Lenalidomide, Bortezomib, and Dexamethasone as Induction Therapy Before Autologous Stem Cell Transplant for Multiple Myeloma

One relevant systematic review and network meta-analysis (which included 1 relevant randomized controlled trial), 4 non-randomized studies, and 6 evidence-based guideline reports, representing 5 evidence-based guidelines were identified in this report. The clinical effectiveness regarding response, relapse, progression-free survival, and overall survival broadly favoured bortezomib-lenalidomide-dexamethasone (RVd) over bortezomib-cyclophosphamide-dexamethasone (CyBorD), although the magnitude and direction of association was not always consistent, and few estimates were statistically significant. Limited evidence on the safety of RVd relative to CyBorD was found. No evidence on the cost-effectiveness of RVd as induction therapy before autologous stem cell transplant for multiple myeloma was found. Among the 5 included guidelines, 3 specifically recommend RVd as a first option for induction therapy among transplant-eligible newly diagnosed multiple myeloma patients, and 2 recommend more broadly defined 3-drug induction regimens that include RVd.

Pepaxto: A New Peptide-Drug Conjugate for Heavily Pretreated Relapsed and Refractory Multiple Myeloma

Objective: The objective of this article was to review existing data of melflufen (Pepaxto) as an additional treatment option for heavily pretreated relapsed and refractory multiple myeloma. Data sources: A PubMed search was completed using the search terms melphalan flufenamide; melflufen; melflufen AND relapsed refractory multiple myeloma; melphalan flufenamide and relapsed refractory multiple myeloma between January 1, 2013, and October 18, 2021. Additional information was obtained from the National Institutes of Health Clinical Trial Registry, Federal Drug Administration (FDA) web updates, and Pepaxto prescribing information. Study selection/data extraction: Clinical trials including melflufen in relapsed refractory multiple myeloma and trials related to safety and clinical pharmacology were included. Data synthesis: The findings of this review show melflufen in combination with dexamethasone can be used as a treatment option for patients with relapsed and refractory multiple myeloma who have previously received greater than 4 previous lines of therapy, and documented resistance to a proteosome inhibitor, an anti-CD38 monoclonal antibody, and an immunomodulator. Relevance to patient care and clinical practice: Melflufen in combination with dexamethasone is a reasonable option for patients with relapsed and refractory multiple myeloma who have received at least 4 previous lines of therapy and considered ineligible for autologous stem cell transplant. Further clinical utilization in earlier lines of therapy is under review, pending the in-depth safety analysis by the FDA. Conclusions: The FDA approval of melflufen in combination with dexamethasone provides an additional therapy option for patients with heavily pretreated relapsed and refractory multiple myeloma.

A Case of Trimethoprim-Sulfamethoxazole-Induced Aseptic Meningitis Masquerading as Septic Shock

ABSTRACT Trimethoprim-sulfamethoxazole-induced aseptic meningitis (TSIAM) is a rare adverse reaction to a commonly prescribed antibiotic. We describe a case of severe TSIAM which resembled septic shock. A 30-year-old male with relapsed Hodgkin’s lymphoma 25 days status post autologous stem cell transplant presented to our clinic for evaluation of trimethoprim-sulfamethoxazole (TMP-SMX) hypersensitivity. After review of patient’s history and records, we had a low suspicion for a TMP-SMX adverse reaction and conducted an oral challenge to one 160 mg/800 mg tab of TMP-SMX. Four hours later, the patient developed vomiting, lightheadedness, and disorientation with progression to rigors, fever, tachycardia, and hypotension. He was admitted for fluid resuscitation and broad-spectrum antibiotic coverage for neutropenic fever and possible septic shock. A lumbar puncture performed due to complaints of headache, photophobia, and neck pain showed 375 white blood cells/µL with 73% neutrophil predominance, normal glucose (75 mg/dL), and elevated protein (101 mg/dL); additional cerebrospinal fluid (CSF) studies were negative for infectious etiologies. Fever and headache resolved by hospital day 4, at which time patient was discharged home. We believe this case represents TSIAM given the characteristic timing of symptom onset, CSF findings, and timing of symptom resolution without other clear etiology found on extensive infectious evaluation. It is important for allergists to recognize TSIAM, including its potential presentation as shock, in order to appropriately diagnose and counsel patients who seek evaluation for TMP-SMX adverse reactions.

ML-18 High-dose chemotherapy supported by autologous stem cell transplant in relapsed and refractory primary CNS lymphoma

While whole brain radiation therapy (WBRT) has been performed as consolidation therapy in primary central nervous system lymphoma (PCNSL), high-dose chemotherapy supported by autologous stem cell transplant (HDC/ASCT) is widely investigated today as an alternative treatment strategy, given the high risk for radiation-induced neurotoxicity in WBRT. Various conditioning regimens have been investigated in phase II trials, which report non-inferiority of HDC/ASCT in efficacy and preservation of neurocognitive function in comparison with WBRT. Besides its promising efficacy, treatment-related deaths are reported in 11% in patients treated by a conditioning regimen using thiotepa, busulfan and cyclophosphamide (TBC), which raises a concern for safety. Among several conditioning regimens, analysis using registry data of Japan Society for Hematopoietic Cell Transplantation has revealed that the use of conditioning regimens containing thiotepa was a positive factor for longer PFS. According to the result of a phase I trial in Japan which investigated HDC/ASCT using thiotepa and busulfan (BuTT), thiotepa was approved by the pharmaceuticals and medical devices agency (PMDA) on March 2020. In comparison with the TBC regimen, cyclophosphamide is omitted, and the dose of thiotepa is lower (250 mg/m2, 3 days in TBC; 5 mg/kg, 2 days in BuTT) in BuTT, therefore BuTT could be less toxic in comparison with TBC, and no treatment-related deaths were observed in the phase I study in Japan. Further investigation on the efficacy and safety of BuTT in actual clinical practice is warranted. We have constituted a multi-disciplinary team in our institution in order to perform HDC/ASCT using BuTT in relapsed/refractory PCNSL. Treatment indications are as follows; 65 years old or younger, previously treated by rituximab, methotrexate, procarbazine and vincristine (R-MPV), good organ function and neurological status. Future directions along with preliminary treatment results will be discussed at the meeting.

Talking about Complimentary and Alternative Medicine: A Conversation Analysis Study

Multiple Myeloma (MM) is a clonal plasma cell malignancy characterized by low blood counts and increased risk of infection, and primarily afflicts older adults. Although MM is incurable, advances in treatment, including autologous stem cell transplant (ASCT) has improved the lifespan of patients. MM patients commonly use over-the-counter complementary and alternative medicines (CAM) alongside conventional cancer therapies which, often without recognition by health care practitioners, may impact their treatment. Using data from an 18-month ethnographic study, we applied conversation analysis to examine 1180 minutes of audio-recordings to describe how patients and nurses interacted about CAM during ASCT education visits. Patients (n=12) had a median age of 62 years (IQR= 54-73), were mostly white (n=12, 75%), male (n=9, 56%), and had a moderate score on the FACT-G7 of 15 (IQR= 10-20). All patients had a caregiver present during their visit. Nurses (n=3) were aged 39 (IQR= 29-49) all with at least five years providing care to patients with blood cancers. Results suggested that nurses rarely provided direct feedback about CAM modalities, instead providing brief responses, and moving on to other topics. Excerpts were categorized into three groups, (1) demonstration of implicit epistemic authority, (2) demonstration of deferred epistemic authority in patient-initiated conversations, and (3) demonstration of deferred epistemic authority in nurse-initiated conversations. Understanding how conversations surrounding CAM are navigated can provide insights into patient-communication in general, and methods for improving ASCT education.

A Phase 2 Multi-Center, Open Label Study of Isatuximab Added to Standard Cybord Induction and Lenalidomide Maintenance Treatments in Newly Diagnosed, Transplant Eligible Multiple Myeloma

Background: Despite recent improvements, myeloma is still incurable. There is need to add new therapeutic tools. For young and fit patients, the current standard first-line therapy is a proteasome inhibitor (PI) containing induction, followed by stem cell collection, high dose Melphalan and autologous stem cell transplantation, followed by maintenance lenalidomide therapy in Canada. The anti-CD38 antibodies showed interesting activity in myeloma, and significant synergism with PI and IMiD based regimens. This CMRG-008 trial is designed to explore the benefit of adding Isatuximab to the current Canadian standard of care (CyBorD induction/Autologous SCT/Maintenance Len) in a single arm phase II trial. Design and Methods: Phase II study. Transplant eligible newly diagnosed myeloma patients (TE-NDMM) will receive Isatuximab added to four cycles of standard induction CyBorD chemotherapy (Cyclophosphamide 300 mg/m 2 PO, Bortezomib 1.5 mg/m 2 SC, and Dex 40 mg PO, all given on days 1, 8, 15 and 22 of 28-day cycles; Isatuximab 10 mg/kg IV days 1, 8, 15 and 22 of cycle 1; days 1 and 15 of cycles 2-4). After the completion of the induction treatment, subjects achieving at least stable disease will receive stem cell mobilization, collection of hematopoietic stem cells, high dose melphalan chemotherapy, and autologous stem cell transplantation. Maintenance treatment will start at 100 days (+/- 7 days) after the transplantation date (and to be continued until disease progression). The maintenance treatment will consist of Isatuximab administered in combination with Lenalidomide in 28-day cycles (Lenalidomide: 10 mg daily on days 1-21 of every cycle; Isatuximab: 10 mg/kg IV on days days 1, 8, 15 and 22 of cycle 1; days 1 & 15 of cycles 2-3; then day 1 of each subsequent cycle). The objectives: To evaluate the benefit of adding Isatuximab to CyBorD (induction = Isa + CyBorD) and Lenalidomide (maintenance = Isa + Lenalidomide) in transplant-eligible myeloma patients. Primary Endpoint: To determine the response rate (VGPR or better) defined by IMWG criteria at 100 days (+/- 7 days) after the autologous stem cell transplant (ASCT). Secondary Endpoints: A) To determine the response rate (VGPR or better) after induction treatment (before ASCT), and at 12 months, 24 months and 36 months. B) To evaluate additional efficacy outcomes including progression free survival (PFS), and overall survival (OS), time to response and duration of response. C) To confirm the feasibility, safety and tolerability of adding Isatuximab to CyBorD and to maintenance lenalidomide in transplant-eligible newly diagnosed myeloma patients. D) To determine the feasibility of autologous stem cell collection after Isa + CyBorD induction treatment. The key inclusion criteria are having a TE-NDMM with a measurable disease; adequate performance status; and adequate organ functions. The key exclusion criteria include previous exposure to anti-CD38 therapy, intolerance to CyBorD, adverse cardiac history, pulmonary disease, central nervous system disease, congenital or acquired immune suppression, and other concurrent severe or uncontrolled medical conditions. Statistics and Sample Size: Considering that the response rate (VGPR or better) after CyBorD induction therapy, high dose chemotherapy and autologous SCT is about 70-78%; and assuming a response rate (VGPR or better) to Isa-CyBorD induction and autologous stem cell transplant at 100 +/- 7 days of 88%; a sample size of 65 evaluable subjects will allow estimating the 95% confidence interval with a precision of +/- 7.9%. For the assumed rate and sample size, the lower bound of the confidence interval will be estimated to be larger than 80%. Assuming a 10% drop out rate, a total study size of 72 patients will be considered. This study is expected to open to recruitment in the third quarter of 2021. Clinicaltrials.gov #: NCT04786028. Disclosures Kotb: Janssen: Honoraria; Merck: Honoraria, Research Funding; Amgen: Honoraria; Akcea: Honoraria; Celgene: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria, Research Funding; Takeda: Honoraria; Karyopharm: Current holder of individual stocks in a privately-held company. Reece: BMS: Honoraria, Research Funding; GSK: Honoraria; Karyopharm: Consultancy, Research Funding; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Millennium: Research Funding; Sanofi: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.

Is There a Higher Incidence of Graft Failure or Delayed Time to Engraftment in Patients Undergoing Autologous Stem Cell Transplantation Who Receive Olanzapine for Anti-Emetic Prophylaxis?

Olanzapine has been shown to significantly decrease nausea and emetic episodes associated with chemotherapy in patients undergoing hematopoietic stem cell transplant (Monson, Greer, Kreikemeier, & Liewer, 2020). Additionally, Olanzapine has been shown to improve clinical outcomes in autologous stem cell transplant patients when added to triplet anti-emetic therapy of ondansetron, fosaprepitant and dexamethasone without any negative effects on time to engraftment (Clemmons, et al., 2018). Although this study did not show any delay in time to engraftment, there is only a small amount of data looking at this question, including Clemmons et al. (2016) and Trifilio et al. (2017). Other studies (Navari et al., 2016) demonstrated a decrease in chemotherapy related nausea and vomiting in patients receiving Olanzapine, but did not provide data on engraftment times as this was in standard chemotherapy recipients. At Colorado Blood Cancer Institute (CBCI), Olanzapine was used for a period of time for anti-emetic prophylaxis both pre and post autologous stem cell transplant. There was concern regarding whether or not Olanzapine was causing delays in time to engraftment or even potentially graft failure and use of the drug in transplant anti-emetic regimens was discontinued. We hypothesized that Olanzapine does not cause higher incidence of graft failure, as compared to patients who do not receive Olanzapine as part of their anti-emetic regimen during the pre and post autologous stem cell transplant period. A retrospective analysis (n = 272) was conducted on patients who underwent autologous stem cell transplant between 2019 and 2020. 134 of these patients received Olanzapine during conditioning and up until time of engraftment, and 138 patients had no Olanzapine exposure throughout their conditioning and transplant. Conditioning regimens were equal between the two groups (Table 1). The average number of days on Olanzapine was 10.7, and the average dose was 7.5mg daily. For the purposes of this study engraftment was defined as the first day post stem cell infusion that the patient had an absolute neutrophil count (ANC) of greater than or equal to 500. Findings showed that the mean day of engraftment in the patients with Olanzapine exposure was 14.69; in the non-Olanzapine group, the mean day of engraftment was 12.64 (Table 2). Using the two-sample t-test, this difference (2.05 days, 95% CI (1.60-2.51)) is significant (p<.0001). Based on our findings, there is evidence to support Olanzapine causing a slightly delayed time to engraftment in autologous stem cell transplant patients, but not a higher incidence of graft failure, although a randomized controlled trial would be needed to fully investigate. There is clear data showing increased ability to manage chemo therapy induced nausea and vomiting. While a randomized controlled trial would be needed to fully investigate, given there is not a proven increase in graft failure, Olanzapine should be considered as a desirable option to treat and prevent chemotherapy induced nausea and vomiting in autologous stem cell transplant patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Olanzapine (Zyprexa) - Used off-label for the treatment and prevention of chemotherapy induced nausea and vomiting