Progressive Multifocal Leukoencephalopathy in Multiple Myeloma: A Single Institution Case Series

Abstract Introduction Progressive multifocal leukoencephalopathy (PML), caused by the John Cunningham (JC) virus, is an infection that requires immunosuppression for its manifestations and is fatal disease in many cases. (1) After asymptomatic primary infection, which occurs in childhood, the virus remains quiescent. (1,4) The classical clinical presentation is that of a subacute symptomatology that develops over weeks or months and consists of diverse sensorimotor abnormalities depending on the site of brain involvement. Approximately 22 cases of PML amongst patients with multiple myeloma (MM) have been reported in the literature between 1965 and April 2020. (5) Methods We performed a retrospective chart review of all myeloma patients who were treated at the Princess Margaret Cancer Center from 2010-2020 to identify cases of PML. Patient and disease characteristics, responses, and survival outcomes were collected from Myeloma and Stem Cell Transplant databases and electronic patient records under REB approval. Results We identified 3 cases of PML in MM patients at our center over the past 10 years, all of which occurred in patients receiving therapy containing an immunomodulatory derivative (IMID), i.e., thalidomide, lenalidomide or pomalidomide. Patient 1 A 52-year-old male with kappa light chain MM presented in 2009 on hemodialysis and received upfront bortezomib and dexamethasone followed by melphalan 200mg/m 2 and autologous stem cell transplantation (ASCT) in March 2010; maintenance with thalidomide was given until July 2011 when he presented to the ER with left-sided weakness, facial droop, and decreased strength. CT scan showed right-sided hypodensity in keeping with demyelination. PML was confirmed by MRI, lumbar puncture with positive PCR for JC virus, and a brain biopsy (Fig 1 A-C). He was treated with mirtazapine, and also developed status epilepticus controlled with phenytoin and phenobarbital. His myeloma treatment was never resumed after the diagnosis of PML due to concerns about viral reactivation. Approximately 3 years after PML diagnosis, his serum free kappa protein levels started to increase; he remained on hemodialysis but experienced no new myeloma-related organ damage and no myeloma treatment was offered. His last follow-up in clinic was in March 2019. However, he succumbed to S. pneumonia septicemia in July 2019. Case 2 A 68-year-old female with IgG kappa MM diagnosed in 2004 was treated with high-dose dexamethasone induction followed by melphalan 200mg/m 2 and ASCT and relapsed 2 years later. She commenced cyclophosphamide and prednisone until July 2011 when treatment was changed to lenalidomide and prednisone; subsequent progression in February 2014 was treated with pomalidomide/bortezomib/prednisone. In November 2014, we noticed worsening vision. Brain MRI showed hyperintensity in T2 in the occipital lobe. Her myeloma treatment was stopped and she received corticosteroids with no improvement. LP in January 2015 was positive for JC virus and the diagnosis of PML was made. She was managed with supportive measures. Her last clinic follow-up was in 2015 and the patient died from progression in September 2015. Case 3 A 52-year-old male with IgA lambda MM diagnosed in 2015 was treated with CYBOR-D induction followed by melphalan 200mg/m 2 and ASCT. He initially received lenalidomide maintenance which was changed to bortezomib due to toxicity. On progression in January of 2019 he was placed on a clinical trial of the anti-BCMA antibody drug conjugate belantamab mafodotin in combination with pomalidomide and dexamethasone on which he achieved a VGPR. In October 2020, he developed confusion and memory problems, as well as involuntary twitching. A brain MRI showed possible demyelination Two LPs were negative for JC virus, but a targeted brain biopsy confirmed the diagnosis of PML (Fig 1 D-F). His myeloma treatment was discontinued, and he was started on mirtazapine. At his most recent clinic visit in May 2021 his speech, memory and functional status had improved considerably and there were no signs of myeloma progression. Conclusion Our current series of PML in MM showcases the potential contribution of IMIDs and other novel agents--such as the newer monoclonal antibodies like belantamab mafotidin-- to the reactivation of JC virus and subsequent PML. Our series also demonstrates that neurologic improvement and longer survival can be observed with earlier management. Figure 1 Figure 1. Disclosures Reece: BMS: Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Millennium: Research Funding; GSK: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.

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Utilization of Autologous Stem Cell Transplantation in Older Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2019-130689 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5701-5701

Author(s):

Justin King ◽

Mark A. Fiala ◽

Scott R. Goldsmith ◽

Keith E. Stockerl-Goldstein ◽

Mark A. Schroeder ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Older Patients ◽

Research Funding ◽

Small Sample ◽

Poor Performance Status ◽

High Dose ◽

Cell Transplant ◽

Newly Diagnosed ◽

Equity Ownership

Historically, high-dose therapy in combination with autologous stem cell transplants (ASCT) for multiple myeloma (MM) was reserved for younger patients. In more recent years, the use of ASCT has expanded in the older population. However, there is still limited data on the utilization and efficacy of ASCT in older patients, particularly those over the age of 75. To further evaluate this issue, we retrospectively analyzed all patients with newly diagnosed MM between the ages of 75-78, the institutional cutoff for ASCT eligibility, that were referred to the stem cell transplant unit at our institution for consultation from the years 2012-2018. Baseline characteristics, anti-myeloma treatments, and patient outcomes were abstracted through chart review. Seventy-five patients were referred to our institution. 71% were male, 29% female. 39% patients were considered ineligible for ASCT by the consulting transplant physician. Most patients were considered transplant ineligible due to comorbidities or poor performance status. Of the 46 patients eligible for ASCT, 52% underwent the procedure during their first-line therapy. The majority of those patients received reduced intensity melphalan (140 mg/m2) while 2 patients received conventional dosing (200 mg/m2). The other 22 patients eligible for ASCT declined or elected to defer the procedure and to be treated with conventional therapy. The characteristics of these three groups were similar and are detailed in Table 1. After a median follow-up of 30 months, 25% of the patients had expired. Estimated median overall survival (OS) was 71.3 months (unable to quantitate 95% CI) for all patients. Compared to transplant eligible patients, regardless of transplant receipt, those who were transplant ineligible had a 186% increase risk for death (HR 2.86; 95% CI 1.12-7.35; p = 0.029). There was also a notable trend for longer OS in those who underwent ASCT compared to those who were eligible but declined the procedure, but it was not statistically significant (HR 0.36; 95% CI 0.10-1.28; p = 0.114). At a transplant center, two-thirds of patients referred for newly diagnosed MM between the ages 75-78 were considered eligible for ASCT and one-third underwent the procedure. Outcomes were better for patients eligible for ASCT, regardless of whether they underwent the procedure. There was also a trend for better OS in patients who underwent the procedure compared to those who declined. While small sample sizes and the retrospective nature of the study limit our ability to draw conclusions, it appears that ASCT has an OS benefit among patients age 75-78. Disclosures Fiala: Incyte: Research Funding. Stockerl-Goldstein:AbbVie: Equity Ownership; Abbott: Equity Ownership. Vij:Genentech: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wildes:Janssen: Research Funding; Carevive: Consultancy.

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Cryotherapy Reduces Mucositis in Multiple Myeloma Patients Receiving High-Dose Melphalan Conditioning Prior to Autologous Stem Cell Transplantation

Blood ◽

10.1182/blood.v120.21.4265.4265 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4265-4265 ◽

Cited By ~ 1

Author(s):

Mabel Rodriguez ◽

Nelly G. Adel ◽

Sean Devlin ◽

Sergio A Giralt ◽

Heather Landau

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Stem Cell ◽

Research Funding ◽

High Dose ◽

Cell Transplant ◽

Grade 3 ◽

High Dose Melphalan ◽

Hospital Days ◽

Severe Mucositis

Abstract Abstract 4265 Background: High-dose melphalan (MEL) followed by autologous stem cell support has been an integral component of multiple myeloma (MM) therapy since the 1980's. In general, high-dose melphalan is well-tolerated however grade 3 and 4 mucositis has been reported in up to 75% of patients (Lilleby et al. Bone Marrow Transpl, 2006). The efficacy of cryotherapy in preventing mucositis was initially documented in patients receiving infusional 5- fluorouracil (Rubenstein et al. Cancer, 2004). It is presumed that vasoconstriction reduces exposure of the oral mucosa to chemotherapy. Due to similar pharmacokinetic properties of melphalan including its short half life, cryotherapy has been used in MM patients undergoing MEL and stem cell transplant (SCT) with small series and one randomized trial supporting its use (Lilleby et al. Bone Marrow Transpl, 2006). At Memorial Sloan-Kettering Cancer Center, ice chips administered for 30 minutes before, during and after melphalan administration was adopted in March 2011 for all MM patients receiving MEL (≥ 140 mg/m2). In this study we sought to determine if the incidence of mucositis has been reduced since instituting cryotherapy into our standard practice. Methods: We retrospectively identified MM patients who received MEL 140 or 200 mg/m2 prior to SCT between January 1, 2009 and June 12, 2012 using our pharmacy database and electronic medical record. We analyzed two groups of patients by date of SCT and confirmed that patients transplanted prior to 3/2011 did not receive cryotherapy while all others did. Mucositis grade was recorded as documented by medical staff or determined by the investigators using the CTCAE version 4 criteria. Disease and treatment characteristics were collected in addition to narcotic use, total parenteral nutrition (TPN) requirement, and days of hospitalization. Fisher's exact test was used to compare the proportion of patients with mucositis, severe mucositis (defined as grade 3 or higher) and those requiring patient controlled analgesia (PCA), by cryotherapy use. Logistic regression was used to adjust for prior radiation and the number of prior lines of therapy. The number of hospital days was compared using a t-test. Results: During the study period, 214 patients underwent one or more autologous SCTs for MM; for patients who had more than one, only the initial SCT was included in this analysis. Of 214 patients, 85 (40%) received cryotherapy of whom 34% developed mucositis compared to 47% who did not receive cryotherapy (P = 0.08). Grade 3 mucositis was seen in 2% and 16% of patients who did and did not receive cryotherapy respectively (P = 0.004). No patient in either group developed grade 4 mucositis. After adjusting for radiation and lines of prior therapy the association between grade 3 mucositis and cryotherapy remained significant (OR: 0.13 (0.02, 0.47); P = 0.01). PCA use was lower in patients who received cryotherapy (19%) compared to those who did not (37%) (P = 0.01), with the median duration of use being 5 days in both groups. TPN was not required for any patient. Hospital days were similar in both groups (P = 0.88). Conclusion: Cryotherapy administration at the time of high-dose melphalan reduces the incidence of severe mucositis and PCA use. Cryotherapy is readily available and should be offered to all MM patients receiving ≥ 140 mg/m2 of melphalan. Disclosures: Landau: Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Research Funding.

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PK-Directed Intravenous Busulfan In Combination With High-Dose Melphalan and Bortezomib As Conditioning Regimen For Patients With Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.5513.5513 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5513-5513

Author(s):

Stefan K Barta ◽

Amitabha Mazumder ◽

Jason Carter ◽

Lawrence Almanzar ◽

Richard Elkind ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Partial Response ◽

Conditioning Regimen ◽

High Dose ◽

Cell Transplant ◽

Treatment Dose ◽

Gi Symptoms ◽

High Dose Melphalan

Abstract Introduction High dose therapy followed by autologous hematopoietic stem cell transplantation (ASCT) has an established role in the treatment of patients with multiple myeloma (MM). The most commonly used conditioning regimen in this setting is high-dose melphalan (200mg/m2; Mel200), which has been shown to result in improved progression free (PFS) and overall survival (OS). Achievement of a complete response (CR) following ASCT is an indicator for freedom from relapse, as well as PFS and OS. The CR rate observed after Mel200 followed by ASCT is between 10-35%. There is evidence that the combination of busulfan (Bu) and melphalan (Mel) results in longer PFS and OS compared to Mel alone. Additionally, the use of bortezomib (Btz) during conditioning with either high dose Mel alone or the combination of Mel and intravenous (i.v.) Bu has shown to be both safe and to have promising efficacy. The objective of our trial is to assess whether the combination of PK-directed Bu, Mel and Btz (BuMelBtz) during conditioning for a first ASCT in MM patients is both safe and efficacious. Methods Patients aged 18-72 with multiple myeloma, who had 1) measurable disease, 2) received less than one year of prior myeloma-directed therapy, 3) adequate organ function and performance status, and 4) an indication for ASCT were eligible. Exclusion criteria were >/= grade 2 neuropathy, prior stem cell transplant, uncontrolled intercurrent illnesses or comorbidities, unresolved >/= grade 2 toxicities from prior therapies, and prior malignancies except non-melanoma skin cancer. Treatment consisted of PK-directed i.v. Bu (4 daily 3-hour infusions from day (D) -6 to -3 to target a total AUC of 20,000 μMxmin), i.v. Mel 140mg/m2 on D-2, and i.v. Btz 1.4mg/m2 on D-6, -4, +1 and +4. The individual daily doses for Bu on D-6 and D-5 were determined by PK measures following a test dose (0.8mg/kg) 5-9 days prior to first Bu treatment dose; the last 2 doses (day -4 and -3) could be adjusted following another PK measure after the first full treatment dose on D -6. Stem cells were infused on D0. Subsequent consolidative or maintenance therapy was left to investigator choice. Primary outcome was CR rate assessed on D +100 post ASCT as per IMWG criteria. Secondary outcomes were overall response rate (ORR), toxicities, PFS and OS. The trial is registered at clinicaltrials.gov (NCT01605032). Results To date, 13 patients have been treated. The median age was 63 years (range 44-70), 62% (n=8) were male, 23% had ISS stage 3 (3/13), no patient had high risk cytogenetic features. The median number of regimens prior to ASCT was 1 (range 1-3) and included bortezomib in 92% (n=12). Prior to BuMelBtz the best treatment response had been stable disease (SD) in 3 patients, partial response (PR) in 8; only 1 patient each had achieved a very good partial response (VGPR) or CR. Following BuMelBtz/ASCT, median days to ANC >/=0.5 x 109/L and platelet count >/=30 x 109/L were 11 (range 10-13) and 17 (11-29), respectively. The most common non-hematological toxicities were alopecia (100%), oral mucositis (62% G3), dysphagia (85% G3, but no patient required TPN or enteral feeding), as well as electrolyte abnormalities (62% G3/4). Other common toxicities were nausea (92%, all G1/2), diarrhea (84% G1/2, 8% G3), while 77% of patients developed fully reversible transaminitis (15% G3). Less common G3 toxicities included delirium (8%), colitis (8%), skin infection (zoster, 8%), other infections (23%), and delirium (8%). One patient developed GI symptoms suggestive of acute GVHD on a gastric biopsy 8 weeks after ASCT. No patient developed sinusoidal obstruction syndrome of the liver. At 100 days post BuMelBtz/ASCT, response assessment was available for 8 patients: 1 achieved a stringent CR (12.5%), 4 VGPR (50%), and 3 PR (37.5%), resulting in a 100% ORR. One patient improved from a VGPR to a stringent CR during follow up. After a median follow up of 5 months (range 1-15) all patients are alive and no patient has relapsed. The trial is ongoing. Conclusion PK directed i.v. Bu in combination with Mel and Btz (BuMelBtz) is an effective and safe conditioning regimen for patients with multiple myeloma. Further evaluation is warranted. Disclosures: Barta: Otsuka: Research Funding; Onyx: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Honoraria. Off Label Use: IV Busulfan for the treatment of multiple myeloma.

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Lenalidomide Related Diarrhea Correlates With Survival In Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.5397.5397 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5397-5397 ◽

Cited By ~ 1

Author(s):

Beth Faiman ◽

Surbhi Sidana ◽

Paul Elson ◽

Kellie Bruening ◽

Hien K. Duong ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Antineoplastic Agents ◽

Research Funding ◽

Proportional Hazards ◽

Late Onset ◽

High Dose ◽

Cell Transplant ◽

Logrank Test ◽

The Impact

Abstract Background We hypothesized lenalidomide (len) related diarrhea (LRD) may correlate with activation of an immune response against multiple myeloma (MM) based on colon biopsies that showed crypt apoptosis reminiscent of GVHD in 3 MM patients with severe LRD but without prior allogeneic stem cell transplantation or gastrointestinal disorder. To investigate whether survival may be influenced by the presence of LRD we performed a retrospective chart review. Methods Patients who developed symptomatic MM on or after 1/1/2005 as defined by the start of anti-MM therapy and had been on len for at least 6 consecutive months by 12/31/2010 were included in the analysis. Significant LRD was considered present if the treating physician attributed the diarrhea to len and recommended supportive therapy in at least two clinic notes. The first time treatment for LRD was recommended was used as the date of onset of LRD. As possible confounding factors age at the start of len therapy, number of prior regimens, prior high dose chemotherapy with autologous stem cell transplant (ASCT), and use of antineoplastic agents other than corticosteroids at any time during the continuous len therapy were collected. The primary outcome was overall survival (OS), which was calculated from the start of len. Fisher’s exact test, Mann-Whitney test, and the logrank test were used to compare characteristics and duration of len between patients with and without LRD. Proportional hazards models were used to assess the impact of LRD on OS. The lag between the start of len and development of LRD was accounted for by treating LRD as a time-varying covariate in these models. Results 161 patients were identified, 47 (29%) had LRD, and 59 (37%) died during follow up. LRD and no LRD groups were balanced for gender, age, number of prior regimens, prior transplant, and use of antineoplastic agents other than corticosteroids with len, but len treatment duration differed; LRD patients had received a median of 43.4 consecutive months of len (range 5.8-82.9) compared to 14.6 (range 5.9-89) for patients without LRD (p=0.001). Onset of LRD occurred after a median of 17.7 months (range 0.3-75.4) of len therapy. In multivariable analyses, development of LRD (HR 0.46, 95% C.I. 0.21-1.00, p=0.05) was associated with improved OS as were the number of prior therapies (0-2, vs >2, HR 0.16, 95% C.I. 0.08-0.32, p<0.0001) and no use of antineoplastic therapy other than corticosteroids during len therapy (HR 0.52, 95% C.I. 0.29-0.93, p=0.03), while age and prior ASCT (p=0.52 and 0.49, respectively) were not. Conclusion Late onset of lenalidomide related diarrhea (LRD) is compatible with an immune mediated effect that may signal anti-MM immune activity since LRD requiring supportive measures correlated with survival in MM in analyses that adjusted for lag time. While more study is needed to prove this hypothesis, our findings suggest that diarrhea on len may argue for continued therapy rather than discontinuation. Disclosures: Faiman: Celgene: Consultancy, Speakers Bureau; Millennium: Consultancy, Speakers Bureau; Onyx: Consultancy, Speakers Bureau. Duong:Celgene: Honoraria, Research Funding. Valent:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Reu:Celgene: Research Funding; Onyx: Speakers Bureau.

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The Role of Total Body Irradiation (TBI) in the High-Dose Regimen of Patients with Follicular Lymphoma (FL) Treated with Autologous Stem Cell Transplant (ASCT) in the Rituximab Era. A Retrospective Study of the EBMT Lymphoma Working Party

Blood ◽

10.1182/blood.v118.21.502.502 ◽

2011 ◽

Vol 118 (21) ◽

pp. 502-502

Author(s):

Inas El-Najjar ◽

Ariane Boumendil ◽

Jian Jian Luan ◽

Catherine Thieblemont ◽

Didier Blaise ◽

...

Keyword(s):

Overall Survival ◽

Multivariate Analysis ◽

Stem Cell ◽

Dose Regimen ◽

Research Funding ◽

High Dose ◽

Cell Transplant ◽

Data Set ◽

High Dose Regimen

Abstract Abstract 502 Background and Aims: Rituximab has become an essential component of FL treatment, either in combination with chemotherapy or as maintenance. However, there is not much data available regarding the influence of prior rituximab on the survival of patients after ASCT. In addition, there is no consensus regarding the best type of high-dose regimen. The aim of this study is to assess the outcome of patients with FL having ASCT according to the high-dose regimen and previous treatment with rituximab. Patients and Methods: Between 1995 and 2007, 7910 patients with FL had their 1st ASCT and were reported to the EBMT registry. A full data set was available for 2233 patients who had ASCT with either TBI containing regimens or BEAM, and constitute the study group. Overall survival (OS) and event-free survival (EFS) were determined using the Kaplan-Meier method, and curves were compared by log-rank test. In multivariate analysis, the relevance of prognostic factors was estimated using Cox regression model. Incidence of relapse (IR) and non-relapse mortality (NRM) were calculated by cumulative incidence curves compared by Gray's test. Multivariate analysis of IR and NRM used Fine and Gray model. Results: Six hundred and eighty patients received a TBI-containing regimen, and 1553 patients BEAM. Seven hundred and thirteen patients (32%) had been treated with monoclonal antibodies (MoAb) before ASCT (confirmed as rituximab in 665). Patients who had TBI were younger (median age: 47) than patients who underwent BEAM (median age: 49; p<0.001), and were transplanted in 1st remission more frequently (61%) than BEAM patients (44%, p<0.001). In contrast, more patients treated with BEAM had received MoAb prior to ASCT (37%) than TBI patients (21%, p<0.001). Peripheral blood was the source of stem cells in 98% of patients having BEAM in comparison with 92% of patients having TBI (p<0.001). After a median follow-up of 60 months, the median overall survival (OS) for the whole group was 146 months and the median EFS, 72 months. Multivariate models for analysis of prognostic value of TBI were all adjusted on disease status at transplant, age, previous MoAb, time from diagnosis to ASCT, and source of stem cell and significant risk factors are shown in the table. In addition there was a trend for patients receiving TBI to have a better OS than patients receiving BEAM (p=0.06). Moreover, females had better EFS (p = 0.011) and OS (p = 0.058) in univariate analysis. However, the gender survival curves did not fulfil the proportional hazards assumption and thus the multivariate analysis of OS and EFS were stratified on gender allowing no estimation of its effect on outcome. Conclusions: In contrast to observations made in patients autografted before 1995 (Montoto Leukemia 2007), in the present series (with a shorter follow-up) the beneficial effect of TBI over BEAM in terms of relapse prevention was not counteracted by an increased NRM, resulting in a significantly better EFS with TBI in the rituximab era. Unlike reported for aggressive lymphoma, use of MoAb (rituximab) prior to ASCT had no detrimental impact on outcome and in fact was associated with significantly better OS. The superior survival of female patients in the rituximab era needs to be confirmed in further studies. Disclosures: Blaise: Laboratoire Pierre Fabre: Research Funding; Celgene: Research Funding. Rambaldi:Italfarmaco S.p.A.: Consultancy, Honoraria. Gribben:Roche: Honoraria; Celgene: Honoraria; GSK: Honoraria; Mundipharma: Honoraria; Gilead: Honoraria; Pharmacyclics: Honoraria. Montoto:Genentech: Research Funding; Roche: Honoraria.

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Thalidomide Combined With High Dose Melphalan Improves Event Free and Overall Survival In Patients With Newly Diagnosed Multiple Myeloma: Extended Follow-Up Of The HOVON-50 Trial

Blood ◽

10.1182/blood.v122.21.3332.3332 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3332-3332 ◽

Cited By ~ 1

Author(s):

Henk Lokhorst ◽

Bronno van der Holt ◽

Sonja Zweegman ◽

Edo Vellenga ◽

Sandra Croockewit ◽

...

Keyword(s):

Multiple Myeloma ◽

Multivariate Analysis ◽

Stem Cell ◽

Research Funding ◽

Previous Analysis ◽

Alpha Interferon ◽

High Dose ◽

Newly Diagnosed ◽

High Dose Melphalan

Abstract Background The randomised, open-label, phase III trial HOVON-50 was designed to evaluate the effect of thalidomide during induction and maintenance in newly diagnosed multiple myeloma patients. The previous analysis showed that thalidomide improved the primary endpoint EFS, but had no impact on OS (Lokhorst et al; Blood 2010 115: 1113-1120). Method Patients with Salmon & Durie stage II or III, age 18-65 years inclusive, were randomly assigned to arm A: 3 cycles of VAD (Vincristine, Adriamycin, Dexamethasone) or to arm B, 3 cycles of TAD (Thalidomide 200 orally, days 1-28 instead of Vincristine) Thalidomide was given from day 1 until 2 weeks before the stem cell mobilization with CAD (Cyclophosphamide 1000 mg/m2 iv day 1)and G-CSF. After induction therapy patients received 1 or 2 courses of high dose Melphalan (HDM) 200 mg/m2 with autologous stem cell rescue followed by maintenance therapy with alpha-Interferon (Arm A) or Thalidomide 50 mg daily (arm B) until relapse or progression. Between November 27, 2001 and May 31, 2005, 556 patients were randomised of which 536 patients were eligible for evaluation. As of July 2013 the median follow up of the 201 patients still alive is 99 months, range 65 – 130 months. Results The best responses achieved on protocol after extended follow-up were improved and significantly higher in the patients randomized to thalidomide: ≥ PR 88% vs 80 % (p<0.01), at least VGPR 66 % vs 55% (p<0.01), CR 31% vs 24 % (p=0.04), respectively. Similar to the previous analysis thalidomide improved EFS (censored at allo-SCT) from median 22 months to 33 months,; HR = 0.63, 95% CI [0.51 - 0.78], p<0.001) and PFS from median 25 to 33 months (HR =0.70, 95% CI [0.58 - 0.84], p<0.001). After 5 years of randomization the overall OS curves diverged and thalidomide improved median OS from 65 to 75 months. 10 years from randomization 27 % of patients randomized to alpha-Interferon are still alive and 35% of patients randomized to Thalidomide. For OS multivariate analysis showed prognostic significance for the whole group of patients for LDH (HR=1.52, 95% CI [1.15-2.00], P= 0.004) and ISS (HR=1.31, 95% CI [1.11-1.53, P=0.001]. For the secondary endpoint OS the thalidomide arm was superior when adjusted for covariates in multivariate analysis (HR = 0.80, 95% CI [0.64 – 0.99], P=0.045). The incidence of second primary malignancies (SPM) was similar between the two arms, as well as the actuarial probability to get an SPM within 5 years from start of the therapy (5-6%) or 10 years (9-10%) Conclusion After long term follow-up thalidomide in induction and maintenance treatment and in combination with HDM improves the quality of response and achieves superior EFS and OS. No increased incidence of SPM was observed as compared to patients not receiving thalidomide. This trial was registered on www. Trialregister.nl as NTR238 and was supported by the Dutch Cancer Foundation. Disclosures: Lokhorst: Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria. Minnema:Janssen Cilag: Consultancy, Honoraria. Sonneveld:Janssen-Cilag: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Research Funding; Millenium: Research Funding; Onyx: Research Funding; Celgene: Research Funding.

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Inferior Survival with Use of Autologous Stem Cell Transplant As Second-Line Therapy in Multiple Myeloma

Blood ◽

10.1182/blood-2019-127710 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2026-2026 ◽

Cited By ~ 1

Author(s):

Cara A. Rosenbaum ◽

Danny Luan ◽

Paul J Christos ◽

Roger Pearse ◽

Danielle Guarneri ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Research Funding ◽

Cell Transplant ◽

Second Line ◽

First Line ◽

Second Line Therapy ◽

Line Therapy ◽

Delayed Group

Background: Multiple myeloma (MM) remains incurable with eventual relapse and death occurring despite multiple lines of chemotherapy. Standard frontline therapy for MM has traditionally consisted of combinations of immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and dexamethasone followed by consolidation with high-dose melphalan and autologous stem cell transplantation (ASCT). A randomized trial using IMiD and PI-based induction demonstrated significant progression-free survival (PFS) benefit with upfront ASCT in consolidation compared to ASCT in second-line at relapse, but no OS benefit (Attal et al, NEJM, 2017). Delay of ASCT to second-line or beyond may in part be due to the aforementioned lack of OS benefit shown with upfront ASCT and increase of sustained deep responses, including MRD negativity, to novel frontline 3 and 4-drug regimens and continuation of therapy in the frontline. We performed a chart review comparing PFS1, PFS2, and overall survival (OS) of patients who underwent upfront ASCT as consolidation to those who received ASCT in the second-line after one relapse ('delayed ASCT'). The study was approved by the Institutional Review Board at Weill Cornell Medical College. Methods: 124 MM patients who underwent ASCT either as consolidation in first-line or delayed ASCT after relapsing on one prior treatment between 2010-2016 were included. Demographics and clinical parameters were extracted from the electronic medical record. PFS1, PFS2, and OS were calculated from date of diagnosis to first relapse, second relapse, and death, respectively. Patients were censored if lost to follow-up prior to experiencing the relevant event. PFS1, PFS2, and OS of patients receiving upfront ASCT were compared to those of patients receiving delayed ASCT. Log-rank tests were used to statistically evaluate differences between Kaplan-Meier PFS/OS curves. Cox proportional hazards models were used to calculate hazard ratios (HR) using upfront ASCT as the reference treatment. Results: Among the 124 patients, 93 underwent upfront ASCT as consolidation and 31 underwent delayed ASCT after relapsing on one prior line of therapy (Table 1). Induction regimens and pre-transplant therapies received are detailed in Table 1. Of the delayed group patients, 6 underwent ASCT directly without second-line induction and 25 as consolidation after second-line therapy. Patients receiving upfront ASCT had significantly longer median PFS1 compared to patients who received delayed ASCT (6.45 vs 1.25 years; P<0.001), with a HR of 0.18 (95% CI, 0.11-0.29) (Figure 1A). Median PFS2 in the upfront ASCT group was likewise significantly longer than in the delayed group (9.19 vs 3.69 years; P<0.001), with a HR of 0.31 (95% CI, 0.18-0.55) (Figure 1B). With a median follow-up of 6.0 and 5.8 years in the upfront and delayed groups, respectively, median OS was not reached in either group but trended towards prolonged survival with upfront ASCT (P=0.052), with a HR of 0.46 (95% CI, 0.20 to 1.03) (Figure 1C). Conclusions: In this cohort of 124 MM patients undergoing ASCT as consolidation in the upfront setting or delayed ASCT in second-line after relapse, upfront ASCT was associated with significantly improved PFS1 and PFS2, similar to findings by Attal et al. However, in that study, no difference in OS was seen between upfront and delayed groups, while our data, with longer follow-up, showed median OS trending towards significance. This has important implications as with use of novel induction regimens and maintenance therapy, ASCT is more commonly being delayed to early relapse in second-line or beyond. If transplant is intended to be used in the first few lines of therapy, our data show that delaying ASCT even to second-line has a significant negative impact on PFS. In addition, a shorter OS with delayed transplant was suggested although did not reach statistical significance, possibly due to small numbers or more patients with high-risk MM in the delayed group. It is also important to note the lack of daratumumab-based regimens which may have improved PFS/OS in either or both arms. Thus, our findings should be prospectively validated in a larger trial of ASCT as consolidation in first-line vs second-line or beyond using novel, monoclonal antibody-based regimens. Disclosures Rosenbaum: Janssen: Research Funding; Honoraria Akcea: Other: Accordant Health. Coleman:Gilead, Bayer, Celgene: Consultancy, Research Funding, Speakers Bureau; Kite Pharmaceuticals: Equity Ownership; Merck: Research Funding; Pharmacyclics: Speakers Bureau. Van Besien:Miltenyi Biotec: Research Funding. Niesvizky:Takeda, Amgen, BMS, Janssen, Celgene: Consultancy, Research Funding.

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Similar Survival with Deferred Versus Salvage Autologous Stem Cell Transplant in Light Chain Amyloidosis

Blood ◽

10.1182/blood-2019-127723 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4579-4579 ◽

Cited By ~ 1

Author(s):

Danny Luan ◽

Koen Van Besien ◽

Paul J Christos ◽

Roger Pearse ◽

Danielle Guarneri ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Light Chain ◽

Research Funding ◽

Small Sample ◽

Renal Amyloidosis ◽

High Dose ◽

Al Amyloidosis ◽

Cell Transplant

Background: Light chain (AL) amyloidosis is characterized by deposition of misfolded monoclonal immunoglobulin light chains leading to organ dysfunction. AL amyloidosis has traditionally been treated with agents used in multiple myeloma, primarily alkylators, proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and high-dose melphalan/autologous stem cell transplantation (ASCT). A retrospective study comparing patients with AL amyloidosis who underwent ASCT as frontline therapy ('upfront ASCT') to those undergoing ASCT following induction ('deferred ASCT') revealed that deferred ASCT was associated with prolonged overall survival (OS) compared to upfront ASCT (Afrough et al, Biol Blood Marrow Transplant, 2018). Given the number of effective new therapies for AL amyloidosis, the potential to delay ASCT after one or more lines of therapy ('salvage ASCT') is feasible. To our knowledge, transplant outcomes of AL amyloidosis patients undergoing deferred vs salvage ASCT following at least one relapse have not been reported. A retrospective chart review was conducted to compare AL amyloidosis patients receiving deferred vs salvage ASCT for progression-free survival (PFS) and overall survival (OS). The study was approved by the Institutional Review Board at Weill Cornell Medical College. Methods: Twenty-four patients with AL amyloidosis who underwent deferred or salvage ASCT between 2000-2018 were included in the analysis. Patients who underwent upfront ASCT without induction chemotherapy were excluded. Demographics and clinical parameters were extracted from the electronic medical record. PFS was calculated from date of ASCT to first relapse and OS was calculated both from date of diagnosis and date of ASCT to death. Patients were censored if lost to follow-up prior to experiencing the relevant event. PFS as well as OS of patients who underwent deferred vs salvage ASCT were compared. Log-rank tests were used to statistically evaluate differences between Kaplan-Meier PFS/OS curves. Cox proportional hazards models were used to calculate hazard ratios (HR) using deferred ASCT as the reference treatment. Results: Among the 24 patients included in this analysis, 13 underwent deferred ASCT with 1 prior line of chemotherapy (e.g., induction), and 11 underwent salvage ASCT with a median of 3 prior lines (Table 1). Ten patients had cardiac amyloidosis, 15 had renal amyloidosis, and 6 had multi-organ involvement. Induction regimens received in the deferred group are included in Table 1. Neither PFS nor OS was significantly different between patients receiving deferred vs salvage ASCT. After median follow-up of 2.9 years, median PFS in patients who received deferred ASCT was 6.5 years and not reached in those who received salvage ASCT (P=0.47), with a HR of 1.74 (95% CI, 0.38-7.85) (Figure 1A). Median OS from date of ASCT was not reached in either group after a median follow-up of 2.8 years (P=0.52), with a HR of 2.16 (95% CI, 0.19-24.04) (Figure 1B). Similarly, median OS calculated from date of diagnosis was not significantly different between deferred vs salvage ASCT (P=0.79) (Figure 1C). Conclusions: In this cohort of 24 AL amyloidosis patients, no significant differences in PFS or OS were seen between patients undergoing deferred ASCT following induction vs salvage ASCT following multiple lines of therapy. Unlike the superior OS seen with deferred vs upfront ASCT, our findings show that either deferred or salvage ASCT may be associated with comparable outcomes and suggest similar OS despite timing of transplant. However, it is important to note the small sample size and that none of our patients received daratumumab-based regimens which may have improved PFS/OS in either or both groups. There were also small differences between groups in use of maintenance (1 vs 3 patients in the deferred and salvage groups, respectively) and proportion of patients receiving higher doses of melphalan 200mg/m2 vs 140 mg/m2 (69% vs 55% in deferred and salvage groups, respectively). Nevertheless, the lack of difference seen in PFS and OS between the two groups suggests that eventual hematologic relapse and organ progression with death occur at similar time intervals despite timing of ASCT. This speaks to the point that in newly diagnosed AL amyloidosis as well as later in the disease, achieving deep responses to prevent organ progression and death regardless of timing of ASCT remains an important treatment goal. Disclosures Van Besien: Miltenyi Biotec: Research Funding. Coleman:Kite Pharmaceuticals: Equity Ownership; Pharmacyclics: Speakers Bureau; Merck: Research Funding; Gilead, Bayer, Celgene: Consultancy, Research Funding, Speakers Bureau. Niesvizky:Takeda, Amgen, BMS, Janssen, Celgene: Consultancy, Research Funding. Rosenbaum:Janssen: Research Funding; Honoraria Akcea: Other: Accordant Health.

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Phase 2 Trial of LDE225 and Lenalidomide Maintenance Post Autologous Stem Cell Transplant for Multiple Myeloma

Blood ◽

10.1182/blood-2019-132035 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1905-1905

Author(s):

Francis K. Buadi ◽

Martha Q. Lacy ◽

Angela Dispenzieri ◽

Gabriela Perez ◽

Morie A. Gertz ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Stem Cell ◽

Maintenance Therapy ◽

Research Funding ◽

Stem Cell Transplant ◽

Autologous Stem Cell Transplant ◽

High Dose ◽

Cell Transplant ◽

Grade 3

Background: Lenalidomide maintenance therapy post-autologous stem cell transplantation (ASCT) is associated with improved progression-free survival (PFS) and possibly overall survival in multiple myeloma (MM). However, almost all patients do relapse as a result of residual multiple myeloma cells that remain after the high-dose chemotherapy. In the myeloma setting it has been found that the hedgehog (Hh) pathway is essential for maintaining a subset of tumor causing stem cells. LDE 225 (Sonidegib) is a potent selective oral bioavailable antagonist of Smoothened (SMO), a component of the Hh signaling pathway. In in vitro experiments, LDE225 treatment of myeloma cell lines resulted in a modest inhibition of cell proliferation at increasing doses. When LDE225 was combined with lenalidomide, a more than additive effect was observed in terms of cell proliferation, an effect that was more pronounced in the context of myeloma cell lines growing in co-culture with marrow derived stromal cells. These findings form the basis of evaluation of LDE 225 as a strategy to enhance the activity of lenalidomide in the post-transplant maintenance setting. The minimal residual state post SCT provides the most optimal situation for evaluation of a drug that is likely to work by inhibiting the tumor cells that escaped high dose therapy. Methods: Multiple myeloma patients without evidence of progression, who were 60 - 120 days after a single autologous stem cell transplant (SCT), performed within 1 year of diagnosis were eligible for the study. Maintenance therapy was started approximately 3 months after SCT. Treatment consisted of lenalidomide 10 mg days 1-21 and LDE225 400 mg days 1-28 in 28-day cycles for a total of 18 cycles. The goal of the study was to assess toxicity of this combination, complete response rate (CR) progression free survival (PFS) at 1 and 2 year and overall survival (OS). CR and PFS were estimated using an exact binomial distribution and Kaplan Meier curves respectively. Results: A total of 28 patients were accrued from Jan 2014 to Aug 2016, 1 patient canceled prior to treatment and 1 patient was deemed ineligible resulting in 26 evaluable pts for CR and PFS. The median age of all pts (n=26) was 60 years (range 43-69) and 50% were males. Seventy-three percent of patients reported one treatment regimen prior to SCT, while 27% reported 2 or more prior regimens. The other characteristics of the patient are summarized in Table 1. Twenty seven pts received at least one cycle of treatment and are evaluable for toxicities (AE). Patients were treated for a median of 12.5 (range 1-18) cycles. While 10 pts (38.5%) completed protocol treatment (18 cycles), the remaining 16 pts went off treatment due to AEs (6, 23%), disease progression (3, 11.5%), refusal of further treatment (3, 11.5%) and other reasons (4, 15.4%). A grade 3 or higher AE at least possibly attributed to either drug was seen in 63%. Grade 3+ hematologic toxicities were noted in 30%, with 7% neutropenia and 4% thrombocytopenia. Notable grade 2+ non-hematologic toxicities with more than 5% incidence were dysgeusia 22%, alopecia 11%, and anorexia 7%. Grade 3+ non-hematologic toxicities were fatigue, myalgia and arthralgia each at 7%. The CR rate in evaluable patients was 46% (5 CRs and 7 sCRs) with a 95% CI of 27% - 66%. CR rate improved from 31% to 46%. VGPR or better improved from 42% to 85%. The 24-month PFS (time from SCT to progression or death due to any cause) was 73% (95% CI: 57.9 - 92.3%) with a median time to censoring of 38 months. Conclusion: Lenalidomide in combination with LDE225 as posttransplant maintenance therapy was associated with some toxicity but manageable. The combination improved the depth of response after autologous stem cell transplant. Long-term follow-up is needed to determine overall survival. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy; Alnylam: Research Funding. Gertz:Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Celgene: Honoraria; Spectrum: Honoraria, Research Funding; Janssen: Honoraria. Kapoor:Glaxo Smith Kline: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; Celgene: Honoraria; Sanofi: Consultancy, Research Funding. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Russell:Imanis: Equity Ownership. Kumar:Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. OffLabel Disclosure: Sonidegib (LDE 225) is a selective oral bioavailable antagonist of Smoothened (SMO), a component of the hedgehog signaling pathway.

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