ctDNA improves prognostic prediction for patients with relapsed/refractory MM receiving ixazomib, lenalidomide, and dexamethasone.

ABSTRACT: It remains elusive how driver mutations, including those detected in circulating tumor DNA (ctDNA), affect prognosis in relapsed/refractory multiple myeloma (RRMM). Here, we performed targeted-capture sequencing using bone marrow plasma cells (BMPCs) and ctDNA of 261 RRMM cases uniformly treated with ixazomib, lenalidomide, and dexamethasone in a multicenter, prospective, observational study. We detected 24 and 47 recurrently mutated genes in BMPC and ctDNA, respectively. In addition to clonal hematopoiesis-associated mutations, varying proportion of driver mutations, particularly TP53 mutations (59.2% of mutated cases), were present in only ctDNA, suggesting their subclonal origin. In univariable analyses, ctDNA mutations of KRAS, TP53, DIS3, BRAF, NRAS, and ATM were associated with worse progression-free survival (PFS). BMPC mutations of TP53 and KRAS were associated with inferior PFS, whereas KRAS mutations were prognostically relevant only when detected in both BMPC and ctDNA. A total number of ctDNA mutations in the 6 relevant genes was a strong prognostic predictor (2-year PFS rates: 57.3%, 22.7%, and 0% for 0, 1, and ≥2 mutations, respectively) and independent of clinical factors and plasma DNA concentration. Using the number of ctDNA mutations, plasma DNA concentration, and clinical factors, we developed a prognostic index, classifying patients into 3 categories with 2-year PFS rates of 57.9%, 28.6%, and 0%. Serial analysis of ctDNA mutations in 94 cases revealed that TP53 and KRAS mutations frequently emerge after therapy. Thus, we clarify the genetic characteristics and clonal architecture of ctDNA mutations and demonstrate their superiority over BMPC mutations for prognostic prediction in RRMM. This study is a part of the C16042 study, which is registered at www.clinicaltrials.gov as #NCT03433001.

A prospective, multicenter, observational study of ixazomib plus lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma in Japan.

Real-world studies permit inclusion of a more diverse patient population and provide more information on the effectiveness of treatments used in routine clinical practice. This prospective, multicenter, observational study investigated the effectiveness and safety of ixazomib plus lenalidomide and dexamethasone (IRd) in 295 patients with relapsed/refractory multiple myeloma (RRMM) in routine clinical practice in Japan. Patients had a median age of 74 years, 80.0% were aged ≥ 65 years, 42.0% had received ≥ 3 lines of prior treatment, and 28.5% were "frail" according to the International Myeloma Working Group frailty score. After a median follow-up of 25.0 months, median progression-free survival (PFS) was 15.3 (95% CI 12.4-19.5) months, while median overall survival was not reached. The overall response rate was 53.9%, and 31.5% of patients had a very good partial response or better. In the subgroup analysis, median PFS was better in patients with 1 versus 2 or ≥ 3 lines of prior treatment (29.0 vs 19.2 or 6.9 months) and paraprotein versus clinical relapse (16.0 vs 7.9 months), but median PFS was not notably affected by frailty score or age group. Dose adjustment was more frequent among patients aged > 75 years, especially early after IRd treatment initiation. Treatment-emergent adverse events (TEAEs) of any grade occurred in 84.4% of patients and 24.7% of patients discontinued treatment due to TEAEs; no new safety concerns were found. These findings suggest that oral IRd triplet regimen is an effective and tolerable treatment option for RRMM patients in real-world settings outside of clinical trials.ClinicalTrials.gov identifier: NCT03433001; Date of registration: 14 February 2018.

Changing trends in the risk factors for second primary malignancies after autologous stem cell transplantation for multiple myeloma before and after the introduction of proteasome inhibitors and immunomodulatory drugs.

The incidence of second primary malignancies (SPM) in long-term survivors of multiple myeloma (MM) is increasing because of increased life expectancy. We retrospectively analyzed the risk factors for SPM in patients with MM after autologous stem cell transplantation (ASCT) before and after the introduction of proteasome inhibitors and immunomodulatory drugs (IMiDs). In total, 2,340 patients newly diagnosed with MM who underwent ASCT between 1995 and 2016 were enrolled in this study. Forty-three patients developed SPM (29 solid, 12 hematological, and 2 unknown tumors), with cumulative incidence rates of 0.8% and 2.5% at 24 and 60 months, respectively. The cumulative incidence rates of hematological and solid SPM at 60 months were 0.8% and 1.8%, respectively. The overall survival (OS) rate at 60 months after ASCT was 62.9% and the OS rates after the diagnosis of SPM at 24 months were 72.2% for hematological SPM and 70.9% for solid SPM. Multivariate analysis revealed that the use of IMiDs (P=0.024) and radiation (P=0.002) were significant independent risk factors for SPM. The probabilities of developing SPM and death due to other causes (mainly MM) at 60 months were 2.5% and 36.5%, respectively, indicating that the risk of SPM was lower than that of death from MM. Furthermore, SPM between the pre-novel and novel agent eras (ASCT between 2007 and 2016) groups significantly increased (1.9% vs. 4.3% at 60 months; P=0.022). The early occurrence of SPM after ASCT should be monitored cautiously.

Outcomes of adult patients with early T-cell precursor (ETP) acute lymphoblastic leukemia/lymphoma (ALL) and non-ETP T-ALL.

Early T-cell precursor (ETP) acute lymphoblastic leukemia/lymphoma (ALL) is generally considered to be a high-risk subtype. We retrospectively analyzed the clinical outcomes of adult patients diagnosed with ETP-ALL or other T-cell ALL (non-ETP T-ALL). The subjects were 82 patients (ETP-ALL: n = 18, non-ETP T-ALL: n = 64) for whom relevant immunophenotype data needed for classification were available. ETP-ALL patients were older (median age, 50.5 vs. 33.5 years, P = 0.042) and had less mediastinal involvement (27.8 vs. 73.4%, P < 0.001). The rate of complete remission (CR) with the first induction therapy was significantly lower in the ETP group (33.3 vs. 64.0%, P = 0.03), but the CR rate within 2 cycles of chemotherapy did not differ significantly (61.1 vs. 76.6%, P = 0.232). The 3-year overall survival (OS) rate was also similar in both groups (43.2 vs. 45.8%, P = 0.992). The ETP phenotype had no impact on survival in the transplant group or the non-transplant group. A multivariate analysis identified the male sex as a poor prognostic factor (HR: 4.43, P < 0.01), but not the immunophenotype of ETP. The prognosis for adult patients with ETP-ALL was comparable to that of non-ETP T-ALL patients. However, further studies aimed at improving the remission rate for ETP-ALL are needed.

Outcomes of poor peripheral blood stem cell mobilizers with multiple myeloma at the first mobilization: A multicenter retrospective study in Japan.

Autologous stem cell transplantation (ASCT) remains an important therapeutic strategy for multiple myeloma; however, a proportion of patients fail to mobilize a sufficient number of peripheral blood stem cells (PBSCs) to proceed to ASCT. In the present study, we aimed to clarify the characteristics and outcomes of poor mobilizers. Clinical data on poorly mobilized patients who underwent PBSC harvest for almost 10 years were retrospectively collected from 44 institutions in the Japanese Society of Myeloma (JSM). Poor mobilizers were defined as patients with less than 2 × 106/kg of CD34+ cells harvested at the first mobilization. The proportion of poor mobilization was 15.1%. A sufficient dataset including overall survival (OS) was evaluable in 258 poor mobilizers. Overall, 92 out of 258 (35.7%) poor mobilizers did not subsequently undergo ASCT, mainly due to an insufficient number of PBSCs. Median OS from apheresis was longer for poor mobilizers who underwent ASCT than for those who did not (86.0 vs. 61.9 mon., p = 0.02). OS from the diagnosis of poor mobilizers who underwent ASCT in our cohort was similar to those who underwent ASCT in the JSM database (3y OS rate, 86.8% vs. 85.9%). In this cohort, one-third of poor mobilizers who did not undergo ASCT had relatively poor survival. In contrast, the OS improved in poor mobilizers who underwent ASCT. However, the OS of extremely poor mobilizers was short irrespective of ASCT.

Myeloid Sarcoma of the Paranasal Sinuses in a Patient with Acute Myeloid Leukemia.

Myeloid sarcoma (MS) is an uncommon extramedullary malignant tumor, and often represents a subgroup of acute myeloid leukemia (AML). MS of paranasal sinus origin is extremely rare. We report an uncommon case of sinonasal MS associated with AML, who was successfully treated with hematopoietic stem-cell transplantation. A 39-year-old male was admitted with complaints of left nasal obstruction and proptosis. Computed tomography and magnetic resonance imaging identified a left ethmoidal mass involving the maxillary sinus, the orbit, and the skull base. Nasal endoscopic examination detected a whitish homogeneous mass occupying the left nasal cavity. Although accumulation of atypical lymphocytes was suspected based on initial pathological inspection, immunohistochemical analysis showed myeloperoxidase-positive myeloid cells. Together with concomitant leukocytosis (149,000/µL) composed of myeloid blast cells and excess of myeloblasts in the bone marrow, the patient was diagnosed as sinonasal MS with AML with maturation (French-American-British Classification M2). The patient was treated by chemotherapy (remission induction therapy with daunorubicin and cytarabine; salvage chemotherapy with high-dose cytarabine), radiotherapy (30 Gy in 10 fractions) and allogeneic hematopoietic stem-cell transplantation, and followed up for 12 months with no recurrence. Early diagnosis is critical for the best improvement of MS. MS of the paranasal sinuses may easily be misdiagnosed as malignant lymphoma or poorly differentiated carcinoma. Prompt hematological and immunohistological investigations with suspicion of MS are essential for correct diagnosis. Furthermore, we concisely review nine previously reported patients with MS and indicate the importance of hematopoietic stem-cell transplantation for good prognosis.