Melflufen in relapsed/refractory multiple myeloma refractory to prior alkylators: A subgroup analysis from the OCEAN study.

Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP ≥ 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators.

Dose/schedule-adjusted Rd-R vs continuous Rd for elderly, intermediate-fit patients with newly diagnosed multiple myeloma.

Lenalidomide-dexamethasone (Rd) is standard treatment for elderly patients with multiple myeloma (MM). In this randomized phase 3 study, we investigated efficacy and feasibility of dose/schedule-adjusted Rd followed by maintenance at 10 mg per day without dexamethasone (Rd-R) vs continuous Rd in elderly, intermediate-fit newly diagnosed patients with MM. Primary end point was event-free survival (EFS), defined as progression/death from any cause, lenalidomide discontinuation, or hematologic grade 4 or nonhematologic grade 3 to 4 adverse event (AE). Of 199 evaluable patients, 101 received Rd-R and 98 continuous Rd. Median follow-up was 37 months. EFS was 10.4 vs 6.9 months (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.51-0.95; P = .02); median progression-free survival, 20.2 vs 18.3 months (HR, 0.78; 95% CI, 0.55-1.10; P = .16); and 3-year overall survival, 74% vs 63% (HR, 0.62; 95% CI, 0.37-1.03; P = .06) with Rd-R vs Rd, respectively. Rate of ≥1 nonhematologic grade ≥3 AE was 33% vs 43% (P = .14) in Rd-R vs Rd groups, with neutropenia (21% vs 18%), infections (10% vs 12%), and skin disorders (7% vs 3%) the most frequent; constitutional and central nervous system AEs mainly related to dexamethasone were more frequent with Rd. Lenalidomide was discontinued for AEs in 24% vs 30% and reduced in 45% vs 62% of patients receiving Rd-R vs Rd, respectively. In intermediate-fit patients, switching to reduced-dose lenalidomide maintenance without dexamethasone after 9 Rd cycles was feasible, with similar outcomes to standard continuous Rd. This trial was registered at www.clinicaltrials.gov as #NCT02215980.

Patient-reported outcomes in relapsed/refractory multiple myeloma treated with melflufen plus dexamethasone: analyses from the Phase II HORIZON study.

Relapsed/refractory multiple myeloma (RRMM) is known to have a high burden of disease and complications associated with refractoriness to prior lines of therapy. Severe pain and fatigue symptoms and impairments in physical and emotional functioning have been strongly linked to reduced health-related quality of life (HRQoL) in patients with RRMM. Assessment of patient reported-outcome measures from the pivotal, Phase II HORIZON study (OP-106; NCT02963493) in patients with RRMM (n = 64) demonstrated that melphalan flufenamide (melflufen) plus dexamethasone treatment preserved HRQoL. Patients had clinically meaningful improvements, even after eight treatment cycles, in relevant scales such as global health status/QoL, physical functioning, emotional functioning, pain, and fatigue. Patients with triple-class-refractory disease (n = 50) displayed similar improvements. Patient-reported outcome deterioration was delayed for a substantial amount of time in patients who experienced a response to melflufen plus dexamethasone treatment relative to patients who did not experience a response. These findings support the notion that treatment with melflufen plus dexamethasone may sustain or improve HRQoL over time in patients with RRMM, including in patients with triple-class-refractory disease for whom outcomes are generally worse. The clinical benefits observed in patients from the HORIZON trial are encouraging and supportive of translation into real-world practice.

Thrombosis in multiple myeloma: risk stratification, antithrombotic prophylaxis, and management of acute events. A consensus-based position paper from an ad hoc expert panel.

The introduction of new therapeutic agents for multiple myeloma (MM), including proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, has improved the outcomes of patients but, in parallel, has changed the frequency and epidemiology of thrombotic events. Thrombosis is now a significant cause of morbidity and mortality in MM patients, and optimal thromboprophylaxis is far from being reached. Moving from the recognition that the above issue represents an unmet clinical need, an expert panel assessed the scientific literature and composed a framework of recommendations for improving thrombosis control in patients who are candidates for active treatment for MM. The panel generated key clinical questions using the criterion of clinical relevance through a Delphi process. It explored four domains, i.e., thrombotic risk factors and risk stratification, primary thromboprophylaxis, management of acute thrombotic events, and secondary thromboprophylaxis. The recommendations issued may assist hematologists in minimizing the risk of thrombosis and guarantee adherence to treatment in patients with MM who are candidates for active treatment.

Pomalidomide, bortezomib, and dexamethasone at first relapse in lenalidomide-pretreated myeloma: A subanalysis of OPTIMISMM by clinical characteristics.

OBJECTIVE: We evaluated the efficacy and safety of pomalidomide, bortezomib, and dexamethasone (PVd) vs bortezomib and dexamethasone (Vd) by age, renal function, and high-risk cytogenetic abnormalities in lenalidomide-pretreated patients with multiple myeloma at first relapse. METHODS: OPTIMISMM was a phase 3, multicenter, open-label, randomized study (NCT01734928; N = 559). The primary endpoint was progression-free survival (PFS). RESULTS: Overall, 226 patients had received one prior line of therapy. PVd significantly prolonged PFS vs Vd in patients aged ≤65 years (median, 22.0 vs 13.1 months; P = .0258) and >65 years (median, 17.6 vs 9.9 months; P = .0369). Median PFS in patients with renal impairment (RI; creatinine clearance <60 mL/min) was 15.1 months with PVd vs 9.5 months with Vd (hazard ratio [HR], 0.67 [95% CI, 0.34-1.34]). In patients without RI, median PFS was 22.0 vs 13.1 months (HR, 0.45 [95% CI, 0.27-0.76]). In patients with high-risk cytogenetics, median PFS was 14.7 vs 9.9 months (HR, 0.39 [95% CI, 0.13-1.17]). PVd significantly improved overall response rate vs Vd in all subgroups. The safety profile of PVd was consistent with previous reports. CONCLUSIONS: These findings confirmed the benefits of PVd at first relapse, including in patients with poor prognostic factors.

Normalization of the Immunological Microenvironment and Sustained Minimal Residual Disease Negativity: Do We Need Both for Long-Term Control of Multiple Myeloma?

Over the past two decades, the treatment landscape for multiple myeloma (MM) has progressed significantly, with the introduction of several new drug classes that have greatly improved patient outcomes. At present, it is well known how the bone marrow (BM) microenvironment (ME) exerts an immunosuppressive action leading to an exhaustion of the immune system cells and promoting the proliferation and sustenance of tumor plasma cells. Therefore, having drugs that can reconstitute a healthy BM ME can improve results in MM patients. Recent findings clearly demonstrated that achieving minimal residual disease (MRD) negativity and sustaining MRD negativity over time play a pivotal prognostic role. However, despite the achievement of MRD negativity, patients may still relapse. The understanding of immunologic changes in the BM ME during treatment, complemented by a deeper knowledge of plasma cell genomics and biology, will be critical to develop future therapies to sustain MRD negativity over time and possibly achieve an operational cure. In this review, we focus on the components of the BM ME and their role in MM, on the prognostic significance of MRD negativity and, finally, on the relative contribution of tumor plasma cell biology and BM ME to long-term disease control.

Lenalidomide-based induction and maintenance in elderly newly diagnosed multiple myeloma patients: updated results of the EMN01 randomized trial.

n the EMN01 trial, the addition of an alkylator (melphalan or cyclophosphamide) to lenalidomide-steroid induction therapy was prospectively evaluated in transplant-ineligible patients with multiple myeloma. After induction, patients were randomly assigned to maintenance treatment with lenalidomide alone or with prednisone continuously. The analysis presented here (median follow-up of 71 months) is focused on maintenance treatment and on subgroup analyses defined according to the International Myeloma Working Group Frailty Score. Of the 654 evaluable patients, 217 were in the lenalidomide-dexamethasone arm, 217 in the melphalan-prednisone-lenalidomide arm and 220 in the cyclophosphamide-prednisone-lenalidomide arm. With regards to the Frailty Score, 284 (43%) patients were fit, 205 (31%) were intermediate-fit and 165 (25%) were frail. After induction, 402 patients were eligible for maintenance therapy (lenalidomide arm, n=204; lenalidomide-prednisone arm, n=198). After a median duration of maintenance of 22.0 months, progression-free survival from the start of maintenance was 22.2 months with lenalidomide-prednisone vs 18.6 months with lenalidomide (hazard ratio 0.85, P=0.14), with no differences across frailty subgroups. The most frequent grade ≥3 toxicity was neutropenia (10% of lenalidomide-prednisone and 21% of lenalidomide patients; P=0.001). Grade ≥3 non-hematologic adverse events were rare (<15%). In fit patients, melphalan-prednisone-lenalidomide significantly prolonged progression-free survival compared to cyclophosphamide-prednisone-lenalidomide (hazard ratio 0.72, P=0.05) and lenalidomide-dexamethasone (hazard ratio 0.72, P=0.04). Likewise, a trend towards a better overall survival was noted for patients treated with melphalan-prednisone-lenalidomide or cyclophosphamide-prednisone-lenalidomide, as compared to lenalidomide-dexamethasone. No differences were observed in intermediate-fit and frail patients. This analysis showed positive outcomes of maintenance with lenalidomide-based regimens, with a good safety profile. For the first time, we showed that fit patients benefit from a full-dose triplet regimen, while intermediate-fit and frail patients benefit from gentler regimens. ClinicalTrials.gov registration number: NCT01093196.

First-line therapy with either bortezomib-melphalan-prednisone or lenalidomide-dexamethasone followed by lenalidomide for transplant-ineligible multiple myeloma patients: a pooled analysis of two randomized trials.

Bortezomib-melphalan-prednisone (VMP) and continuous lenalidomide-dexamethasone (Rd) represent the standard treatment of transplant-ineligible patients with newly diagnosed multiple myeloma (MM). To date, no randomized trial has compared VMP to Rd, and there is no evidence of the optimal treatment for newly diagnosed MM, particularly in patients with high-risk cytogenetics [del(17p), t(4;14) or t(14;16)]. We pooled together data from patients with newly diagnosed MM treated with VMP or Rd induction followed by lenalidomide maintenance 10 mg (Rd-R) enrolled in the GIMEMA-MM-03-05 and EMN01 trials, to evaluate the efficacy of these treatments in different subgroups of patients, focusing on those with standard- and high-risk cytogenetics. Overall, 474 patients were analyzed (VMP: 257 patients; Rd-R: 217 patients). No differences in progression-free survival (hazard ratio=0.96) and overall survival (hazard ratio=1.08) were observed between standard-risk patients treated with VMP or Rd-R, whereas among the high-risk patients, the probabilities of progression (hazard ratio=0.54) and death (hazard ratio=0.73) were lower in the patients treated with VMP than in those treated with Rd-R. In particular, standard-risk patients >75 years benefited less from VMP than from Rd-R (hazard ratio for progression-free survival=0.96; hazard ratio for overall survival=1.81). In this non-randomized analysis, VMP and Rd-R were equally effective in younger (≤75 years), standard-risk patients, while older ones (>75 years) benefited more from Rd-R. In high-risk patients, VMP improved progression-free survival and overall survival irrespective of age. The source trials are registered at ClinicalTrials.gov (NCT01063179 and NCT01093196).

High rate of profound clonal and renal responses with daratumumab treatment in heavily pre-treated patients with light chain (AL) amyloidosis and high bone marrow plasma cell infiltrate.

Daratumumab demonstrated activity in the treatment of AL amyloidosis in two recently concluded phase II clinical trials in relapsed and refractory patients. Its role in upfront therapy is under evaluation in a phase III study. In this report we evaluated the safety and efficacy of 28-day cycles of daratumumab (single agent or combined with bortezomib or lenalidomide) in 72 previously treated patients with multiple myeloma and AL amyloidosis. Fifty (69%) were refractory to the last line of therapy. After eight infusions of daratumumab, 59 patients (82%) achieved a hematologic response, with 12 (16%) complete responses (CRs) and 30 (42%) very good partial responses (VGPRs). After 16 infusions, the quality of response improved with 22 patients (30%) achieving CR and 21 (29%) attaining VGPR. Cardiac response was observed in 11 of 37 evaluable patients (29%) and renal response in 23 of 38 patients (60%). Daratumumab is highly effective in heavily pretreated patients with relapsed/refractory AL amyloidosis and high bone marrow plasma cell burden. Renal responses, which are usually rare in this setting, were frequently observed.

Minimal residual disease by flow cytometry and allelic-specific oligonucleotide real-time quantitative polymerase chain reaction in patients with myeloma receiving lenalidomide maintenance: A pooled analysis.

BACKGROUND: Minimal residual disease (MRD) is one of the most relevant prognostic factors in patients with multiple myeloma (MM); however, the impact of maintenance therapy on MRD levels remains unclear. Among patients with newly diagnosed MM (NDMM) who received lenalidomide maintenance until they developed disease progression, the role of MRD status as a predictor of progression-free survival (PFS) was evaluated by multiparameter flow cytometry (MFC) and allelic-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR) analysis. METHODS: Seventy-three patients with NDMM enrolled in the RV-MM-EMN-441 (clinical trials.gov identifier, NCT01091831) and RV-MM-COOP-0556 (clinicaltrials.gov identifier, NCT01208766; European Myeloma Network EMN02/HO95 MM Trial) phase 3 trials who achieved at least a very good partial response after intensification/consolidation were included. The median patient age was 57 years (interquartile range, 53-61 years), and all patients received lenalidomide maintenance until they developed progression. MRD was evaluated on bone marrow after intensification/consolidation, after 6 courses of maintenance, and every 6 months thereafter until clinical relapse using both ASO-RQ-PCR (sensitivity, 10-5 ) and MFC (sensitivity, from 10-4 to 10-5 ). RESULTS: After intensification/consolidation, 33 of 72 patients (46%) achieved a molecular complete response (m-CR), and 44 of 70 (63%) achieved a flow complete response (flow-CR). Almost 27% of patients who were MRD-positive after consolidation became MRD-negative during maintenance. After a median follow-up of 38 months, PFS was prolonged in patients who achieved negative MRD status during maintenance according to results from both ASO-RQ-PCR analysis (hazard ratio, 0.29; 95% confidence interval, 0.14-0.62; P = .0013) and MFC (hazard ratio, 0.19; 95% confidence interval, 0.09-0.41; P < .001). The impact of negative MRD status on PFS was similar in all subgroups (ASCT and no-ASCT; International Staging System stages I, II, and III; high-risk and standard-risk cytogenetics), and the two techniques were highly correlated. CONCLUSIONS: MRD status is a stronger predictor of PFS than standard risk factors, and lenalidomide maintenance further increases the rate of negative MRD results.

Once-weekly versus twice-weekly carfilzomib in patients with newly diagnosed multiple myeloma: a pooled analysis of two phase I/II studies.

Twice-weekly carfilzomib is approved at 27 and 56 mg/m2 to treat relapsed multiple myeloma patients. In the phase III study ARROW, once-weekly 70 mg/m 2 carfilzomib prolonged the median progression-free survival of relapsed multiple myeloma patients in comparison with twice-weekly 27 mg/m2 carfilzomib, without adding significant toxicity. Data were pooled from two phase I/II studies of newly diagnosed multiple myeloma patients who received nine induction cycles of carfilzomib (either 70 mg/m2 once-weekly or 36 mg/m2 twice-weekly), cyclophosphamide and dexamethasone, followed by carfilzomib maintenance. Overall, 121 transplant-ineligible patients with newly diagnosed multiple myeloma were analyzed (once-weekly, n=63; twice-weekly, n=58). We found no significant difference in median progression-free survival [35.7 months (95%CI: 23.7-not reached, NR) vs 35.5 months (95%CI: 24.3-NR); HR: 1.39; P=0.26] and 3-year overall survival [70% [95%CI: 59%-84%) vs 72% (95%CI: 60%-85%); HR: 1.27; P=0.5] between once-weekly and twice-weekly carfilzomib. From the start of maintenance, 3-year progression-free survival [47% (95%CI: 33%-68%) vs 51% (95%CI: 38%-70%); HR: 1.04; P=0.92] and overall survival [72% (95%CI: 58%-89%) vs 73% (95%CI: 59%-90%); HR: 0.82; P=0.71] were similar in the once- versus twice-weekly carfilzomib. The rate of grade 3-5 hematologic (24% vs 30%; P=0.82) and non-hematologic (38% vs 41%; P=0.83) adverse events was similar in the two groups. Once-weekly 70 mg/m2 carfilzomib as induction and maintenance therapy for newly diagnosed multiple myeloma patients was as safe and effective as twice-weekly 36 mg/m2 carfilzomib and provided a more convenient schedule. The trials are registered at clinicaltrials.gov identifiers: 01857115 (IST-CAR-561) and 01346787 (IST-CAR-506).

Cardiovascular adverse events in modern myeloma therapy - Incidence and risks. A review from the European Myeloma Network (EMN) and Italian Society of Arterial Hypertension (SIIA).

Cardiovascular disease in patients with multiple myeloma may derive from factors unrelated to the disease (age, diabetes, dyslipidemia, obesity, prior cardiovascular diseases), related to the disease (cardiac AL-amyloidosis, hyperviscosity, high-output failure, arteriovenous shunting, anemia, renal dysfunction) and/or related to anti-myeloma treatment (anthracyclines, corticosteroids, alkylating agents, immunomodulatory drugs, proteasome inhibitors). Good knowledge of cardiovascular events, effective dose reductions, prevention and management of early and late cardiovascular side effects of chemotherapeutic agents are essential in current clinical practice. Myeloma experts are obliged to carefully balance the efficacy and toxicity of drugs for each individual patient. This review summarizes current data and novel insights into cardiovascular adverse events of today's anti-myeloma treatment, focusing on carfilzomib, as a starting point for developing consensus recommendations on preventing and managing cardiovascular side effects in patients with multiple myeloma.

European Myeloma Network recommendations on tools for the diagnosis and monitoring of multiple myeloma: what to use and when.

The diagnosis of multiple myeloma can be challenging, even for experienced physicians, and requires close collaboration between numerous disciplines (orthopedics, radiology, nuclear medicine, radiation therapy, hematology and oncology) before the final diagnosis of myeloma is made. The definition of multiple myeloma is based on the presence of clinical, biochemical, histopathological, and radiological markers of disease. Specific tests are needed both at presentation and during follow-up in order to reach the correct diagnosis and characterize the disease precisely. These tests can also serve prognostic purposes and are useful for follow-up of myeloma patients. Molecular analyses remain pivotal for defining high-risk myeloma and are used in updated patient stratifications, while minimal residual disease assessment via flow cytometry, molecular techniques and radiological approaches provides additional prognostic information on patients' long-term outcome. This pivotal information will guide our future treatment decisions in forthcoming clinical trials. The European Myeloma Network group updated their guidelines on different diagnostic recommendations, which should be of value to enable appropriate use of the recommendations both at diagnosis and during follow-up.

Elderly patients with multiple myeloma: towards a frailty approach?

PURPOSE OF REVIEW: To describe how to better identify frail multiple myeloma patients and to treat them appropriately. RECENT FINDINGS: Proteasome inhibitors, such as bortezomib, carfilzomib, and ixazomib, and immunomodulatory agents (IMiDs), such as thalidomide, lenalidomide, and pomalidomide, have significantly improved the outcome of multiple myeloma patients in the last decade. However, both in clinical trials and in daily clinical practice, elderly multiple myeloma patients have shown lesser benefit. This is mainly due to less stringent use of proteasome inhibitors and IMiDs, increased toxicity, and subsequent early discontinuation of therapy in elderly. SUMMARY: Multiple myeloma typically affects elderly patients. Approximately one-third of patients are older than 75 years at diagnosis. Moreover, at least 30% are frail, both due to disease-related symptoms and (age-related) decline in physical capacity, presence of comorbidities, frailty, polypharmacy, nutritional status, and cognitive impairment. Treatment regimens that are investigated in clinical trials for transplant-ineligible patients have largely been investigated in fit, rather than frail patients, the latter being typically excluded or highly underrepresented therein. Data on the feasibility and efficacy of current standards of care are therefore lacking in frail patients. Preliminary data suggest a higher toxicity and discontinuation rate, loss of efficacy, and impaired quality of life in frail patients. Geriatric assessment helps to identify frail patients according to their functional and cognitive status. Both the International Myeloma Working Group (IMWG)-frailty index and Revised Myeloma Comorbidity Index constitute recently proposed algorithms that easily identify intermediate-fit and frail patients. Ongoing and future clinical trials, specifically designed for frail patients, will hopefully define frailty-directed treatment selection.

How I treat fragile myeloma patients.

Multiple myeloma is a disease typical of elderly people, with a median age at diagnosis of 70 years. Much progress has been made in the past few years thanks to the introduction of new drugs. However, increases in survival were much less pronounced in patients aged 60 to 69 years, and no improvement was seen in older patients. Furthermore, the currently approved treatment regimens were tested in clinical trials with stringent inclusion criteria. Aging is associated with a high prevalence of frailty, that is, a state of increased vulnerability to stressors due to a critical decline in physiologic reserves. Elderly people may be categorized as fit or frail according to clinical, functional, cognitive, and socioeconomic criteria. The presence of frailty may complicate the management and outcome of myeloma patients. To date, the choice of treatment of myeloma patients has focused primarily on chronological age and performance status as markers of frailty. However, the elderly population is highly heterogeneous, and improved assessment strategies are needed to define the frailty profile of patients and provide them with the most adequate treatment, thus avoiding the overtreatment of frail patients and the undertreatment of fit patients. The geriatric assessment is a fundamental tool for the evaluation of cognitive and functional status.

Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report.

We conducted a pooled analysis of 869 individual newly diagnosed elderly patient data from 3 prospective trials. At diagnosis, a geriatric assessment had been performed. An additive scoring system (range 0-5), based on age, comorbidities, and cognitive and physical conditions, was developed to identify 3 groups: fit (score = 0, 39%), intermediate fitness (score = 1, 31%), and frail (score ≥2, 30%). The 3-year overall survival was 84% in fit, 76% in intermediate-fitness (hazard ratio [HR], 1.61; P = .042), and 57% in frail (HR, 3.57; P < .001) patients. The cumulative incidence of grade ≥3 nonhematologic adverse events at 12 months was 22.2% in fit, 26.4% in intermediate-fitness (HR, 1.23; P = .217), and 34.0% in frail (HR, 1.74; P < .001) patients. The cumulative incidence of treatment discontinuation at 12 months was 16.5% in fit, 20.8% in intermediate-fitness (HR, 1.41; P = .052), and 31.2% in frail (HR, 2.21; P < .001) patients. Our frailty score predicts mortality and the risk of toxicity in elderly myeloma patients. The International Myeloma Working group proposes this score for the measurement of frailty in designing future clinical trials. These trials are registered at www.clinicaltrials.gov as #NCT01093136 (EMN01), #NCT01190787 (26866138MMY2069), and #NCT01346787 (IST-CAR-506).

Salvage therapy in first relapse: a retrospective study in a large patient population with multiple myeloma.

OBJECTIVE: There is no strong evidence to guide therapeutic approach to multiple myeloma (MM) patients who experience first relapse. The treatment choice can be difficult since currently all patients are exposed to novel agents as thalidomide, bortezomib and lenalidomide. METHODS: In this retrospective analysis, we evaluated the best therapeutic sequence, the role of retreatment, and the most beneficial cutoff of first remission in order to choose retreatment, analyzing 476 patients relapsed after first-line therapy. RESULTS: Bortezomib-based regimens upfront followed by lenalidomide-based regimens at first relapse resulted in significantly better second progression-free survival (2ndPFS), PFS2, and overall survival (OS) compared to the opposite sequence. Changing therapy resulted in significantly better 2ndPFS in the whole population, whereas PFS2 was significantly longer only in patients who underwent maintenance therapy. Moreover, until PFS1 was shorter than 27 months, changing therapy at first relapse significantly extended 2ndPFS and PFS2 compared to retreatment, whereas similar outcomes were observed between the two strategies, when PFS1 was longer than 27 months. CONCLUSION: Lacking randomized trials, our study could help to choose the most appropriate therapy algorithm in patients with MM.

Lenalidomide and low-dose dexamethasone (Rd) versus bortezomib, melphalan, prednisone (VMP) in elderly newly diagnosed multiple myeloma patients: A comparison of two prospective trials.

There are currently no direct head-to-head clinical trials evaluating bortezomib-melphalan-prednisone (VMP) versus lenalidomide and low-dose dexamethasone (Rd). VMP (257 cases) and Rd (222 cases) arms of two randomized phase III trials were employed to assess the treatment influence on outcome in untreated elderly MM patients. Progression free survival (PFS) and overall survival (OS) were the primary and secondary end-points, respectively, and were investigated according to treatments administered over a 60-months follow-up period. While VMP significantly reduced the disease progression rate between enrolment and 12 months of follow-up, no difference between the two schedules was found between 12 and 32 months. After 32 months, Rd-treated patients had a lower incidence of disease progression. A statistically significant higher OS rate was seen in the VMP arm, which was maintained after data adjustment for potential confounders. Both approaches showed acceptable toxicity profiles. The profound tumor reduction by VMP over Rd justifies the initial higher PFS rate in favor of the bortezomib schedule, while the Rd regimen overcomes this evident initial drawback in reducing the tumor burden by long-term drug administration, gaining a subsequent improved disease control. VMP is associated with a significant reduced risk of death. This study may help physicians make a more informed therapy choice.

Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study.

This multicenter, open-label phase 2 trial determined the safety and efficacy of carfilzomib, a novel and irreversible proteasome inhibitor, in combination with cyclophosphamide and dexamethasone (CCyd) in patients with newly diagnosed multiple myeloma (NDMM) ≥65 years of age or who were ineligible for autologous stem cell transplantation. Patients (N = 58) received CCyd for up to 9 28-day cycles, followed by maintenance with carfilzomib until progression or intolerance. After a median of 9 CCyd induction cycles (range 1-9), 95% of patients achieved at least a partial response, 71% achieved at least a very good partial response, 49% achieved at least a near complete response, and 20% achieved stringent complete response. After a median follow-up of 18 months, the 2-year progression-free survival and overall survival rates were 76% and 87%, respectively. The most frequent grade 3 to 5 toxicities were neutropenia (20%), anemia (11%), and cardiopulmonary adverse events (7%). Peripheral neuropathy was limited to grades 1 and 2 (9%). Fourteen percent of patients discontinued treatment because of adverse events, and 21% of patients required carfilzomib dose reductions. In summary, results showed high complete response rates and a good safety profile. This trial was registered at clinicaltrials.gov as #NCT01346787.