Deep Hematologic Responses Research Articles

PS1410 DARATUMUMAB IS WELL TOLERATED AND INDUCES A RAPID HEMATOLOGICAL RESPONSE IN NON IG‐M LIGHT CHAIN AMYLOIDOSIS WITH SEVERE CARDIAC IMPAIRMENT

Background:Patients suffering from non‐IgM light chain (AL) amyloidosis with severe cardiac dysfunction have a poor prognosis. A deep hematologic response can translate into a cardiac response and improve the survival of these patients. The Cyclophosphamide Bortezomib Dexamethasone (CyBorD) regimen is widely used as the first‐line regimen, but therapeutic options are limited in relapsed/refractory patients. Recently, Daratumumab has emerged as an attractive option in this indication and has been evaluated in several prospective trials (NCT02841033, NCT02816476, NCT03201965, NCT03283917). Patients with severe heart failure (stage IIIb) have been excluded from these studies and data regarding the use of Daratumumab in patients with severe cardiac involvement are lacking.Aims:Evaluate the safety and efficacity of daratumumab in patients with cardiac stage III AL amyloidosis.Methods:Consecutive patients with cardiac stage III AL amyloidosis treated with Daratumumab were included in this monocentric retrospective study. The diagnosis of AL amyloidosis, evaluation of organ involvement and response were established according to consensus criteria. The cardiac stage was determined by the Mayo Stage 2004 with European modification wich distinguish stage IIIa (NT‐proBNP < 8500 ng/L) and stage IIIb (NT‐proBNP > 8500 ng/L).Results:Ten patients (4 with stage IIIa and 6 with stage IIIb) have been treated between June 2017 and July 2018. Median age was 77,5 years (62–83), the median number of organs impairment was 2 (1–5) and 6 patients had renal impairment. All patients except one received previous treatment with CyBorD and the median number of previous lines was 1 (0–4). Six patients were refractory to their previous treatment, 2 had non‐optimal response and one patient relapsed after reaching VGPR. At Daratumumab initiation, the median value of dFLC was 116,95 mg/dL (37,6–480,9), median value of NT‐proBNP was 12104 ng/L (1329–62759) and median value of Troponin‐T was 148 ng/L (83–287). The median NYHA score was 3 (2–4). Patients received a median of 2 cycles (0,25–11) of daratumumab in association with dexamethasone for 7 of them. Lenalidomide was associated with Daratumumab after 3 cycles in one patient with an unsatisfactory response. Grade 1–2 infusion reactions occurred in 2 patients (20%), but no grade 3 or 4 reactions was observed. Two patients were not evaluable for haematological response, one because of dFLC<50 mg/L at daratumumab initiation and one because of early death 8 days after starting the treatment, thus 8 patients were evaluable for hematological response. After a median follow up of 12,1 months, 6 patients (75%) had a response including 1 CR, 2 VGPR and 3 partial response. One patient had a stable disease and 1 had progressive disease. Median time to first response was 1 month and the median time to best response was 2,5 months. No cardiac response was observed, but 4 patients had stable disease, 4 had progressive disease and 2 were not evaluable. One patient received heart transplantation in partial response after 2 cycles. Four patients died from cardiac events, 2 of infection and 1 because of suicide. Overall survival was 7,2 months (not reach in IIIa and 3,65 months in IIIb groups).Summary/Conclusion:Daratumumab is safe and can result in rapid haematological responses in patients with cardiac stage III AL amyloidosis, most of them being refractory to bortezomib based therapy. However, cardiac response remains absent and survival short in these patients, stressing the need to develop new therapies aiming at improving the cardiac function.image

PS1394 FLOW-MEDIATED DILATATION AND AORTIC BLOOD PRESSURE PREDICT CARDIOVASCULAR ADVERSE EVENTS DURING CARFILZOMIB TREATMENT: A PROSPECTIVE STUDY IN PATIENTS WITH RELAPSED/ REFRACTORY MULTIPLE MYELOMA

Background: Bortezomib/dexamethasone with cyclophosphamide or melphalan are commonly used as primary treatment for AL amyloidosis, but limited data exist on the safety and activity of bortezomib with IMiDs combinations. Aims: To evaluate the safety and activity of VRD combination in newly diagnosed, previously untreated patients with AL amyloidosis. Methods: Between March 2017 and March 2018, 34 consecutive newly diagnosed patients with AL amyloidosis were treated with VRD; standard organ involvement and updated organ and hematologic response criteria were used. Results: The median age of all patients was 66.5 years (range 46–84); 71% were males, 75% had cardiac involvement, median NTproBNP was 3649 pg/ml (81- >30000), per Mayo stage 14%, 54%, 14% and 18% were stage 1, 2, 3A and 3B respectively; 54% had renal involvement, median eGFR was 59 ml/min/1.73 m2 (range 10–133) and renal stage distribution was 13%, 53% and 33% for stages 1, 2 & 3. Measurable FLCs (i.e. a dFLC≥40 mg/L) were present in 29 (85%) patients; in 4 patients baseline dFLC was >20 mg/dl and were also evaluable for response. Twenty-two patients completed the planned 8 cycles, 9 died prior to completion of planned therapy, 1 patient discontinued therapy for personal reasons (while in VGPR), 1 discontinued therapy after physician's decision (while in VGPR) and one discontinued due to bortezomib-related toxicity (while in CR). After the first cycle of VRD, 24/34 (70.5%) patients had achieved a hematologic response (42% a VGPR or CR and 27% a PR). After 3 months of VRD, 82% of the evaluable patients (N = 27) had achieved at least VGPR, including CR in 6 (22%), and PR in 5 (18%). After 6 VRD cycles, CR, VGPR and PR rates among evaluable (N = 24) patients were 9 (37.5%), 13 (54%), and 2 (8%) respectively. On intent to treat, best hematologic response was CR in 11/34 (32%) and among CR patients 5/11 were MRD negative by NGF; 17/34 (50%) achieved VGPR and in 9 of them dFLC was <10 mg/dl; 2/34 (7%) achieved a PR. Median time to first response (at least a PR) was 28 days (1 treatment cycle), median time to at least VGPR was 84 days (3 cycles of therapy). Cytogenetics were available in 28 patients; among patients with t(11;14) (N = 7), all achieved at least a VGPR (3 a CR and 4 a VGPR). Organ responses were documented in 12 (35%) patients. Median follow up for all patients is 12.5 months and 6 and 12 month survival is 73.5% (100%, 85% and 71% for stage 1, 2 & 3A patients respectively, but only 20% for stage 3B). Starting lenalidomide dose was 5 mg in 86% of patients. Hematologic toxicity was mild; common non-hematologic toxicities included rash (Gr3/4:16%), infections (≥Gr3:12%), constipation (≥Gr3:9%), peripheral neuropathy (Gr2:20%), while, 37.5% of patients required lenalidomide dose reduction, 27% discontinued lenalidomide before planned therapy completion, 38% required bortezomib dose reduction and 12% discontinued bortezomib. We then compared the efficacy of VRD to that of CyBorD given in 68 patients matched for Mayo stage and baseline dFLC and found a trend for deeper responses at 3 months in patients treated with VRD (≥VGPR in 82% vs 45%) and at 6 months (≥VGPR in 92% vs 61%, p = 0.049). Summary/Conclusion: VRD with weekly bortezomib and low dose lenalidomide is a very effective and rapidly acting regimen that can induce deep hematologic responses within 3 months of therapy. However, toxicity of VRD in patients with AL amyloidosis is significant, despite the use of low doses of lenalidomide.

PS1393 PRIMARY TREATMENT OF LIGHT CHAIN (AL) AMYLOIDOSIS WITH BORTEZOMIB, LENALIDOMIDE AND DEXAMETHASONE (VRD)

Background:Bortezomib/dexamethasone with cyclophosphamide or melphalan are commonly used as primary treatment for AL amyloidosis, but limited data exist on the safety and activity of bortezomib with IMiDs combinations.Aims:To evaluate the safety and activity of VRD combination in newly diagnosed, previously untreated patients with AL amyloidosis.Methods:Between March 2017 and March 2018, 34 consecutive newly diagnosed patients with AL amyloidosis were treated with VRD; standard organ involvement and updated organ and hematologic response criteria were used.Results:The median age of all patients was 66.5 years (range 46–84); 71% were males, 75% had cardiac involvement, median NTproBNP was 3649 pg/ml (81‐ &gt;30000), per Mayo stage 14%, 54%, 14% and 18% were stage 1, 2, 3A and 3B respectively; 54% had renal involvement, median eGFR was 59 ml/min/1.73 m2 (range 10–133) and renal stage distribution was 13%, 53% and 33% for stages 1, 2 &amp; 3. Measurable FLCs (i.e. a dFLC≥40 mg/L) were present in 29 (85%) patients; in 4 patients baseline dFLC was &gt;20 mg/dl and were also evaluable for response. Twenty‐two patients completed the planned 8 cycles, 9 died prior to completion of planned therapy, 1 patient discontinued therapy for personal reasons (while in VGPR), 1 discontinued therapy after physician's decision (while in VGPR) and one discontinued due to bortezomib‐related toxicity (while in CR). After the first cycle of VRD, 24/34 (70.5%) patients had achieved a hematologic response (42% a VGPR or CR and 27% a PR). After 3 months of VRD, 82% of the evaluable patients (N = 27) had achieved at least VGPR, including CR in 6 (22%), and PR in 5 (18%). After 6 VRD cycles, CR, VGPR and PR rates among evaluable (N = 24) patients were 9 (37.5%), 13 (54%), and 2 (8%) respectively. On intent to treat, best hematologic response was CR in 11/34 (32%) and among CR patients 5/11 were MRD negative by NGF; 17/34 (50%) achieved VGPR and in 9 of them dFLC was &lt;10 mg/dl; 2/34 (7%) achieved a PR. Median time to first response (at least a PR) was 28 days (1 treatment cycle), median time to at least VGPR was 84 days (3 cycles of therapy). Cytogenetics were available in 28 patients; among patients with t(11;14) (N = 7), all achieved at least a VGPR (3 a CR and 4 a VGPR). Organ responses were documented in 12 (35%) patients. Median follow up for all patients is 12.5 months and 6 and 12 month survival is 73.5% (100%, 85% and 71% for stage 1, 2 &amp; 3A patients respectively, but only 20% for stage 3B). Starting lenalidomide dose was 5 mg in 86% of patients. Hematologic toxicity was mild; common non‐hematologic toxicities included rash (Gr3/4:16%), infections (≥Gr3:12%), constipation (≥Gr3:9%), peripheral neuropathy (Gr2:20%), while, 37.5% of patients required lenalidomide dose reduction, 27% discontinued lenalidomide before planned therapy completion, 38% required bortezomib dose reduction and 12% discontinued bortezomib. We then compared the efficacy of VRD to that of CyBorD given in 68 patients matched for Mayo stage and baseline dFLC and found a trend for deeper responses at 3 months in patients treated with VRD (≥VGPR in 82% vs 45%) and at 6 months (≥VGPR in 92% vs 61%, p = 0.049).Summary/Conclusion:VRD with weekly bortezomib and low dose lenalidomide is a very effective and rapidly acting regimen that can induce deep hematologic responses within 3 months of therapy. However, toxicity of VRD in patients with AL amyloidosis is significant, despite the use of low doses of lenalidomide.

Consolidation with a Short Course of Daratumumab Improves Complete Response Rates in Patients with AL Amyloidosis or Lcdd

Consolidation with a Short Course of Daratumumab Improves Complete Response Rates in Patients with AL Amyloidosis or Lcdd

Primary Treatment of Light Chain (AL) Amyloidosis with Bortezomib, Lenalidomide and Dexamethasone (VRD)

Primary Treatment of Light Chain (AL) Amyloidosis with Bortezomib, Lenalidomide and Dexamethasone (VRD)

Outcome of Patients With Newly Diagnosed Systemic Light-Chain Amyloidosis Associated With Deletion of 17p

IntroductionDeletion 17p (del 17p) portends a poor prognosis in myeloma, but its significance in light-chain amyloidosis is unknown. Patients and MethodsWe identified patients with light-chain amyloidosis and del 17p at diagnosis, and analyzed presenting characteristics, treatments, and clinical outcomes. All had baseline biopsy results showing amyloid and serologic and marrow studies, including standard fluorescence in-situ hybridization determinations of del 17p using commercial probes. Consensus criteria for hematologic and organ involvement, progression, and response were used. Kaplan-Meier (log rank) analyses and Cox regression analysis of baseline variables were used to identify predictors of overall and progression-free survival (PFS). Six-month landmark analyses were performed to assess the impact of treatment-related variables. ResultsWe identified 44 patients from 7 countries with median marrow and del 17p plasma cells of 22% (range, 3%-100%) and 30% (2%-93%). Ninety-five percent had cardiac involvement, including 44% stage III. Two-thirds of the patients initially received bortezomib-based therapy. Forty-nine percent of patients experienced complete response or very good partial response, with median time to best response of 4 months (range, 1-28 months). Median overall survival and PFS were 49 and 32 months. Cardiac stage and hematologic response were the key predictors of outcomes. Patients with > 50% and ≤ 50% del 17p in clonal plasma cells had median survivals of 28 and 52 months, respectively (P = .08). In landmark analyses, only hematologic response predicted both overall survival and PFS. ConclusionCardiac stage, hematologic response, and del 17p percentage impact outcomes in these cases. Emphasis should be placed on optimizing supportive care and achieving a deep hematologic response.

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.

Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis

AbstractThe majority of patients with immunoglobulin light chain amyloidosis (AL) fail to achieve a complete response (CR) to standard light chain suppressive chemotherapy, and almost all patients eventually experience hematologic relapse and progression of organ involvement. Additional well-tolerated treatment options are needed. We present our retrospective experience of 25 consecutive previously treated AL patients who received daratumumab, a CD38-directed monoclonal antibody approved for the treatment of multiple myeloma. Daratumumab was administered at 16 mg/kg weekly for 8 weeks, then every 2 weeks for 8 doses, and then every 4 weeks. Patients had received a median of 3 prior lines of therapy, with a previous hematologic CR in only 5 patients. The overall hematologic response rate to daratumumab was 76%, including CR in 36% and very good partial response in 24%. Median time to response was 1 month. Therapy was well tolerated, even among the 72% of patients with cardiac AL involvement. Grade 1-2 infusion reactions occurred in 15 patients, but no grade 3 or 4 reactions were observed. Daratumumab is a highly effective agent that produced rapid and deep hematologic responses without unexpected toxicity in our cohort of heavily pretreated AL patients.

The use of proteasome inhibitors among patients with POEMS syndrome.

e19530 Background: Neuropathy is a universal symptom of patients with POEMS syndrome, which makes the use of bortezomib less appealing. However, proteasome inhibitors (PIs) can provide rapid and deep hematologic responses in plasma cell disorders. Because there is very little data regarding the use PIs in POEMS syndrome, we performed a study of patients with POEMS syndrome treated with PIs. Methods: Among the 167 patients with POEMS syndrome seen at our institution between 2001-2016, we identified 12 patients who received a PI. One patient receiving &lt; 1 cycle of bortezomib because of worsening neuropathy was included but was excluded from response analyses. One patient received 2 different PIs at separate points during the disease course and each course was considered separately. Four response categories were considered: hematologic, PET, VEGF and clinical as previously described (Dispenzieri et. al AJH 2015). Results: Among the 12 patients who received 13 courses of therapy, the median age at PI initiation was 59; 8 patients were male. Median number of prior therapies was 1 (0-4) and median time from diagnosis to initiation of PI was 75 months. Excluding steroids, regimens were as follows: bortezomib, n=3; bortezomib and cyclophosphamide, n=4; carfilzomib, n=1; and ixazomib, n=1. With a median follow-up from PI initiation of 18 months, the median duration of treatment was 7 months (1-18). Three patients achieved a hematologic CR. Of 6 patients with an abnormal baseline VEGF, 3 achieved normalization VEGF levels. Of 5 patients with an abnormal baseline PET, 2 achieved normalization of their PET. Two patients had improvement of their neuropathy, with the rest having stable symptoms. Of 9 patients with fluid overload, 8 improved. Only 2 patients stopped therapy due to worsening neuropathy related to PIs. Median PFS and OS from initiation of PI were 50 months and 53 months, respectively. Conclusions: We show that PI use in patients with POEMS syndrome can be safe and effective. Nearly 75% of patients treated with bortezomib had no exacerbation of their neuropathy. Clinical improvement in severe fluid overload symptoms (edema, ascites, pleural effusions) is almost universal, making PI-based therapy an attractive potential option in these patients.

Outcomes of patients with renal monoclonal immunoglobulin deposition disease.

Recent reports suggest that deep hematologic responses to chemotherapy are associated with improved renal outcomes in monoclonal immunoglobulin deposition disease (MIDD). Here we describe the long term outcomes and identify prognostic factors after first line treatment of the largest reported series of patients with MIDD. Between March 1992 and December 2014, 88 patients with MIDD were seen at Mayo Clinic, MN. Renal responses were defined using criteria used for light chain amyloidosis (AL) or those used by the IMWG. Sixty-one (69%) patients had a GFR < 30 mL/min/1.73 m2 and 16 (18%) were on renal replacement therapy at diagnosis. The interval between albuminuria or elevation in creatinine and MIDD diagnosis was 12 months suggesting a delay in diagnosis. Thirty-seven patients (42%) had at least a hematologic CR/VGPR. Fifty-three (60%) received an autologous stem cell transplant (ASCT) or proteasome inhibitor (PI)-based treatments. Patients receiving ASCT or PI-based therapies were more likely to achieve at least a hematologic CR/VGPR compared to those receiving other therapies: 66% vs 2%, p < 0.0001. Patients that achieved a hematologic CR were more likely to achieve a renal response (53% vs 24%, p = 0.001). Five year overall and renal survival for the entire cohort was 67% and 57%, respectively. In multivariate analyses, a baseline GFR < 20 mL/min/1.73 m2 and a renal response (using AL or IMWG criteria) were independently predictive of progression to dialysis. This study confirms that deep hematologic responses, best achieved with ASCT or PI-based therapies, are a prerequisite to achieving renal responses. Am. J. Hematol. 91:1123-1128, 2016. © 2016 Wiley Periodicals, Inc.