Outcomes of methotrexate-associated lymphoproliferative disorders in rheumatoid arthritis patients treated with disease-modifying anti-rheumatic drugs.

Recently, the use of targeted synthetic or biological disease-modifying anti-rheumatic drugs (ts/bDMARDs) in addition to conventional synthetic (cs)DMARDs including methotrexate (MTX) for rheumatoid arthritis (RA) has increased. However, whether ts/bDMARDs are associated with the development and clinicopathological features of MTX-associated lymphoproliferative disorder (MTX-LPD) in patients with RA remains unknown. Therefore, we evaluated the clinical outcomes of 121 patients with MTX-LPD. Results showed that prior use of ts/bDMARDs was not associated with the different histopathological subtypes of MTX-LPD. Patients with polymorphic-type LPD had a better event-free survival than those with diffuse large B-cell lymphoma (DLBCL), classical Hodgkin lymphoma and peripheral T-cell lymphoma. The pathological subtype of lymphoma could predict the clinical outcome of MTX-LPD. In patients with DLBCL, the use of tumour necrosis factor-alpha (TNF-α) inhibitors prior to MTX-LPD onset was associated with a higher non-relapse mortality. Further, patients with RA previously treated with Janus kinase (JAK) inhibitors more commonly required chemotherapy than those treated with csDMARDs alone, indicating disease aggressiveness. Hence, special caution should be observed when managing patients with MTX-LPD previously treated with JAK or TNF-α inhibitors for RA.

Tyrosine kinase inhibitors induce alternative spliced BCR-ABLIns35bp variant via inhibition of RNA polymerase II on genomic BCR-ABL.

To elucidate dynamic changes in native BCR-ABL and alternatively spliced tyrosine kinase inhibitor (TKI)-resistant but function-dead BCR-ABLIns35bp variant, following commencement or discontinuation of TKI therapy, each transcript was serially quantified in patients with chronic myeloid leukemia (CML) by deep sequencing. Because both transcripts were amplified together using conventional PCR system for measuring International Scale (IS), deep sequencing method was used for quantifying such BCR-ABL variants. At the initial diagnosis, 7 of 9 patients presented a small fraction of cells possessing BCR-ABLIns35bp , accounting for 0.8% of the total IS BCR-ABL, corresponding to actual BCR-ABLIns35bp value of 1.1539% IS. TKI rapidly decreased native BCR-ABL but not BCR-ABLIns35bp , leading to the initial increase in the proportion of BCR-ABLIns35bp . Thereafter, both native BCR-ABL and BCR-ABLIns35bp gradually decreased in the course of TKI treatment, whereas small populations positive for TKI-resistant BCR-ABLIns35bp continued fluctuating at low levels, possibly underestimating the molecular response (MR). Following TKI discontinuation, sequencing analysis of 54 patients revealed a rapid relapse, apparently derived from native BCR-ABL+ clones. However, IS fluctuating at low levels around MR4.0 marked a predominant persistence of cells expressing function-dead BCR-ABLIns35bp , suggesting that TKI resumption was unnecessary. We clarified the possible mechanism underlying mis-splicing BCR-ABLIns35bp , occurring at the particular pseudo-splice site within intron8, which can be augmented by TKI treatment through inhibition of RNA polymerase II phosphorylation. No mutations were found in spliceosomal genes. Therefore, monitoring IS functional BCR-ABL extracting BCR-ABLIns35bp would lead us to a correct evaluation of MR status, thus determining the adequate therapeutic intervention.

Comparison of calcineurin inhibitors in combination with conventional methotrexate, reduced methotrexate, or mycophenolate mofetil for prophylaxis of graft-versus-host disease after umbilical cord blood transplantation.

Umbilical cord blood transplantation (UCBT) is a curative treatment for hematological malignancies. However, appropriate prophylaxis against graft-versus-host disease (GVHD), aimed at obtaining rapid and stable engraftment and avoiding toxicity, remains controversial in UCBT. We retrospectively compared outcomes in 409 patients who received calcineurin inhibitors (CIs) plus conventional-dose methotrexate (conv-MTX/CIs, n = 77; methotrexate, 10 mg/m2 on day 1, 7 mg/m2 on days 3 and 6) with those who received CIs plus reduced-dose methotrexate (reduced-MTX/CIs, n = 209; methotrexate, 5 mg/m2 or 5 mg/body on days 1, 3, and 6) or CIs with mycophenolate mofetil (MMF/CIs, n = 123) for GVHD prophylaxis after UCBT. The cumulative incidence of neutrophil engraftment was significantly higher in the reduced-MTX/CI (82.3%) and MMF/CI (86.6%) groups than the conv-MTX/CI (71.4%) group (p = 0.014), although there were no differences in platelet recovery or infectious complications among the three groups. The incidence and severity of GVHD were comparable among the three groups, and there were no significant differences in transplantation-related mortality among the three groups. In conclusion, GVHD prophylaxis with reduced-dose methotrexate and MMF was closely associated with high incidence of neutrophil engraftment without an effect on the incidence and severity of GVHD, which was compared to GVHD prophylaxis with conventional-dose methotrexate.

A distinct subtype of Epstein-Barr virus-positive T/NK-cell lymphoproliferative disorder: adult patients with chronic active Epstein-Barr virus infection-like features.

The characteristics of adult patients with chronic active Epstein-Barr virus infection are poorly recognized, hindering early diagnosis and an improved prognosis. We studied 54 patients with adult-onset chronic active Epstein-Barr virus infection diagnosed between 2005 and 2015. Adult onset was defined as an estimated age of onset of 15 years or older. To characterize the clinical features of these adults, we compared them to those of 75 pediatric cases (estimated age of onset <15 years). We compared the prognosis of adult-onset chronic active Epstein-Barr virus infection with that of patients with nasal-type (n=37) and non-nasal-type (n=45) extranodal NK/T-cell lymphoma. The median estimated age of onset of these lymphomas was 39 years (range, 16-86 years). Compared to patients with pediatric-onset disease, those in whom the chronic active Epstein-Barr virus infection developed in adulthood had a significantly decreased incidence of fever (P=0.005), but greater frequency of skin lesions (P<0.001). Moreover, hypersensitivity to mosquito bites and the occurrence of hydroa vacciniforme were less frequent in patients with adult-onset disease (P<0.001 and P=0.0238, respectively). Thrombocytopenia, high Epstein-Barr virus nuclear antigen antibody titer, and the presence of hemophagocytic syndrome were associated with a poor prognosis (P=0.0087, P=0.0236, and P=0.0149, respectively). Allogeneic hematopoietic stem cell transplantation may improve survival (P=0.0289). Compared to pediatric-onset chronic active Epstein-Barr virus infection and extranodal NK/T-cell lymphoma, adult-onset chronic active Epstein-Barr virus infection had a poorer prognosis (P<0.001 and P=0.0484, respectively). Chronic active Epstein-Barr virus infection can develop in a wide age range, with clinical differences between adult-onset and pediatric-onset disease. Adult-onset chronic active Epstein-Barr virus infection is a disease with a poor prognosis. Further research will be needed.

Significance of Salvage Autologous Stem Cell Transplantation for Relapsed Multiple Myeloma: A Nationwide Retrospective Study in Japan.

Autologous stem cell transplantation (ASCT) has been employed for patients with relapsed multiple myeloma (MM) after up-front ASCT. The present retrospective study aimed to examine the survival benefit from salvage ASCT. Among 446 patients with relapsed MM after up-front single ASCT, 70 patients received salvage ASCT, the employment of which reduced the risk of mortality after relapse (p = 0.041). Using the parameters before initial ASCT, the advantage of salvage ASCT compared to standard therapy was confirmed in the subgroup with an international staging system stage of I or II (p = 0.040), good performance status (PS; p = 0.043), or no/mild renal comorbidity (p = 0.029). The advantage of salvage ASCT was also confirmed in the subgroup excluding those with early relapse within 7 months after initial ASCT (p = 0.026). Among patients who received salvage ASCT, a favorable prognosis is apparent for those with a time to relapse after initial ASCT of longer than 24 months. The overall survival after salvage ASCT was favorable excluding patients with the following factors: early relapse, poor PS, moderate/severe renal comorbidity, and progressive disease (p < 0.001). In conclusion, our results reinforced the evidence for encouraging salvage ASCT for eligible patients.

Comparative analysis of pulmonary hypertension in patients treated with imatinib, nilotinib and dasatinib.

Pulmonary hypertension (PH) is a rare, but life-threatening, adverse event in patients treated with tyrosine kinase inhibitors (TKIs), such as dasatinib, but has not been fully evaluated in patients treated with imatinib or nilotinib. We used echocardiography to noninvasively assess the incidence of PH in 105 patients with chronic myeloid leukaemia (CML) treated with imatinib (n = 37), nilotinib (n = 30) or dasatinib (n = 38). The mean triscupid regurgitation peak gradient (TRPG), which reflects pulmonary arterial pressure, was 22·7 mmHg in the imatinib group, 23·1 mmHg in the nilotinib group and 23·4 mmHg for dasatinib group. These values were not significantly different, but higher than those (19·0 mmHg) in newly diagnosed CML patients. A TRPG > 31 mmHg, marking possible PH onset, was detected in 9 of 105 patients: one (2·7%) treated with imatinib, three (10·0%) with nilotinib and five (13·2%) with dasatinib. Only three patients complained of dyspnoea, whereas the other six were asymptomatic. In addition, there was a tendency toward correlation of TRPG value and age or TKI treatment duration. These results suggested that treatment with not only dasatinib, but also imatinib and nilotinib, can be associated with subclinical PH. Noninvasive echocardiography is useful for screening, especially in older patients with long-term TKI treatment.

Comparison of clinicopathological characteristics between T-cell prolymphocytic leukemia and peripheral T-cell lymphoma, not otherwise specified.

OBJECTIVES: T-cell prolymphocytic leukemia (T-PLL) is a very rare, aggressive T-cell neoplasm. Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is also a highly aggressive lymphoma. These two diseases can often be confused with each other; therefore, we aimed to determine the clinical and pathological differences between T-PLL and PTCL-NOS. METHODS: We analyzed 15 T-PLL and 91 PTCL-NOS patients and also compared clinical features between T-PLL and PTCL-NOS with leukemic presentation. Peripheral blood images and biopsy specimens were analyzed, and treatment responses were determined via imaging modalities. The clinicopathological characteristics were statistically compared. RESULTS: T-PLL cells were smaller in size than those of PTCL-NOS with leukemic presentation (P=.0068); moreover, PTCL-NOS cells with leukemic presentation were smaller than those of PTCL-NOS without leukemic presentation (P=.0017). Immunophenotypic patterns in T-PLL and PTCL-NOS were similar. Five-year overall survival rates of T-PLL and all PTCL-NOS patients were 57.5% and 36.8%, respectively. No significant differences were found in clinical manifestations or prognoses; T-PLL and PTCL-NOS with leukemic presentation had essentially equivalent characteristics. CONCLUSION: T-PLL and PTCL-NOS may share common biological and clinical characteristics in Japanese patients.

Mogamulizumab Treatment Prior to Allogeneic Hematopoietic Stem Cell Transplantation Induces Severe Acute Graft-versus-Host Disease.

Mogamulizumab (MOG), a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, has recently played an important role in the treatment of adult T cell leukemia/lymphoma (ATLL). Because CCR4 is expressed on normal regulatory T cells as well as on ATLL cells, MOG may accelerate graft-versus-host disease (GVHD) by eradicating regulatory T cells in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is limited information about its safety and efficacy in patients treated with MOG before allo-HSCT. In the present study, 25 patients with ATLL were treated with MOG before allo-HSCT, after which 18 patients (72%) achieved remission. The overall survival and progression-free survival at 1 year post-transplantation were 20.2% (95% CI, 6.0% to 40.3%) and 15.0% (95% CI, 4.3% to 32.0%), respectively. The cumulative incidence of acute GVHD was 64.0% (95% CI, 40.7% to 80.1%) for grade II-IV and 34.7% (95% CI, 15.8% to 54.4%) for grade III-IV. The cumulative incidence of transplantation-related mortality (TRM) was 49.0% (95% CI, 27.0% to 67.8%). Six of 7 patients with acute GVHD grade III-IV died from GVHD, which was the leading cause of death. In particular, a shorter interval from the last administration of MOG to allo-HSCT was associated with more severe GVHD. MOG use before allo-HSCT may decrease the ATLL burden; however, it is associated with an increase in TRM due to severe GVHD. Because MOG is a potent anti-ATLL agent, new treatment protocols should be developed to integrate MOG at suitable doses and timing of administration to minimize unwanted GVHD development.

Efficacy and adverse events of azacitidine in the treatment of hemodialysis patients with high-risk myelodysplastic syndrome.

We describe two hemodialysis patients with high-risk myelodysplastic syndrome (MDS) treated with azacitidine. A 65-year-old woman (case 1) received azacitidine at 75 mg/m(2) for 7 days, and a 52-year-old man (case 2) with liver cirrhosis received a 70% dose of azacitidine. Both cases developed grade 4 cytopenia, but they achieved transfusion independence after 3 and 2 courses, and the durations of remission were 10 and 11 months, respectively. Case 1 had the complication of febrile neutropenia (FN) twice during the 1(st) and 2(nd) courses, but continued to receive azacitidine treatment thereafter. Case 2 developed infectious peritonitis during the sixth course, and azacitidine treatment was thus discontinued. After a 4-month treatment interruption, he became transfusion-dependent, and re-induction of azacitidine was successful. Of note, the course of case 1 was complicated by erythema nodosum on admission, which then disappeared after one course of azacitidine treatment. The mean durations of hospitalization were 17.5 and 23 days per course of azacitidine treatment, respectively. Though there are few reports of azacitidine treatment for hemodialysis patients with high-risk MDS, we advocate administering azacitidine to such patients, while paying close attention to the dose intensity of azacitidine and taking prompt action to manage infectious complications.

[Clinical courses and risk factors for progression of smoldering multiple myeloma: a nationwide cohort study in Japan].

We carried out a cohort study of smoldering multiple myeloma (SMM) in Japan. The clinical data of 207 patients with SMM, median age 69 years (range: 27-90), were collected from 63 institutions. The subtype of myeloma was IgG type in 168, IgA type in 30, and Bence Jones type in 9 patients. At a median follow-up of 39 months, 53% of the patients had progressed to symptomatic MM (within 5 years of the initial diagnosis). As previously described, a serum free light chain ratio>8 or <0.125, along with the number of bone marrow plasma cells being 10% or more and the serum M-protein level being at least 3 g/dl, was a significant predictor of rapid progression. We found that the rate of increase in serum M-protein levels correlated negatively with the risk of progression. The probability of progression within 5 years was 100% in patients whose rate of serum M-protein level increase was 2 mg/dl/day or higher. This indicates that the serum M-protein level increase rate might be a useful predictor of disease progression in SMM.

Decrease in venous irritation by adjusting the concentration of injected bendamustine.

Intravenous injection of bendamustine often causes venous irritation and also deteriorates the patient's quality of life. Thus, we evaluated the risk factors associated with venous irritation induced by bendamustine in patients with follicular lymphoma or mantle cell lymphoma. We also evaluated the effectiveness of intervention of changing the preparation procedure for bendamustine. All data were retrospectively collected from the electronic medical record system. In the initial analysis of the total 43 courses of bendamustine therapy, most patients (88%) were administered bendamustine with 250 mL of diluent according to the bendamustine package insert in Japan. The median concentration of bendamustine solution (0.56 mg/mL vs. 0.24 mg/mL) and the incidences of venous irritation (66% vs. 0%, p=0.01) were significantly different between the patients receiving bendamustine at 250 mL and 500 mL of diluent. Based on this result, we proposed changing the final volume of bendamustine dissolution from 250 to 500 mL, which is recommended in other countries. After this intervention, the incidence of venous irritation was significantly reduced from 58 to 20% (p=0.02). The incidence of venous irritation increased in a concentration-dependent manner (≤0.40 mg/mL: 6%; 0.41-0.60 mg/mL: 62%, p<0.001; >0.60 mg/mL: 75%, p<0.001). We conclude that a high concentration bendamustine solution is a risk factor for venous irritation and that 500 mL of diluent is ideal. To further reduce the incidence of venous irritation, the concentration of bendamustine solution is recommended to be 0.40 mg/mL or less.

Effectiveness and safety of antiemetic aprepitant in Japanese patients receiving high-dose chemotherapy prior to autologous hematopoietic stem cell transplantation.

For patients receiving high-dose chemotherapy, a 5-hydroxytryptamine 3 receptor antagonist combined with dexamethasone is a standard antiemetic therapy. Despite this prophylactic anti-emetic treatment, many patients still suffer from uncontrollable emesis. In this study, we retrospectively evaluated the antiemetic effectiveness and safety of aprepitant (a neurokinin-1 receptor antagonist) in addition to 5-HT3 antagonist in Japanese patients with hematologic malignancy receiving high-dose chemotherapy prior to autologous peripheral blood stem cell transplantation (auto-PBSCT). Twenty-six patients received aprepitant and granisetron (the aprepitant group), whereas, 22 patients received granisetron alone (the control group). All patients received 3 mg of granisetron intravenously 30 min before chemotherapy administration. Patients in the aprepitant group additionally received 125 mg of aprepitant 60-90 min before administration of the first moderately to highly emetogenic chemotherapy. On the next day or thereafter, 80 mg of aprepitant was administered in the morning until the last administration of moderately to highly emetogenic anticancer drugs. The percentage of patients who achieved complete response (CR), defined as no emesis with only grade 1-2 nausea, in the aprepitant group was significantly higher than that in the control group (42% vs. 5%, p=0.003). Logistic regression analysis showed that non-prophylactic use of aprepitant was significantly associated with non-CR. The frequencies of adverse drug events (ADEs) were not significantly different between two groups. In conclusion, the results of this study suggest that the addition of aprepitant to granisetron can improve the antiemetic effect without increasing ADEs in patients receiving high-dose chemotherapy prior to auto-PBSCT.

[Effect of bortezomib-based induction therapy on the peripheral blood stem cell harvest in multiple myeloma].

A high dose of melphalan followed by autologous stem cell transplantation (ASCT) is considered as the standard therapy for multiple myeloma. For induction therapy, 78 patients received conventional regimens (control group) and 32 patients received bortezomib-containing regimens (bortezomib group). We retrospectively compared the yield of harvested CD34+ cells between the two groups. In order to mobilize CD34+ cells, 83% of the control group and 63% of the bortezomib group received a high dose of cyclophosphamide followed by G-CSF, and 12% of the control group received a high dose of etoposide instead of cyclophosphamide. Furthermore, 5% of the control group and 38% of the bortezomib group received G-CSF alone for CD34+ cell mobilization. Overall, the yield of CD34+ cells was higher in the control group than in the bortezomib group (7.4 vs. 5.2×10(6)/kg, P=0.004). Regarding the patients mobilized by a high dose of cyclophosphamide followed by G-CSF, the rate of achieving CD34+ cells >2.0×10(6) cells/kg was similar. Bortezomib did not significantly affect the successful collection of at least CD34+ cells > 2.0×10(6) cells/kg after mobilization with a high dose of cyclophosphamide followed by G-CSF.

[Acute lung injury in a patient with concurrent diffuse large B-cell lymphoma and myelodysplastic syndrome].

A 67-year-old man developed a diffuse large B-cell lymphoma, and was simultaneously diagnosed as myelodysplastic syndrome(refractory cytopenia with multilineage dysplasia). Acute lung injury was complicated after the 6th course of rituximab injection, but was recovered by steroid pulse therapy. At that moment, marked leucocytosis was prominent due to the disease progression of myelodysplastic syndrome. Two months later, he relapsed into lymphoma systematically. During salvage chemotherapy without rituximab, the patient deteriorated into lethal respiratory failure. Autopsy findings revealed the diffuse alveolar damage with microscopic evidence of an adenovirus infection. His bone marrow showed the transformation of myelodysplastic syndrome into acute myeloid leukemia. The coincidence of myeloproliferative and lymphoproliferative diseases in the same patient is a rare phenomenon. We should be cautious when acute lung injury occurs during such a condition.

[B-cell lymphoma possessing t(14;18)(q32;q21)in a patient with rheumatoid arthritis receiving methotrexate treatment].

There is evidence of a slight increase in malignant lymphoma among rheumatoid arthritis(RA)patients receiving methotrexate( MTX). Increased rates of lymphoma have been attributed to reactivation of the Epstein-Barr virus(EBV). A 72-yearold woman was admitted to our hospital for generalized lymph adenopathy. She suffered from RA and has been treated with MTX for 7 years; the total amount of MTX received was around 2, 700 mg. The cervical lymph node revealed a diffuse proliferation of large atypical lymphocytes. An immunophenotype revealed CD10+, CD19+, CD20+, and k+. The chromosome analysis showed a complex abnormality containing t(14;18)(q32;q21). The tumor cells were positive for EBV sequences by in situ hybridization(ISH). A rituximab containing regimen was effective, but a systemic relapse occurred 4 years later. The biopsied sample was diagnosed as diffuse large B-cell lymphoma. FISH analysis revealed positive for t(14;18)(q32;q21), however, EBV was negative using ISH. In general, the concurrence of t(14;18)(q32;q21)and EBV in the B-cell lymphoma is rare. In addition, the negative change in EBV in the relapsed lymphoma cells revealed a quite rare phenomenon.

[Safety evaluation of bortezomib in multiple myeloma patients with severe renal failure].

Recently, the safety and effectiveness of bortezomib for patients with multiple myeloma and renal failure has been reported. In this study, we retrospectively analyzed the 8 myeloma patients with renal failure who have received bortezomib in our hospital.One patient had already required constant hemodialysis before bortezomib.Bortezomib treatment was performed for 229 days, during which time it was injected 30 times.The other 2 patients with chronic renal failure also showed no further renal impairment due to bortezomib.In the remaining 5 patients, serum creatinine levels decreased through 2 cycles(total: 8 injection)of bortezomib treatment.Two patients were complicated with herpes zoster, and 2 patients were complicated with neuropathy in grade 3.We showed the safety and efficacy of bortezomib in Japanese patients with multiple myeloma complicated with renal failure.We should positively consider the therapeutic choice of bortezomib for the refractory myeloma with renal failure.

[Chronic myeloid leukemia complicated with cerebellar hemorrhage and acute hydrocephalus successfully treated with imatinib and intensive supportive care].

We report a case of a 46-year-old female demonstrating general fatigue and visual disturbances with retinal bleeding. She had a white blood cell count of 419,300/mm. Thereafter, she developed vomiting associated with vertigo caused by cerebellar hemorrhage, deteriorating to acute hydrocephalus secondary to obstruction of the cerebral aqueduct. Emergency procedures for cerebral protection, such as hyperventilation, administration of mannitol, and barbiturate coma, were performed. Bone marrow examination showed a positive BCR-ABL/t(9;22)(q34;q11) chromosomal translocation detected by FISH and RT-PCR (masked Ph) and she was diagnosed as having chronic myeloid leukemia (CML) in the chronic phase (CP). She was administered Ara-C, together with imatinib 600 mg/d through a nasogastric tube. Eight days later, she underwent successful extubation and recovered without any neurological defect. She was maintained on imatinib 400 mg/d and demonstrated a major molecular response at 15 months. Physicians need to be aware that brain hemorrhage may develop as an initial symptom of CML patients in CP.

Atypical Hemolytic Uremic Syndrome following Acute Type A Aortic Dissection.

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA)-related disease that manifests as a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI) and is caused by uncontrolled activation of the complement system. We report the case of a 61-year-old woman with acute type A aortic dissection that subsequently developed into aHUS. The hematologic disorders underlying aHUS improved after treatment with the complement inhibitor eculizumab. It is important to consider aHUS when a patient clinically develops a triad of microangiopathic hemolytic anemia, thrombocytopenia, and an increasing creatinine level following cardiovascular surgery.

Phase I/II study of bortezomib, lenalidomide, and dexamethasone treatment for relapsed and refractory multiple myeloma.

Use of novel agents, including proteasome inhibitors and immunomodulatory drugs, has markedly improved outcomes in multiple myeloma (MM) patients. However, most MM patients eventually relapse and require salvage treatments. We report herein the result of a phase I/II study, performed from 2014 to 2017 to assess the feasibility and efficacy of a maximum tolerated dose (MTD) of lenalidomide (Len) combined with a fixed dose of once weekly subcutaneous (sc) 1.3 mg/m2 of bortezomib plus 20 mg of dexamethasone (scVRd regimen) in relapsed/refractory MM patients in the Japanese population. In the phase I part, dose-limiting toxicities were observed in three of six patients treated with 20 mg of Len; the MTD was accordingly defined as 15 mg in our cohort. In the phase II part, the recommended dose of the scVRD regimen showed a 71.4% best overall response rate, with a median overall survival of 14.8 months and a median progression-free survival of 8 months. Severe adverse events (≥ grade 3) were observed in ~ 15% of the patients, indicating the tolerability and efficacy of the regimen. Less prior treatment was associated with higher probability of durable response. This scVRd regimen may thus be a better fit for MM patients in early-stage relapse.