Smoldering multiple myeloma (SMM) is a heterogeneous disease in terms of progression to myeloma (MM), but its standard of care continues to be observation.
The QuiRedex phase 3 trial initiated in ...2007 included 119 high-risk patients with SMM randomized to treatment or observation. Treatment consisted of nine 4-week induction cycles (lenalidomide Rd, 25 mg on days 1-21 plus dexamethasone, 20 mg on days 1-4 and 12-15), followed by maintenance (R, 10 mg on days 1-21) for up to 2 years. The primary end-point was time to progression (TTP) to myeloma based on per protocol population. Secondary end-points were overall survival (OS), response rate, and safety. An update of the trial after a long-term follow-up is presented here. This trial was registered with ClinicalTrials.gov (NCT00480363).
After a median follow-up time of 12.5 years (range: 10.4-13.6), the median TTP to MM was 2.1 years in the observation arm and 9.5 years in the Rd arm (HR: 0.28, 95% CI: 0.18-0.44, p < 0.0001). The median OS was 8.5 years in the abstention arm and not reached in the Rd group (HR: 0.57, 95% CI: 0.34-0.95, p = 0.032). Patients who progressed received optimized treatments according to the standards of care, and the OS from progression was comparable in both arms (p = 0.96).
This analysis confirms that early treatment with Rd for high-risk SMM translates into a sustained benefit in both TTP and OS.
Pethema (Spanish Program for the Treatment of Hematologic Diseases), Spain.
•ISS 3, high CTC levels, and a longer time to first MRD negativity are significant predictors of MRD resurgence and/or progressive disease.
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The role of measurable residual disease ...(MRD) negativity as a biomarker to stop treatment is being investigated in transplant-eligible patients with multiple myeloma (MM). Thus, it is important to identify risk factors of MRD resurgence and/or progressive disease (PD) among patients achieving undetectable MRD to avoid undertreating them. Here, we studied 267 newly diagnosed transplant-eligible patients with MM enrolled in the GEM2012MENOS65 and GEM2014MAIN clinical trials who achieved MRD negativity by next-generation flow cytometry. After a median follow-up of 73 months since the first MRD negative assessment, 111 of the 267 (42%) patients showed MRD resurgence and/or PD. The only prognostic factors at diagnosis that predicted MRD resurgence and/or PD were an International Staging System (ISS) 3 and the presence of ≥0.01% circulating tumor cells (CTCs). Failure to achieve MRD negativity after induction also predicted higher risk of MRD resurgence and/or PD. Patients having 0 vs 1 vs ≥2 risk factors (ISS 3, ≥0.01% CTCs, and late MRD negativity) showed 5-year rates of MRD resurgence and/or PD of 16%, 33%, and 57%, respectively (P < .001). Thus, these easily measurable risk factors could help refine the selection of patients for whom treatment cessation after MRD negativity is being investigated in clinical trials. This trial was registered at www.clinicaltrials.gov as NCT01916252 and NCT02406144.
Two articles examine relapse of patients with multiple myeloma despite achieving measurable residual disease negativity (MRDneg). D’Agostino and colleagues monitored 306 patients for a median follow-up of 50.4 months from achieving MRDneg, with loss of negativity occurring in 39% of patients. In the second study, Guerrero and colleagues addressed the same question for 267 newly diagnosed patients who were MRD negative following primary treatment and autograft with remarkably similar results, with 42% having recurrent MRD or relapse with a median follow-up of 73 months. In both studies, prolonged time to reach MRDneg, circulating tumor cells at diagnosis, and high-risk cytogenetics all predict for relapse.
Although rituximab is generally well‐tolerated, infusion‐related reactions (IRRs) are common with the initial dose when administered intravenously according to standard recommendations. To prevent ...IRRs, premedication and low‐speed infusion rates have been recommended. Consequently, intravenous (i.v.) infusion of rituximab can become a labor‐intensive process. Rapid i.v. rituximab infusion over 90 min has demonstrated a favorable safety profile for the second and subsequent infusions during the course of therapy. The aim of this study was to investigate the safety and tolerability of 90‐min rapid infusion of Sandoz rituximab biosimilar (SDZ‐RTX) for patients with CD20+ lymphoma or chronic lymphocytic leukemia (CLL). We retrospectively reviewed all patients with CD20+ lymphoma or CLL who received SDZ‐RTX infusions in 90 min from July 2019 to July 2021 at seven Spanish hospitals. The primary end point was the incidence of IRRs. We identified 124 patients and 576 rapid administrations of SDZ‐RTX, with an average of five rapid infusions per patient. Most rapid infusions of SDZ‐RTX were in combination with CHOP/CHOP‐like therapy (48.4%), followed by SDZ‐RTX alone (15.1%), in combination with bendamustine (14.5%), or with other regimens (22%). The 90‐min SDZ‐RTX infusion schedule was well‐tolerated with no grade 3/4 IRRs. The incidence of any grade IRR during the first rapid infusion was 1% (5 grade 1 IRRs and 1 grade 2 IRR). In conclusion, rapid 90‐min i.v. administration of SDZ‐RTX for the second and subsequent infusions during the course of therapy is well‐tolerated in patients with CD20+ lymphoma or CLL.
Summary Background The standard of care for smouldering multiple myeloma is observation. We did the QuiRedex study to compare early treatment with lenalidomide plus dexamethasone with observation in ...patients with high-risk smouldering multiple myeloma. Here we report the long-term follow-up results of the trial. Methods We did this open-label, randomised, controlled phase 3 study at 19 centres in Spain and three centres in Portugal. Patients aged 18 years or older with high-risk smouldering multiple myeloma were randomly assigned (1:1), via a computerised random number generator, to receive either early treatment with lenalidomide plus dexamethasone or observation, with dynamic balancing to maintain treatment balance within the two groups. Randomisation was stratified by time from diagnosis of smouldering multiple myeloma to study enrolment (≤6 months vs >6 months). Patients in the treatment group received nine 4-week induction cycles (lenalidomide 25 mg per day on days 1–21, plus dexamethasone 20 mg per day on days–1–4 and days 12–15), followed by maintenance therapy (lenalidomide 10 mg per day on days 1–21 of each 28-day cycle) up to 2 years. Group allocation was not masked from study investigators or patients. The primary endpoint was time from randomisation to progression to symptomatic myeloma. The primary analysis was based on the per-protocol population, restricted to patients who fulfilled the protocol in terms of eligibility. Safety assessments were based on the intention-to-treat population. This trial is registered with ClinicalTrials.gov , number NCT00480363. Findings Between Nov 8, 2007, and June 9, 2010, 125 patients were enrolled and underwent randomisation. 119 patients comprised the per-protocol population and were randomly assigned to receive either lenalidomide plus dexamethasone (n=57) or observation (n=62). The cutoff date for this update was June 30, 2015. Median follow-up for surviving patients was 75 months (IQR 67–85). Lenalidomide plus dexamethasone continued to provide a benefit on time to progression compared with observation (median time to progression not reached 95% CI 47 months–not reached vs 23 months 16–31; hazard ratio HR 0·24 95% CI 0·14–0·41; p<0·0001). Progression to multiple myeloma occurred in 53 (86%) of 62 patients in the observation group compared with 22 (39%) of 57 patients in the treatment group. At data cutoff, ten (18%) patients had died in the treatment group and 22 (36%) patients had died in the observation group; median overall survival from the time of study entry had not been reached in either group (95% CI 65 months–not reached vs 53 months–not reached; HR 0·43 95% CI 0·21–0·92, p=0·024). Survival in patients who had received subsequent treatments at the time of progression to active disease did not differ between groups (HR 1·34 95% CI 0·54–3·30; p=0·50). The most frequently reported grade 3 adverse events in patients given lenalidomide plus dexamethasone were infection (four 6%), asthenia (four 6%), neutropenia (three 5%), and skin rash (two 3%); these events all occurred during induction therapy. No grade 4 adverse events occurred, but one (2%) patient in the lenalidomide plus dexamethasone group died from a respiratory infection during induction therapy The frequency of second primary malignancies was higher in patients in the treatment group than in those in the observation group (six 10% of 62 patients vs one 2% of 63 patients), but the cumulative risk of development did not differ significantly between the groups (p=0·070). Interpretation This study is, to our knowledge, the first randomised trial in which early treatment has been assessed in selected patients with high-risk smouldering multiple myeloma. Positive results from ongoing trials would support the use of early treatment for patients with high-risk disease in the near future. Funding Pethema (Spanish Program for the Treatment of Hematologic Diseases).
Infections remain a common complication in patients with multiple myeloma (MM) and are associated with morbidity and mortality. A risk score to predict the probability of early severe infection could ...help to identify the patients that would benefit from preventive measures. We undertook a post hoc analysis of infections in four clinical trials from the Spanish Myeloma Group, involving a total of 1347 patients (847 transplant candidates). Regarding the GEM2010 > 65 trial, antibiotic prophylaxis was mandatory, so we excluded it from the final analysis. The incidence of severe infection episodes within the first 6 months was 13.8%, and majority of the patients experiencing the first episode before 4 months (11.1%). 1.2% of patients died because of infections within the first 6 months (1% before 4 months). Variables associated with increased risk of severe infection in the first 4 months included serum albumin ≤30 g/L, ECOG > 1, male sex, and non-IgA type MM. A simple risk score with these variables facilitated the identification of three risk groups with different probabilities of severe infection within the first 4 months: low-risk (score 0-2) 8.2%; intermediate-risk (score 3) 19.2%; and high-risk (score 4) 28.3%. Patients with intermediate/high risk could be candidates for prophylactic antibiotic therapies.
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Continuous treatment with lenalidomide (R) and dexamethasone (d) is a standard of care for multiple myeloma (MM) patients (pts) not candidates for autologous stem cell transplantation (ASCT). As ...previously reported, the addition of Clarithromycin (C) to Rd has proven to be safe and effective, and case-control analyses suggested a significant additive value with the combination. C optimizes the therapeutic effect of glucocorticoids by increasing the area under the curve, has immunomodulatory effects and may have direct antineoplastic properties. However, there are not randomized phase III trials confirming these results.
GEM-Claridex in an open, randomized, phase III trial for untreated newly diagnosed MM pts ineligible for ASCT. Enrolled pts were randomly assigned 1:1 to receive 28-day cycles of R (25mg po qd days 1-21), d (40mg po 20mg in pts >75 years, days 1, 8, 15 and 22) plus or minus C (500mg po bid) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), overall survival (OS) and minimal residual disease (MRD) negativity rate and safety. MRD was evaluated in 99 pts using Euroflow NGF (limit of detection, 2x10-6). As expected, most pts in CR were tested for MRD whereas the majority of pts with missing MRD data achieved VGPR or less and were thus considered as MRD-positive for intent to treat analyses.
Two hundred and eighty-eight pts were included (144 to C-Rd and 144 to Rd). Median age was 76 (range: 65-93), 36.8% of pts had ISS 3 and 15.6% presented with high-risk cytogenetic abnormalities. Key baseline characteristics were well balanced between the two arms.
The addition of C to Rd resulted in deeper responses with a ≥ complete response (CR) rate of 20.1% in the C-Rd arm compared to 11.2% in the Rd arm (p = 0.037). Also, the ≥ very good partial response (VGPR) rate was 52.8% in the C-Rd arm as compared to the 37.1% in the Rd arm (p = 0.007). MRD analysis was performed at suspected CR and yearly afterwards. On intent-to-treat, 5/144 (3,5%) and 9/143 (6,2%) of pts achieved undetectable MRD with C-Rd and Rd, respectively (p = 0,7).
With a median follow-up of 16 months (range, 1-47), no significant differences were observed in PFS: in the C-Rd arm the median was 23 months and has not been reached in the Rd arm (p = 0.09); furthermore, although disease progression and/or death rate was comparable in both arms (C-Rd: 57/144 39.6% vs Rd: 45/144 31.2%), a trend towards shorter PFS was observed in the C-Rd group (Figure 1). This effect was less evident in younger (<75) pts (median PFS, C-Rd: 24 months vs Rd NR, p = 0,588) but, in older pts (≥ 75), the addition of C to Rd resulted into a significant deleterious effect on PFS (median PFS, C-Rd: 19 vs Rd 28 months, p = 0.03) (Figure 2a and 2b). Irrespectively of treatment arm, pts with MRD negative had significantly longer PFS (NR vs 26 months, p = 0,03). Concerning OS, no differences have been identified (p = 0.41), although median has not been reached yet in any arm. Out of the 33 and 28 deaths documented in the C-Rd and Rd arms respectively, the percentage of pts dying w/o documented PD was significantly higher in the C-Rd group (27/33 82% vs 13/27 48%, p = 0.004). Furthermore, in the C-Rd arm, the most frequent causes of death were severe infections (14/27 52% and cardiovascular events 6/27 22%) the majority of them occurring in older (≥75) pts (20/27, 74%).
The most common G3-4 adverse events (AE) in the C-Rd and Rd arms were hematologic (neutropenia: 10,4% vs 16,7% p = ns and anemia: 2,1% vs 6,9% p = 0,04, respectively). G3-4 infections occurred in 16% of cases in both arms and were the most frequent non-hematological AE. 7% of pts in both arms developed G3-4 GI toxicity and there were no differences between the two arms in G3-4 skin-related AEs (2,8% vs 3,5%). Only one case of invasive SPM (colon cancer) in the C-Rd arm was reported.
In conclusion, the addition of C to Rd in transplant ineligible newly diagnosed MM pts significantly increases the rate and depth of responses but it is not associated with an improved PFS and OS due to a higher proportion of deaths in the C-Rd arm, mostly infectious, in pts > 75 years and being early deaths. Overexposure to steroids due to the delayed clearance induced by C in this elderly population could explain our results.
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Puig:The Binding Site: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Rosinol Dachs:Janssen, Celgene, Amgen and Takeda: Honoraria. De Arriba:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Honoraria. Oriol:Celgene Corporation: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau. De La Rubia:AbbVie: Consultancy; AMGEN: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Amor:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Martín Sánchez:GILEAD SCIENCES: Research Funding. Rossi:BMS: Research Funding; Janssen, Celgene, Amgen: Consultancy. Coleman:Merck: Research Funding; Pharmacyclics: Speakers Bureau; Kite Pharmaceuticals: Equity Ownership; Gilead, Bayer, Celgene: Consultancy, Research Funding, Speakers Bureau. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; unrestricted grants from Celgene, EngMab, Sanofi, and Takeda; and consultancy for Celgene, Janssen, and Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Bladé:Jansen, Celgene, Takeda, Amgen and Oncopeptides: Honoraria. Niesvizky:Takeda, Amgen, BMS, Janssen, Celgene: Consultancy, Research Funding. Mateos:EDO: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria.
There is evidence of reduced SARS-CoV-2 vaccine effectiveness in patients with hematological malignancies. We hypothesized that tumor and treatment-related immunosuppression can be depicted in ...peripheral blood, and that immune profiling prior to vaccination can help predict immunogenicity. We performed a comprehensive immunological characterization of 83 hematological patients before vaccination and measured IgM, IgG, and IgA antibody response to four viral antigens at day +7 after second-dose COVID-19 vaccination using multidimensional and computational flow cytometry. Health care practitioners of similar age were the control group (n = 102). Forty-four out of 59 immune cell types were significantly altered in patients; those with monoclonal gammopathies showed greater immunosuppression than patients with B-cell disorders and Hodgkin lymphoma. Immune dysregulation emerged before treatment, peaked while on-therapy, and did not return to normalcy after stopping treatment. We identified an immunotype that was significantly associated with poor antibody response and uncovered that the frequency of neutrophils, classical monocytes, CD4, and CD8 effector memory CD127low T cells, as well as naive CD21+ and IgM+D+ memory B cells, were independently associated with immunogenicity. Thus, we provide novel immune biomarkers to predict COVID-19 vaccine effectiveness in hematological patients, which are complementary to treatment-related factors and may help tailoring possible vaccine boosters.
Melphalan flufenamide (melflufen), an alkylating peptide-drug conjugate, plus dexamethasone showed clinical activity and manageable safety in the phase 2 HORIZON study. We aimed to determine whether ...melflufen plus dexamethasone would provide a progression-free survival benefit compared with pomalidomide plus dexamethasone in patients with previously treated multiple myeloma.
In this randomised, open-label, head-to-head, phase 3 study (OCEAN), adult patients (aged ≥18 years) were recruited from 108 university hospitals, specialist hospitals, and community-based centres in 21 countries across Europe, North America, and Asia. Eligible patients had an ECOG performance status of 0-2; must have had relapsed or refractory multiple myeloma, refractory to lenalidomide (within 18 months of randomisation) and to the last line of therapy; and have received two to four previous lines of therapy (including lenalidomide and a proteasome inhibitor). Patients were randomly assigned (1:1), stratified by age, number of previous lines of therapy, and International Staging System score, to either 28-day cycles of melflufen and dexamethasone (melflufen group) or pomalidomide and dexamethasone (pomalidomide group). All patients received dexamethasone 40 mg orally on days 1, 8, 15, and 22 of each cycle. In the melflufen group, patients received melflufen 40 mg intravenously over 30 min on day 1 of each cycle and in the pomalidomide group, patients received pomalidomide 4 mg orally daily on days 1 to 21 of each cycle. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat (ITT) population. Safety was assessed in patients who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03151811, and is ongoing.
Between June 12, 2017, and Sept 3, 2020, 246 patients were randomly assigned to the melflufen group (median age 68 years IQR 60-72; 107 43% were female) and 249 to the pomalidomide group (median age 68 years IQR 61-72; 109 44% were female). 474 patients received at least one dose of study drug (melflufen group n=228; pomalidomide group n=246; safety population). Data cutoff was Feb 3, 2021. Median progression-free survival was 6·8 months (95% CI 5·0-8·5; 165 67% of 246 patients had an event) in the melflufen group and 4·9 months (4·2-5·7; 190 76% of 249 patients had an event) in the pomalidomide group (hazard ratio HR 0·79, 95% CI 0·64-0·98; p=0·032), at a median follow-up of 15·5 months (IQR 9·4-22·8) in the melflufen group and 16·3 months (10·1-23·2) in the pomalidomide group. Median overall survival was 19·8 months (95% CI 15·1-25·6) at a median follow-up of 19·8 months (IQR 12·0-25·0) in the melflufen group and 25·0 months (95% CI 18·1-31·9) in the pomalidomide group at a median follow-up of 18·6 months (IQR 11·8-23·7; HR 1·10 95% CI 0·85-1·44; p=0·47). The most common grade 3 or 4 treatment-emergent adverse events were thrombocytopenia (143 63% of 228 in the melflufen group vs 26 11% of 246 in the pomalidomide group), neutropenia (123 54% vs 102 41%), and anaemia (97 43% vs 44 18%). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) in the pomalidomide group, the most common of which were pneumonia (13 6% vs 21 9%), COVID-19 pneumonia (11 5% vs nine 4%), and thrombocytopenia (nine 4% vs three 1%). 27 12% patients in the melflufen group and 32 13% in the pomalidomide group had fatal treatment-emergent adverse events. Fatal treatment-emergent adverse events were considered possibly treatment related in two patients in the melflufen group (one with acute myeloid leukaemia, one with pancytopenia and acute cardiac failure) and four patients in the pomalidomide group (two patients with pneumonia, one with myelodysplastic syndromes, one with COVID-19 pneumonia).
Melflufen plus dexamethasone showed superior progression-free survival than pomalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma.
Oncopeptides AB.
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