysregulation at baseline (compared to the presence thereof) was associated with better overall survival (HR 0.77, 95% CI 0.61-0.97, P = 0.025, n = 771). The absence of immune dysregulation at 1 month (compared to the persistence or development thereof) was associated with better overall survival (HR 0.63, 95% CI 0.50-0.80, P < 0.001, n = 771). Early immune reconstitution (compared to the persistence or development of immune dysregulation) was associated with better overall survival (HR 0.62, 95% CI 0.43-0.92, P = 0.016, n = 771). Cytogenetic high-risk disease was negatively, and treatment with immunomodulators positively, associated with early immune reconstitution. The presence or development of immune dysregulation in newly diagnosed multiple myeloma is an independent risk factor. The favorable impact of early immune reconstitution suggests immune dysregulation to be a potentially modifiable risk factor that may be exploited for therapeutic benefit.

Overall survival of transplant eligible patients with newly diagnosed multiple myeloma: comparative effectiveness analysis of modern induction regimens on outcome.

Overall survival (OS) of multiple myeloma has improved remarkably over time, with the recent Intergroupe Francophone du Myelome (IFM) 2009 randomized trial reporting a 4-year OS rate of approximately 82% in patients receiving modern therapy. However, survival estimates from clinical trials may overestimate outcomes seen in clinical practice even with the adjustment for age and other key characteristics. The purpose of this study was to determine the OS of myeloma patients seen in routine clinical practice who resembled the cohort studied in the IFM 2009 trial. A second goal was to conduct a brief comparative effectiveness analysis of bortezomib, lenalidomide, dexamethasone, and other major induction regimens used during the study period. We studied all patients with myeloma 65 years of age and younger, seen at the Mayo Clinic between January 1, 2010 and August 31, 2015, who had a stem cell harvest performed within 12 months of initial diagnosis. Patients with baseline serum creatinine >2 mg/dL were excluded. Five hundred and eighteen patients were studied. The 4-year OS rate was 82.3%, comparable to results achieved in the contemporaneous IFM randomized trial. The 4-year OS rates for standard and high-risk myeloma were 86.3% and 68.2%, respectively.

Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria.

In 2014, the International Myeloma Working Group reclassified patients with smoldering multiple myeloma (SMM) and bone marrow-plasma cell percentage (BMPC%) ≥ 60%, or serum free light chain ratio (FLCr) ≥ 100 or >1 focal lesion on magnetic resonance imaging as multiple myeloma (MM). Predictors of progression in patients currently classified as SMM are not known. We identified 421 patients with SMM, diagnosed between 2003 and 2015. The median time to progression (TTP) was 57 months (CI, 45-72). BMPC% > 20% [hazard ratio (HR): 2.28 (CI, 1.63-3.20); p < 0.0001]; M-protein > 2g/dL [HR: 1.56 (CI, 1.11-2.20); p = 0.01], and FLCr > 20 [HR: 2.13 (CI, 1.55-2.93); p < 0.0001] independently predicted shorter TTP in multivariate analysis. Age and immunoparesis were not significant. We stratified patients into three groups: low risk (none of the three risk factors; n = 143); intermediate risk (one of the three risk factors; n = 121); and high risk (≥2 of the three risk factors; n = 153). The median TTP for low-, intermediate-, and high-risk groups were 110, 68, and 29 months, respectively (p < 0.0001). BMPC% > 20%, M-protein > 2 g/dL, and FLCr > 20 at diagnosis can be used to risk stratify patients with SMM. Patients with high-risk SMM need close follow-up and are candidates for clinical trials aiming to prevent progression.

Analysis of Clinical Factors and Outcomes Associated with Nonuse of Collected Peripheral Blood Stem Cells for Autologous Stem Cell Transplants in Transplant-Eligible Patients with Multiple Myeloma.

Collection and storage of peripheral blood stem cells (PBSCs) for use in autologous stem cell transplantation (ASCT) upon first disease relapse is an accepted practice for eligible patients with multiple myeloma (MM). However, little is known about the factors and outcomes associated with nonuse of these collected and stored PBSCs by MM patients who intended to have a delayed ASCT. From January 1, 2004 to December 31, 2014 we identified 342 patients who underwent collection and storage of their PBSCs in anticipation of a delayed ASCT upon first disease relapse. Among these, 176 patients (11%) had not proceeded to a delayed ASCT at the time of this study analysis. The most common reason for not undergoing an ASCT was not experiencing a relapse on first-line therapy (53%, n = 94). However, 11% of patients (n = 37) who planned for a delayed ASCT were unable to undergo an ASCT at disease relapse. Comparison with a control group of MM patients who underwent an upfront ASCT suggested a worse overall survival from diagnosis in these patients who were ASCT ineligible at disease relapse (112 versus 80 months, P = .011). This study provides valuable data for patients and care providers to take into consideration when deciding on whether to pursue an upfront or a delayed ASCT.

Time to plateau as a predictor of survival in newly diagnosed multiple myeloma.

Response 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. TPlat was defined as time from initiation of first-line therapy to best response to first-line therapy. The median TPlat was 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 prolonged TPlat could 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.

Prognostic significance of circulating plasma cells by multi-parametric flow cytometry in light chain amyloidosis.

We evaluated the prognostic impact of clonal circulating plasma cells (cPCs) detected by six-color multi-parametric flow cytometry (MFC) in light chain (AL) amyloidosis at diagnosis. Of the 154 patients who underwent MFC, cPCs were detected in 42% (n = 65) patients. Median number of cPCs was 81 per 150,000 events (range: 6-17,844). High bone marrow plasma cell percentage was an independent predictor of presence of cPCs. Presence of cPCs at diagnosis was associated with inferior overall survival (OS) (90 vs. 98 months, p = 0.003) and inferior progression free survival (PFS) (31 vs. 52 months, p = 0.02). Estimated 1, 2 and 5 year OS in the two groups was: 74, 64 and 57 and 89, 87, and 80%, respectively. Estimated PFS at 1, 2, and 5 years was: 69, 56, and 23% and 80, 74, and 37%, respectively. Furthermore, the presence of cPCs at diagnosis was an independent adverse predictor of OS in multivariable analysis. Achieving a very-good partial response, or better, was able to overcome the adverse impact of cPCs at diagnosis. Patients with cPCs at diagnosis may warrant closer monitoring post-treatment, especially if they do not achieve a deep hematologic response.

Impact of prior melphalan exposure on stem cell collection in light chain amyloidosis.

Use of melphalan in multiple myeloma was observed to have a deleterious effect on stem cell collection in older studies. There is limited data on the impact of melphalan in light chain (AL) amyloidosis, especially in the plerixafor era. We retrospectively evaluated stem cell mobilization in 610 patients with AL amyloidosis, of which 79 had prior exposure to melphalan, 167 to other chemotherapeutics, while 364 had no chemotherapy exposure. Collection of CD34+ stem cells × 106/kg was lower in the melphalan group. Median total yields in the melphalan, non-melphalan, and no chemotherapy groups were 5.5, 7.7, and 7.8, respectively; p < 0.001. Day-1 yields were 2.7, 3.5, and 4.0 (p = 0.0003), respectively, and median yields per collection were 2.0, 3.3, and 4.0 (p < 0.001), respectively. Similar results were observed in the sub-group analysis after plerixafor was integrated in our collection algorithm (2009). Patients in the melphalan group had higher failure rate of 9% vs. 2% each in the other two groups (p = 0.006). Impact of melphalan was dose-dependent, with cumulative melphalan exposure of >150 mg (median: three cycles) resulting in lower yields. Therefore, duration of melphalan exposure prior to stem cell collection should be limited, ideally, not exceeding more than two cycles of treatment.

Efficacy of VDT PACE-like regimens in treatment of relapsed/refractory multiple myeloma.

Experience 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.

OCULAR MANIFESTATIONS OF SYSTEMIC AMYLOIDOSIS.

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.

Ocular Manifestations of Familial Transthyretin Amyloidosis.

PURPOSE: Among patients with familial amyloidosis, mutation in the transthyretin (TTR) protein is the most common type. Patients with TTR amyloidosis have been noted to have ocular, especially vitreous, involvement. In this report, an analysis of the types and frequency of ocular manifestations in TTR amyloidosis is presented. DESIGN: Observational case series. METHODS: Two hundred and sixty-three patients who presented to Mayo Clinic with TTR amyloidosis between January 1, 1970, and November 1, 2014, consented to be included in the Mayo Clinic amyloidosis database maintained by the Department of Hematology. Fifty-four patients had ocular examinations at a mean of 4.25 ± 3.93 months after systemic symptoms. RESULTS: Of 108 examined eyes in 54 patients with TTR amyloidosis, there were 26 eyes (24%) in 13 patients with ocular involvement. Patients with ocular involvement were more likely to be women than those without ocular involvement (46% vs 15%, respectively, P = .008) and have significantly worse visual acuity (VA) at presentation (logMAR 0.24 [Snellen equivalent 20/30] vs logMAR 0.00 [Snellen equivalent 20/20], P = .017). The ophthalmic findings included vitreous amyloid (26/26, 100%), neurotrophic keratitis (2/26, 8%), glaucoma (5/26, 19%), and tortuous retinal vessels (4/26, 15%). The glaucoma was classified as open-angle (2/26), exfoliative (2/26), and neovascular following central retinal vein occlusion from amyloidosis (1/26). Ten patients underwent vitrectomy for visually significant vitreous amyloidosis, which significantly improved VA from a baseline of logMAR 0.70 (Snellen equivalent 20/100) to logMAR 0.05 (Snellen equivalent ∼20/20), P = .003. Three TTR mutations, Glu89Lys, Gly47Arg, and homozygous Gly6Ser, not previously described, were associated with vitreous amyloid. CONCLUSION: In this large cohort of patients with TTR amyloidosis, female sex and decreased VA were associated with ocular amyloid. Three mutations that have not been previously reported to have vitreous involvement were described: Glu89Lys, Gly47Arg, and homozygous Gly6Ser.

Predictors of early treatment failure following initial therapy for systemic immunoglobulin light-chain amyloidosis.

We analysed factors predicting early treatment failure (ETF), after first-line therapy for light-chain amyloidosis (AL). AL amyloidosis patients seen at Mayo Clinic within 90 days of diagnosis, from 2006 to 2015, excluding those who died within 3 months of initial therapy, were analysed retrospectively. ETF was defined as progression requiring treatment change or death within 12 (ETF12) or 24 (ETF24) months of first-line treatment. Non-ETF included those with a follow-up of more than 12 or 24 months who had progression beyond 12 or 24 months. A total of 724 patients met the study criteria; 244 (33.7%) had ETF12 and 388 (53.6%) had ETF24. Patients with ETF12 were older (64.1 vs. 62.2 years) with higher prevalence of cardiac (81 vs. 64.1%) and multi-organ involvement (67.2 vs. 45.4%) and higher proportion of patients with t(11; 14) (58.5 vs. 44.3%) or in higher Mayo 2012 stage (58.5 vs. 41.1%).The median follow-up was 5.4 years from start of initial therapy. In multivariate analysis, presence of t(11; 14) and non-incorporation of autologous transplant in initial therapy are significant predictors of ETF12 (p = .01and p = .003) and ETF24 (p = .0001 and p = .005) while Mayo stage is predictive of ETF24 (p = .002), but not ETF12.