Nidhi Tandon

Clinical use and applications of histone deacetylase inhibitors in multiple myeloma

The incorporation of various novel therapies has resulted in a significant survival benefit in newly diagnosed and relapsed patients with multiple myeloma (MM) over the past decade. Despite these advances, resistance to therapy leads to eventual relapse and fatal outcomes in the vast majority of patients. Hence, there is an unmet need for new safe and efficacious therapies for continued improvement in outcomes. Given the role of epigenetic aberrations in the pathogenesis and progression of MM and the success of histone deacetylase inhibitors (HDACi) in other malignancies, many HDACi have been tried in MM. Various preclinical studies helped us to understand the antimyeloma activity of different HDACi in MM as a single agent or in combination with conventional, novel, and immune therapies. The early clinical trials of HDACi depicted only modest single-agent activity, but recent studies have revealed encouraging clinical response rates in combination with other antimyeloma agents, especially proteasome inhibitors. This led to the approval of the combination of panobinostat and bortezomib for the treatment of relapsed/refractory MM patients with two prior lines of treatment by the US Food and Drug Administration. However, it remains yet to be defined how we can incorporate HDACi in the current therapeutic paradigms for MM that will help to achieve longer disease control and significant survival benefits. In addition, isoform-selective and/or class-selective HDAC inhibition to reduce unfavorable side effects needs further evaluation.

Clinical presentation and outcomes in light chain amyloidosis patients with non-evaluable serum free light chains

Hematologic response criteria in light chain (AL) amyloidosis require the difference in involved and uninvolved free light chains (dFLC) to be at least 5 mg/dl. We describe the clinical presentation and outcomes of newly diagnosed amyloidosis patients with dFLC <5 mg/dl (non-evaluable dFLC; 14%, n=165) compared with patients with dFLC ⩾5 mg/dl (evaluable dFLC; 86%, n=975). Patients with non-evaluable dFLC had less cardiac involvement (40% vs 80%, P<0.001), less liver involvement (11% vs 17%, P=0.04) and a trend toward less gastrointestinal involvement (18% vs 25%, P=0.08). However, significantly higher renal involvement (72% vs 56%, P=0.0002) was observed in the non-evaluable dFLC cohort. Differences in treatment patterns were observed, with 51% of treated patients undergoing upfront stem cell transplantation in the non-evaluable cohort compared with 28% in the evaluable dFLC group (P<0.001). Progression-free survival (61 vs 13 months, P<0.001) and overall survival (OS; 101 vs 29 months, P<0.001) were significantly longer in the non-evaluable dFLC cohort. Normalization of involved light chain levels and decrease in dFLC <1 mg/dl (baseline at least 2 mg/dl) were predictive of OS and associated with better dialysis-free survival and may be used for response assessment in patients with non-evaluable FLC levels.

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.

Treatment Patterns and Outcome Following Initial Relapse or Refractory Disease in Patients with Systemic Light Chain Amyloidosis

We analyzed the outcomes following initial relapse or refractory disease in systemic light chain amyloidosis (AL) and the impact of type of therapy employed.A total of 1327 patients with AL seen at Mayo Clinic within 90 days of diagnosis, between 2006 and 2015, were reviewed. The study included 366 patients experiencing a documented hematological or organ relapse or refractory disease requiring start of second line therapy. Overall survival (OS) and time to next treatment (TTNT) were calculated from start of second line treatment.The median time to require second line treatment was 16.2 months (1‐93) from the start of first line therapy. At relapse, patients received proteasome inhibitors (PI; 45.1%), immunomodulators (IMiD; 22.7%), alkylators (9%), PI and IMiD combination (4.1%), autologous transplant (3.8%), steroids and other therapies (4.9%). Among these, 124 (33.9%) required change or reinstitution of therapy. The median time to require third line treatment was 31 months (95% CI; 24, 40.5) and the median overall survival (OS) was 38.8 months (95% CI; 29.6, 52.6) from the start of second line treatment. Retreatment with same therapy at relapse significantly reduced TTNT (22 m vs 32.3 m; P = .01) as compared to different therapy; but did not have any impact OS (30.8 m vs 51.1 m; P = .5). In conclusion, this study provides important information about outcomes of patients with AL who require second line treatment for relapsed/refractory disease . Treatment with a different therapy at relapse improves time to next therapy but does not impact OS.

Clinical utility of the Revised International Staging System in unselected patients with newly diagnosed and relapsed multiple myeloma

We analyzed the utility of Revised International staging system (RISS) in an unselected cohort of newly diagnosed multiple myeloma (NDMM; cohort 1), and relapsed/refractory multiple myeloma (RRMM; cohort 2) patients. Cohort 1 included 1900 patients seen within 90 days of diagnosis, from 2005 to 2015, while cohort 2 had 887 patients enrolled in 23 clinical trials at Mayo Clinic. The overall survival (OS) and progression-free survival (PFS) was calculated from the time since diagnosis or trial registration. The median estimated follow up was 5 and 2.3 years for Cohorts 1 and 2, respectively. Among 1067 patients evaluable in Cohort 1, the median OS and PFS was 10 and 2.8 years for RISS stage I, 6 and 2.7 years for RISS stage II and 2.6 and 1.3 years for RISS stage III (P<0.0001). Among 456 patients evaluable in Cohort 2, the median OS and PFS was 4.3 and 1.1 years for RISS stage I, 2 and 0.5 years for RISS stage II and 0.8 and 0.2 years for RISS stage III (P<0.0001). In conclusions, RISS gives a better differentiation of NDMM as well as RRMM patients into three survival subgroups and should be used to stratify patients in future clinical trials.

The importance of bone marrow examination in patients with light chain amyloidosis achieving a complete response

Current response criteria for evaluating hematologic response in light chain (AL) amyloidosis do not require a bone marrow examination to evaluate for residual plasma cells [1]. Complete response (CR) is defined as achieving a normal free light chain (FLC) ratio and negative immunofixation in serum and urine. In a study of multiple myeloma patients [2], 10% of patients achieving all the serum criteria for stringent CR by conventional International Myeloma Working Group (IMWG) response criteria [3] had increased plasma cells in the bone marrow. Moreover, patients who had less than 5% plasma cells in the marrow had better outcomes, thereby reinforcing the importance of bone marrow biopsy in response evaluation in multiple myeloma. More recently, it has been demonstrated than achieving even deeper responses with minimal residual disease (MRD) negativity is associated with superior survival outcomes in multiple myeloma [4, 5]. Recent work from our institution in AL amyloidosis found that in patients achieving a very good partial response, those with less than 0.1% monotypic plasma cells in the bone marrow on six color multi-parametric flow cytometry displayed a trend towards better PFS [6]. The objective of our study was to evaluate if bone marrow biopsy findings provide additional prognostic value in patients with AL amyloidosis who achieve a CR by current response criteria. Following IRB approval, we identified 80 patients with newly diagnosed AL amyloidosis from 2006–2015, who achieved a CR with therapy as defined above and concomitantly underwent a bone marrow biopsy. All patients had given written informed consent for review of their medical records for research. Bone marrow examination included a morphological evaluation of the aspirate and core biopsy for assessment of plasma cells in all patients, as well as flow cytometry in 78 of 80 patients to identify clonality of the residual plasma cells. Flow cytometric evaluation included antibodies towards CD19, CD38, CD45, CD138, and kappa and lambda light chains in 76 patients and evaluation of CD38, CD45, kappa and lambda light chains in two patients. Patients were categorized in two groups based on whether any of the residual plasma cells were found to be monotypic on flow cytometry or if they were all normal polytypic cells. Organ response rates using existing criteria [1, 7] were reported for the following time points: 6 months, 12 months and best response at any time from start of therapy. Organ responses between the two groups at a given time point were compared using chi-square or Fischer’s exact test. McNemar’s test for paired proportions was used for comparing improvement in organ response between 6 and 12 month landmarks. Survival was estimated using the Kaplan-Meier method and survival curves were compared using Log-Rank test. Overall survival (OS) was defined as time from diagnosis to death or last follow-up. Progressionfree survival (PFS) was defined as time from diagnosis to progression requiring change in therapy or death. Baseline characteristics of the patients are described in Table 1. Transplant based therapy was most common, with 71% patients undergoing an autologous stem cell transplant (ASCT). Median time to achieve CR was 3 months from start of therapy and median time to bone marrow biopsy was 3.5 months from start of therapy. Median bone marrow plasma cell (BMPC) percentage at the time of CR was 1% (range 0–6). Of the 80 patients who underwent a bone marrow examination, only five patients had 5% or more BMPCs. Two of the patients had 5% BMPCs and three had 6% BMPCs. However, on flow cytometry, only one of them was found to have monotypic plasma cells. In the remaining four patients, plasma cells were polytypic. Monotypic bone marrow plasma cells were present in 29 (37%) of the 78 patients. * Shaji K. Kumar kumar.shaji@mayo.edu

Impact of involved free light chain (FLC) levels in patients achieving normal FLC ratio after initial therapy in light chain amyloidosis (AL)

Achievement of a normal FLC ratio (FLCr) following treatment indicates hematologic response and suggests better outcomes in light chain amyloidosis (AL). We examined if elevated involved free light chain (hiFLC) impacts outcomes in patients achieving normal FLCr. We retrospectively analyzed 345 AL patients who were diagnosed within a 10‐year period (2006‐2015) and had 2 consecutive normal FLCr values after 1st line treatment. Among these, patients with hiFLC at 1st reading of normal FLCr (hiFLC1; n = 166; 48.1%) were compared to those who did not (n = 179; 51.9%). Patients with AL who have hiFLC1 after initial therapy had higher rates of multi‐organ involvement (63.3 vs 46.4%; P = .002) and patients in advanced Mayo stage (42.9 vs 32.2%; P = .04) at diagnosis. The median progression free survival [PFS; 38.2 (95%CI; 26.4, 55.4) vs 67.1 (95%CI; 55.8, 88) months; P = .0002] and overall survival [OS; 94.4 (95%CI; 78, 107.1) vs not reached (NR, 95%CI; 116.1, NR) months; P < .0001] were lower in those who had hiFLC1. A more stringent comparison for patients with 2 consecutive hiFLC (hIFLC2; n = 111; 32.2%) versus not (n = 2234; 67.8%) showed consistent results [PFS; 27.1 (95%CI; 23, 53.8) vs 63.3 (95%CI; 55.4, 77) months; P < .0001 and OS; 78 (95% CI; 54.6, 98.8) vs NR (95%CI; NR, NR); P < .0001]. This poor prognostic impact of hiFLC on survival was independent of serum creatinine, Mayo stage, negative immunofixation status and inclusion of transplant in initial therapy on multivariate analysis. Hence, persistent elevation of iFLC predicts poor prognosis even among patients achieving normal ratio after initial therapy in AL.

The evolution of stem-cell transplantation in multiple myeloma:

Autologous stem-cell transplantation (ASCT) remains an integral part of treatment for previously untreated, and may have value in the treatment of relapsed patients with, multiple myeloma (MM). The addition of novel agents like immunomodulators and proteasome inhibitors as induction therapy before and as consolidation/maintenance therapy after ASCT has led to an improvement in complete response (CR) rates, progression-free survival (PFS) and overall survival (OS). With advances in supportive care, older patients and patients with renal insufficiency are now able to safely undergo the procedure. The data concerning the timing of ASCT (early in the disease course or at first relapse), single versus tandem (double) ASCT and the role and duration of consolidation and maintenance therapy post ASCT remain conflicting. This review aims to discuss the evolution of stem-cell transplant over the past 3 decades and its current role in the context of newer, safer and more effective therapeutic agents.

Plasmacytoma—Current Approach to Diagnosis and Management

About 3–5 % of patients with plasma cell dyscrasias present with either a single bone lesion, or less commonly, a soft tissue mass made up of monoclonal plasma cells without evidence of bone marrow involvement or end-organ damage known as a solitary plasmacytoma (SP). SP of bone mostly occurs in axial skeleton, while it most often affects the head and neck region in case of extramedullary tumors. Their median age is 55 years and mostly present with bony pain, spinal cord, or nerve root compression. A whole body (WB) or spine and pelvic magnetic resonance imaging (MRI) scan or WB fluorodeoxyglucose–positron emission tomography (FDG–PET) scan should be included in staging of these patients. The standard of care for SP is radiotherapy (RT) given with curative intent. Surgery may be required for patients with retropulsed bone, structural instability of the bone, or rapidly progressive neurological symptoms from spinal cord compression. The role of adjuvant RT after complete surgical resection, adjuvant chemotherapy, or adjuvant bisphosphonates is not well defined and hence not recommended.

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.