The real-world use and efficacy of pomalidomide for relapsed and refractory multiple myeloma in the era of CD38 antibodies.

Pomalidomide-dexamethasone (Pd) has been a standard care treatment for relapsed and refractory multiple myeloma since 2013. However, the outcomes of Pd after exposure to CD38 antibodies are not known. Here we describe the real-world use and efficacy of pomalidomide in a Danish, nationwide cohort of daratumumab-exposed patients. We identified 328 patients that were treated with pomalidomide. Of these, 137 received Pd, 65 daratumumab-pomalidomide-dexamethasone (DPd), 43 pomalidomide-cyclophosphamide-dexamethasone (PCd), 19 carfilzomib-pomalidomide-dexamethasone (KPD), 11 pomalidomide-bortezomib-dexamethasone (PVd), and 52 pomalidomide in other combinations. Patients treated with Pd in this cohort had a partial response or better (≥ PR) rate of 35.8% and median time to next treatment (mTNT) of 4.9 months, almost identical to the results of previous prospective clinical trials. Although treatment with the various pomalidomide-containing triplet regimens resulted in higher ≥ PR rates (PCd: 46.5%, PVd: 63.6%, DPd: 55.4%, KPd: 63.2%), the mTNT achieved was not significantly better than with Pd in most cases (PCD: 5.4, PVD: 5.3, DPD: 4.7 months). The exception to this was KPd (mTNT 7.4 months), but this regimen was mainly used earlier in the course of the disease (median time from diagnosis 2.3 years vs. 3.7-4.3 years). The most important predictor of outcomes was not the choice of index regimen (p = 0.72), but prior exposure (p = 0.0116). Compared to CD38 antibody-naïve patients, triple-class-exposed patients achieved reduced ≥ PR rate (38.0% vs. 47.3%), shorter mTNT (4.0 vs. 5.9 months), and shorter median overall survival (12.4 vs. 24.2 months) with pomalidomide treatment.

Longitudinal minimal residual disease assessment in multiple myeloma patients in complete remission - results from the NMSG flow-MRD substudy within the EMN02/HO95 MM trial.

BACKGROUND: Multiple myeloma remains an incurable disease with multiple relapses due to residual myeloma cells in the bone marrow of patients after therapy. Presence of small number of cancer cells in the body after cancer treatment, called minimal residual disease, has been shown to be prognostic for progression-free and overall survival. However, for multiple myeloma, it is unclear whether patients attaining minimal residual disease negativity may be candidates for treatment discontinuation. We investigated, if longitudinal flow cytometry-based monitoring of minimal residual disease (flow-MRD) may predict disease progression earlier and with higher sensitivity compared to biochemical assessments. METHODS: Patients from the Nordic countries with newly diagnosed multiple myeloma enrolled in the European-Myeloma-Network-02/Hovon-95 (EMN02/HO95) trial and undergoing bone marrow aspiration confirmation of complete response, were eligible for this Nordic Myeloma Study Group (NMSG) substudy. Longitdudinal flow-MRD assessment of bone marrow samples was performed to identify and enumerate residual malignant plasma cells until observed clinical progression. RESULTS: Minimal residual disease dynamics were compared to biochemically assessed changes in serum free light chain and M-component. Among 20 patients, reaching complete response or stringent complete response during the observation period, and with ≥3 sequential flow-MRD assessments analysed over time, increasing levels of minimal residual disease in the bone marrow were observed in six cases, preceding biochemically assessed disease and clinical progression by 5.5 months and 12.6 months (mean values), respectively. Mean malignant plasma cells doubling time for the six patients was 1.8 months (95% CI, 1.4-2.3 months). Minimal malignant plasma cells detection limit was 4 × 10-5. CONCLUSIONS: Flow-MRD is a sensitive method for longitudinal monitoring of minimal residual disease dynamics in multiple myeloma patients in complete response. Increasing minimal residual disease levels precedes biochemically assessed changes and is an early indicator of subsequent clinical progression. TRIAL REGISTRATION: NCT01208766.

Carfilzomib and dexamethasone maintenance following salvage ASCT in multiple myeloma: A randomised phase 2 trial by the Nordic Myeloma Study Group.

OBJECTIVE: We investigated the efficacy and safety of carfilzomib-containing induction before salvage high-dose melphalan with autologous stem-cell transplantation (salvage ASCT) and maintenance with carfilzomib and dexamethasone after salvage ASCT in multiple myeloma. METHODS: This randomised, open-label, phase 2 trial included patients with first relapse of multiple myeloma after upfront ASCT who were re-induced with four cycles of carfilzomib, cyclophosphamide and dexamethasone. Two months after salvage, ASCT patients were randomised to either observation or maintenance therapy with iv carfilzomib 27 â†’ 56 mg/sqm and p.o. dexamethasone 20 mg every second week. The study enrolled 200 patients of which 168 were randomised to either maintenance with carfilzomib and dexamethasone (n = 82) or observation (n = 86). RESULTS: Median time to progression (TTP) after randomisation was 25.1 months (22.5-NR) in the carfilzomib-dexamethasone maintenance group and 16.7 months (14.4-21.8) in the control group (HR 0.46, 95% CI 0.30-0.71; P = .0004). The most common adverse events during maintenance were thrombocytopenia, anaemia, hypertension, dyspnoea and bacterial infections. CONCLUSION: In summary, maintenance therapy with carfilzomib and dexamethasone after salvage ASCT prolonged TTP with 8 months. The maintenance treatment was in general well-tolerated with manageable toxicity.

The real-world outcomes of multiple myeloma patients treated with daratumumab.

Most patients cannot be included in randomized clinical trials. We report real-world outcomes of all Danish patients with multiple myeloma (MM) treated with daratumumab-based regimens until 1 January 2019. METHODS: Information of 635 patients treated with daratumumab was collected retrospectively and included lines of therapy (LOT), hematologic responses according to the International Myeloma Working Group recommendations, time to next treatment (TNT) and the cause of discontinuation of treatment. Baseline characteristics were acquired from the validated Danish Multiple Myeloma Registry (DMMR). RESULTS: Daratumumab was administrated as monotherapy (Da-mono) in 27.7%, in combination with immunomodulatory drugs (Da-IMiD) in 57.3%, in combination with proteasome inhibitors (Da-PI) in 11.2% and in other combinations (Da-other) in 3.8% of patients. The median number of lines of therapy given before daratumumab was 5 for Da-mono, 3 for Da-IMiD, 4 for Da-PI, and 2 for Da-other. In Da-mono, overall response rate (ORR) was 44.9% and median time to next treatment (mTNT) was 4.9 months. In Da-IMiD, ORR was 80.5%, and mTNT was 16.1 months. In Da-PI, OOR was 60.6% and mTNT was 5.3 months. In patients treated with Da-other, OOR was 54,2% and mTNT was 5.6 months. The use of daratumumab in early LOT was associated with longer TNT (p<0.0001). Patients with amplification 1q had outcome comparable to standard risk patients, while patients with t(4;14), t(14;16) or del17p had worse outcome (p = 0.0001). Multivariate analysis indicated that timing of treatment (timing of daratumumab in the sequence of all LOT that the patients received throughout the course of their disease) was the most important factor for outcome (p<0.0001). CONCLUSION: The real-world outcomes of multiple myeloma patients treated with daratumumab are worse than the results of clinical trials. Outcomes achieved with daratumumab were best when daratumumab was used in combination with IMIDs and in early LOT. Patients with high-risk CA had worse outcomes, but patients with amp1q had similar outcomes to standard-risk patients.

Outcome of treatment with carfilzomib before and after treatment with daratumumab in relapsed or refractory multiple myeloma patients.

Real world evidence is important since most patients cannot be included in randomized clinical trials (RCTs). In a nationwide, cohort of relapsed/refractory multiple myeloma patients treated with daratumumab (N = 635), we retrospective studied patients treated with carfilzomib (N = 251). Data were collected by audit of medical records. We compared characteristics of patients treated with carfilzomib before daratumumab (Car-Da; N = 150) and after daratumumab (Da-Car; N = 101) with those not treated with carfilzomib (N = 384). Furthermore, we examined effectiveness and safety of carfilzomib. The group of patients treated with carfilzomib differed from patients not treated with carfilzomib in the following parameters: They were younger, more were treated up-front with high dose melphalan and autologous stem cell transplantation (HDM-ASCT)and had relapse within 18 months thereafter, and more had high-risk cytogenetic abnormalities (CA) and amplification 1q (amp1q). In patients treated with Car-Da, 30.3% had high-risk CA and 30.1% had amp1q and in Da-Car it was 43.3% and 41%, respectively. In the Car-Da cohort, 34.4% experienced early relapse after HDM-ASCT versus 47.4% in the Da-Car cohort. The percentage of patients with very good partial remission was higher in patients treated with Car-Da compared to Da-Car (31.7% vs. 17.4%). The median duration of treatment and time to next treatment (TNT) of Car-Da/Da-Car were 4.6/4.3 months and 7.1/4.3 months and only a trend toward superior TNT for Car-Da was found (p = 0.06). Toxicity of carfilzomib was the same as reported in RCT. A similar poor TNT of daratumumab was found when used before (5.6 months) or after carfilzomib (4.9 months). In this cohort of patients with sequential treatment with carfilzomib and daratumumab or vice versa, a high percentage of patients were high-risk by CA, amp1q, and early relapse after HDM-ASCT. Outcome of Car-DA and outcome of Da-Car were equally poor. These patients should be considered for new promising treatment strategies.

Use of bisphosphonates in multiple myeloma patients in Denmark, 2005-2015.

PURPOSE: To describe use of bisphosphonates in newly diagnosed multiple myeloma patients in Denmark. METHODS: Using data from the Danish National Multiple Myeloma Registry, we conducted a population-based cohort study. Among patients newly diagnosed with multiple myeloma from 2005 to 2015, we examined use of bisphosphonates at first- and at progression/second-line anti-myeloma treatment overall, by patient characteristics, and myeloma complications. RESULTS: Of 2947 patients starting first-line anti-myeloma treatment, 2207 patients (74.9%) received bisphosphonates. During a median follow-up of 27.6 (quartiles, 10.6-52.5) months, disease progression post-first-line treatment was recorded in 1546 patients, of whom 1065 (68.9%) were treated with bisphosphonates. Altogether, 80.9% of patients with and 37.6% of patients without myeloma bone disease were treated with bisphosphonates at first line and 73.0% and 42.7%, respectively, at progression/second line. Moreover, the proportion of patients treated with bisphosphonates decreased with increasing severity of renal impairment at first and at progression/second-line treatment. CONCLUSION: The proportion of patients treated with bisphosphonates as part of first- and second-line anti-myeloma treatment increased with presence of myeloma bone disease and decreased by presence and severity of renal impairment. Overall, 25% of newly diagnosed multiple myeloma patients had no record of bisphosphonate treatment, potentially indicating an unmet need.

Validation of the UK myeloma research alliance risk profile, a new clinical prediction model for outcome in patients with newly diagnosed multiple myeloma not eligible for autologous stem cell transplantation; a population-based study from the Danish national multiple myeloma registry.

In 2019 the UK Myeloma Research Alliance introduced the Myeloma Risk Profile (MRP) for prediction of outcome in patients with newly diagnosed multiple myeloma (MM), ineligible for autologous stem cell transplantation. To validate the MRP in a population-based setting we performed a study of the entire cohort of transplant ineligible MM patients above 65 years in the Danish National MM Registry. Our data confirmed the value of the MRP. In a cohort of 1,377 patients, the MRP score separated patients into three distinct risk-groups with an observed hazard ratio of 2.91 for early death in high-risk versus low-risk patients.

Peptide Vaccination Against PD-L1 With IO103 a Novel Immune Modulatory Vaccine in Multiple Myeloma: A Phase I First-in-Human Trial.

Background: Immune checkpoint blockade with monoclonal antibodies targeting programmed death 1 (PD-1) and its ligand PD-L1 has played a major role in the rise of cancer immune therapy. We have identified naturally occurring self-reactive T cells specific to PD-L1 in both healthy donors and cancer patients. Stimulation with a PD-L1 peptide (IO103), activates these cells to exhibit inflammatory and anti-regulatory functions that include cytotoxicity against PD-L1-expressing target cells. This prompted the initiation of the present first-in-human study of vaccination with IO103, registered at clinicaltrials.org (NCT03042793). Methods: Ten patients with multiple myeloma who were up to 6 months after high dose chemotherapy with autologous stem cell support, were enrolled. Subcutaneous vaccinations with IO103 with the adjuvant Montanide ISA 51 was given up to fifteen times during 1 year. Safety was assessed by the common toxicity criteria for adverse events (CTCAE). Immunogenicity of the vaccine was evaluated using IFNγ enzyme linked immunospot and intracellular cytokine staining on blood and skin infiltrating lymphocytes from sites of delayed-type hypersensitivity. The clinical course was described. Results: All adverse reactions to the PD-L1 vaccine were below CTCAE grade 3, and most were grade 1-2 injection site reactions. The total rate of adverse events was as expected for the population. All patients exhibited peptide specific immune responses in peripheral blood mononuclear cells and in skin-infiltrating lymphocytes after a delayed-type hypersensitivity test. The clinical course was as expected for the population. Three of 10 patients had improvements of responses which coincided with the vaccinations. Conclusion: Vaccination against PD-L1 was associated with low toxicity and high immunogenicity. This study has prompted the initiation of later phase trials to assess the vaccines efficacy. Clinical Trial Registration: clinicaltrials.org, identifier NCT03042793.

Strategies to improve patient-reported outcome completion rates in longitudinal studies.

PURPOSE: The quality of patient-reported outcome (PRO) data can be compromised by non-response (NR) to scheduled questionnaires, particularly if reasons for NR are related to health problems, which may lead to unintended bias. The aim was to investigate whether electronic reminders and real-time monitoring improve PRO completion rate. METHODS: The population-based study "Quality of life in Danish multiple myeloma patients" is a longitudinal, multicentre study with consecutive inclusion of treatment-demanding newly diagnosed or relapsed patients with multiple myeloma. Education of study nurses in the avoidance of NR, electronic reminders, 7-day response windows and real-time monitoring of NR were integrated in the study. Patients complete PRO assessments at study entry and at 12 follow-up time points using electronic or paper questionnaires. The effect of the electronic reminders and real-time monitoring were investigated by comparison of proportions of completed questionnaires before and after each intervention. RESULTS: The first 271 included patients were analysed; of those, 249 (85%) chose electronic questionnaires. Eighty-four percent of the 1441 scheduled PRO assessments were completed within the 7-day response window and 11% after real-time monitoring, achieving a final PRO completion rate of 95%. A significant higher proportion of uncompleted questionnaires were completed after the patients had received the electronic reminder and after real-time monitoring. CONCLUSIONS: Electronic reminders and real-time monitoring contributed to a very high completion rate in the study. To increase the quality of PRO data, we propose integrating these strategies in PRO studies, however highlighting that an increase in staff resources is required for implementation.

Immunoparesis in newly diagnosed Multiple Myeloma patients: Effects on overall survival and progression free survival in the Danish population.

Immunoparesis (hypogammaglobulinemia) is associated to an unfavorable prognosis in newly diagnosed Multiple myeloma (MM) patients. However, this finding has not been validated in an unselected population-based cohort. We analyzed 2558 newly diagnosed MM patients in the Danish Multiple Myeloma Registry representing the entire MM population in Denmark from 2005-2013. Two-thousand two hundred and fifty three patients (90%) presented with reduction below lower normal levels of at least one uninvolved immunoglobulin. Using multivariable Cox regression we found that high age, high ISS score, high LDH and IgA MM were associated to both shorter overall survival and progression free survival. Furthermore, bone marrow plasma cell % was associated to short progression free survival. Immunoparesis had no independent significant effect on OS (HR 0.9 (95%CI: 0.7;1.0; p = 0.12)). Likewise, the number of suppressed immunoglobulins or the relative degree of suppressed uninvolved immunoglobulins from lower normal level (quantitative immunoparesis) was not associated to OS in the multivariable analysis. However, quantitative immunoparesis with at least 25% reduction (from lower normal level) of uninvolved immunoglobulins was associated to shorter PFS for the entire population. The impact of quantitative immunoparesis on PFS was present irrespective of calendar periods 2005-2008 and 2009-2013. Our population-based study does not confirm that immunoparesis at diagnosis is an independent prognostic factor regarding OS. However, quantitative immunoparesis is associated to a shorter PFS.

The impact of comorbidity on mortality in multiple myeloma: a Danish nationwide population-based study.

To describe the prevalence of comorbidity and its impact on survival in newly diagnosed multiple myeloma patients compared with population controls. Cases of newly diagnosed symptomatic multiple myeloma during the 2005-2012 period were identified in the Danish National Multiple Myeloma Registry. For each myeloma patient, 10 members of the general population matched by age and sex were chosen from the national Civil Registration System. Data on comorbidity in the myeloma patients and the general population comparison cohort were collected by linkage to the Danish National Patient Registry (DNPR). Cox proportional hazards regression models were used to evaluate the prognostic significance of comorbidity. The study included 2190 cases of multiple myeloma and 21,900 population controls. The comorbidity was increased in multiple myeloma patients compared with population controls, odds ratio (OR) 1.4 (1.1-1.7). The registration of comorbidity was highly increased within the year preceding diagnosis of multiple myeloma (OR 3.0 [2.5-3.5]), which was attributable to an increased registration of various diseases, in particular, renal disease with OR 11.0 (8.1-14.9). The median follow-up time from diagnosis of multiple myeloma for patients alive was 4.3 years (interquartile range 2.4-6.3). Patients with registered comorbidity had increased mortality compared with patients without comorbidity, hazard ratio 1.6 (1.5-1.8). Multiple myeloma patients have increased comorbidity compared with the background population, in particular during the year preceding the diagnosis of myeloma.

The Danish National Multiple Myeloma Registry.

AIM: The Danish National Multiple Myeloma Registry (DMMR) is a population-based clinical quality database established in January 2005. The primary aim of the database is to ensure that diagnosis and treatment of plasma cell dyscrasia are of uniform quality throughout the country. Another aim is to support research. Patients are registered with their unique Danish personal identification number, and the combined use of DMMR, other Danish National registries, and the Danish National Cancer Biobank offers a unique platform for population-based translational research. STUDY POPULATION: All newly diagnosed patients with multiple myeloma (MM), smoldering MM, solitary plasmacytomas, and plasma cell leukemia in Denmark are registered annually; ~350 patients. Amyloid light-chain amyloidosis, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), monoclonal gammopathy of undetermined significance and monoclonal gammopathy of undetermined significance with polyneuropathy have been registered since 2014. MAIN VARIABLES: The main registered variables at diagnosis are patient demographics, baseline disease characteristics, myeloma-defining events, clinical complications, prognostics, first- and second-line treatments, treatment responses, progression free, and overall survival. DESCRIPTIVE DATA: Up to June 2015, 2,907 newly diagnosed patients with MM, 485 patients with smoldering MM, 64 patients with plasma cell leukemia, and 191 patients with solitary plasmacytomas were registered. Registration completeness of new patients is ~100%. A data validation study performed in 2013-2014 by the Danish Myeloma Study Group showed >95% data correctness. CONCLUSION: The DMMR is a population-based data validated database eligible for clinical, epidemiological, and translational research.

Smoldering multiple myeloma risk factors for progression: a Danish population-based cohort study.

Several risk scores for disease progression in patients with smoldering multiple myeloma (SMM) have been proposed; however, all have been developed using single-center registries. To examine risk factors for time to progression (TTP) to multiple myeloma (MM) for SMM, we analyzed a nationwide population-based cohort of 321 patients with newly diagnosed SMM registered within the Danish Multiple Myeloma Registry between 2005 and 2014. Significant univariable risk factors for TTP were selected for multivariable Cox regression analyses. We found that both an M-protein ≥30 g/L and immunoparesis significantly influenced TTP (HR 2.7, 95%CI (1.5;4.7), P = 0.001, and HR 3.3, 95%CI (1.4;7.8), P = 0.002, respectively). High free light chain (FLC) ratio did not significantly influence TTP in our cohort. Therefore, our data do not support recent IMWG proposal of identifying patients with FLC ratio above 100 as having ultra high-risk of transformation to MM. Using only immunoparesis and M-protein ≥30 g/L, we created a scoring system to identify low-, intermediate-, and high-risk SMM. This first population-based study of patients with SMM confirms that an M-protein ≥30 g/L and immunoparesis remain important risk factors for progression to MM.