scholarly journals The changing landscape of relapsed and/or refractory multiple myeloma (MM): fundamentals and controversies

2022 ◽  
Vol 10 (1) ◽  
Author(s):  
José-Ángel Hernández-Rivas ◽  
Rafael Ríos-Tamayo ◽  
Cristina Encinas ◽  
Rafael Alonso ◽  
Juan-José Lahuerta

AbstractThe increase in the number of therapeutic alternatives for both newly diagnosed and relapsed/refractory multiple myeloma (RRMM) patients has widened the clinical scenario, leading to a level of complexity that no algorithm has been able to cover up to date. At present, this complexity increases due to the wide variety of clinical situations found in MM patients before they reach the status of relapsed/refractory disease. These different backgrounds may include primary refractoriness, early relapse after completion of first-line therapy with latest-generation agents, or very late relapse after chemotherapy or autologous transplantation. It is also important to bear in mind that many patient profiles are not fully represented in the main randomized clinical trials (RCT), and this further complicates treatment decision-making. In RRMM patients, the choice of previously unused drugs and the number and duration of previous therapeutic regimens until progression has a greater impact on treatment efficacy than the adverse biological characteristics of MM itself. In addition to proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies and corticosteroids, a new generation of drugs such as XPO inhibitors, BCL-2 inhibitors, new alkylators and, above all, immunotherapy based on conjugated anti-BCMA antibodies and CAR-T cells, have been developed to fight RRMM. This comprehensive review addresses the fundamentals and controversies regarding RRMM, and discusses the main aspects of management and treatment. The basis for the clinical management of RRMM (complexity of clinical scenarios, key factors to consider before choosing an appropriate treatment, or when to treat), the arsenal of new drugs with no cross resistance with previously administered standard first line regimens (main phase 3 clinical trials), the future outlook including the usefulness of abandoned resources, together with the controversies surrounding the clinical management of RRMM patients will be reviewed in detail.

2021 ◽  
Vol 10 (3) ◽  
pp. 470
Author(s):  
Marta Martín-Richard ◽  
Maria Tobeña

Different strategies of maintenance therapy (sequential CT, intermittent CT, intermittent CT and MAbs, or de-escalation MAbs monotherapy) after first-line treatment are undertaken. Many randomized clinical trials (RCT), which evaluated these approaches, suffer from incorrect design, heterogenous primary endpoints, inadequate size, and other methodology flaws. Drawing any conclusions becomes challenging and recommendations are mainly vague. We evaluated those studies from another perspective, focusing on the design quality and the clinical benefit measure with a more objective and accurate methodology. These data allowed a clearer and more exact overview of the statement in maintenance treatment.


Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 22-23
Author(s):  
Maria-Victoria Mateos ◽  
Rohan Medhekar ◽  
Istvan Majer ◽  
Mehmet Turgut

Introduction: The majority of newly diagnosed multiple myeloma (NDMM) patients are currently treated with lenalidomide-based regimens as their first line of therapy. This trend is likely to continue in the coming years. Typically, lenalidomide is administered until disease progression and has significantly contributed to better outcomes in these patients. However, most patients relapse, and prognosis worsens with each relapse. The choice of optimal treatment for patients who relapse while receiving lenalidomide as first line of therapy is unclear. Moreau et al (Blood Cancer J. 9, 38 [2019]) concluded that there is limited data on approved combinations for treating these patients and are restricted by the low number of lenalidomide-refractory patients enrolled in the pivotal trials. Results from the ongoing clinical trials of the combination of carfilzomib and anti-CD38 antibodies were not available at the time of the Moreau et al publication. The aim of this targeted literature review was to include this new data and to summarize currently available evidence on progression-free survival (PFS) for the treatment of RRMM patients who progressed on lenalidomide-based regimens. Methods: A targeted literature review was conducted to identify registrational clinical trials in patients with RRMM reporting PFS outcomes. PubMed, congress proceedings, and product labels were searched between Jan 2014 to July 2020. In addition to PFS, demographic, disease characteristics and treatment history were extracted for the trial populations to contextualize potential variations in study outcomes. The regimens studied in these trials were classified as lenalidomide-based, proteasome inhibitor (PI)-based and pomalidomide-based. Number of prior lines of therapy, prior exposure and refractoriness to lenalidomide and bortezomib were reported. Results: Twelve registrational trials were identified based on the search criteria (Table 1). Most pivotal trials assessing lenalidomide-based regimens (POLLUX, ELOQUENT-II, TOURMALINE-MM1) except the ASPIRE trial excluded patients who were refractory to lenalidomide. Trials evaluating PI-based regimens (e.g., CANDOR) or pomalidomide-based regimens (e.g., OPTIMISMM) included these patients, with more recent studies enrolling a larger proportion. Percentage of lenalidomide-exposed (and lenalidomide refractory) ranged from 40% (32%) in CANDOR to 98% (90%) in ELOQUENT III. These studies also enrolled a larger proportion of patients who were bortezomib-exposed, although most of these patients were at first relapse, with the exception of ELOQUENT III and ICARIA where most patients were at third relapse. Among lenalidomide-refractory patients, the median-PFS (mPFS) observed for the pomalidomide-based regimens ranged from 9.5 to 10.1 months and that observed for PI-based regimens ranged from 4.9 to 25.7 months. PFS in the lenalidomide-refractory subgroup was considerably shorter than in the ITT population. The mPFS for patients receiving carfilzomib/daratumumab/dexamethasone (KDd; CANDOR) and isatuximab/carfilzomib/dexamethasone (IsaKd; IKEMA) was not reached at median follow-up of 16.9 and 20.7 months respectively. While the mPFS for (KDd) for lenalidomide-refractory patients in CANDOR trial was not yet reached at median follow up of 16.9 months; the mPFS of 25.7 months for KDd in the MMY-1001 trial appears to be the longest among the assessed regimens. Conclusion: Patients refractory to lenalidomide have shorter PFS and represent a population with high unmet need. This targeted literature review suggests that the PI-based KDd regimen provides longer PFS compared to other lenalidomide-sparing regimens in lenalidomide-refractory populations. Heterogeneity across trial populations may limit the comparability of these treatments. Disclosures Mateos: Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaMar-Zeltia: Consultancy; GlaxoSmithKline: Consultancy. Medhekar:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Majer:Amgen (Europe) GmbH: Current Employment, Current equity holder in publicly-traded company.


Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-3
Author(s):  
Saad Ullah Malik ◽  
Nazma Hanif ◽  
Priyanka Kumari ◽  
Khadija Noor Sami ◽  
Chase Warner ◽  
...  

Introduction: During recent years there has been a boom in the availability of treatments for multiple myeloma (MM). Based on the status of disease (newly diagnosed or relapsed/refractory), several regimens have successfully improved progression free survival (PFS) and overall survival (OS) in these two types of patients. Triple drug regimen is considered the current standard of care for newly diagnosed MM patients. However, with the advent of four drug regimens, some studies demonstrated a significant improvement in PFS and OS compared to standard of care where as others showed marginal to no difference. Also, it remains unclear whether the benefits of using four drug regimen outweigh the risks. Thus, the aim of our meta-analysis was to compare the efficacy and safety of four drug versus three drug regimens among newly diagnosed multiple myeloma patients. Methods: We built a PICO based search strategy using keywords like "multiple myeloma", "randomized clinical trials" and ran literature search on PubMed, Embase, Wiley Cochrane Library, Web of Science and ClinicalTrials.gov ranging from the date of inception till 16th July, 2020. A pre-validated data extraction sheet was used to extract data on PFS, OS and ≥Grade 3 hematologic adverse events at the longest follow-up. We included only randomized clinical trials (RCTs) comparing four versus three drug regimen in newly diagnosed MM patients. We excluded studies other than RCTs, studies conducted on relapsed refractory MM patients or other plasma cell dyscrasias. A generic variance weighted random effects model (DerSimonian and Laird) was used to derive hazard ratio estimates along with their 95% confidence intervals (CIs) for PFS and OS. Risk ratio along with its 95% CIs was estimated for Grade ≥3 hematologic adverse events. Heterogeneity was assessed with Cochrane Q -statistic and was quantified with I2 test (I2 >50% was consistent with a high degree of heterogeneity). A pre-specified sensitivity analysis was also performed for risk of adverse events. Cochrane Collaboration's tool was used to assess the quality of included RCTs and GRADE was used to rate the quality of evidence. Results: Initial search retrieved 7622 titles. After duplicate removal, 4880 articles were left. Following initial screening, 58 articles were considered for full text review. Of these only 3 studies (n=2277) met inclusion criteria. Four drug regimens included daratumumab, bortezomib, melphalan-prednisone (D-VMP), daratumumab, bortezomib, thalidomide-dexamethasone (D-VTd) and bortezomib and melphalan prednisone and thalidomide (VMPT-VT) respectively. Whereas, three drug regimens were bortezomib, melphalan-prednisone (VMP), bortezomib, thalidomide-dexamethasone (VTd) and bortezomib, melphalan and prednisone (VMP) respectively. There was a significant improvement in PFS when 4 vs 3 drug regimens were compared in patients with newly diagnosed MM (HR: 0.53, 95% CI: 0.46-0.62, p-value:<0.001, I2: 0%). Also, OS improved significantly in four drug regimen group (HR: 0.62, 95% CI: 0.51-0.76, p-value:<0.001, I2: 3.5%). There was no statistically significant difference in any grade ≥3 hematologic adverse events when 4 vs 3 drug regimens were compared (RR: 1.26, 95% CI: 0.93-1.73, p-value:0.14, I2: 93%). Sensitivity analysis after removing D-VTd regimen from any grade ≥3 hematologic adverse events revealed similar results (RR: 1.05, 95% CI: 0.97-1.13, p-value:0.23, I2: 23%) confirming the robustness of analysis. When each hematologic adverse event was looked at separately, there was no difference between 4 vs 3 drug regimen in rates of anemia (RR: 0.99, 95% CI: 0.76-1.28, p-value:0.92, I2: 0%), neutropenia (RR: 1.39, 95% CI: 1.00-1.94, p-value:0.05, I2: 85%) and thrombocytopenia (RR: 1.13, 95% CI: 0.92-1.39, p-value:0.24, I2: 33%). There was low risk of bias and strength of evidence was of moderate. Conclusion: Using four drug regimens, compared to three drug regimens, significantly improves PFS and OS among newly diagnosed multiple myeloma patients without any difference in the risk of ≥3 grade hematologic adverse events. Further randomized clinical trials are required to establish four drug regimen as standard of care for patients with newly diagnosed multiple myeloma. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.


Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-6
Author(s):  
Israr Khan ◽  
Abdul Rafae ◽  
Anum Javaid ◽  
Zahoor Ahmed ◽  
Haifza Abeera Qadeer ◽  
...  

Background: Multiple myeloma (MM) is a plasma cell disorder and demonstrates overexpression of B cell maturation antigen (BCMA). Our objective is to evaluate the safety and efficacy of chimeric antigen receptor T cells (CAR-T) against BCMA in patients with relapsed/refractory multiple myeloma (RRMM). Methods: We conducted a systematic literature search using PubMed, Cochrane, Clinicaltrials.gov, and Embase databases. We also searched for data from society meetings. A total of 935 articles were identified, and 610 were screened for relevance. Results: Data from thirty-one original studies with a total of 871 patients (pts) were included based on defined eligibility criteria, see Table 1. Hu et al. reported an overall response rate (ORR) of 100% in 33 pts treated with BCMA CAR-T cells including 21 complete response (CR), 7 very good partial response (VGPR), 4 partial response (PR). Moreover, 32 pts achieved minimal residual disease (MRD) negative status. Chen et al. reported ORR of 88%, 14% CR, 6% VGPR, and 82% MRD negative status with BCMA CAR-T therapy in 17 RRMM pts. In another clinical trial by Han et al. BCMA CAR-T therapy demonstrated an ORR of 100% among 7 evaluable pts with 43% pts having ≥ CR and 14% VGPR. An ORR of 100% with 64% stringent CR (sCR) and 36% VGPR was reported with novel anti-BCMA CART cells (CT103A). Similarly, Li et al. reported ORR of 87.5%, sCR of 50%, VGPR 12.5%, and PR 25% in 16 pts. BCMA targeting agent, JNJ-4528, showed ORR of 91%, including 4sCR, 2CR, 10MRD, and 7VGPR. CAR-T- bb2121 demonstrated ORR of 85%, sCR 36%, CR 9%, VGPR 57%, and MRD negativity of 100% (among 16 responsive pts). GSK2857916, a BCMA targeting CAR-T cells yielded ORR of 60% in both clinical trials. Three studies utilizing bispecific CART cells targeting both BCMA & CD38 (LCARB38M) reported by Zhao et al., Wang et al., and Fan et al. showed ORR of 88%, 88%, & 100% respectively. Topp et al. reported ORR of 31% along with 5 ≥CR and 5 MRD negative status in 42 pts treated with Bi T-cells Engager BiTE® Ab BCMA targeting antigen (AMG420). One clinical trial presented AUTO2 CART cells therapy against BCMA with an ORR of 43%, VGPR of 14%, and PR of 28%. CT053CAR-BCMA showed 14sCR and 5CR with a collective ORR of 87.5% and MRD negative status of 85% in 24 and 20 evaluable pts, respectively. Likewise, Mikkilineni et al. reported an ORR of 83%, sCR of 16.7%, and VGPR & PR of 25% and 41% in 12 pts treated with FHVH-BCMA T cells. Similar results are also reported in other clinical trials of BCMA targeting CART therapy (Table 1). The most common adverse effects exhibited were grade 1-3 hematologic (cytopenia) and cytokine release syndrome (CRS) (mostly reversible with tocilizumab). Conclusion: Initial data from ongoing clinical trials using BCMA targeting CAR-T therapy have yielded promising results both in terms of improved outcome and tolerable toxicity profiles. Although two phase 3 trails are ongoing, additional data is warranted to further ensure the safety and efficacy of anti-BCMA CAR-T cells therapy in pts with RRMM for future use. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.


2018 ◽  
Vol 2 (13) ◽  
pp. 1633-1644 ◽  
Author(s):  
Ajai Chari ◽  
A. Keith Stewart ◽  
Stuart D. Russell ◽  
Philippe Moreau ◽  
Joerg Herrmann ◽  
...  

2015 ◽  
Vol 57 (6) ◽  
pp. 1463-1466 ◽  
Author(s):  
Annette E. Hay ◽  
Alli Murugesan ◽  
Ashley M. DiPasquale ◽  
Tom Kouroukis ◽  
Irwindeep Sandhu ◽  
...  

Author(s):  
George G. Zhanel ◽  
Andrew J. Walkty ◽  
James A. Karlowsky

Fosfomycin is a new agent to Canada approved for the treatment of acute uncomplicated cystitis (AUC) in adult women infected with susceptible isolates ofE. coliandEnterococcus faecalis. We reviewed the literature regarding the use of oral fosfomycin for the treatment of AUC. All English-language references from 1975 to October 2015 were reviewed. In Canada, fosfomycin tromethamine is manufactured as Monurol® and is available as a 3-gram single dose sachet. Fosfomycin has a unique chemical structure, inhibiting peptidoglycan synthesis at an earlier site compared toβ-lactams with no cross-resistance with other agents. Fosfomycin displays broad-spectrum activity against ESBL-producing, AmpC-producing, carbapenem-non-susceptible, and multidrug-resistant (MDR)E. coli. Resistance to fosfomycin inE. coliis rare (<1%). Fosfomycin is excreted unchanged in the urine by glomerular filtration with peak urinary concentration ~4000 µg/mL and remains at concentrations >100 µg/mL for 48 hours after a single 3-gram oral dose. No dosage adjustments are required in elderly patients, in pregnant patients, or in either renal or hepatic impairment. Fosfomycin demonstrates a favorable safety profile, and clinical trials have demonstrated efficacy in AUC that is comparable to ciprofloxacin, nitrofurantoin, and trimethoprim-sulfamethoxazole. Fosfomycin’s in vitro activity against common uropathogens, including MDR isolates, its favorable safety profile including pregnancy patients, drug interactions, and clinical trials data demonstrating efficacy in AUC, has resulted in Canadian, US, and European guidelines/authorities recommending fosfomycin as a first line agent for the treatment of AUC.


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