Mıkhael, Joseph

Solitary plasmacytomas (SPs) are rare localized tumors of clonal plasma cells, either in the bone (solitary bone plasmacytoma) or in soft tissue/extraosseous (extramedullary) with either no or with minimal bone marrow (BM) infiltration (<10% clonal plasma cells by immunohistochemistry) and no evidence of systemic involvement or myeloma defining events. Approximately 50% of SPs will progress to symptomatic myeloma within 5 years after initial definitive local radiotherapy. Increased availability of improved diagnostic and monitoring tools has increased the sensitivity of detection of additional lesions and marrow involvement and has implications for the follow-up strategy after treatment. Thus, the definitions and requirements for the diagnosis and follow-up of SPs are evolving. The diagnosis of SP requires the careful exclusion of multiple myeloma (MM) that would require systemic therapy, by using all the available methods to detect systemic disease (advanced imaging, sensitive BM assessment methods, blood and urine tests). Local radiotherapy remains the mainstay of therapy, and despite the availability of innovative drugs for MM, the clinical benefit of systemic therapy currently remains poorly defined. The International Myeloma Working Group provides here updated recommendations for the diagnosis, evaluation, treatment, and response assessment of patients with SPs, incorporating recent data and advances in diagnostic tools.

ABSTRACT Cancer mortality is inequitably distributed across the U.S. and globally, with historically marginalized groups, particularly racial and ethnic minorities, being disproportionately affected. Disproportionate representation in clinical cancer research is a consequence of inequitable access as well as a central factor contributing to outcome disparities; it limits efficacy and safety data for underrepresented groups while directing drug development to be most beneficial for those enrolled. To tackle this problem and improve the efficacy and safety of commercially available therapies, a consensus conference on strategies to promote Diversity, Equity, Inclusion, and Accessibility (DEIA) in cancer research was empaneled in September 2022. The resulting “Indianapolis Black Paper” presented here is an international collaborative white paper with authors from industry, academia, and the government, as well as patient advocacy and community health groups. First, it outlines the roles and responsibilities of key groups involved in clinical cancer research, as they relate to representation and equity. The Black Paper then delineates five steps to promote diversity in clinical research. This actionable strategy is called “DRIVE,” and it involves: incorporating a Diversity officer into clinical research studies, Ranking clinical studies for diversity, developing an Individual diversity, equity, inclusion, and access plan, a process for Verifying study diversity, and Elevating and Enhancing training of minority investigators and research team members. Finally, we outline the timeline and milestones of implementation. Purposefully ambitious and crosscutting industry, academia, and governmental policy, the Black Paper aims to address “injustices in health” with enhanced safety, purpose, and humanity.

This guideline has been updated. This ASCO Living Guideline is reviewed on an eight-week cycle. Please see the online dynamic version for the latest updates. ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature, and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and Appendix 2 (online only) for more . PURPOSE To provide updated guidance regarding the therapy for multiple myeloma. METHODS ASCO and Ontario Health (Cancer Care Ontario) convened a joint Expert Panel and conducted an updated systematic review of the literature. RESULTS The updated review identified a total of 161 relevant randomized trials. UPDATED RECOMMENDATIONS Daratumumab therapy may be offered to patients with high-risk smoldering myeloma. Quadruplet therapy with daratumumab or isatuximab, combined with bortezomib, lenalidomide, and dexamethasone, should be offered as initial therapy for transplant eligible patients. They should also be offered at least lenalidomide maintenance, with or without daratumumab, carfilzomib, and/or dexamethasone. Quadruplet therapy with daratumumab or isatuximab, combined with bortezomib, lenalidomide, and dexamethasone, should be offered as therapy for suitable transplant-ineligible patients. Patients with relapsed or refractory multiple myeloma should be offered triplet therapy or T-cell redirecting therapies according to a set of recommended principles. Additional information is available at www.asco.org/hematologic-malignancies-guidelines .

Background: The management of multiple myeloma (MM) continues to evolve with the emergence of new classes of therapy, most recently including BCMA-targeted therapies. Considering the expanding MM treatment armamentarium, we sought to identify contemporary practice patterns among healthcare professionals (HCPs) for MM and compare them with those of experts using an online decision support tool. Methods: An online decision support tool was developed with input from 5 experts providing therapy recommendations for 192 unique patient case scenarios based on considerations including disease setting, treatment history, access to therapy, and specific comorbidities. HCP tool users entered specific patient criteria to define a case along with their intended management for that case. The tool then showed the 5 expert recommendations for that same case scenario, and users were asked if the recommendations impacted their intended approach. An analysis of expert recommendations and user-selected therapy was performed. Results: Between April 2023 and July 2023, 207 patient cases were entered by 144 participating HCPs. HCP and expert treatment recommendations were frequently discordant, regardless of treatment setting (Table). The highest concordance between HCP and expert recommendations (47%; P &lt;.0001) was in the induction setting (n = 111). In this setting, experts were more likely to recommend quadruplet regimens compared with HCPs (62% vs 27%, respectively; P &lt;.0001). Treatment selection concordance was lower in the maintenance (n = 17; 24%; P &lt;.0001) and relapsed/refractory settings (n = 79; 20%; P &lt;.0001). The lowest concordance (10%; P &lt;.0001) between HCP and expert treatment recommendations was noted in the relapsed/refractory setting specifically among patients who were refractory to earlier lines of therapy (n = 41; P &lt;.0001). For patients who are refractory to earlier lines of therapy, experts were more likely to recommend an anti-CD38-based combination regimen compared with HCPs (81% vs 32; P &lt;.0001). When recommending treatment for patients with triple- or penta-refractory disease, experts were significantly more likely to recommend BCMA-targeted agents (83% vs 39%; P &lt;.0001). For HCPs whose treatment plan did not match expert recommendations in these scenarios, 53% of respondents indicated that expert recommendations confirmed or changed their intended therapy, but 31% indicated that there were barriers to implementing those recommendations. Conclusions: These data suggest ongoing challenges with incorporating the newest therapies and combinations across the spectrum of MM into patient care, particularly multidrug regimens in the induction and maintenance settings and BCMA-targeted therapies in those with triple- or penta-refractory disease. Continued education and development of resources for HCPs, including online decision support tools, may be increasingly important as the treatment of MM continues to grow in complexity.

Abstract Minimal residual disease (MRD) assays allow response assessment in patients with multiple myeloma (MM), and negativity is associated with improved survival outcomes. The role of highly sensitive next generation sequencing (NGS) MRD in combination with functional imaging remains to be validated. We performed a retrospective analysis on MM patients who underwent frontline autologous stem cell transplant (ASCT). Patients were evaluated at day 100 post-ASCT with NGS MRD and positron emission tomography (PET-CT). Patients with ≥ 2 MRD measurements were included in a secondary analysis for sequential measurements. 186 patients were included in the analysis. At day 100, 45 (24.2%) patients achieved MRD negativity at a sensitivity threshold of 10− 6. MRD negativity was the most predictive factor for longer time to next treatment (TTNT). Negativity rates did not differ according to MM subtype, R-ISS Stage nor cytogenetic risk. PET-CT and MRD positivity had poor agreement. Patients with sustained MRD negativity had longer TTNT, regardless of baseline risk characteristics. Our results show that the “real world” ability to measure deeper and sustainable responses distinguishes a subpopulation of patients with better outcomes. Achieving MRD negativity was the strongest prognostic marker and could help guide therapy-related decisions and serve as a response marker for clinical trials.

Summary: The multiple myeloma treatment landscape has changed dramatically. This change, paralleled by an increase in scientific knowledge, has resulted in significant improvement in survival. However, heterogeneity remains in clinical outcomes, with a proportion of patients not benefiting from current approaches and continuing to have a poor prognosis. A significant proportion of the variability in outcome can be predicted on the basis of clinical and biochemical parameters and tumor-acquired genetic variants, allowing for risk stratification and a more personalized approach to therapy. This article discusses the principles that can enable the rational and effective development of therapeutic approaches for high-risk multiple myeloma.

Abstract Background: In clinical practice there is little consensus on treating patients with chronic immune thrombocytopenic purpura (ITP) beyond first line therapy with steroids. Objectives: Describe the demographic and disease characteristics of adult ITP patients who receive treatment; Obtain the treatment approach for patients with ITP beyond first line treatment with steroids, with an emphasis on splenectomy; and Evaluate adverse bleeding outcomes associated with ITP. Methods: A retrospective chart review of ITP patients after initial therapy with steroids was conducted. Ten physicians (oncologists and hematologists) were recruited from across Canada and each physician provided at least 5 ITP cases for review. A total of 51 cases were reviewed and patients (&gt; 18 years old) were required to have had more than 1 course of steroids as treatment to be eligible. Results: The average age of patients at diagnosis was 42 (range 3 to 82 years); 37 (73%) of the patients were female, and 37 (73%) were Caucasian. The median platelet count upon presentation was 5×109/L. Median lines of therapy after initial therapy was 3 (range 0 to 6). Second line therapies varied, but most commonly patients underwent splenectomy (43%), followed by continued steroid treatment (16%), steroids plus IV Ig (16%), IV Ig alone (14%), immunosuppressant alone (2%), and anti-D plus steroids (2%). Of the patients reviewed, 40 (78%) eventually underwent splenectomy. Of the 40 splenectomized patients, 27 were splenectomized within the first year of diagnosis and 35 underwent splenectomy during the first 5 years. In addition, 62 of the splenectomies were laparoscopic, and the median hospital stay for all procedures was 5 days (range 1 to 60 days). Immediate failure of splenectomy occurred in 18% of patients, and the one- and five- year relapse/failure rates (defined as platelet count &lt; 30×109/L) were 38% and 55%, respectively. Other therapies following splenectomy included IV Ig, azathioprine, cyclosporine, danazol, mycophenolate, rituximab, vincristine, cyclophosphamide, and anti-D. Only 6% of IV Ig use was for chronic maintenance therapy and 74% of use was for urgent therapy. A total of 61 bleeding events occurred, of which 10 were major (upper GI, mouth, rectal, and nose). Major bleeding events required hospitalization of the patient with an average length of stay of 5 days (range 2 to 14 days). Conclusions: Notwithstanding several limitations, the retrospective chart review suggests that there is wide variation in long-term therapy for patients with chronic ITP in Canada. Splenectomy was the most widely used second line therapy, although 18% of the patients were non-responders and the five-year relapse/failure rate was 55%.

Abstract Oral cyclophosphamide and prednisone is a convenient regimen in relapsed and refractory multiple myeloma (MM), with a partial response (PR) rate of 40% and median progression-free survival of 19 months in our retrospective analysis of patients in first or second relapse after autologous stem cell transplantation (ASCT) (Trieu Y, et al, Mayo Clin Proc2005; 80: 1582). We sought to enhance the efficacy of this regimen by adding oral lenalidomide (Revlimid®), a potent anti-myeloma agent, in a phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15, lenalidomide on days 1–21, and prednisone 100 mg every other day in a 28-day cycle. ASA 81 mg/day was given to all patients (pts) as prophylaxis for DVT. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2008, 15 pts with relapsed/refractory MM were entered onto study. Median age was 60 (45–78) years and 60% were male. Immunoglobulin subtype was IgGκ:λ in 10:1; IgA κ:λ in 2:1 and κ light chain in 1. Median number of prior regimens was 2 (1–3) and 14 had undergone previous ASCT, including double transplants in 2 pts. Prior therapy also included thalidomide in 3 (20%) and bortezomib in 6 (40%). FISH cytogenetics were available in 9, but none had 13q deletion, t(4;14) or p53 deletion. At the time of protocol entry, median β2-microglobulin level was 222 (92–325) nm/L, albumin 38 (35–46) g/L, creatinine 78 (50–100) μmol/L, platelet count 230 (93–318) x 109/L and ANC 2.5 (1.9–9.0) x 109/L. Protocol treatment is summarized in Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 9 2 3 150 25 100 6 3 6 300 25 100 4 3 (expanded) 3 300 25 100 1 Dose limiting toxicity was not observed during cycle 1 at any of the dose levels and the maximum tolerated dose of this regimen has not yet been reached at the highest dose level planned; all pts remain on active therapy. Grade 3/4 thrombocytopenia was seen in 1 pt (cohort 2) and neutropenia in 4 pts (1 in cohort 1, 1 in cohort 2 and 2 in cohort 3) and were managed with dose reduction and/or growth factor support. No episodes of febrile neutropenia occurred in any pt. Only 1 pt experienced varicella zoster; routine antiviral prophylaxis was not used. Other grade 3/4 non-hematologic toxicities were uncommon and included abdominal pain/bacteremia in 1 pt in cohort 1, hypokalemia in 1 pt in cohort 2, and DVT in 1 pt in cohort 3. Mild grade 1/2 constipation (47%), muscle cramps (33%) and fatigue (33%) were also noted. To date, best response includes the following: dose level 1 (1 near complete remission [nCR], 2 PR); dose level 2 (3 PR); dose level 3 (4 PR, 2 minimal response [MR]); expanded cohort 3 (1 MR, 2 too early). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28-day cycle with minimal toxicity; 2) the overall response rate (nCR + PR + MR) in 13 evaluable pts to date is 87%; 3) no pts have progressed in this preliminary analysis; 4) longer follow-up is required to assess the long-term efficacy of this regimen.

Abstract p53 deletion by fluorescence in situ hybridization (FISH) has been reported in about 10% of newly diagnosed patients (pts) with multiple myeloma (MM) and has been associated with a poor prognosis. Previous data from our centre has demonstrated that the progression-free survival (PFS) and overall survival (OS) of these pts after a single autologous stem cell transplant (ASCT) is only 16.9 and 48.2 months, respectively, compared to 24.4 and 76.6 mos, respectively, in all pts transplanted during the same time period (Mikhael et al, Blood2007; 110: abstract 953). Minimal information is available on the treatment (Tx) and course of these pts following disease progression. Therefore, we performed a retrospective review of all MM pts treated at our institution who were found to have p53 deletion. We identified 31 pts with relapsed/refractory (rel/ref) MM with this cytogenetic abnormality. At diagnosis, median age was 54 years (range, 31–70), hemoglobin 97 g/L (range, 67–149), creatinine 96 μmol/L (range, 28–1751), beta 2-microglobulin 314 nmol/L (range, 225–437), CRP 3 mg/L (range, 2–7) and LDH 205 U/L (range, 82–478); 58% were male. Immunoglobulin subtypes included: IgG (14 pts), IgA (8 pts), IgD (2 pts) and light chain only (7 pts). Concomitant cytogenetic abnormalities included 13q deletion in 68% and t(4;14) in 67% of pts evaluable. Thirty-nine percent developed plasma cell leukemia (PCL) at some point in the disease course, which was associated with a poor OS (p=0.005). All but 5 had undergone prior ASCT with a median time from diagnosis to ASCT of 8 (95% CI, 4–145) mos. Txs given for rel/ref MM consisted of the following regimens: thalidomide-based in 15, bortezomib-based in 12, lenalidomide-based in 11, alkylating agents in 9 and steroids only in 5 pts, and other regimens (D-PACE or investigational drugs) in 7 pts. The median follow-up from diagnosis in these pts is 45 (95% CI, 4–145) mos. The overall response rate (≥PR) (ORR), median PFS and median OS from the start of each regimen is shown below. Agent Median duration of Tx (mos) ORR(%) Median PFS (mos) Median OS (mos) Thalidomide 6.2 20% 5.0 11.9 Bortezomib 5.2 50% 5.6 36.1 Lenalidomide 10.6 60% 4.8 36.1 Alkylating agents 6.0 11% 5.1 30.0 Steroids 1.9 20% 1.9 33.4 Other 2.2 43% 6.3 33.4 We conclude: 1) Median PFS in pts with the p53 deletion is less than 6 months, with an OS of 2.5–3 yrs; 2) novel agents other than thalidomide produce the highest ORR in rel/ref MM with p53 deletion; 3) the short OS in the thalidomide group is likely related to the unavailability of other novel agents for subsequent relapses, as the majority of the pts were treated before 2004; 4) better strategies/drugs are required for these pts.