Maintenance lenalidomide in newly diagnosed transplant eligible and non-eligible myeloma patients; profiling second primary malignancies in 4358 patients treated in the Myeloma XI Trial.

Background: Early trials of long-term lenalidomide use reported an increased incidence of second primary malignancy (SPM), including acute myeloid leukaemia and myelodysplastic syndrome. Later, meta-analysis suggested the link to be secondary to lenalidomide in combination with melphalan. Methods: Myeloma XI is a large, phase III randomised trial in-which lenalidomide was used at induction and maintenance, in transplant eligible (TE) and non-eligible (TNE) newly diagnosed patients (NCT01554852). Here we present an analysis of SPM incidence and profile the SPM type to determine the impact of autologous stem cell transplantation (ASCT) and lenalidomide exposure in 4358 patients treated on study. Data collection took place from the start of the trial in May 2010, to May 2019, as per the protocol timeline. The Median follow-up following maintenance randomisation was 54.5 and 46.1 months for TE and TNE patients, respectively. Findings: In the TE pathway, the overall SPM incidence was 7.7% in lenalidomide maintenance patients compared to 3.2% in those being observed (p = 0.006). Although the TNE lenalidomide maintenance patients had the greatest SPM incidence (15.4%), this was not statistically significant when compared to the observed patients (10%, p = 0.10).The SPM incidence was higher in patients who received lenalidomide at induction and maintenance (double exposure), when compared to those treated with lenalidomide at one time point (single exposure). Again, this was most marked in TNE patients where the overall SPM incidence was 16.9% in double exposed patients, compared to 11.7% in single exposed patients, and 11.2% in patients who did not receive lenalidomide (p = 0.04). This is likely an effect of treatment duration, with the median number of cycles being 27 in the TNE double exposed patients, vs 6 in the single exposure patients.Haematological SPMs were uncommon, diagnosed in 50 patients (incidence 1.1%). The majority of cases were diagnosed in TE patients treated with lenalidomide maintenance (n = 25, incidence 2.8%), suggesting a possible link with melphalan. Non-melanoma skin cancer incidence was highest in patients receiving lenalidomide maintenance, particularly in TNE patients, where squamous cell carcinoma and basal cell carcinoma were diagnosed in 5.5% and 2.6% of patients, respectively. The incidence of most solid tumour types was higher in lenalidomide maintenance patients.Mortality due to progressive myeloma was reduced in patients receiving lenalidomide maintenance, noted to be 16.6% compared 22.6% in those observed in TE patients and 32.7% compared to 41.5% in TNE patients. SPM related mortality was low, 1.8% and 6.1% in TE and TNE lenalidomide maintenance patients, respectively, compared to 0.4% and 2.8% in those being observed. Interpretation: This provides reassurance that long-term lenalidomide treatment is safe and associated with improved outcomes in TE and TNE populations, although monitoring for SPM development should be incorporated into clinic review processes. Funding: Primary financial support was from Cancer Research UK [C1298/A10410].

Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, and Dexamethasone as Induction and Extended Consolidation Improves Outcome in Ultra-High-Risk Multiple Myeloma.

PURPOSE: The multicenter OPTIMUM (MUKnine) phase II trial investigated daratumumab, low-dose cyclophosphamide, lenalidomide, bortezomib, and dexamethasone (Dara-CVRd) before and after autologous stem-cell transplant (ASCT) in newly diagnosed patients with molecularly defined ultra-high-risk (UHiR) multiple myeloma (NDMM) or plasma cell leukemia (PCL). To provide clinical context, progression-free survival (PFS) and overall survival (OS) were referenced to contemporaneous outcomes seen in patients with UHiR NDMM treated in the recent Myeloma XI (MyeXI) trial. METHODS: Transplant-eligible all-comers NDMM patients were profiled for UHiR disease, defined by presence of ≥2 genetic risk markers t(4;14)/t(14;16)/t(14;20), del(1p), gain(1q), and del(17p), and/or SKY92 gene expression risk signature. Patients with UHiR MM/PCL were offered treatment with Dara-CVRd induction, V-augmented ASCT, extended Dara-VR(d) consolidation, and Dara-R maintenance. UHiR patients treated in MyeXI with carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide, or lenalidomide, dexamethasone, and cyclophosphamide, ASCT, and R maintenance or observation were identified by mirrored molecular screening. OPTIMUM PFS at 18 months (PFS18m) was compared against MyeXI using a Bayesian framework, and patients were followed up to the end of consolidation for PFS and OS. RESULTS: Of 412 screened NDMM OPTIMUM patients, 103 were identified as UHiR or PCL and subsequently treated on trial with Dara-CVRd; 117 MyeXI patients identified as UHiR formed the external comparator arm, with comparable clinical and molecular characteristics to OPTIMUM. Comparison of PFS18m per Bayesian framework resulted in a 99.5% chance of OPTIMUM being superior to MyeXI. At 30 months' follow-up, PFS was 77% for OPTIMUM versus 39.8% for MyeXI, and OS 83.5% versus 73.5%, respectively. Extended post-ASCT Dara-VRd consolidation therapy was highly deliverable, with limited toxicity. CONCLUSION: Our results suggest that Dara-CVRd induction and extended post-ASCT Dara-VRd consolidation markedly improve PFS for UHiR NDMM patients over conventional management, supporting further evaluation of this strategy.

Immune responses to COVID-19 booster vaccinations in intensively anti-CD38 antibody treated patients with ultra-high-risk multiple myeloma: results from the Myeloma UK (MUK) nine OPTIMUM trial.

Multiple myeloma (MM) and anti-MM therapy cause profound immunosuppression, leaving patients vulnerable to coronavirus disease 2019 (COVID-19) and other infections. We investigated anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antibodies longitudinally in ultra-high-risk patients with MM receiving risk-adapted, intensive anti-CD38 combined therapy in the Myeloma UK (MUK) nine trial. Despite continuous intensive therapy, seroconversion was achieved in all patients, but required a greater number of vaccinations compared to healthy individuals, highlighting the importance of booster vaccinations in this population. Reassuringly, high antibody cross-reactivity was found with current variants of concern, prior to Omicron subvariant adapted boostering. Multiple booster vaccine doses can provide effective protection from COVID-19, even with intensive anti-CD38 therapy for high-risk MM.

The addition of vorinostat to lenalidomide maintenance for patients with newly diagnosed multiple myeloma of all ages: results from 'Myeloma XI', a multicentre, open-label, randomised, phase III trial.

Lenalidomide is an effective maintenance agent for patients with myeloma, prolonging first remission and, in transplant eligible patients, improving overall survival (OS) compared to observation. The 'Myeloma XI' trial, for newly diagnosed patients, aimed to evaluate whether the addition of the histone deacetylase inhibitor vorinostat to the lenalidomide maintenance backbone could improve outcomes further. Patients included in this analysis were randomised to maintenance therapy with lenalidomide alone (10 mg/day on days 1-21 of each 28-day cycle), or in combination with vorinostat (300 mg/day on day 1-7 and 15-21 of each 28-day cycle) with treatment continuing until unacceptable toxicity or progressive disease. There was no significant difference in median progression-free survival between those receiving lenalidomide-vorinostat or lenalidomide alone, 34 and 40 months respectively (hazard ratio [HR] 1.18, 95% confidence interval [CI] 0.96-1.44, p = 0.109). There was also no significant difference in median OS, not estimable and 75 months respectively (HR 0.99, 95% CI 0.76-1.29, p = 0.929). Subgroup analysis demonstrated no statistically significant heterogeneity in outcomes. Combination lenalidomide-vorinostat appeared to be poorly tolerated with more dose modifications, fewer cycles of maintenance therapy delivered and higher rates of discontinuation due to toxicity than lenalidomide alone. The trial did not meet its primary end-point, there was no benefit from the addition of vorinostat to lenalidomide maintenance.

Minimal Residual Disease After Autologous Stem-Cell Transplant for Patients With Myeloma: Prognostic Significance and the Impact of Lenalidomide Maintenance and Molecular Risk.

PURPOSE: Minimal residual disease (MRD) can predict outcomes in patients with multiple myeloma, but limited data are available on the prognostic impact of MRD when assessed at serial time points in the context of maintenance therapy after autologous stem-cell transplant (ASCT) and the interaction between MRD and molecular risk. METHODS: Data from a large phase III trial (Myeloma XI) were examined to determine the relationship between MRD status, progression-free survival (PFS), and overall survival (OS) in post-ASCT patients randomly assigned to lenalidomide maintenance or no maintenance at 3 months after ASCT. MRD status was assessed by flow cytometry (median sensitivity 0.004%) before maintenance random assignment (ASCT + 3) and 6 months later (ASCT + 9). RESULTS: At ASCT + 3, 475 of 750 (63.3%) patients were MRD-negative and 275 (36.7%) were MRD-positive. MRD-negative status was associated with improved PFS (hazard ratio [HR] = 0.47; 95% CI, 0.37 to 0.58 P < .001) and OS (HR = 0.59; 95% CI, 0.40 to 0.85; P = .0046). At ASCT + 9, 214 of 326 (65.6%) were MRD-negative and 112 (34.4%) were MRD-positive. MRD-negative status was associated with improved PFS (HR = 0.20; 95% CI, 0.13 to 0.31; P < .0001) and OS (HR = 0.33; 95% CI, 0.15 to 0.75; P = .0077). The findings were very similar when restricted to patients with complete response/near complete response. Sustained MRD negativity from ASCT + 3 to ASCT + 9 or the conversion to MRD negativity by ASCT + 9 was associated with the longest PFS/OS. Patients randomly assigned to lenalidomide maintenance were more likely to convert from being MRD-positive before maintenance random assignment to MRD-negative 6 months later (lenalidomide 30%, observation 17%). High-risk molecular features had an adverse effect on PFS and OS even for those patients achieving MRD-negative status. On multivariable analysis of MRD status, maintenance therapy and molecular risk maintained prognostic impact at both ASCT + 3 and ASCT + 9. CONCLUSION: In patients with multiple myeloma, MRD status at both ASCT + 3 and ASCT + 9 is a powerful predictor of PFS and OS.

Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial.

BACKGROUND: Carfilzomib is a second-generation irreversible proteasome inhibitor that is efficacious in the treatment of myeloma and carries less risk of peripheral neuropathy than first-generation proteasome inhibitors, making it more amenable to combination therapy. METHODS AND FINDINGS: The Myeloma XI+ trial recruited patients from 88 sites across the UK between 5 December 2013 and 20 April 2016. Patients with newly diagnosed multiple myeloma eligible for transplantation were randomly assigned to receive the combination carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) or a triplet of lenalidomide, dexamethasone, and cyclophosphamide (Rdc) or thalidomide, dexamethasone, and cyclophosphamide (Tdc). All patients were planned to receive an autologous stem cell transplantation (ASCT) prior to a randomisation between lenalidomide maintenance and observation. Eligible patients were aged over 18 years and had symptomatic myeloma. The co-primary endpoints for the study were progression-free survival (PFS) and overall survival (OS) for KRdc versus the Tdc/Rdc control group by intention to treat. PFS, response, and safety outcomes are reported following a planned interim analysis. The trial is registered (ISRCTN49407852) and has completed recruitment. In total, 1,056 patients (median age 61 years, range 33 to 75, 39.1% female) underwent induction randomisation to KRdc (n = 526) or control (Tdc/Rdc, n = 530). After a median follow-up of 34.5 months, KRdc was associated with a significantly longer PFS than the triplet control group (hazard ratio 0.63, 95% CI 0.51-0.76). The median PFS for patients receiving KRdc is not yet estimable, versus 36.2 months for the triplet control group (p < 0.001). Improved PFS was consistent across subgroups of patients including those with genetically high-risk disease. At the end of induction, the percentage of patients achieving at least a very good partial response was 82.3% in the KRdc group versus 58.9% in the control group (odds ratio 4.35, 95% CI 3.19-5.94, p < 0.001). Minimal residual disease negativity (cutoff 4 × 10-5 bone marrow leucocytes) was achieved in 55% of patients tested in the KRdc group at the end of induction, increasing to 75% of those tested after ASCT. The most common adverse events were haematological, with a low incidence of cardiac events. The trial continues to follow up patients to the co-primary endpoint of OS and for planned long-term follow-up analysis. Limitations of the study include a lack of blinding to treatment regimen and that the triplet control regimen did not include a proteasome inhibitor for all patients, which would be considered a current standard of care in many parts of the world. CONCLUSIONS: The KRdc combination was well tolerated and was associated with both an increased percentage of patients achieving at least a very good partial response and a significant PFS benefit compared to immunomodulatory-agent-based triplet therapy. TRIAL REGISTRATION: ClinicalTrials.gov ISRCTN49407852.

Bortezomib, Vorinostat, and Dexamethasone Combination Therapy in Relapsed Myeloma: Results of the Phase 2 MUK four Trial.

INTRODUCTION: Outcomes continue to improve in relapsed myeloma as more effective treatment options emerge. We report a multicenter single-arm phase 2 trial evaluating toxicity and efficacy of the histone deacetylase (HDAC) inhibitor vorinostat in combination with bortezomib and dexamethasone. PATIENTS AND METHODS: Sixteen patients who had received a median of 1 prior treatment line received bortezomib subcutaneously 1.3 mg/m2 days 1, 4, 8, and 11; dexamethasone 20 mg orally days 1-2, 4-5, 8-9, and 11-12; vorinostat 400 mg orally days 1-4, 8-11, and 15-18 of a 21-day cycle. After receipt of a minimum of 3 cycles of therapy, participants received maintenance vorinostat (400 mg days 1-4 and 15-18 of a 28-day cycle). RESULTS: Overall response was 81.3%: complete response occurred in 4 of 16, very good partial response in 2 of 16, and partial response 7 of 16. Clinical benefit response rate was 100%; median progression-free survival was 11.9 months. A total of 75% patients experienced a dose reduction or stopped treatment as a result of intolerability. CONCLUSION: Although toxicity and dose reductions were observed, this study demonstrates that the combination of vorinostat, bortezomib, and dexamethasone is effective in relapsed myeloma with good response rates, suggesting there is an ongoing rationale for further optimization of HDAC inhibitor-based combinations in the treatment of myeloma to improve tolerability and enhance efficacy.

Optimising the value of immunomodulatory drugs during induction and maintenance in transplant ineligible patients with newly diagnosed multiple myeloma: results from Myeloma XI, a multicentre, open-label, randomised, Phase III trial.

Second-generation immunomodulatory agents, such as lenalidomide, have a more favourable side-effect profile than the first-generation thalidomide, but their optimum combination and duration for patients with newly diagnosed transplant-ineligible myeloma (ND-TNE-MM) has not been defined. The most appropriate delivery and dosing regimens of these therapies for patients at advanced age and frailty status is also unclear. The Myeloma XI study compared cyclophosphamide, thalidomide and dexamethasone (CTDa) to cyclophosphamide, lenalidomide and dexamethasone (CRDa) as induction therapy, followed by a maintenance randomisation between ongoing therapy with lenalidomide or observation for patients with ND-TNE-MM. CRDa deepened response but did not improve progression-free (PFS) or overall survival (OS) compared to CTDa. However, analysis by age group highlighted significant differences in tolerability in older, frailer patients that may have limited treatment delivery and impacted outcome. Deeper responses and PFS and OS benefits with CRDa over CTDs were seen in patients aged ≤70 years, with an increase in toxicity and discontinuation observed in older patients. Our results highlight the importance of considering age and frailty in the approach to therapy for patients with ND-TNE-MM, highlighting the need for prospective validation of frailty adapted therapy approaches, which may improve outcomes by tailoring treatment to the individual.

Lenalidomide before and after autologous stem cell transplantation for transplant-eligible patients of all ages in the randomized, phase III, Myeloma XI trial.

The optimal way to use immunomodulatory drugs as components of induction and maintenance therapy for multiple myeloma is unresolved. We addressed this question in a large phase III randomized trial, Myeloma XI. Patients with newly diagnosed multiple myeloma (n = 2042) were randomized to induction therapy with cyclophosphamide, thalidomide, and dexamethasone (CTD) or cyclophosphamide, lenalidomide, and dexamethasone (CRD). Additional intensification therapy with cyclophosphamide, bortezomib and dexamethasone (CVD) was administered before ASCT to patients with a suboptimal response to induction therapy using a response-adapted approach. After receiving high-dose melphalan with autologous stem cell transplantation (ASCT), eligible patients were further randomized to receive either lenalidomide alone or observation alone. Co-primary endpoints were progression-free survival (PFS) and overall survival (OS). The CRD regimen was associated with significantly longer PFS (median: 36 vs. 33 months; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.75-0.96; P = 0.0116) and OS (3-year OS: 82.9% vs. 77.0%; HR, 0.77; 95% CI, 0.63-0.93; P = 0.0072) compared with CTD. The PFS and OS results favored CRD over CTD across all subgroups, including patients with International Staging System stage III disease (HR for PFS, 0.73; 95% CI, 0.58-0.93; HR for OS, 0.78; 95% CI, 0.56-1.09), high-risk cytogenetics (HR for PFS, 0.60; 95% CI, 0.43-0.84; HR for OS, 0.70; 95% CI, 0.42-1.15) and ultra high-risk cytogenetics (HR for PFS, 0.67; 95% CI, 0.41-1.11; HR for OS, 0.65; 95% CI, 0.34-1.25). Among patients randomized to lenalidomide maintenance (n = 451) or observation (n = 377), maintenance therapy improved PFS (median: 50 vs. 28 months; HR, 0.47; 95% CI, 0.37-0.60; P < 0.0001). Optimal results for PFS and OS were achieved in the patients who received CRD induction and lenalidomide maintenance. The trial was registered with the EU Clinical Trials Register (EudraCT 2009-010956-93) and ISRCTN49407852.

Copy number evolution and its relationship with patient outcome-an analysis of 178 matched presentation-relapse tumor pairs from the Myeloma XI trial.

Structural chromosomal changes including copy number aberrations (CNAs) are a major feature of multiple myeloma (MM), however their evolution in context of modern biological therapy is not well characterized. To investigate acquisition of CNAs and their prognostic relevance in context of first-line therapy, we profiled tumor diagnosis-relapse pairs from 178 NCRI Myeloma XI (ISRCTN49407852) trial patients using digital multiplex ligation-dependent probe amplification. CNA profiles acquired at relapse differed substantially between MM subtypes: hyperdiploid (HRD) tumors evolved predominantly in branching pattern vs. linear pattern in t(4;14) vs. stable pattern in t(11;14). CNA acquisition also differed between subtypes based on CCND expression, with a marked enrichment of acquired del(17p) in CCND2 over CCND1 tumors. Acquired CNAs were not influenced by high-dose melphalan or lenalidomide maintenance randomization. A branching evolution pattern was significantly associated with inferior overall survival (OS; hazard ratio (HR) 2.61, P = 0.0048). As an individual lesion, acquisition of gain(1q) at relapse was associated with shorter OS, independent of other risk markers or time of relapse (HR = 2.00; P = 0.021). There is an increasing need for rational therapy sequencing in MM. Our data supports the value of repeat molecular profiling to characterize disease evolution and inform management of MM relapse.

Ixazomib, lenalidomide, and dexamethasone is effective and well tolerated in multiply relapsed (≥2nd relapse) refractory myeloma: a multicenter real world UK experience.

There are limited real world data on ixazomib, lenalidomide, and dexamethasone (IRd) in multiply relapsed myeloma. We analyzed outcomes of 116 patients who received IRd predominantly at second and subsequent relapse including those refractory to proteasome inhibitors (PIs). With a median follow up 16.3 months, the overall response rate was 66.9%; median progression-free survival (PFS) was 17.7 months with median overall survival (OS) not reached (NR). PFS and OS were significantly shorter in advanced disease (PFS; 12.6 vs. 21.2 months (p = .01), OS; 15.9 months vs. NR (p = .01) for ISS3 vs. ISS 1&2, respectively). PFS and OS were significantly shorter in clinical high risk (CHR) compared to standard risk (SR) patients (PFS; 9.3 months vs. NR (p = .001), OS; 11.5 months vs. NR (p < .001), respectively). There was a trend toward shorter PFS in PI-refractory patients 13.7 vs. 19.6 months for non-PI refractory (p = .2). The triplet combination was generally well tolerated.

Thrombosis in patients with myeloma treated in the Myeloma IX and Myeloma XI phase 3 randomized controlled trials.

Newly diagnosed multiple myeloma (NDMM) patients treated with immunomodulatory drugs are at high risk of venous thromboembolism (VTE), but data are lacking from large prospective cohorts. We present thrombosis outcome data from Myeloma IX (n = 1936) and Myeloma XI (n = 4358) phase 3 randomized controlled trials for NDMM that treated transplant-eligible and transplant-ineligible patients before and after publication of thrombosis prevention guidelines. In Myeloma IX, transplant-eligible patients randomly assigned to cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) induction had higher risk of VTE compared with patients treated with cyclophosphamide, thalidomide, and dexamethasone (CTD) (22.5% [n = 121 of 538] vs 16.1% [n = 89 of 554]; adjusted hazard ratio [aHR],1.46; 95% confidence interval [95% CI], 1.11-1.93). For transplant-ineligible patients, those randomly assigned to attenuated CTD (CTDa) induction had a higher risk of VTE compared with those treated with melphalan and prednisolone (MP) (16.0% [n = 68 of 425] vs 4.1% [n = 17 of 419]; aHR, 4.25; 95% CI, 2.50-7.20). In Myeloma XI, there was no difference in risk of VTE (12.2% [n = 124 of 1014] vs 13.2% [n = 133 of 1008]; aHR, 0.92; 95% CI, 0.72-1.18) or arterial thrombosis (1.2% [n = 12 of 1014] vs 1.5% [n = 15 of 1008]; aHR, 0.80; 95% CI, 0.37-1.70) between transplant-eligible pathways for patients treated with cyclophosphamide, lenalidomide, and dexamethasone (CRD) or CTD. For transplant-ineligible patients, there was no difference in VTEs between attenuated CRD (CRDa) and CTDa (10.4% [n = 95 of 916] vs 10.7% [n = 97 of 910]; aHR, 0.97; 95% CI, 0.73-1.29). However, arterial risk was higher with CRDa than with CTDa (3.1% [n = 28 of 916] vs 1.6% [n = 15 of 910]; aHR, 1.91; 95% CI, 1.02-3.57). Thrombotic events occurred almost entirely within 6 months of treatment initiation. Thrombosis was not associated with inferior progression-free survival (PFS) or overall survival (OS), apart from inferior OS for patients with arterial events (aHR, 1.53; 95% CI, 1.12-2.08) in Myeloma XI. The Myeloma XI trial protocol incorporated International Myeloma Working Group (IMWG) thrombosis prevention recommendations and compared with Myeloma IX, more patients received thromboprophylaxis (80.5% vs 22.3%) with lower rates of VTE for identical regimens (CTD, 13.2% vs 16.1%; CTDa, 10.7% vs 16.0%). However, thrombosis remained frequent in spite of IMWG-guided thromboprophylaxis, suggesting that new approaches are needed.

Real-world effectiveness and safety of ixazomib-lenalidomide-dexamethasone in relapsed/refractory multiple myeloma.

Real-world data on regimens for relapsed/refractory multiple myeloma (RRMM) represent an important component of therapeutic decision-making. This multi-centric, retrospective, observational study conducted by the treating physicians evaluated the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in 155 patients who received ixazomib via early access programs in Greece, the UK, and the Czech Republic. Median age was 68 years; 17% had an Eastern Cooperative Oncology Group performance status ≥ 2; median number of prior therapies was 1 (range 1-7); 91%, 47%, and 17% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Median duration of exposure to ixazomib was 9.6 months. Overall response rate was 74%, including 35% very good partial response or better (16% complete response). Median progression-free survival (PFS) was 27.6 months (27.6 and 19.9 months in patients with 1 or > 1 prior lines, respectively). IRd treatment for ≥ 6 months was associated with longer PFS (hazard ratio 0.06). Fourteen patients (9%) discontinued IRd due to adverse events/toxicity in the absence of disease progression. Peripheral neuropathy was reported in 35% of patients (3% grades 3-4). These findings support the results of the phase III TOURMALINE-MM1 trial in a broader real-world RRMM population.

Daratumumab monotherapy for patients with intermediate-risk or high-risk smoldering multiple myeloma: a randomized, open-label, multicenter, phase 2 study (CENTAURUS).

Current guidelines for smoldering multiple myeloma (SMM) recommend active monitoring until the onset of multiple myeloma (MM) before initiating treatment or enrollment in a clinical trial. Earlier intervention may delay progression to MM. In CENTAURUS, 123 patients with intermediate-risk or high-risk SMM were randomly assigned to daratumumab 16 mg/kg intravenously on extended intense (intense), extended intermediate (intermediate), or short dosing schedules. At the prespecified primary analysis (15.8-month median follow-up), the complete response (CR) rates (co-primary endpoint) were 2.4%, 4.9%, and 0% for intense, intermediate, and short dosing, respectively; the co-primary endpoint of CR rate >15% was not met. Progressive disease (PD)/death rates (number of patients who progressed or died divided by total duration of progression-free survival [PFS] in patient-years; co-primary endpoint) for intense, intermediate, and short dosing were 0.055 (80% confidence interval [CI], 0.014-0.096), 0.102 (80% CI, 0.044-0.160), and 0.206 (80% CI, 0.118-0.295), respectively, translating to a median PFS ≥24 months in all arms (P < 0.0001, <0.0001, and =0.0213, respectively). With longer follow-up (median follow-up, 25.9 months), CR rates were 4.9%, 9.8%, and 0% for intense, intermediate, and short dosing, respectively. PD/death rates for intense, intermediate, and short dosing were 0.059 (80% CI, 0.025-0.092), 0.107 (80% CI, 0.058-0.155), and 0.150 (80% CI, 0.089-0.211), respectively, again translating to a median PFS ≥ 24 months in all arms (P < 0.0001 for all arms). Twenty-four-month PFS rates were 89.9% (90% CI, 78.5-95.4%), 82.0% (90% CI, 69.0-89.9%), and 75.3% (90% CI, 61.1-85.0%) for intense, intermediate, and short dosing, respectively. Pharmacokinetic analyses indicated that intense dosing maintained target-saturating trough concentrations in most patients throughout weekly, every-2-week, and every-4-week dosing periods. No new safety signals were observed. These data provide the basis for an ongoing phase 3 study of daratumumab in SMM.

Response-adapted intensification with cyclophosphamide, bortezomib, and dexamethasone versus no intensification in patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Multiple myeloma has been shown to have substantial clonal heterogeneity, suggesting that agents with different mechanisms of action might be required to induce deep responses and improve outcomes. Such agents could be given in combination or in sequence on the basis of previous response. We aimed to assess the clinical value of maximising responses by using therapeutic agents with different modes of action, the use of which is directed by the response to the initial combination therapy. We aimed to assess response-adapted intensification treatment with cyclophosphamide, bortezomib, and dexamethasone (CVD) versus no intensification treatment in patients with newly diagnosed multiple myeloma who had a suboptimal response to initial immunomodulatory triplet treatment which was standard of care in the UK at the time of trial design. METHODS: The Myeloma XI trial was an open-label, randomised, phase 3, adaptive design trial done at 110 National Health Service hospitals in the UK. There were three potential randomisations in the study: induction treatment, intensification treatment, and maintenance treatment. Here, we report the results of the randomisation to intensification treatment. Eligible patients were aged 18 years or older and had symptomatic or non-secretory, newly diagnosed multiple myeloma, had completed their assigned induction therapy as per protocol (cyclophosphamide, thalidomide, and dexamethasone or cyclophosphamide, lenalidomide, and dexamethasone) and achieved a partial or minimal response. For the intensification treatment, patients were randomly assigned (1:1) to cyclophosphamide (500 mg daily orally on days 1, 8, and 15), bortezomib (1·3 mg/m2 subcutaneously or intravenously on days 1, 4, 8, and 11), and dexamethasone (20 mg daily orally on days 1, 2, 4, 5, 8, 9, 11, and 12) up to a maximum of eight cycles of 21 days or no treatment. Patients were stratified by allocated induction treatment, response to induction treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, assessed from intensification randomisation to data cutoff, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009-010956-93, and has completed recruitment. FINDINGS: Between Nov 15, 2010, and July 28, 2016, 583 patients were enrolled to the intensification randomisation, representing 48% of the 1217 patients who achieved partial or minimal response after initial induction therapy. 289 patients were assigned to CVD treatment and 294 patients to no treatment. After a median follow-up of 29·7 months (IQR 17·0-43·5), median progression-free survival was 30 months (95% CI 25-36) with CVD and 20 months (15-28) with no CVD (hazard ratio [HR] 0·60, 95% CI 0·48-0·75, p<0·0001), and 3-year overall survival was 77·3% (95% Cl 71·0-83·5) in the CVD group and 78·5% (72·3-84·6) in the no CVD group (HR 0·98, 95% CI 0·67-1·43, p=0·93). The most common grade 3 or 4 adverse events for patients taking CVD were haematological, including neutropenia (18 [7%] patients), thrombocytopenia (19 [7%] patients), and anaemia (8 [3%] patients). No deaths in the CVD group were deemed treatment related. INTERPRETATION: Intensification treatment with CVD significantly improved progression-free survival in patients with newly diagnosed multiple myeloma and a suboptimal response to immunomodulatory induction therapy compared with no intensification treatment, but did not improve overall survival. The manageable safety profile of this combination and the encouraging results support further investigation of response-adapted approaches in this setting. The substantial number of patients not entering this trial randomisation following induction therapy, however, might support the use of combination therapies upfront to maximise response and improve outcomes as is now the standard of care in the UK. FUNDING: Cancer Research UK, Celgene, Amgen, Merck, Myeloma UK.

Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Patients with multiple myeloma treated with lenalidomide maintenance therapy have improved progression-free survival, primarily following autologous stem-cell transplantation. A beneficial effect of lenalidomide maintenance therapy on overall survival in this setting has been inconsistent between individual studies. Minimal data are available on the effect of maintenance lenalidomide in more aggressive disease states, such as patients with cytogenetic high-risk disease or patients ineligible for transplantation. We aimed to assess lenalidomide maintenance versus observation in patients with newly diagnosed multiple myeloma, including cytogenetic risk and transplantation status subgroup analyses. METHODS: The Myeloma XI trial was an open-label, randomised, phase 3, adaptive design trial with three randomisation stages done at 110 National Health Service hospitals in England, Wales, and Scotland. There were three potential randomisations in the study: induction treatment (allocation by transplantation eligibility status); intensification treatment (allocation by response to induction therapy); and maintenance treatment. Here, we report the results of the randomisation to maintenance treatment. Eligible patients for maintenance randomisation were aged 18 years or older and had symptomatic or non-secretory multiple myeloma, had completed their assigned induction therapy as per protocol and had achieved at least a minimal response to protocol treatment, including lenalidomide. Patients were randomly assigned (1:1 from Jan 13, 2011, to Jun 27, 2013, and 2:1 from Jun 28, 2013, to Aug 11, 2017) to lenalidomide maintenance (10 mg orally on days 1-21 of a 28-day cycle) or observation, and stratified by allocated induction and intensification treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009-010956-93, and has completed recruitment. FINDINGS: Between Jan 13, 2011, and Aug 11, 2017, 1917 patients were accrued to the maintenance treatment randomisation of the trial. 1137 patients were assigned to lenalidomide maintenance and 834 patients to observation. After a median follow-up of 31 months (IQR 18-50), median progression-free survival was 39 months (95% CI 36-42) with lenalidomide and 20 months (18-22) with observation (hazard ratio [HR] 0·46 [95% CI 0·41-0·53]; p<0·0001), and 3-year overall survival was 78·6% (95% Cl 75·6-81·6) in the lenalidomide group and 75·8% (72·4-79·2) in the observation group (HR 0·87 [95% CI 0·73-1·05]; p=0·15). Progression-free survival was improved with lenalidomide compared with observation across all prespecified subgroups. On prespecified subgroup analyses by transplantation status, 3-year overall survival in transplantation-eligible patients was 87·5% (95% Cl 84·3-90·7) in the lenalidomide group and 80·2% (76·0-84·4) in the observation group (HR 0·69 [95% CI 0·52-0·93]; p=0·014), and in transplantation-ineligible patients it was 66·8% (61·6-72·1) in the lenalidomide group and 69·8% (64·4-75·2) in the observation group (1·02 [0·80-1·29]; p=0·88). By cytogenetic risk group, in standard-risk patients, 3-year overall survival was 86·4% (95% CI 80·0-90·9) in the lenalidomide group compared with 81·3% (74·2-86·7) in the observation group, and in high-risk patients, it was 74.9% (65·8-81·9) in the lenalidomide group compared with 63·7% (52·8-72·7) in the observation group; and in ultra-high-risk patients it was 62·9% (46·0-75·8) compared with 43·5% (22·2-63·1). Since these subgroup analyses results were not powered they should be interpreted with caution. The most common grade 3 or 4 adverse events for patients taking lenalidomide were haematological, including neutropenia (362 [33%] patients), thrombocytopenia (72 [7%] patients), and anaemia (42 [4%] patients). Serious adverse events were reported in 494 (45%) of 1097 patients receiving lenalidomide compared with 150 (17%) of 874 patients on observation. The most common serious adverse events were infections in both the lenalidomide group and the observation group. 460 deaths occurred during maintenance treatment, 234 (21%) in the lenalidomide group and 226 (27%) in the observation group, and no deaths in the lenalidomide group were deemed treatment related. INTERPRETATION: Maintenance therapy with lenalidomide significantly improved progression-free survival in patients with newly diagnosed multiple myeloma compared with observation, but did not improve overall survival in the intention-to-treat analysis of the whole trial population. The manageable safety profile of this drug and the encouraging results in subgroup analyses of patients across all cytogenetic risk groups support further investigation of maintenance lenalidomide in this setting. FUNDING: Cancer Research UK, Celgene, Amgen, Merck, and Myeloma UK.

Subclonal TP53 copy number is associated with prognosis in multiple myeloma.

Multiple myeloma (MM) is a genetically heterogeneous cancer of bone marrow plasma cells with variable outcome. To assess the prognostic relevance of clonal heterogeneity of TP53 copy number, we profiled tumors from 1777 newly diagnosed Myeloma XI trial patients with multiplex ligation-dependent probe amplification (MLPA). Subclonal TP53 deletions were independently associated with shorter overall survival, with a hazard ratio of 1.8 (95% confidence interval, 1.2-2.8; P = .01). Clonal, but not subclonal, TP53 deletions were associated with clinical markers of advanced disease, specifically lower platelet counts (P < .001) and increased lactate dehydrogenase (P < .001), as well as a higher frequency of features indicative of genomic instability, del(13q) (P = .002) or del(1p) (P = .006). Biallelic TP53 loss-of-function by mutation and deletion was rare (2.4%) and associated with advanced disease. We present a framework for identifying subclonal TP53 deletions by MLPA, to improve patient stratification in MM and tailor therapy, enabling management strategies.

Idiotypic DNA vaccination for the treatment of multiple myeloma: safety and immunogenicity in a phase I clinical study.

We report on the safety and immunogenicity of idiotypic DNA vaccination in a phase I, non-randomised, open-label study in patients with multiple myeloma. The study used DNA fusion gene vaccines encoding patient-specific single chain variable fragment, or idiotype (Id), linked to fragment C (FrC) of tetanus toxin. Patients in complete or partial response following high-dose chemotherapy and autologous stem cell transplant were vaccinated intramuscularly with 1 mg DNA on six occasions, beginning at least 6 months post-transplant; follow-up was to week 52. Fourteen patients were enrolled on study and completed vaccinations. Idiotypic DNA vaccines were well tolerated with vaccine-related adverse events limited to low-grade constitutional symptoms. FrC- and Id-specific T-cell responses were detected by ex vivo ELISPOT in 9/14 and 3/14 patients, respectively. A boost of pre-existing anti-FrC antibody (Ab) was detected by ELISA in 8/14 patients, whilst anti-Id Ab was generated in 1/13 patients. Overall, four patients (29 %) made an immune response to FrC and Id, with six patients (43 %) responding to FrC alone. Over the 52-week study period, serum paraprotein was undetectable, decreased or remained stable for ten patients (71 %), whilst ongoing CR/PR was maintained for 11 patients (79 %). The median time to progression was 38.0 months for 13/14 patients. Overall survival was 64 % after a median follow-up of 85.6 months.