A real-world retrospective-prospective analysis of efficacy and safety of combined ixazomib, lenalidomide, and dexamethasone in relapsed/refractory multiple myeloma: The northern Italy experience.

INTRODUCTION: Ixazomib, lenalidomide, and dexamethasone (IRd) have been approved for the treatment of relapsed/refractory multiple myeloma (RRMM) based on the results of the TOURMALINE-MM1. OBJECTIVES AND METHODS: We conducted a retrospective-prospective analysis of 106 RRMM patients (pts) treated with IRd in 21 centers in Northern Italy, with the aim to evaluate the efficacy and safety of IRd in real life. RESULTS: At IRd initiation, 34% of pts were aged ≥75 (median 72.5), 8.5% had an ECOG performance status ≥2, 54.7% of evaluable pts carried high-risk cytogenetic abnormalities [del17p and/or t(4;14) and/or t(14;16) and/or 1 g gain/amp], 60.2% had received ≥2 prior lines of therapy (pLoT), 57.5% were lenalidomide (Len)-exposed (including both Len-sensitive and Len-refractory pts), and 22% were Len-refractory. Main G ≥3 adverse events (AEs) were thrombocytopenia (16%) and neutropenia (12.3%). G ≥3 non-hematologic AEs included infections (9.4%) and GI toxicity (diarrhea 5.7%, hepatotoxicity 2.8%), VTE, skin rash, and peripheral neuropathy were mainly G1-2. The overall response rate was 56.4% (≥VGPR 30%). With a median follow-up of 38 m, median PFS (mPFS) was 16 m and the 1-year OS rate was 73%. By subgroup analysis, an extended PFS was observed for pts achieving ≥VGPR (mPFS 21.2 m), time from diagnosis to IRd ≥5 years (26.2 m), 1 pLoT (34.4 m), Len-naïve (NR), age ≥70 (20 m). In pts exposed to Len, non-refractory in any prior line and immediately prior to IRd, mPFS was 16 and 18 m, respectively. An inferior PFS was seen in Len-refractory pts (4.6 m). By multivariate analysis, independent predictors of PFS were age ≥70 (HR 0.6), time from diagnosis ≥5 years (HR 0.32), refractoriness to Len in any prior line (HR 3.33), and immediately prior (HR 4.31). CONCLUSION: IRd might be effective and safe in RRMM pts with an indolent disease, in early lines of treatment, and who proved Len-sensitive, independent of age, and cytogenetic risk.

Anti-CD38 monoclonal antibody impairs CD34+ mobilization and affects clonogenic potential in multiple myeloma patients.

BACKGROUND: Induction with daratumumab-based regimens followed by autologous stem cell transplantation is the current standard for newly diagnosed multiple myeloma (NDMM) patients eligible for intensive chemotherapy. However, concerns emerged regarding potential negative effects following daratumumab-based treatment on CD34+ mobilization. We here compared CD34+ mobilization and clonogenic potential between daratumumab and non-daratumumab based therapy without upfront plerixafor administration among patients affected by NDMM. MATERIALS AND METHODS: Clinical, mobilization and clonogenic data from 41 consecutively enrolled NDMM patients were analyzed. Patients underwent collection of autologous CD34+ by apheresis at the ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy, from January 2021 to March 2023. Clonogenicity analysis was performed on BFU-E and CFU-GM. RESULTS: Seventy-five percent of daratumumab-treated patients underwent >1 apheresis, compared to 24% of non-daratumumab patients (p=0.0017). Daratumumab-treated patients had significantly lower CD34+ count (mean 38 vs 79/µL, respectively; p=0.0011), with a median CD34+ harvest of 3.98×106/kg (range 1.68-9.18) vs 6.87×106/kg (range 1.63-16.85) in non-daratumumab-treated (p=0.0006). In multivariate analysis the likelihood of undergoing >1 apheresis was significantly higher in older patients (OR 1.2, 95% CI 1-1.4, Z=2.10, p=0.03) and daratumumab-treated patients (OR 15, 95% CI 2.8-129, p=0.004). Moreover, daratumumab-based induction therapy demonstrated an independent negative association with BFU-E colony formation (p=0.0148), even when accounting for patient age and CD34+ levels. DISCUSSION: Our findings underscore the impact of daratumumab-based treatment on CD34+ mobilization in a real-life, upfront plerixafor-free population of NDMM patients. Higher probability of requiring multiple apheresis occurred among daratumumab-treated patients. Interestingly, the observation that daratumumab might negatively impact BFU-E colony formation, independent of CD34+ cell count, offers novel biological perspectives. Appropriate strategies should be adopted by the Apheresis teams to mitigate these potential negative effects.

Preclinical discovery and initial clinical data of WVT078, a BCMA × CD3 bispecific antibody.

B-cell maturation antigen (BCMA) is an ideal target in multiple myeloma (MM) due to highly specific expression in malignant plasma cells. BCMA-directed therapies including antibody drug conjugates, chimeric antigen receptor-T cells and bispecific antibodies (BsAbs) have shown high response rates in MM. WVT078 is an anti-BCMA× anti-CD3 BsAb that binds to BCMA with subnanomolar-affinity. It was selected based on potent T cell activation and anti-MM activity in preclinical models with favorable tolerability in cynomolgus monkey. In the ongoing first-in-human phase I dose-escalation study (NCT04123418), 33 patients received intravenous WVT078 once weekly at escalated dosing. At the active doses of 48-250 µg/kg tested to date (n = 26), the overall response rate (ORR) was 38.5% (90% CI: 22.6-56.4%) and the complete response rate (CRR, stringent complete response + complete response) was 11.5%, (90% CI: 3.2-27.2%). At the highest dose level tested, the ORR was 75% (3 of 4 patients). 26 (78.8%) patients reported at least one Grade ≥3 AE and 16 of these AEs were suspected to be drug related. 20 patients (60.6%) experienced cytokine release syndrome. WVT078 has an acceptable safety profile and shows preliminary evidence of clinical activity at doses tested to date.

Bortezomib, cyclophosphamide, dexamethasone versus lenalidomide, cyclophosphamide, dexamethasone in multiple myeloma patients at first relapse.

Bortezomib- and lenalidomide-containing regimens are well-established therapies in multiple myeloma (MM). However, despite their extensive use, head-to-head comparisons have never been performed. Therefore, we compared bortezomib and lenalidomide in fixed-duration therapies. In this open-label, phase III study, we randomized MM patients at first relapse to receive either nine cycles of bortezomib plus cyclophosphamide plus dexamethasone (VCD) or lenalidomide plus cyclophosphamide plus dexamethasone (RCD). The primary endpoint was achievement of a very good partial response (VGPR) or better at six weeks after nine treatment cycles. From March 2011 to February 2015, 155 patients were randomized. VGPR or better was achieved by 12 patients (15%) in the VCD arm and 14 patients (18%) in the RCD arm (P = 0·70). Median progression-free survival (PFS) was 16·3 (95% CI: 12·1-22·4) with VCD and 18·6 months (95% CI: 14·7-25·5) with RCD, and the two-year overall survival (OS) was 75% (95% CI: 66-86%) and 74% (95% CI: 64-85%) respectively. In subgroup analyses, no differences in PFS were observed in bortezomib- and lenalidomide-naïve patients, nor in patients who received a bortezomib-based regimen in first line. Adverse events were consistent with the well-established safety profiles of both drugs. Bortezomib and lenalidomide treatments were equally effective in terms of depth of response, PFS, and OS in MM patients at first relapse.

Lenalidomide Maintenance with or without Prednisone in Newly Diagnosed Myeloma Patients: A Pooled Analysis.

: We conducted a pooled analysis of two phase III trials, RV-MM-EMN-441 and EMN01, to compare maintenance with lenalidomide-prednisone vs. lenalidomide in newly diagnosed transplant-eligible and -ineligible myeloma patients. Primary endpoints were progression-free survival, progression-free survival 2 and overall survival with both regimens. A secondary aim was to evaluate the impact of duration of maintenance on overall survival and on outcome after relapse. A total of 625 patients (lenalidomide-prednisone arm, n = 315; lenalidomide arm, n = 310) were analyzed. The median follow-up was 58 months. Median progression-free survival (25 vs. 19 months; p = 0.08), progression-free survival 2 (56 vs. 49 months; p = 0.9) and overall survival (73 months vs. NR; p = 0.08) were not significantly different between the two arms. Toxicity profiles of lenalidomide-prednisone and lenalidomide were similar, with the exception of neutropenia that was higher in the lenalidomide arm (grade ≥ 3: 9% vs. 19%, p < 0.001), without an increase in the rate of infections. Overall survival (median NR vs. 49 months, p < 0.001), progression-free survival from relapse (median 35 vs. 24 months, p = 0.004) and overall survival from relapse (median not reached vs. 41 months, p = 0.002) were significantly longer in patients continuing maintenance for ≥2 years. We showed that the addition of prednisone at 25 or 50 mg every other day (eod) to lenalidomide maintenance did not induce any significant advantage.

Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma.

Patients with relapsed and/or refractory multiple myeloma (RRMM) have poor prognosis. The STRATUS study assessed safety and efficacy of pomalidomide plus low-dose dexamethasone in the largest cohort to date of patients with RRMM. Patients who failed treatment with bortezomib and lenalidomide and had adequate prior alkylator therapy were eligible. Pomalidomide 4 mg was given on days 1-21 of 28-day cycles with low-dose dexamethasone 40 mg (20 mg for patients aged >75 years) on days 1, 8, 15, and 22 until progressive disease or unacceptable toxicity. Safety was the primary end point; secondary end points included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Among 682 patients enrolled, median age was 66 years, and median time since diagnosis was 5.3 years. Median number of prior regimens was 5. Most patients were refractory to both lenalidomide and bortezomib (80.2%). Median follow-up was 16.8 months; median duration of treatment was 4.9 months. Most frequent grade 3/4 treatment-emergent adverse events were hematologic (neutropenia [49.7%], anemia [33.0%], and thrombocytopenia [24.1%]). Most common grade 3/4 nonhematologic toxicities were pneumonia (10.9%) and fatigue (5.9%). Grade 3/4 venous thromboembolism and peripheral neuropathy were rare (1.6% each). The ORR was 32.6%, and the median DOR was 7.4 months. Median PFS and OS were 4.6 months and 11.9 months, respectively. We present the largest trial to date evaluating pomalidomide plus low-dose dexamethasone in patients with RRMM, further confirming that this regimen offers clinically meaningful benefit and is generally well tolerated. www.Clinicaltrials.gov identifier NCT01712789.

Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide.

Lenalidomide plus dexamethasone is effective in the treatment of multiple myeloma (MM) but is associated with an increased risk of venous thromboembolism (VTE). This prospective, open-label, randomized substudy of a phase 3 trial compared the efficacy and safety of thromboprophylaxis with low-dose aspirin (ASA) or low-molecular-weight heparin (LMWH) in patients with newly diagnosed MM, treated with lenalidomide and low-dose dexamethasone induction and melphalan-prednisone-lenalidomide consolidation. Overall, 342 patients who did not have clinical indications or contraindications to antiplatelet or anticoagulant therapy were randomly assigned to receive ASA 100 mg/d (n = 176) or LMWH enoxaparin 40 mg/d (n = 166). The incidence of VTE was 2.27% in the ASA group and 1.20% in the LMWH group. Compared with LMWH, the absolute difference in the proportion of VTE was 1.07% (95% confidence interval, -1.69-3.83; P = .452) in the ASA group. Pulmonary embolism was observed in 1.70% of patients in the ASA group and none in the LMWH group. No arterial thrombosis, acute cardiovascular events, or sudden deaths were reported. No major hemorrhagic complications were reported. In previously untreated patients with MM receiving lenalidomide with a low thromboembolic risk, ASA could be an effective and less-expensive alternative to LMWH thromboprophylaxis.

Response-adjusted ISS (RaISS) is a simple and reliable prognostic scoring system for predicting progression-free survival in transplanted patients with multiple myeloma.

Complete response (CR) is associated with better outcome in patients with multiple myeloma (MM) treated with autologous transplant even though the progression-free survival (PFS) can be very variable among patients with good response. No simple and reliable prognostic scoring system, able to predict the duration of response, are so far available. Aim of this study was to identify any correlation between baseline clinical findings, response after transplant and the length of PFS, and thus develop a prognostic model. The new prognostic model was developed in a learning cohort of 549 patients with MM transplanted in five Italian hospitals. The prognostic value of this new score was confirmed in a validation cohort of 276 distinct patients with MM transplanted in two different Italian hospital. Univariate and multivariate analyses were performed using Cox models. The most important independent baseline predictor of transplant outcome, together with response after transplant, was International Staging System (ISS). We thus incorporated response to transplant and baseline ISS in a new scoring system, named response-adjusted international scoring system (RaISS), that was able to classify patients in three risk groups (low, intermediate, high) with different probabilities of progression after transplant (median PFS 35.9-15.4 months). The prognostic value of this new score was confirmed in the validation cohort. In conclusion, RaISS is a new simple and easily available scoring system that, accurately defining the risk of progression, can allow to identify patients who could deserve further treatment after transplant (consolidation, maintenance).

Bortezomib plus dexamethasone can improve stem cell collection and overcome the need for additional chemotherapy before autologous transplant in patients with myeloma.

The aim of this phase II trial was to investigate the efficacy of bortezomib plus dexamethasone (Vel-Dex) as induction therapy in patients with multiple myeloma (MM) and to define the role of intensification before transplantation. Fifty-seven patients were treated with four courses of Vel-Dex, two cycles of dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP), and a single autologous transplant. Fourteen patients (25%) went off-study: seven after Vel-Dex, seven after DCEP. All patients yielded high numbers of stem cells (median CD34+ cells 7.5 x 106/kg); 54 of the 57 patients (94%) collected > or =4 x 106/kg CD34+ cells, 60% with a single leukapheresis. The overall response rate (ORR) after Vel-Dex was 86% (70% had a very good partial response [VGPR] or better) regardless of cytogenetic abnormalities and International Staging System stage (ISS). The response at the end of the two DCEP cycles remained unchanged in 35 patients (70%), worsened in 15 (20%), and improved in 5 (10%). Because of the consistent drop-out, the ORR in intention-to-treat analysis decreased significantly from 86% after Vel-Dex to 76% after DCEP, and 73% after transplantation. However, when considering the subset of 43 patients who completed the program, the ORR was 96% (complete response 39%, VGPR 41%, partial response 16%). In conclusion, Vel-Dex produces high response rates, improves stem cell collection, and overcomes the need for intensification before autologous transplantation.

Long-term outcome in relapsed and refractory multiple myeloma treated with thalidomide. Balancing efficacy and side-effects.

A total of 303 MM patients were retrospectively reviewed to evaluate long-term efficacy and toxicity of thalidomide alone or in combination with steroids. Overall response rate was 57% (CR/VGPR 12%). Median TTP, PFS and OS were 13.4 months, 20.6 months, and 26.2 months, respectively. PFS and OS were significantly different according to response (p < 0.0001), with better outcome in patients achieving CR/VGPR (PFS and OS 35.4 months and 63 months, respectively). PFS and OS of patients achieving SD or PR were overlapping (p = 0.3). The addition of steroids significantly increased the response rate (p = 0.01). The most clinically relevant complications were neuropathy (40%), constipation (26%), thromboembolic events (7%). Thalidomide was reduced for toxicity in 68 patients (24%) and permanently discontinued in 36 (12%). In conclusion, thalidomide produces high response rate in relapsed/refractory MM. The best outcome is observed in patients with good quality response, but even patients with suboptimal response may obtain durable survival.

Twice daily fludarabine/Ara-C associated to idarubicin, G-CSF and ATRA is an effective salvage regimen in non-promyelocytic acute myeloid leukemia.

Preclinical data suggest that all-trans retinoic acid (ATRA) synergizing with granulocyte colony stimulating factor (G-CSF), can improve the effectiveness of chemotherapy in acute myeloid leukemia (AML). Fludarabine 15 mg/m(2) is the minimum dose able to optimize intensification with fludarabine-arabinosylcytosine regimen. In this study 52 patients with relapsed/refractory AML obtained a complete remission (CR) rate of 69.2% after FLAIRG regimen (Fludarabine and arabinosylcytosine twice daily, idarubicin, G-CSF, ATRA). This schedule resulted effective and tolerable enabling 53% of the responding patients to receive transplant procedure. FLAIRG regimen could be proposed as a "bridge" to transplant treatment in this poor risk setting.

Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: definition and management of the risk related to zoledronic acid.

PURPOSE: Bisphosphonates (BPs) are currently used to treat bone lesions in patients with multiple myeloma (MM). Osteonecrosis of the jaw (ONJ) has been reported as an adverse event of such treatment, especially after treatment with zoledronic acid (ZA). The aim of this study was to evaluate incidence, risk factors, management, and prevention strategies of ONJ in order to optimize the current standard use of BPs in MM. PATIENTS AND METHODS: We reviewed the medical records of 105 patients with MM treated in 2 hematology departments with monthly pamidronate 90 mg and/or ZA 4 mg and evaluated for > or = 12 months. Because they are risk factors for ONJ development, we analyzed patient and disease features, previous MM treatments, type and number of BP infusions, and previous history of dental procedures. RESULTS: Seventeen patients (16%) with MM treated with BPs developed ONJ after a median number of 43 BP infusions (vs. 28 in patients without ONJ; P = .035). In 11 of 17 patients, ONJ arose after a tooth extraction. Among risk factors, the administered doses of ZA were significantly associated with ONJ, and 12 consecutive doses of ZA proved to double the risk of developing this complication. Regular hard- and soft-tissue oral assessment was of benefit in the prevention of further ONJ occurrence. CONCLUSION: The most important risk factor for ONJ is represented by the number of ZA infusions. Tooth extractions and invasive procedures should be avoided. A multidisciplinary approach including oncohematologists and dental teams proved critical to better identify, prevent, and manage ONJ.

High-dose idarubicin in combination with Ara-C in patients with relapsed or refractory acute lymphoblastic leukemia: a pharmacokinetic and clinical study.

OBJECTIVE: High dose (HD) Ara-C combined with a single HD idarubicin dose (IDA) is an efficient and safe salvage regimen for patients with refractory or relapsed acute lymphoblastic leukemia as indicated by phase II studies. No data are available on the pharmacokinetics of IDA after a rapid HD intravenous infusion. An open phase II pharmacokinetic and clinical study was performed to evaluate antileukemic efficacy, IDA pharmacokinetics and to investigate the presence of IDA and its reduced metabolite idarubicinol (IDAol) in cerebrospinal fluid (CSF) of patients treated with HD-IDA. PATIENTS AND METHODS: Twenty-five patients with refractory or relapsed acute lymphoblastic leukemia received Ara-C 3 g/m2 from days 1-5, idarubicin (HD-IDA) 40 mg/m2 as rapid intravenous (i.v.) infusion on day 3 and subcutaneous G-CSF 5 microg/kg from day 7 until PMN recovery. Pharmacokinetics of IDA was evaluated after HD idarubicin administration in nine of these patients. CSF samples were collected in 15 patients at different times. IDA and IDAol concentrations were quantified by a validated HPLC assay described in detail elsewhere. RESULTS: Eleven patients (44%, 95% CI: 23-65%) achieved complete remission with median disease free survival for 6 months. After administration of HD-IDA i.v. bolus of 40 mg/m2, plasma level profiles of unchanged drug and IDAol were similar to those previously described after standard dose and measured with the same analytical method. The mean terminal half-life measured for IDA in this group of patients (14.9 h) was not significantly different from the mean value observed after standard dose (13.9 h, P=0.72). IDAol t1/2 was also similar after HD-IDA (46.2 h) and standard dose (39.4 h, P=0.79). Pharmacokinetic data reveal that in our series of patients IDA and IDAol clearances are significantly higher than those observed in patients treated with 12 mg/m2 of IDA but, although the administered dose (mg/m2) of the drug is 3.3 times higher, IDA exposure (measured in terms of AUC) is only 2.3 times and IDAol exposition 2.1 times greater. Furthermore, HD infusion resulted in a ratio between the AUC of parent drug and idarubicinol not different from the value observed with the standard-dose. IDA and IDAol were measurable only in 3 of the 15 cerebrospinal fluid samples collected. CONCLUSION: Responses observed in our series are comparable to those reported with other salvage regimens. The IDA exposure lower than expected may explain the safety of the single i.v. administration of 40 mg/m2 of IDA, combined with HD Ara-C, with a degree of myelosuppression equivalent to that reported with this agent administered in standard doses. Our data do not allow us to clearly attribute this behavior to a pharmacokinetic non-linearity since the baseline creatinine clearance, even within normal values, and patient age are significantly different in the two groups. Cerebrospinal fluid penetration was poor, reaching levels not considered as cytotoxic.

Safety and efficacy of subcutaneous Campath-1H for treating residual disease in patients with chronic lymphocytic leukemia responding to fludarabine.

BACKGROUND AND OBJECTIVES: Recent observations suggested that targeted monoclonal antibodies might be best employed in lymphoid malignancies under conditions of minimal residual disease. This prompted us to investigate the role of Campath-1H as treatment for patients with chronic lymphocytic leukemia (CLL) in whom fludarabine (FAMP) had produced a marked disease debulking with persistence of bone marrow (BM) infiltration or a complete remission (CR) without the disappearance of the molecular aberration (IgH monoclonal expression). As intravenous Campath-1H is almost invariably associated with reactions, sometimes of WHO grade 3-4, we adopted the subcutaneous route of administration, which proved to induce rare and mild adverse reactions but had comparable efficacy. DESIGN AND METHODS. Nine patients (7 males, 2 females) with a median age of 55 years (range 41-61) who responded to FAMP (1 had a CR, 5 a nodular partial remission [PRN], and 3 a partial remission [PR]), according to NCI Working Group Criteria, received subcutaneous Campath-1H, three times a week for 6 weeks in escalating doses up to 10 mg. Monoclonal rearrangement of IgH was present in all patients before immunotherapy. Patients received acyclovir and cotrimoxazole as infection prophylaxis. Granulocyte colony-stimulating factor (G-CSF), at the dosage of 5-10 microg/kg/die, or intermediate-dose Ara-C (800 mg/m(2)/q 12h x 6 doses), was administered to obtain peripheral blood stem cell (PBSC) mobilization. RESULTS: All patients were evaluable for response. Five patients, 2 in PR and 3 in PRN after FAMP treatment, reached a CR. Three patients, one in PR, one in PRN and one in CR, converted to a molecular remission. In four out of seven patients PBSC harvesting was successful; more than 2.5 x 10(6) cells/kg were collected from all these patients. Collection was polyclonal for IgH gene rearrangement in three cases. One patient has been transplanted after cyclophosphamide and total body irradiation as conditioning regimen, without complications and with rapid hemopoietic engraftment. All patients were evaluable for toxicity. A WHO grade 1-2 skin reaction was observed in 5 patients at the site of injection. No infectious episodes were recorded. Two out of three patients presenting cytomegalovirus reactivation, without pneumonia, were successfully treated with oral gancyclovir. INTERPRETATION AND CONCLUSIONS: Subcutaneous Campath-1H administered to CLL patients with residual BM disease after FAMP proved to be safe and effective. Of nine patients, three obtained a molecular CR and five converted into a morphologic and immunophenotypic CR. In four of seven patients submitted to PBSC mobilization, this treatment also allowed a harvest uncontaminated by CD5/CD19 double-positive CLL cells, which was polyclonal for IgH gene rearrangement in three cases.