Safety and efficacy of bortezomib‐based regimens for multiple myeloma patients with renal impairment: a retrospective study of Italian Myeloma Network GIMEMA

Renal impairment (RI) is a severe complication throughout the course of multiple myeloma (MM). Bortezomib has been shown to be highly active in MM patients with RI. We designed this retrospective analysis to investigate the safety and efficacy of bortezomib‐based therapy in 117 MM patients with RI, 14 cases required dialysis. A total of 603 cycles of bortezomib were administered (median number, five cycles/patient). Ten patients required early discontinuation of bortezomib because of WHO grade IV toxicity. The rate of bortezomib discontinuation in cases with severe, moderate and mild RI was 11%, 5% and 0%, respectively (P = NS). Overall, 91 episodes of WHO grade III/IV toxicity were observed. At least a partial response was documented in 83/113 evaluable patients (73%), including complete response (19%) and near complete response (8%). The overall response rate was similar across RI subgroups. Reversal of RI was documented in 41% of patients after a median of 2.3 months (range 0.4–7.9). In three of 14 patients on dialysis, renal replacement therapy was discontinued after 1, 1 and 4 months. The 2‐yr estimate of response duration and overall survival was 70% and 51%, respectively. In conclusion, bortezomib‐based regimens are safe and effective and should be considered as appropriate treatment options for MM patients with any degree of RI.     

Bortezomib‐based triplets are associated with a high probability of dialysis independence and rapid renal recovery in newly diagnosed myeloma patients with severe renal failure or those requiring dialysis

Renal failure (RF) is a common and severe complication of symptomatic myeloma, associated with significant morbidity and mortality. Such patients are commonly excluded from clinical trials. Bortezomib/dexamethasone (VD)‐based regimens are the backbone of the treatment of newly diagnosed MM patients who present with severe RF even those requiring dialysis. We analyzed the outcomes of 83 consecutive bortezomib‐treated patients with severe RF (eGFR < 30 ml/min/1.73 m²), of which 31 (37%) required dialysis. By IMWG renal response criteria, 54 (65%) patients achieved at least MRrenal, including CRrenal in 35% and PRrenal in 12%. Triplet combinations (i.e., VD plus a third agent) versus VD alone were associated with higher rates of renal responses (72 vs. 50%; P = 0.06). Fifteen of the 31 (48%) patients became dialysis independent within a median of 217 days (range 11–724). Triplets were associated with a higher probability of dialysis discontinuation (57 vs. 35%). Serum free light chain (sFLC) level ≥11,550 mg/L was associated with lower rates of major renal response, longer time to major renal response, lower probability, and longer time to dialysis discontinuation. Rapid myeloma response (≥PR within the first month) was also associated with higher rates of renal response. Patients who became dialysis‐independent had longer survival than those remaining on dialysis. In conclusion, VD‐based triplets are associated with a significant probability of renal response and dialysis discontinuation, improving the survival of patients who became dialysis independent. Rapid disease response is important for renal recovery and sFLCs are predictive of the probability and of the time required for renal response. Am. J. Hematol. 91:499–502, 2016. © 2016 Wiley Periodicals, Inc.     

Management of myeloma-associated renal dysfunction in the era of novel therapies

Multiple myeloma (MM) is a plasma cell neoplasm often associated with renal impairment (RI), with myeloma cast nephropathy recognized as the most common cause. While RI is present in over 50% of MM patients at some point in their disease course, it is associated with higher tumor burden, more aggressive disease, diminished quality of life, development of complications and increased mortality. The introduction of novel therapies, including bortezomib, lenalidomide and thalidomide, has revolutionized the management of MM. They are now considered first-line therapies in induction, maintenance and salvage therapy for MM. In addition to their anti-MM effect, they can improve outcome in patients with RI, especially when combined, and bortezomib with dexamethasone may have a renal protective effect. This review focuses on the use of these agents in patients with MM and RI, and evaluates their efficacy, safety, need for dose adjustment and impact on RI.     

A phase 2 study of modified lenalidomide,bortezomib and dexamethasone in transplant‐ineligible multiple myeloma

We sought a regimen that incorporates optimal novel agents and balances efficacy with toxicity in transplant‐ineligible multiple myeloma (MM) patients. Our study evaluated modified lenalidomide‐bortezomib‐dexamethasone (RVD lite) in this population and was administered over a 35‐day cycle. Lenalidomide 15 mg was given orally on days 1–21; bortezomib 1·3 mg/m² weekly subcutaneously on days 1, 8, 15 and 22; and dexamethasone 20 mg orally was given on the day of and day after bortezomib for 9 cycles followed by 6 cycles of consolidation with lenalidomide and bortezomib. The primary objective was to evaluate the overall response rate (ORR); secondary objectives included safety, progression‐free survival (PFS) and overall survival (OS). Fifty‐three eligible patients were screened between April 2013 and May 2015; 50 received at least one dose of therapy. Median age at study entry was 73 years (range 65–91). The ORR was 86% and 66% of patients achieved a very good partial response or better. Median PFS was 35·1 months (95% confidence interval 30·9–not reached) and median OS was not reached at a median follow‐up of 30 months. Peripheral neuropathy was reported in 31 (62%) patients with only 1 patient experiencing grade 3 symptoms. RVD lite is a well‐tolerated and highly effective regimen, with robust PFS and OS, in the transplant‐ineligible MM population.     

Long‐term outcome after allogeneic stem‐cell transplantation with reduced‐intensity conditioning in patients with multiple myeloma

This study examines the long‐term outcomes of a cohort of patients with myeloma who were treated with reduced‐intensity conditioning (RIC) regimens after a minimum follow‐up of 5 years at our centre. A total of 53 patients with multiple myeloma (MM) who received allogeneic hematopoietic stem‐cell transplantation (Allo‐SCT) between January 2000 and January 2007 were identified. The median follow‐up of living patients was 84 months (51–141). The median age of the MM patients was 50 (28–70) years. Fifty‐one patients (96%) received a transplant from a sibling donor. The median time between diagnosis and Allo‐SCT was 34 months (6–161), and the median time between auto‐SCT and Allo‐SCT was 10 months (1–89). Fifty‐one patients (96%) received at least one auto‐SCT; 24 patients (45%) received a tandem auto‐Allo‐SCT. At last follow‐up, 21 patients (40%) are alive > 5 years post RIC Allo‐SCT. At last follow‐up, 14 (26%) are in first complete remission (CR), and four patients (8%) in second CR after donor lymphocyte infusion or re‐induction with one of the new anti‐myeloma drugs (bortezomib or lenalidomide) after Allo‐SCT. Eight patients (38%) among these long survivors received one of these new drugs as induction or relapse treatment before Allo‐SCT. Disease status and occurrence of cGvHD were significantly associated with progression‐free survival (PFS); hazard ratio (HR) = 0.62 (0.30–1.29, P = 0.20). Acute GvHD was correlated with higher transplant‐related mortality; HR = 4.19 (1.05–16.77, P = 0.04). No variables were associated with overall survival (OS). In conclusion, we observe that long‐term disease control can be expected in a subset of MM patients undergoing RIC Allo‐SCT. After 10 years, the OS and PFS were 32% and 24%, respectively. The PFS curve after Allo‐SCT stabilizes in time with a plateau after 6 years post Allo‐SCT. Am. J. Hematol. 88:370–374, 2013. © 2013 Wiley Periodicals, Inc.     

Extracorporeal light chain elimination: high cut-off (HCO) hemodialysis parallel to chemotherapy allows for a high proportion of renal recovery in multiple myeloma patients with dialysis-dependent acute kidney injury

Acute kidney injury (AKI) is frequent in multiple myeloma (MM) patients and strongly affects prognosis, with particularly poor outcomes in patients requiring hemodialysis. Introduction of the novel therapeutic agents to MM therapy has improved myeloma response and renal outcome. This case series reviews the efficacy of combined systemic and extracorporeal therapy to further optimize time to light chain (serum-free light chain (sFLC)) reduction and renal recovery in MM patients with dialysis-dependent AKI (n = 19). High cut-off (HCO) hemodialysis for extracorporeal sFLC removal was initiated in parallel to chemotherapy. Combined therapy resulted in early sFLC response after a median of 13 (range 4–48) days and 6 (3–22) HCO hemodialysis sessions. Time to sFLC response was shorter in patients recovering renal function. Median time to dialysis independence was 15 (4–64) days. By intent-to-treat analysis, sustained renal recovery was achieved in 73.7% (77.8% adjusted for death) of patients. In multivariate analysis, duration of AKI prior to initiation of therapy was an independent predictor of renal functional outcome. Combining HCO hemodialysis for extracorporeal sFLC elimination and effective chemotherapy is a novel treatment strategy allowing for early and sustained sFLC reduction and a high proportion of renal recovery in these patients. Timely diagnosis and onset of therapy is essential for improving renal outcome.     

Phase 2 study of two sequential three‐drug combinations containing bortezomib,cyclophosphamide and dexamethasone,followed by bortezomib,thalidomide and dexamethasone as frontline therapy for multiple myeloma

Novel sequential combination therapy for induction may improve the quality of response and therefore prolong survival in newly diagnosed multiple myeloma (MM) patients. We report results from a phase 2 study of two sequential three‐drug combinations. Forty‐four previously untreated, symptomatic MM patients received: bortezomib 1·3 mg/m² (days 1, 4, 8, 11), cyclophosphamide 300 mg/m² (days 1, 8), plus dexamethasone 40 mg (day of and day after bortezomib) for three 21‐day cycles, followed by bortezomib 1·0 mg/m², dexamethasone 40 mg and thalidomide 100 mg daily for three cycles. Overall response rate for 42 evaluable patients was 95%, including 19% stringent complete response (sCR), 26% CR, and 57%≥ very good partial response. Twenty‐two patients have undergone stem‐cell transplantation. After a median follow‐up of 20·9 months, five patients have died; none was induction therapy‐related. Median event‐free survival (EFS) and overall survival (OS) have not been reached; estimated 1‐year EFS and OS rates were 81% and 91% respectively. Both three‐drug combinations were well tolerated; 82% of patients completed all six cycles. Toxicities were predictable and manageable; the most‐commonly reported grade 3/4 toxicity was neuropathy (11%). This novel sequential three‐drug combination therapy is effective and well‐tolerated in previously untreated MM patients.     

Combination therapy with bortezomib,continuous low‐dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients

Combination therapy for longer periods but at low dose might be an effective and tolerable manner to treat patients with relapsed multiple myeloma (MM). We used bortezomib, dexamethasone and low‐dose oral cyclophosphamide as an induction regimen, followed by 1 year of maintenance consisting of bortezomib and cyclophosphamide. Relapsed MM patients were treated with six cycles of bortezomib twice weekly, cyclophosphamide 50 mg daily and dexamethasone. Maintenance therapy was given for 1 year. Primary endpoints were toxicity during re‐induction and maintenance therapy. Secondary endpoints were response to treatment and progression‐free (PFS) and overall survival (OS). This study included 59 patients. Myelosuppression and neuropathy were the most common side effects. Median follow‐up was 27·1 (0·46–54·4) months with an overall response of 71%, and a very good partial response or more of 33%. During maintenance, improved responsiveness was observed in 19% of the patients. The median PFS was 18·4 months (range 0·13–43·5) and the median OS was 28·1 months (range 0·13–54·4). In conclusion, our study demonstrates that treatment with bortezomib, dexamethasone and low‐dose cyclophosphamide is an effective and manageable regimen. Adding 1 year of maintenance was feasible, with limited side effects and an increased response rate.     

Individual myeloma‐specific T‐cell clones eliminate tumour cells and correlate with clinical outcomes in patients with multiple myeloma

Despite novel treatment strategies, multiple myeloma (MM) remains an incurable disease with low immunogenicity and multiple immune defects. We developed an ex vivo strategy for inducing myeloma‐specific cytotoxic T lymphocytes (CTLs) and demonstrate the possibility of identification and long‐term in vivo monitoring of individual myeloma‐specific T‐cell clones using the most sensitive clonotypic assay that is able to detect low frequencies of T‐cell clones (1 clonotypic cell in 10⁶ cells). Ten patients with MM were examined for the presence of tumour‐reactive T cells using dendritic cells loaded with autologous tumour cells. All patients had detectable myeloma‐reactive T cells in vitro. Expanded myeloma‐reactive T cells demonstrated specific cytotoxic effects against autologous tumour cells in vitro (median 39·6% at an effector:target ratio of 40:1). The clonality of myeloma‐specific T cells was studied with a clonotypic assay, which demonstrated both oligoclonal and monoclonal populations of myeloma‐specific T cells. CD8⁺ CTLs were the most immunodominant myeloma‐specific T‐cell clones and clinical responses were closely associated with the in vivo expansion and long‐term persistence of individual CD8⁺ T‐cell clones, usually at very low frequencies (10^?3–10^?6). We conclude that the clonotypic assay is the most sensitive tool for immunomonitoring of low‐frequency T cells.     

Clinically-suspected cast nephropathy: A retrospective,national, real-world study

Presentation with severe acute kidney injury due to cast nephropathy (CN) is a medical emergency in multiple myeloma (MM), with high risk of dialysis-dependent renal failure and death. Accrual of patients with CN into interventional studies is difficult, while phase III trials exclude patients with severe renal insufficiency. Real-world data are warranted. We assessed 2252 patients from the population-based Danish Multiple Myeloma Registry (DMMR) who were diagnosed between 2013 and 2017. We identified 204 patients with clinically-suspected CN, defined as serum creatinine concentration >177 μmol/L and serum free light chain (sFLC) concentration >1000 mg/L at the time of diagnosis. The median age was 72 years. Thirty-one percent of patients presented with dialysis-dependent renal failure. Kidney biopsies were performed in 19% of patients and showed CN in 74% of cases. Despite prompt initiation of bortezomib-based therapy in 94% of patients, 33% of patients died in the first year after diagnosis. Compared with the rest of the patients in the DMMR with symptomatic MM, patients with clinically-suspected CN had worse overall survival (OS) irrespective of transplant eligibility. Achievement of renal recovery was associated with deep reductions of involved sFLC. Achievement of very good partial response or better in the first line of therapy and/or deep reduction of involved sFLC at 3 months after initiation of therapy were associated with superior OS. In conclusion, MM patients presenting with clinically-suspected CN have an alarmingly high one-year mortality when treated with current standards of care. Early and deep hematologic response is crucial for survival.     

Bortezomib and dexamethasone in previously untreated multiple myeloma associated with renal failure and reversal of renal failure

Multiple myeloma (MM) associated with renal failure carries a worse prognosis when compared with MM without renal failure. Bortezomib, a reversible proteosome inhibitor, is a new drug indicated for the treatment of refractory or relapsed myeloma. Published data on the use of bortezomib in patients with myeloma and renal failure are few. We report our experience with bortezomib and dexamethasone in 3 previously untreated and 1 relapsed patient with MM and renal failure. All patients achieved rapid improvement in their renal function as measured by serum creatinine levels with only 1-2 cycles of bortezomib (+/- dexamethasone), 3 of 4 patients had a near complete response and 1 patient had a partial response. The rapid reversal of renal dysfunction with bortezomib (+/- dexamethasone) treatment may be an effective strategy to prevent end stage renal failure in MM, thereby improving the morbidity and mortality in this otherwise poor prognosis subset of patients with myeloma.     

An open‐label phase I/II study of cyclophosphamide,bortezomib, pegylated liposomal doxorubicin,and dexamethasone in newly diagnosed myeloma

We conducted a phase 1/2 trial evaluating the combination of cyclophosphamide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone (CVDD) for newly diagnosed multiple myeloma (MM). The primary objective of the phase 1 was to evaluate the safety and tolerability of maximum planned dose (MPD) and the phase 2 was to assess the overall response rate. Patients received 6–8 cycles of CVDD at four dose levels. There were no dose‐limiting toxicities. The MPD was cyclophosphamide 750 mg/m² IV on day 1, bortezomib 1.3 mg/m² IV on days 1, 4, 8, 11, pegylated liposomal doxorubicin 30 mg/m² IV on day 4, and dexamethasone 20 mg orally on the day of and after bortezomib (21‐d cycle). Forty‐nine patients were treated at the MPD of which 22% had high‐risk myeloma. The most common grade ≥3 toxicities included myelosuppression, infection, and fatigue. Overall response and complete response rates were 91% and 26% in standard‐risk, and 100% and 58% in high‐risk cohort, respectively. After a median follow‐up of 34 months, the median progression‐free survival was 31.3 months. The 2‐yr overall survival was 91.1% in the standard‐risk and 88.9% in the high‐risk cohort, respectively. CVDD regimen was well tolerated and was highly active in newly diagnosed MM.     

Outcomes of lenalidomide‐ or bortezomib‐based regimens in older patients with plasma cell myeloma

The “triplet” regimen of lenalidomide, bortezomib, and dexamethasone (RVD) showed survival advantage over lenalidomide‐dexamethasone (RD) in clinical trials, but older patients with myeloma often receive doublet regimens (RD or bortezomib‐dexamethasone, VD), or VD plus cyclophosphamide (VCD). We compared these first‐line regimens using real‐world data from Medicare beneficiaries receiving therapy between 2007 and 2015. In each comparative analysis, we balanced confounding characteristics using a propensity score. Outcomes included overall (OS) and event‐free survival (EFS, reporting hazard ratios [HR] with 95% confidence intervals [CI]), adverse events, and costs. We identified 6076 patients with median age 76 and median OS of 2.6 years. In the comparison of RVD vs RD/VD doublets, RVD showed significantly better OS (HR = 0.83; 95% CI, 0.72‐0.95) and EFS (HR = 0.68; 95% CI, 0.61‐0.76). So, RVD was associated with more frequent hospitalizations, anemia, and neuropathy, but no increase in thromboembolism or secondary cancers. Costs were higher with RVD. In the comparison of RD vs VD, RD demonstrated better EFS (HR = 0.74; 95% CI, 0.68‐0.81) and marginally better OS (HR = 0.91; 95% CI, 0.83‐0.99). And, RD resulted in significantly more thromboembolic events, less neuropathy, and no significant difference in hospitalizations, transfusions, or secondary cancers. In the comparison of VCD vs VD, we observed no significant difference in any outcome. Superior survival favors RVD over doublet regimens, but even in 2015 RVD was applied for only about 25% of Medicare beneficiaries with myeloma. For patients not eligible for RVD due to toxicity, VCD offers no survival benefit over VD. Lenalidomide‐dexamethasone may be the preferred line doublet considering its advantage over VD.     

A phase 1, open‐label,dose‐escalation study of pralatrexate in combination with bortezomib in patients with relapsed/refractory multiple myeloma

Pralatrexate inhibits folic acid metabolism, and preclinical studies have shown that it is cytotoxic to multiple myeloma cells. This phase 1 study investigated the safety and efficacy of pralatrexate in combination with bortezomib in adults with relapsed or refractory multiple myeloma. A standard 3 + 3 design was used. Patients received intravenous pralatrexate at doses ranging from 10 to 30 mg/m² and intravenous bortezomib at a dose of 1·3 mg/m² on days 1, 8 and 15 of each 4‐week cycle. Eleven patients were enrolled and completed a median of two cycles. The maximum tolerated dose was 20 mg/m². Two patients experienced dose‐limiting toxicity of mucositis. The most frequent non‐haematological toxicities were fatigue (55%) and mucositis (45%). There were three serious adverse events in three patients: rash, sepsis and hypotension. One patient (9%) had a very good partial response, 1 (9%) had a partial response, 1 (9%) had minimal response and two (18%) had progressive disease. The median duration of response was 4 months, the median time to next treatment was 3·4 months and the median time to progression was 4 months. Pralatrexate, in combination with bortezomib, was generally safe and demonstrated modest activity in relapsed or refractory multiple myeloma. Clinicaltrials.gov identifier: NCT01114282.     

Detection of renal impairment as one specific comorbidity factor in multiple myeloma: multicenter study in 198 consecutive patients

Objectives: Comorbidity factors have been reported in cancer patients to predict progression free survival (PFS) and overall survival (OS). Renal impairment (RI) is postulated as one negative prognostic factor in multiple myeloma (MM). The study aim was to detect the best way to define RI and the impact of different RI stages on MM outcome. Methods: In this multicenter analysis, we determined RI [serum creatinine, estimated glomerular filtration rate (eGFR) by modification of diet in renal disease (MDRD) and Cockcroft‐Gault] and other prognostic factors in 198 MM patients to ascertain their value on PFS and OS. Results: Median serum creatinine was 0.9 mg/dL in all patients, whereas the eGFR – being decreased with a median of 80 mL/min/1.73 m²– allowed to detect early stages of RI. Via univariate analysis, we observed increasing hazard ratios (HRs) for impaired OS with deteriorating eGFR: with eGFR_MDRD<90 and <30, HRs were 1.3 and 2.9, respectively. Multivariate analysis determined RI with eGFR<30 and <50 as well as age >59 yr as most important variables for OS. By incorporating eGFR<30 as the most relevant factor determined via multivariate analysis and β₂‐microglobulin (β₂‐MG) in a novel MM‐risk score, we identified patients with significantly differing OS: median survival with 0, 1 or 2 risk factors were 71, 48, and 24 months, respectively. Conclusions: These findings demonstrate that RI is frequent in MM, best detected via eGFR determination and an important prognostic factor. eGFR in combination with β₂‐MG allows definitive risk stratification with largely differing survival in MM.     

Bortezomib plus intermediate‐dose dexamethasone and thalidomide in elderly untreated patients with multiple myeloma: A Chinese experience

Bortezomib has proven to be active in patients with multiple myeloma (MM), including elderly patients. The aim of this study was to evaluate the efficacy and toxicity of bortezomib in combination with intermediate‐dose dexamethasone (Dex) and thalidomide in untreated MM patients aged ≥65 years in a Chinese single center. In this study, 18 patients were treated with bortezomib at 1.3 mg/m² IV on Days 1, 4, 8, and 11 and Dex at 20 mg/day IV on Days 1–4 and 8–11 simultaneously. Thalidomide at dose of 100 mg/day was given everyday. The mean number of cycles of bortezomib treatment was 2.06. Three patients (17%) achieved a complete response (CR), four (22%) a very good partial response (VGPR), and nine (50%) a PR, resulting in an overall response rate of 89%. The median time to response was 22 days (range 14–50 days). The duration of response was significantly longer in patients achieving a CR/VGPR with respect to those achieving only a PR (8.5 vs. 4.2 months, P = 0.03). Grade 3–4 toxicities occurring in patients comprised weakness, thrombocytopenia, diarrhea, infection, and neuropathy. Only one patient suffered from deep vein thrombosis. This preliminary experience in Chinese patients indicated that bortezomib‐Dex‐thalidomide is highly effective in elderly untreated patients with MM, even in patients with poor prognostic features. Am. J. Hematol. 2010. © 2010 Wiley‐Liss, Inc.     

Retreatment with bortezomib alone or in combination for patients with multiple myeloma following an initial response to bortezomib

This clinical trial was conducted to determine the safety and efficacy of bortezomib retreatment in patients with multiple myeloma (MM) who had previously responded to bortezomib. Patients with progressive MM who had previously tolerated bortezomib as a single agent or in combination with other drugs, with a minimum of partial response (PR; ≥50% M‐protein reduction) for ≥4 months, who had not received intervening MM therapy, were retreated with bortezomib (days 1, 4, 8, and 11 of a 21‐day cycle) with a starting dose being the dose at which the patient ended the initial treatment. Patients were allowed to receive bortezomib on retreatment in combination with dexamethasone, thalidomide, or doxorubicin. Thirty‐two patients received bortezomib retreatment (most with added dexamethasone). The median treatment‐free interval (last dose of initial bortezomib treatment to first dose of retreatment) was 9.9 (range 2.5–34.0) months. The median duration of retreatment was 2.8 (<1–7.9) months; median total duration of bortezomib treatment was 6.7 (2.5–19.8) months. Based on the investigators' assessment of best response, the overall response rate (complete plus PR) was 50%. The median time from start of retreatment to progressive disease (PD) was 6.6 (95% confidence interval: 5.1–9.6) months. Thirteen patients (41%) experienced PN; bortezomib‐related SAEs were reported in four patients. Retreatment with bortezomib alone or in combination is effective and well tolerated in patients with MM who have responded to their initial bortezomib treatment. Am. J. Hematol., 2009. © 2009 Wiley‐Liss, Inc.     

Effect of cumulative bortezomib dose on survival in multiple myeloma patients receiving bortezomib‐melphalan‐prednisone in the phase III VISTA study

This analysis, using data from the bortezomib‐melphalan‐prednisone (VMP) arm of the Phase III VISTA study, investigated whether increased cumulative bortezomib dose could improve overall survival (OS) in transplant‐ineligible patients with previously untreated multiple myeloma. Median cumulative bortezomib dose received by the 340 patients was 39 mg/m²; this was selected as the cut‐off for defining the dose groups to be compared for OS. Patient characteristics were well balanced between dose groups except for age. OS was significantly longer in the higher (≥39 mg/m²) versus lower (<39 mg/m²) cumulative bortezomib dose group (median 66.3 vs. 46.2 months; hazard ratio (HR) 0.533, P < 0.0001; age‐adjusted HR 0.561, P = 0.0002). To overcome confounding effects of early discontinuations/deaths, which were more common in the lower cumulative dose group (27 vs. 4% of patients discontinued due to adverse events (AEs) in the lower and higher cumulative dose groups, respectively), a landmark analysis was conducted at 180 days, eliminating patients who died or discontinued before this time from the analysis. OS from this landmark remained significantly longer in the higher dose group (median 60.4 vs. 50.3 months; HR 0.709, P = 0.0372). Thus, higher cumulative bortezomib dose, reflecting prolonged treatment duration and/or dose intensity, appears associated with improved OS. Approaches to achieve higher cumulative doses could include subcutaneous bortezomib administration, dose/schedule modifications, continuing therapy in responding patients, and proactive AE management. Am. J. Hematol. 90:314–319, 2015. © 2015 Wiley Periodicals, Inc.     

Good clinical activity and favorable toxicity profile of once weekly bortezomib,fotemustine, and dexamethasone (B‐MuD) for the treatment of relapsed multiple myeloma

Since multiple myeloma (MM) is still not‐curable, the management of relapse remains challenging. Given the known efficacy of alkylating agents in MM, we conducted a phase I/II study to test a new three drug combination in which Fotemustine (Muphoran), an alkylating agent of nitrosurea family, was added to bortezomib + dexamethasone backbone (B‐MuD) for the treatment of MM relapsed patients. Fotemustine was administered at two dose levels (80–100 mg/m² i.v.) on day 1. The original 21‐day schedule was early amended for extra‐hematological toxicity and a 35‐day schedule was adopted (Bortezomib 1.3 mg/m² i.v. on days 1, 8, 15, and 22, Dexamethasone 20 mg i.v. on days 1, 8, 15, and 22) for a total of six courses. Twenty‐four patients were enrolled. The maximum tolerated dose of Fotemustine was 100 mg/m². The overall response rate was of 62% (CR 8%, VGPR 33%, and PR 21%). The median OS was 28.5 months, the median progression‐free survival (PFS) was 19.1 months. B‐MuD resulted effective in patients previous exposed to bortezomib without difference of response (P = 0.25) and PFS (P = 0.87) when compared to bortezomib‐naive patients. Thrombocytopenia was the most common AE overall. In conclusion, B‐MuD is an effective and well tolerated combination in relapsed MM patients even in advanced disease phase. © Am. J. Hematol., 88:102–106, 2013. © 2012 Wiley Periodicals, Inc.     

The proteasome inhibitor CEP‐18770 enhances the anti‐myeloma activity of bortezomib and melphalan

The anti‐multiple myeloma (MM) efficacy of bortezomib has led to the development of other proteasome inhibitors (PI), including CEP‐18770 which has shown anti‐MM effects in preclinical studies. However, the efficacy of orally (PO) or intravenously (IV) administered CEP‐18770 in multiple MM models and in combination with conventional anti‐MM therapies has not been evaluated. Herein, we show that CEP‐18770 combined with melphalan or bortezomib induces synergistic inhibition of MM cell viability in vitro. In MM xenograft models, the addition of CEP‐18770 IV to melphalan completely prevented the growth of both melphalan‐sensitive and melphalan‐resistant tumours. The combination of CEP‐18770 IV and bortezomib induced complete regression of bortezomib‐sensitive tumours and markedly delayed progression of bortezomib‐resistant tumours compared to treatment with either agent alone. Single agent CEP‐18770 PO also showed marked anti‐MM effects in these xenograft models. These studies provide strong preclinical rationale for further development of this novel PI in the treatment of MM as a monotherapy as well as combined with either melphalan or bortezomib.