The notion that plasma cells (PCs) are terminally differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n = 20) that the CD19 − CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19 − CD81+ and CD19 − CD81 − BMPCs. Afterwards, we demonstrated in 225 newly diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully differentiated (CD19 − CD81 −) clones, 38% intermediate- Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts differentiated (CD19 − CD81+) and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR: 1.7; P = 0.005) and overall survival (HR: 2.1; P = 0.006). Longitudinal comparison of diagnostic vs minimal-residual-disease samples (n = 40) unraveled that in 20% of patients, less-differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less-differentiated clonal PCs retain high expression of genes related to preceding B-cell stages (for example: PAX5), and show distinct mutation profile vs fully differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harbouring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles.
Patients from groups BA and BB presented with a significantly higher number of adverse prognostic factors, reflecting that we were dealing with high tumor MM cases, as compared with patients from group AA. The number of mononuclear cells, CD34+ cells and CFU-GM cells collected in patients with non-reversible renal insufficiency was similar to those harvested in MM patients with normal renal function. Moreover, neutrophil and platelet engraftments were identical in patients with and without renal failure (days +11 and +12, respectively). By contrast, transplant-related mortality (TRM) was significantly higher in group BB patients (29%) than in groups BA (4.1%) and AA (3.3%). In multivariate analysis only three variables showed independent influence on TRM: poor performance status (ECOG 3), hemoglobin <9.5 g/dl and serum creatinine > or =5 mg/dl. The response to high dose therapy was independent of renal function. Interestingly, 43% of patients from group BB showed an improvement in renal function (creatinine < 2 mg/dl) after transplant. The three-year overall survival from transplantation was 56, 49 and 61% for the BB, BA and AA groups, respectively, with a statistically significant difference favoring group AA (P<0.01). PFS did not differ significantly between the three groups of patients. In multivariate analysis the only unfavorable independent prognostic factors for overall survival were poor performance status either at diagnosis or at transplant, high beta(2)-microglobulin levels, and no response to transplant. According to these results, ASCT is an attractive alternative for MM patients with renal insufficiency, and it should not constitute a criterion for exclusion from transplant unless patients display poor performance status and very high creatinine levels (>5 mg/dl).
Background: For patients with smoldering multiple myeloma (SMM), the standard of care is observation. However, high-risk patients may benefit from early intervention. Methods: In this phase 3 trial, 119 patients with high-risk SMM were randomized to treatment or observation. The high risk populationwas defined by the presence of both PC_ 10% and MC_ 3g/dl or ifonly one criterion was present, patients must have a proportionof aPC within the total PCBM compartment by immunophenotypingof 95% plus immunoparesis. Patients in the treatment group received nine 4-week induction cycles (lenalidomide at a dose of 25 mg per day on days 1 to 21, plus dexamethasone at a dose of 20 mg per day on days 1 to 4 and days 12 to 15), followed by maintenance (lenalidomide at a dose of 10 mg per day on days 1 to 21 of each 28-day cycle) up to 2 years. The primary end point was time to progression (TTP) to myeloma. Secondary end points were overall survival (OS), response rate and safety. Results: After a median follow-up of 75 months (range: 57-100), there was a 57% reduction in the risk of death for the early treatment with lenalidomide-dexamethasone versus not treatment (hazard ratio, 0.43; 95% confidence interval, 0.2 to 0.9; P=0.02). Median overall survival has not been reached in either group, but 86% and 62% of patients are alive at 6 years in the early treatment and observation arms, respectively (Figure 1). The benefit in TTP is also highly sustained (hazard ratio: 0.24 (95% confidence interval, 0.14 to 0.41; P<0.0001). Progression to MM occurred in 53 out of the 62 patients (86%) in the abstention arm while only 22 out of 57 patients (38%) in the len-dex arm. At the time of progression patients received optimized treatments: bortezomib-based combinations were administered to thirteen out of 22 patients (59%) in the len-dex arm and to 23 out of 53 patients (43%) in the observation arm; lenalidomide-based combinations to 3 out of 22 patients (14%) in the experimental and to 8 out of 53 patients (15%) in the control arm; two out of 22 patients in the len-dex arm (9%) received bortezomib plus immunomodulatory agents whilst 16 out of 53 patients (30%) in the observation group received this combination; four out of 22 patients (18%) and six out of 53 patients (11%) in the len-dex and observation groups, respectively, were treated with chemotherapy; four patients (18%) in the experimental arm and 15 (28%) in the observation groups received an ASCT. Most patients responded to rescue therapies in both arms, resulting in overall response rates of 78% (17/22) and 86% (45/53) in the experimental and control arm, respectively. We compared survival from start of subsequent therapy in the patients population who progressed to active disease; the outcome was similar in both arms: at 6 years, 62% (16/22) of the patients in the len-dex arm remain alive and 49% (31/53) in the observation arm (P=0.50; Fig. 2C). The survival benefit observed was independent of the classification model used for defining high risk SMM ( Mayo Clinic and Spanish model) Conclusion: This long term follow-up analysis confirms that early treatment with lenalidomide-dexamethasone for high-risk SMM translates into a significant benefit in TTP but also in a sustained significant prolongation of the OS. The early exposure to lenalidomide-dexamethasone does not induce more resistant relapses. Figure 1 Figure 1. Disclosures Mateos: Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria. De La Rubia:Amgen, Bristol Myers, Celgene, Janssen: Consultancy. Paiva:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; EngMab: Research Funding; Amgen: Honoraria; Binding Site: Research Funding. Oriol: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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.
Background VMP and Rd are two of the most efficient and widely accepted regimens in the treatment of elderly newly diagnosed MM patients. In order to further improve the outcome of elderly patients, one possibility would be to use regimens including all these drugs simultaneously, but this may result into high toxicity. Alternatively, the use of these regimens (VMP and Rd) in a sequential or alternating scheme could improve the treatment of elderly patients. We hypothesized the alternating scheme would minimize the emergence of resistant clones, and would reduce the cumulative toxicity. In order to test this hypothesis we decided to compare VMP and RD in a sequential vs an alternating scheme. Patients and methods 241 patients were randomized to receive a sequential scheme consisting on 9 cycles of VMP followed by 9 cycles of Rd or the same regimens in an alternating approach (one cycle of VMP alternating with one Rd (half of the patients started by VMP and half by Rd) up to 18 cycles). VMP included the iv administration of bortezomib 1.3 mg/m2 twice weekly for 1 six-weeks cycle, followed by once weekly for 8 four-weeks cycles in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1–4 of each cycle. Rd treatment consisted on lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly. Results 121 patients were allocated to receive the sequential scheme and 120 the alternating regimen. Both arms were well balanced according to the baseline characteristics. 52% patients in the sequential arm and 55% in the alternating and had high risk cytogenetic abnormalities (t(4;14), t(14;16), del17p or 1q gains). After 9 cycles of treatment, in the sequential arm, 35 out of 66 (54%) achieved at least VGPR vs 51 out of 65 patients (78%) in the alternating arm (p=0.002), including sCR/CR rate of 28% vs 38% in the sequential and alternating arms, respectively (p=NS). Seven patients in each arm achieved immunophenotypic CR. Moreover, while four patients progressed in the sequential arm under treatment with VMP, no patients in the alternating scheme developed disease progression during the first 9 cycles, After a median follow up of 12 months, there was a trend for shorter TTP in the sequential as compared with the alternating scheme (18 m-TTP of 83% vs 89% (p=NS)). In terms of OS, 83% of patients in the sequential arm were alive at 18 m versus 93% in the alternating (p=NS). Patients who achieved sCR/CR had a significantly longer 18 m-TTP as compared with patients who didn’t achieve it in both sequential (100% vs 71%; p=0.006) and alternating arms (100% vs 79%; p=0.006) and this translated into a significant benefit in OS. No differences were observed in overall response rates and CR rates in standard and high risk patients. The 18 m-TTP was similar in standard and high risk groups in both sequential (86% vs 81%) and alternating arms (84% vs 94%), noting that 94% of patients receiving the alternating scheme were progression-free at 18 months. Regarding hematologic toxicity, the frequency of G3-4 neutropenia was slightly lower in the sequential than in the alternating arm (16% and 23%) and the same trend was observed for G3-4 thrombocytopenia (16% vs 20%). Concerning non-hematologic toxicity, 5% and 4% of the patients in the sequential and alternating arms developed G3-4 infections, respectively; the rate of G3-4 skin rash was 4% in the sequential and 3% in the alternating arm; 4% of patients in the sequential arm developed G3-4 peripheral neuropathy and 3% in the sequential arm. The rate of grade 3-4 thrombotic events was 2% in both arms. Nevertheless, the detailed evaluation of the toxicity will be done at the completion of the trial when all patients will have received the same amount of drugs in either a sequential or an alternating scheme (at the present time, 42 patients in the sequential arm were not yet at risk for the development of lenalidomide-related side effects). Conclusions The administration of melphalan, bortezomib, lenalidomide and steroids in elderly MM patients in a sequential or alternating scheme is feasible. Although longer follow-up is necessary, the alternating scheme may be superior in terms of response rate and outcome, as result of the early exposure of the plasma cell to different agents. Toxicity profile is acceptable. Aparently both schemes of therapy seems to overcome the poor prognosis of high risk cytogenetic. Disclosures: Mateos: Janssen, Celgene: Honoraria. Off Label Use: Lenalidomide plus dexamethasone is not approved for newly diagnosed MM patients. Ocio:Onyx: Consultancy, Research Funding; Novartis: Consultancy; Array Biopharma: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding. San Miguel:Janssen, Celgene: Membership on an entity’s Board of Directors or advisory committees.
MM patients are living longer with increasingly effective therapies, but long-term complications including second primary malignancies (SPMs) are becoming new challenges in designing optimal patient care. It has been demonstrated in large studies that amongst others, risk is particularly high for SPMs such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Importantly, such increased risk of MDS/AML has also been observed in MGUS patients, suggesting that increased risk for MDS/AML may not only be treatment related but inheritably high in MGUS/MM. Thus, there is need to investigate for biomarkers that uncover cellular alterations predisposing for higher risk of MDS/AML in MM. Here, we started by investigating in 312 newly diagnosed MM patients the presence of MDS-like phenotypic abnormalities (MDS-PA) in bone marrow (BM) neutrophil, monocytic, and erythroid lineages, using multidimensional flow cytometry 8 color combinations (CD138, CD27, CD38, CD56, CD45, CD19, CD117, CD81; and HLADR, CD45, CD36, CD13, CD34, CD117, CD11b, CD71). Up to 33/312 (11%) patients showed MDS-PA at diagnosis, which were more frequently observed in the neutrophil lineage (6%), followed by monocytic (4%) and erythroid (4%) lineages. Four cases had multilineage MDS-PA. Afterwards, we investigated if the presence of MDS-PA was associated with underlying somatic mutations by performing targeted sequencing of 54 MDS/AML related genes (depth ≥500x) in 44 patients from the previous series (10 with MDS-PA and 34 without). Next generation sequencing was performed, at diagnosis and after HDT/ASCT in FACS sorted CD34+ hematopoietic stem cells (HSCs) and dysplastic cell lineages from patients with MDS-PA, as well as in HSC from cases without MDS-PA. CD138+ BM plasma cells (PCs) from both cohorts were also sequenced using the same panel. Six out of the 10 cases with MDS-PA showed somatic mutations. Namely, HSCs from one patient had two mutations in TET2 [allele fraction (AF): 18%, ≥ 26017x] one in CALR (AF: 14%, 1158x) and another in ASXL1 (AF: 7%, 1339x). None of these mutations were present in myeloid/erythroid cells. A second patient had NPM1 mutated in HSCs (AF: 7%, 12825x), which was absent in neutrophils. A third case had TET2 mutated in HSCs (AF: 16%, 1233x) as well as in dysplastic monocytes (AF: 27%, 16647x) and neutrophils (AF: 23%, 21719x). In the fourth case, a mutation in BCORL1 was noted in dysplastic erythroid cells (AF: 10%, 796x). The fifth patient had TET2 mutated in both HSCs and dysplastic monocytes (AF: 45%-63%; ≥21799x). The sixth case had PHF6 mutated in HSCs (AF: 8%; 800x). In none of the patients were the mutations found in HSCs and/or dysplastic lineages, present in PCs. Within the control cohort of the 34 patients without MDS-PA, only two of them displayed somatic mutations in HSCs; one case had DNMT3A mutated (AF: 26%, 1900x) and the other TET2 (AF: 13%, 3400x). After demonstrating a correlation between MDS-PA and MDS/AML-related somatic mutations, we sought to analyze the prognostic significance of such alterations in MM. Since the follow-up of the present series of 312 cases is relatively short, we focused on a large series of 965 patients with longer follow up (median of 6.5 years) enrolled in GEM clinical trials, and for which the presence of CD56+ aberrant monocytes could be readily investigated. Noteworthy, this particular MDS-PA was again observed in a similar frequency as noted above (n=63; 6.5%) and as compared to the overall MM population, patients with MDS-PA showed significantly higher age, lower hemoglobin values and higher BMPC infiltration at diagnosis. Furthermore, they experienced more frequently hematological toxicity including anemia and neutropenia during treatment. Most interestingly, as compared to the overall MM population, patients with MDS-PA had significantly inferior progression-free (medians of 24 vs 37 months; P=.006) and overall survival (medians of 47 vs 73 months; P=.01). In conclusion, we showed for the first time that a fraction of newly diagnosed MM patients harbors MDS/AML-related somatic mutations in HSCs and myeloid/erythroid lineages, and that such patients could be predicted through flow-based screening for MDS-PA. The presence of MDS-PA identifies a subset of patients that experience more frequently hematological toxicity and display inferior survival; accordingly, screening for MDS-PA could become an important biomarker to tailor treatment in MM. Disclosures Paiva: Celgene: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; EngMab: Research Funding; Amgen: Honoraria; Binding Site: Research Funding. Oriol:Amgen: Honoraria, Other: Expert board committee; Janssen: Honoraria, Other: Expert board committee. Mateos:Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria.
Background: VMP and Rd are two of the most effective regimens in the treatment of elderly newly diagnosed MM pts. In order to further improve its outcome, one possibility would be to use regimens including all these drugs simultaneously, but this may result toxic. Alternatively, the use of these regimens (VMP and Rd) in a sequential or alternating scheme could improve the treatment of these pts. We hypothesized the alternating scheme would minimize the emergence of resistant clones, and would reduce the cumulative toxicity. In order to test this hypothesis we decided to compare VMP and Rd in a sequential vs an alternating scheme. Pts and methods: 242 pts were randomized to receive a sequential scheme consisting on 9 cycles of VMP followed by 9 cycles of Rd or the same regimens in an alternating approach (one cycle of VMP alternating with one Rd, up to 18 cycles. VMP included the iv administration of weekly bortezomib (except in the first cycle that was given twice weekly) at 1.3 mg/m2 in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1–4. Rd treatment consisted on lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly. Results: 233 pts were evaluable for safety and efficacy (118 in the sequential and 115 in the alternating arm). Both arms were well balanced according to the baseline characteristics. Of note, 55% of pts in the sequential and 44% in the alternating arm were older than 75 yrs. Fifty-one percent in the sequential arm and 52% in the alternating had high risk cytogenetic abnormalities (t(4;14), t(14;16), del17p or 1q gains). After 9 cycles, the sCR/CR rate was lower in the sequential (20%) than in the alternating arm (32%)(p=0.02). However, among the 179 pts that were evaluable for efficacy after the 18 planned cycles of treatment, the pattern reversed: 51% achieved sCR/CR in the sequential vs 38% in the alternating arm (p=0,05). The flow-CR rate among patients in sCR/CR was 66% and 48% in the sequential vs alternating arms, respectively (P=0.16). To achieve flow-CR was associated with a significantly longer TTP (median not reached vs 15 months since the end of treatment; P=.01). After a median f/u of 27 months, median PFS was of 30 months in both sequential and alternating arms (p=NS). Median OS has not been reached, and 68% and 67% of pts are alive at 3 yrs (p=NS). Pts who achieved sCR/CR had significantly longer PFS and OS as compared with pts who did not (3-yrs PFS for sCR/CR of 76% vs 18% for <CR (p<0.0001), and 3-yrs OS of 94% vs 53% for sCR/CR vs <CR (p<0.0001)) in both arms. The achievement of flow-CR has been also associated with 3-yrs PFS of 84% vs 38% months for pts who did not achieve flow-CR. This benefit has been observed in both arms. Pts younger than 75 yrs showed a significantly longer survival as compared to pts ≥75y (3-yrs PFS of 55% vs 27m, p=0.04) and 3-yrs OS of 89% vs 35m, p<0.0001 ) , with no significant differences between sequential and alternating arms. No differences were observed in overall response rates and sCR/CR rates in standard and high risk pts, but there was a trend toward shorter PFS and OS in the subgroup of high-risk CA (median PFS of 28 months and 3-yrs OS of 64%, pNS) vs standard-risk (3-yrs PFS of 54% and 3-yrs OS of 80%, pNS). Regarding hematologic toxicity, no significant differences were observed between the sequential and alternating arms in the frequency of G3-4 neutropenia (19% and 22%) or thrombocytopenia (21% and 20%). Concerning non-hematologic toxicity, 3% and 6% of the pts in the sequential and alternating arms had G3-4 infections. No differences were observed neither in the the incidence of peripheral neuropathy in the sequential and alternating arms (4% and 3%, respectively) nor in the rate of grade 3-4 thrombotic events (1% and 2%). The rate of early discontinuations (15%) and deaths (4%) before the cycle 9 were identical in both arms; of note 71% of early discontinuations occurred in pts aged over 75 yrs and all early deaths but one were also in pts older than 75 yrs. Conclusions: The alternating regimen has demonstrated to be not superior to the sequential approach. Toxicity profile is acceptable. This Total Therapy approach, including the four active anti-myeloma agents (melphalan, bortezomib, lenalidomide and steroids) is particularly active in pts between 65-75 years old, with similar survival to that of transplant candidate pts with outstanding outcome when sCR/CR is achieved. Disclosures Mateos: Celgene: 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. Off Label Use: Lenalidomide as first-line combination therapy for AL amyloidosis.. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Ocio:Celgene Corporation: Honoraria, Research Funding. Pérez de Oteyza:Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Oriol:Celgene Corporation: Consultancy. De La Rubia:Janssen: Honoraria; Celgene: Honoraria. Bladé:Janssen: Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Grant support, Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Janssen: Honoraria; Celgene: Honoraria.
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