Upfront Ixazomib Plus Dexamethasone Induce Promptly Hematological Response in Patients with Light-Chain Amyloidosis

Background: CyBorD (bortezomib, cyclophosphamide, and dexamethasone) is considered as an effective induction regimen in newly diagnosed light chain amyloidosis (AL) patients. Although a full dose of dexamethasone (Dex) leads to a higher response rate, the dose is strictly limited, usually because of fluid retention. Additionally, supervised administration of bortezomib weekly, if applied, increases the cost and inconvenience of treatment for service providers and patients.Ixazomib(IXA), an oral proteasome inhibitor, was reported highly effective as a single agent in relapsed or refractory AL amyloidosis. The objective of this observation is to evaluate the feasibility and efficiency of adding a lower dose of Dex to IXA (Id) as an upfront regimen in AL pts. Patients and Methods: Between 9/29/2018-4/1/2019, twenty-five newly diagnosed (ND) AL pts were sequentially enrolled. All AL pts had positive Congo Red staining in biopsy specimens confirmed by immunoelectron microscopy(IEM). Ixazomib 4mg D1,8,15 and Dexamethasone 10mg D1,8,15,22 were given for a 28-day schedule until disease progression or intolerance. Efficiency and safety profiles were assessed at the beginning of each cycle. Patients who had not achieved PR after 3 cycles received additional oral cyclophosphamide (50mg daily). The patients not achieving PR after 3 more cycles would switch to salvage therapies such as lenalidomide-base regimens or melphalan-based regimens. Upfront Id regimen can be prolonged for 2 cycles after a best hematological response (CR) has been achieved. The primary objective was to determine the response rate of this regimen and to evaluate the safety and tolerability of Upfront Id. Secondary objectives included PFS and OS. Results: Patients(n=25) received a median of 4 cycles (1-8) of Id regimen. Most patients were at late stage (20 pts in MAYO stage III, 4 pts in stage I and 1 pts in stage II). The interphase FISH analysis in BM plasma cells finds translocation t(11,14) in 8 pts.(Table 1) All patients were evaluable for toxicity and twenty-four for the response. The ORR was 66.7%(16/24) post cycle 1 and 70.8%(17/24) post cycle 4. Best hematological response achieved to date of this study is CR in 10pts, VGPR in 5 pts. 5 of the 7 pts did not reach their hematological remission have a t(11,14) translocation. With a median of 197 days (34-281) follow-up, 68%(17/25) of the patients were still alive, and 41.7%(10/24) with their best hematological response. 4 of the patients died of sudden and the rest due to the progression of heart failure. (Figure 1) According to CTC AE 5.0, Grade III/IV AEs (no. of pts) included: diarrhea 16%(4), thrombocytopenia 12%(3), general edema 8%(2), hypokalemia 8%(2), AST increased 4%(1), hyperuricemia 4%(1), and pneumonitis 4%(1). All the 4 patients with serious diarrhea quit therapy because of intolerance. (Table 2) Conclusions: Adding low dose dexamethasone to Ixazomib can induce rapid and profound hematological remission in newly diagnosed AL pts, especially in patients without t(11,14). This entirely oral, chemotherapy-free combination regimen ensures patients' compliance. The relatively low incidence of Grade III/IV AEs also makes the regimen seemingly a broad usage in MAYO stage III pts. However, diarrhea and thrombocytopenia in these patients still need awareness. OffLabel Disclosure: Ixazomib (Ixa) is the first oral proteasome inhibitor that approved for the use in patients with relapsed/refractory multiple myeloma (RRMM) in > 60 countries including US and China. In this single-center real-world study, we present the efficacy and safety profile of Ixazomib-based therapy as frontline therapy in patients with AL amyloidosis.

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Outcomes of patients with light chain amyloidosis who had autologous stem cell transplantation with three or more organs involved.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.8011 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 8011-8011

Author(s):

Abdullah Al Saleh ◽

M Hasib Sidiqi ◽

Angela Dispenzieri ◽

Eli Muchtar ◽

Francis Buadi ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Light Chain ◽

Stage Iii ◽

Induction Treatment ◽

Al Amyloidosis ◽

Cell Transplant ◽

Light Chain Amyloidosis ◽

Hematological Response

8011 Background: Literature suggests that three or more organ involvement is a contraindication for autologous stem cell transplant (ASCT) in light chain amyloidosis (AL). Most centers limit transplantation to patients who have no more than two organs significantly involved. Methods: We retrospectively reviewed all patients with AL Amyloidosis involving three or more organs and who had ASCT between 1996-2015 at Mayo clinic, Rochester, Minnesota. Results: Seventy five patients underwent ASCT with three or more organs involved. Median age at diagnosis was 54 years and 67% were males. The heart was involved in 95%, followed by kidneys (84%). Thirty eight patients (51%) had no induction treatment prior to ASCT. Full dose melphalan (200mg/m2) was given in 45%, and the remaining received a reduced dose (140mg/m2). Overall response rate (hematological) was 75%. The median progression-free (PFS) and overall survival (OS) were 16.3 and 68.9 months, respectively. The 100-day mortality was 16% and overall forty four patients (59%) died during the follow up period. The most common causes of death were cardiovascular events (32%) and progressive amyloidosis (25%). On multivariable analysis, predictors for PFS were Mayo stage III/IV (RR 3.3, P = 0.0012) and hematological response (≥VGPR, RR 0.4, P = 0.012). An NT-ProBNP level of ≥2000 pg/ml was an independent predictor for shorter PFS (RR 2.6, P = 0.013). Predictors for OS included any hematological response (RR 0.1, P < 0.0001) and Mayo stage III/IV (RR 7, P < 0.0001). When looking at the NT-ProBNP, a level ≥2000 was prognostic (RR 5.5, P = 0.001). Number of organs involved (3 vs. 4-5) was not significant in either PFS or OS. Conclusions: We conclude that the high prevalence of cardiac involvement is the main driver for the poor outcome in patients who have three or more organs involved. Using selection criteria defined for safe transplantation in cardiac amyloidosis should result in low therapy-related mortality independent of the number of organs involved. The concept of considering patients with three organs involved ineligible for stem cell transplantation should be abandoned.

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Response to Bortezomib Based Induction Therapy in Newly Diagnosed Light Chain (AL) Amyloidosis.

Blood ◽

10.1182/blood.v114.22.1867.1867 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1867-1867 ◽

Cited By ~ 1

Author(s):

Veerpal Singh ◽

Ayman Saad ◽

Jeanne Palmer ◽

Jasleen K Randhawa ◽

Parameswaran N. Hari

Keyword(s):

Light Chain ◽

Liver Dysfunction ◽

Cardiac Involvement ◽

Response Rate ◽

Initial Therapy ◽

Al Amyloidosis ◽

Karnofsky Performance Score ◽

Significant Activity ◽

Newly Diagnosed ◽

Organ Response

Abstract Abstract 1867 Poster Board I-892 Bortezomib has been shown to have significant activity in the suppression of light chain production and induction of responses in patients with relapsed refractory AL Amyloidosis. We analyzed the outcomes of 16 (9 male) newly diagnosed biopsy proven AL Amyloidosis patients treated with Bortezomib based regimens at our institution. All patients received initial therapy with Bortezomib and dexamethasone (dex). Patients with a Karnofsky performance score ( KPS) >70 received Bortezomib at starting doses of 1.3 mg/m2 along with dexamethasone 40 mg on days 1,4,8, 11 ( with a 10 day rest period). Patients with a lower KPS received Bortezomib/Dex on a weekly schedule as tolerated. Dose adjustments were made based on side effects such as neuropathy, hypotension, GI disturbances or electrolyte imbalances. Patients tolerating Bortezomib/dex with improvement in KPS had cyclophosphamide (4) or lenalidomide (1) added to their initial therapy. Patients: Median age was 64 years (39–88). Nine had kappa light chain involvement. Organ involvement was renal (73%), cardiac (63%), hepatic (25%), tongue or soft tissue (20%), GI (30%). Median KPS was 70 (50 –100). Ten of the 16 patients were treated as in-patients due to multi-organ dysfunction. Five patients required hemodialysis within a month of diagnosis. Cardiac involvement was stage 3 (Mayo risk group) in 25%. Three patients were unevaluable: 2 dying before 2 cycles and 1 discontinued therapy (Grade 3 liver dysfunction). Median follow up was 5 months (range 2–33 mo). Results: Evaluable (receiving at least 2 cycles) patients have all had a free light chain response. The overall hematological response rate was 100% with 55% partial remission (PR) and 45% complete remission (CR). Median cycles to achievement of a light chain response was 2 (range 1–4). Four patients underwent autologous stem cell transplantation with no mortality. Five (40%) of the responders have had an organ response (3 renal, 1 macroglossia, 1 cardiac) with only patients alive for >5 months having any evidence of organ response. Five (40%) of the evaluable patients have died with progressive cardiac involvement (2), relapsed disease (2) or renal failure (1) with refusal of dialysis. In patients receiving at least one dose of bortezomib, non-hematologic toxicity (>grade 2) included -neuropathy (20%), hypotension (20%), severe diarrhea (12%), sepsis (12%), paralytic ileus (6%), liver dysfunction (6%), sudden death (6%). Conclusions: Bortezomib in combination with dexamethasone has a high response rate in newly diagnosed AL amyloidosis. This regimen was well tolerated in a cohort of severe, multisystem amyloidosis patients with low treatment related mortality. Light chain responses were fast whereas organ responses were not seen prior to 5 months of therapy. The regimen also served as a platform for further intensification with the addition of lenalidomide, cyclophosphamide or autologous transplant in responders. Disclosures: Off Label Use: Bortezomib for the therapy of amyloidosis. Hari:Millenium: Honoraria, Research Funding.

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Therapeutic Activity of Combining BCL-2 and HMG-CoA Reductase Inhibition in Systemic Light-Chain Amyloidosis

Blood ◽

10.1182/blood-2020-142656 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 23-24

Author(s):

Ping Zhou ◽

Hashim Mann ◽

Xun Ma ◽

Teresa Fogaren ◽

Yifei Zhang ◽

...

Keyword(s):

Light Chain ◽

Research Funding ◽

Plasma Cells ◽

Response Rate ◽

Cardiac Response ◽

Al Amyloidosis ◽

Light Chain Amyloidosis ◽

Hematologic Response ◽

Coa Reductase

Introduction: Overexpression of BCL-2 in association with t(11;14) in multiple myeloma (MM) and systemic light-chain amyloidosis (AL) makes it a therapeutic target for the BCL-2 inhibitor venetoclax; response rates of 60-80% in t(11;14) have been reported in MM (Kumar S, Blood 2017 & Vaxman I, Expert Rev Hematol 2018). Addition of HMG-CoA reductase inhibitors (statins) may augment venetoclax activity (Lee JS, Sci Transl Med 2018). We now report ex-vivo functional activity of venetoclax with AL patient CD138-selected plasma cells and provide clinical outcomes of 8 patients with relapsed/refractory AL who were treated with venetoclax and a statin. Methods: To construct a functional assay NCI-H929 and KMS-12-PE cells were used as controls and incubated with venetoclax to assess the IC50. Cell viability was measured with CellTiter-Glo and caspase activity with Caspase-Glo 3/7 (Promega, Madison, WI). H929 cells were the negative and KMS cells the positive control. From patient marrows CD138+ cells were isolated (Miltenyi Biotec, Auburn, CA) as previously described (Ma X, Gene Ther 2016) and incubated with 100 nM of venetoclax for 18 hours with controls. In AL patients, Venetoclax was started at 200 mg daily and escalated to 400 mg daily after 2 weeks if tolerated. Statin (atorvastatin, 10-40 mg daily or simvastatin 40 mg daily) was started concurrently or for lack of response to venetoclax alone. Bone marrow assessment was performed prior to starting venetoclax and response assessment was performed monthly. Results: Venetoclax induced apoptosis in a dose escalated manner with KMS-12-PE cells (t(11;14) positive) when compared with H929 cells (Figure 1A-B). CD138-selected plasma cells from 20 patients (17 AL, 2 MM, 1 MGUS) were incubated with venetoclax (100 nM) for 18 hours and had a median caspase 3/7 activity level that was significantly higher in patients with t(11;14) (Figure 1C). Eight patients were treated with venetoclax in combination with a statin. Baseline characteristics are provided in Table 1. Median age of the cohort was 70 (range, 59 - 77), of which five (63%) were male, and 6 were λ-type (1-kappa, 1-heavy chain). At diagnosis, four (50%) patients had involvement of two or more organ systems (cardiac, renal, gastrointestinal, vascular, and/or neurological). Cardiac involvement was the most common (88%). Seven patients had t(11;14) and/or positive cyclin D1 staining on pre-treatment marrow studies. The median number of prior therapies was 2 (1 - 5), and all except one had been previously treated with daratumumab. Venetoclax-statin combination was started due to hematologic progression (4), organ progression (1), or suboptimal response to prior therapy (3). At a median follow-up of 8 weeks (5 - 25), overall hematologic response rate is 63% (1 CR, 3 VGPR, 1 PR and 1 progression). Cardiac response was seen in 2 patients. One patient who lacked the t(11;14) mutation had early disease progression. One patient with stage-3 cardiac AL amyloidosis experienced cardiac progression without hematologic response on venetoclax alone but responded promptly with both hematologic and cardiac response to addition of simvastatin, 40 mg daily. Statin dose was reduced in 1 patient due to grade 1 myalgia. All responders continue on treatment at their most recent follow-up. Conclusion: In this cohort of 8 patients with AL amyloidosis treated with a combination of venetoclax and statin, hematologic response rate was 63% and >VGPR was seen in 50%. The combination was well tolerated. Consistent with the preclinical activity of venetoclax in MM, functional activity of venetoclax was similarly higher in plasma cells from AL patients harboring t(11;14). As t(11;14) is the most common cytogenetic abnormality in systemic AL amyloidosis, venetoclax and statin combination may provide a potent therapeutic alternative for relapsed/refractory AL patients and requires validation in clinical trials. Disclosures Chaulagain: Sanofi Genzyme: Honoraria. Comenzo:Takeda: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Amgen: Consultancy; Karyopharm: Consultancy, Research Funding; Caleum: Consultancy; Unum: Consultancy; Sanofi: Consultancy. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor and currently approved for non-Hodgkin's lymphoma and Acute myeloid leukemia. Venetoclax has shown clinical activity in clinical trials with multiple myeloma, especially patients who harbor t(11;14). Given the preclinical and clinical evidence of its efficacy, we treated 8 relapsed/refractory patients with systemic light-chain amyloidosis with a combination of venetoclax and a statin.

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Efficacy and Toxicity of Dose-Reduced Bortezomib/Dexamethasone Chemotherapy In Patients with High Risk Cardiac Light Chain Amyloidosis (Mayo Clinic stage III)

Blood ◽

10.1182/blood.v116.21.1960.1960 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1960-1960 ◽

Cited By ~ 1

Author(s):

Stefan O Schonland ◽

Tilmann Bochtler ◽

Anthony D. Ho ◽

Ute Hegenbart

Keyword(s):

Light Chain ◽

Mayo Clinic ◽

Cardiac Amyloidosis ◽

Cardiac Involvement ◽

Early Death ◽

Stage Iii ◽

Al Amyloidosis ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Grade 3

Abstract Abstract 1960 Purpose: Severe cardiac involvement is known to confer a poor prognosis in patients with light chain (AL-) amyloidosis. These patients do not qualify for high-dose chemotherapy regimens. In a recent analysis we could show that melphalan/dexamethasone therapy was not able to overcome this poor prognosis (Dietrich et al, 2010). Since bortezomib is known to rapidly lower the involved light chain levels (iFLC), it appears a promising alternative regimen. There is only one prospective phase I/II trial in AL amyloidosis using single agent bortezomib (Reece et al., 2009). However, patients with advanced cardiac amyloidosis had been excluded. We therefore assessed the feasibility of bortezomib/dexamethasone (Bd) in patients with high-risk cardiac amyloidosis as defined by Mayo Clinic stage III (median overall survival (OS) 3.5 months (mo), Dispenzieri et al, 2004). Patients and Method: We retrospectively evaluated 38 consecutive patients with systemic AL amyloidosis, who were classified as Mayo Clinic stage III cardiac amyloidosis based on their elevated cardiac biomarkers NT-proBNP, TNT and hsTNT values (patient characteristics table 1). 14 patients were untreated. For the sake of tolerability Bd was administered twice weekly with a reduced bortezomib dosage of 4 × 1.0 mg/m2 and dexamethasone 8 × 8 mg in a 3 week schedule. Result: Median observation of living patients is 5 mo after start of Bd. Median OS is 9 mo (Figure 1a). 18 patients died; among them 11 (29%) during ongoing bd. Median OS of the first line therapy group was 7 mo versus 13 mo in the relapsed group (p=0.056, Figure 1b). 21 patients achieved a hematological remission (HR) after a median of 3 cycles (64% out of 33 evaluable patients, 2 CRs and 19 PRs), whereas 3 patients died during the first Bd cycle and further 2 just started with Bd. Hematologic toxicity grade 3 or 4 according to NCI criteria was observed in 9 patients (24%) (toxicities are listed in table 1). Apart from the 11 early deaths we observed non-hematologic toxicity grade 3 in 8 patients and grade 4 in 6 patients. In 3 patients, the bortezomib dose had to be reduced due to toxicity. Therapy was stopped before the planned 6 – 8 cycles in 11 patients, in 4 cases due to toxicity, in 5 cases due to lacking HR and in 2 cases due to patient‘s choice. 9 patients completed their therapy regularly in HR while therapy is still ongoing in 5 patients. It is planned to update these data in November 2010. Discussion: The goal of this study was to assess whether patients with severe cardiac amyloidosis as defined by Mayo Clinic stage III benefit from Bd therapy. As already known from other studies, we observed a fast reduction of iFLC within 3 months from 203 to 81 mg/l (of evaluable patients) in median. Overall, HR rate was 64%, which is comparable to 71% previously reported by Kastritis et al, 2010. However, toxicity and early death rate were considerable. Main problem of the newly diagnosed patients was the severity of cardiac involvement (median NTpro BNP 11.346 ng/l) leading to a high early mortality. Main problem of the pretreated patients was the lower HR rate of 52% versus 83% of the newly diagnosed patients. Though we observed substantial toxicities in spite of the reduced Bd dosages, the rather poor OS does not appear to be largely due to toxicity. Conclusion: Dose-reduced Bd might be an important treatment option for patients with severe cardiac AL amyloidosis Mayo Clinic stage III because of its high efficacy. However, the toxicity is still significant. Inpatient care for the first cycle of Bd might lead to a reduction of the early death rate. Disclosures: No relevant conflicts of interest to declare.

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Front-line daratumumab in newly diagnosed AL amyloidosis patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e20569 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e20569-e20569

Author(s):

Vanessa Elaine Kennedy ◽

Nina Shah ◽

Jeffrey Lee Wolf ◽

Thomas G. Martin ◽

Sandy Wai Kuan Wong

Keyword(s):

Median Time ◽

Light Chain ◽

Stage I ◽

Stage Ii ◽

Stage Iii ◽

Al Amyloidosis ◽

Newly Diagnosed ◽

First Line ◽

Best Response ◽

First Response

e20569 Background: Light chain amyloidosis (AL) is a plasma cell dyscrasia characterized by organ dysfunction, morbidity, and early mortality. Treatment focuses on suppressing monoclonal light chain production as measured by hematologic response criteria (Comenzo et al., 2012). Daratumumab (DARA), a monoclonal CD38 antibody, has demonstrated efficacy in heavily pretreated AL patients (Kaufman et al., 2017). We report the outcomes of newly diagnosed AL patients treated with a DARA-based regimen. Methods: A single-center retrospective chart review with an IRB-approved protocol was performed on newly diagnosed AL patients treated with first line DARA-based regimens between 1/2018 – 12/2019. Results: Fourteen patients were evaluated. The median age was 69 years (45 – 87), 50% were male, and 50% produced monoclonal lambda light chains. All patients had cardiac and renal involvement. Per the 2004 Mayo staging system, 1/14 (7%) patients had stage I cardiac disease, 2/14 (14%) had stage II, and 11/14 (79%) had stage III, of which two were stage IIIb. Regarding renal staging (Palladini et al., 2014), 10/14 (71%) patients were stage I, 3/14 (21%) stage II, and 1/4 (7%) stage III. Most patients (11/14) received DARA in combination with bortezomib and dexamethasone, while one patient received DARA and dexamethasone (DEX). Two patients received DARA in combination with bortezomib, cyclophosphamide, and DEX. Patients received a median of 5 cycles of DARA (1 – 14). After a median follow-up of 4.4 months (1 – 19), all patients were still receiving DARA. DARA was well tolerated, with 4 patients (29%) experiencing grade 1 infusion reactions and no additional toxicities observed. Responses were rapid, with a median time of 11 days (7 – 61) to first response and 46 days (9 8– 168) to best response. First response was classified as partial response (PR) in 8/14 patients (57%), very good PR (VGPR) in 3/14 (21%), and complete response (CR) in 1/14 (7%). Best response included a PR in 3/14 (21%), VGPR in 7/14 (50%), and CR in 2/14 (14%). In most patients, responses deepened over time. Cardiac response was seen in 5/7 (71%) evaluable patients with median time to response of 39 days (21 – 263). Renal response was seen in 2/4 (50%) evaluable patients with median time to response of 152 days (94 – 194). Conclusions: First line use of DARA in AL amyloidosis produced rapid and deep hematologic and organ response, resulting in a 93% objective hematologic response rate. DARA was well-tolerated and efficacious even among patients with extensive organ involvement and cardiac dysfunction. Prospective studies of first line DARA are warranted.

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Diagnostic approach to light-chain cardiac amyloidosis and its differential diagnosis

Acta Haematologica Polonica ◽

10.2478/ahp-2018-0002 ◽

2018 ◽

Vol 49 (1) ◽

pp. 9-14

Author(s):

Monika Adamska ◽

Anna Komosa ◽

Tatiana Mularek ◽

Joanna Rupa-Matysek ◽

Lidia Gil

Keyword(s):

Differential Diagnosis ◽

Light Chain ◽

Cardiac Amyloidosis ◽

Cardiac Involvement ◽

Diagnosis And Treatment ◽

Diagnostic Approach ◽

Al Amyloidosis ◽

Delay In Diagnosis ◽

Light Chain Amyloidosis ◽

Novel Approaches

AbstractCardiac amyloidosis is a rare and often-misdiagnosed disorder. Among other forms of deposits affecting the heart, immunoglobulin-derived light-chain amyloidosis (AL amyloidosis) is the most serious form of the disease. Delay in diagnosis and treatment may have a major impact on the prognosis and outcomes of patients. This review focuses on the presentation of the disorder and current novel approaches to the diagnosis of cardiac involvement in AL amyloidosis.

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Outcomes with early response to first-line treatment in patients with newly diagnosed multiple myeloma

Blood Advances ◽

10.1182/bloodadvances.2018022806 ◽

2019 ◽

Vol 3 (5) ◽

pp. 744-750 ◽

Cited By ~ 4

Author(s):

Nidhi Tandon ◽

Surbhi Sidana ◽

S. Vincent Rajkumar ◽

Morie A. Gertz ◽

Francis K. Buadi ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Light Chain ◽

Progression Free Survival ◽

Early Response ◽

Stage Iii ◽

Newly Diagnosed ◽

Best Response ◽

Light Chain Disease ◽

The Impact

Abstract We evaluated the impact of achieving a rapid response in 840 newly diagnosed multiple myeloma patients from 2004 to 2015. Rates of very good partial response (VGPR) or better were 29% (240/840) after 2 cycles of treatment, 42% (350/840) after 4 cycles of treatment, and 66% (552/840) as best response. Early responders after 2 cycles of treatment had higher rates of light chain disease, anemia, renal failure, International Staging System (ISS) stage III disease, and high-risk cytogenetics, especially t(4;14), and were more likely to have received triplet therapy and undergo transplant. Median progression-free survival (PFS) and overall survival (OS) were not different among patients with ≥VGPR and <VGPR after 2 cycles (PFS, 28 vs 30 months, P = .6; OS, 78 vs 96 months, P = .1) and 4 cycles (PFS, 31 vs 29 months; OS, 89 vs 91 months, P = .9), although both were improved, with ≥VGPR as best response (PFS, 33 vs 22 months, P < .001; OS, 102 vs 77 months, P = .003). On multivariate analysis stratified by transplant status, achievement of ≥VGPR after 2 cycles was not associated with improved PFS (hazard ratio [95% confidence interval]; transplant cohort, 1.1 [0.7-1.6]; nontransplant cohort, 1.2 [0.8-1.7]) or OS (transplant cohort, 1.6 [0.9-2.9]; nontransplant cohort, 1.5 [1.0-2.4]). Covariates in the model included high-risk cytogenetics, ISS stage III, triplet therapy, creatinine ≥2 mg/dL, light chain disease, and age. Although patients with high-risk disease are more likely to achieve early response, a rapid achievement of a deep response by itself does not affect long-term outcomes.

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