P.L. McCarthy

New Drugs and Novel Mechanisms of Action in Multiple Myeloma in 2013: A Report from the International Myeloma Working Group (IMWG)

Treatment in medical oncology is gradually shifting from the use of nonspecific chemotherapeutic agents toward an era of novel targeted therapy in which drugs and their combinations target specific aspects of the biology of tumor cells. Multiple myeloma (MM) has become one of the best examples in this regard, reflected in the identification of new pathogenic mechanisms, together with the development of novel drugs that are being explored from the preclinical setting to the early phases of clinical development. We review the biological rationale for the use of the most important new agents for treating MM and summarize their clinical activity in an increasingly busy field. First, we discuss data from already approved and active agents (including second- and third-generation proteasome inhibitors (PIs), immunomodulatory agents and alkylators). Next, we focus on agents with novel mechanisms of action, such as monoclonal antibodies (MoAbs), cell cycle-specific drugs, deacetylase inhibitors, agents acting on the unfolded protein response, signaling transduction pathway inhibitors and kinase inhibitors. Among this plethora of new agents or mechanisms, some are specially promising: anti-CD38 MoAb, such as daratumumab, are the first antibodies with clinical activity as single agents in MM. Moreover, the kinesin spindle protein inhibitor Arry-520 is effective in monotherapy as well as in combination with dexamethasone in heavily pretreated patients. Immunotherapy against MM is also being explored, and probably the most attractive example of this approach is the combination of the anti-CS1 MoAb elotuzumab with lenalidomide and dexamethasone, which has produced exciting results in the relapsed/refractory setting.

Autologous stem cell transplantation in multiple myeloma patients <60 vs ≥60 years of age

Summary:The role of autologous stem cell transplantation (AuSCT) in older multiple myeloma patients is unclear. Using data from the Autologous Blood and Marrow Transplant Registry, we compared the outcome of 110 patients ⩾the age of 60 (median 63; range 60–73) years, undergoing AuSCT with that of 382 patients <60 (median 52; range 30–59) years. The two groups were similar except that older patients had a higher β2-microglobulin level at diagnosis (P=0.016) and fewer had lytic lesions (P=0.007). Day 100 mortality was 6% (95% confidence interval 4–9) and 1-year treatment-related mortality (TRM) was 9% (6–13) in patients <60 years, compared with 5% (2–10) and 8% (4–14), respectively, in patients ⩾60 years. The relapse rate, progression-free survival (PFS) and overall survival (OS) in the two groups were also similar. Multivariate analysis of all patients identified only an interval from diagnosis to AuSCT >12 months and the use of two prior chemotherapy regimens within 6 months of AuSCT as adverse prognostic factors. Our results indicate that AuSCT can be safely performed in selected older patients: the best results were observed in patients undergoing AuSCT relatively early in their disease course.

Severe respiratory depression after dimethylsulphoxide-containing autologous stem cell infusion in a patient with AL amyloidosis

Adverse reactions with DMSO-cryopreserved stem cell infusion are well-recognized. However, severe, life-threatening anaphylactic reactions with DMSO are very rarely described in the literature. We report here a 58-year-old female with AL amyloidosis who developed an unexpected episode of respiratory arrest a few seconds after the beginning of thawed stem cell product infusion. Fortunately, the patient was resuscitated successfully without the need for intubation. The prompt development of the reaction just a few seconds after the stem cell infusion convincingly implicates DMSO as the potential suspect. The presence of amyloid cardiomyopathy might have also contributed to this adverse event. Bone Marrow Transplantation (2000) 25, 1299–1301.

Management of relapsed multiple myeloma: Recommendations of the international myeloma working group

The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM.

High prevalence of early-onset osteopenia/osteoporosis after allogeneic stem cell transplantation and improvement after bisphosphonate therapy

Osteopenia/osteoporosis (O/O) has been associated with allogeneic stem cell transplantation (alloSCT). We retrospectively reviewed 102 patients undergoing a first alloSCT from 2000 to 2005 at our center to evaluate the prevalence of O/O ⩽6 and >6 months post-alloSCT. Fifty-six patients did not have a dual energy X-ray absorptiometry (DXA) scan following alloSCT. Approximately half (n=13/27) of those with a first DXA scan ⩽6 months post-alloSCT had O/O and a similar rate (n=9/19) was seen in those with a first DXA scan >6 months. There were no significant differences in patient characteristics between the normal and O/O groups. The dual femur (DF) appeared to be more vulnerable to alloSCT-induced bone mineral density (BMD) loss than the lumbar spine (LS), regardless of screening time. O/O patients were treated with bisphosphonates and 41% had a repeat DXA scan post-treatment. No patient developed jaw osteonecrosis and significant BMD improvement was seen at the LS (mean BMD, 1.03±0.13 vs 1.08±0.12, P=0.004) but not the DF (mean BMD, 0.84±0.06 vs 0.85±0.08, P=0.29), indicating BMD loss at the DF is more resistant than the LS to antiresorptive therapy. Our results demonstrate that O/O is an early and late complication post-alloSCT and bisphosphonate treatment reverses BMD loss at the LS.

Effect of rituximab on peripheral blood stem cell mobilization and engraftment kinetics in non-Hodgkin's lymphoma patients

Summary:Rituximab is used for in vivo tumor cell purging for non-Hodgkins lymphoma (NHL) patients prior to autologous peripheral blood stem cell transplantation (PBSCT). However, its effects on PBSC mobilization and function are poorly understood. We compared the mobilization characteristics and engraftment kinetics of 13 NHL patients receiving and 34 NHL patients not receiving rituximab 6 months before PBSC mobilization. In the rituximab group, there was a significantly longer time to neutrophil engraftment (P=0.0466), a trend toward the need for BM harvest to supplement low-yield PBSC collections (31 vs 9%, P=0.08) and a significantly increased rate of bacteremia episodes (62 vs 26%, P=0.025). Median progression-free survival (PFS) and overall survival (OS) were significantly longer in the rituximab compared to the nonrituximab patients (P=0.049 and 0.042, respectively). However, patients in the nonrituximab group were at high risk for recurrence and expected to have shorter survival. Rituximab used within 6 months prior to collection may have a detrimental effect on PBSC mobilization and engraftment. However, rituximab is a major therapeutic breakthrough for NHL treatment and this negative effect may be offset by improved survival. Further studies are warranted in larger populations to determine the impact of rituximab on engraftment, PFS and OS.

Relationship of Race/Ethnicity and Survival after Single Umbilical Cord Blood Transplantation for Adults and Children with Leukemia and Myelodysplastic Syndromes

The relationship of race/ethnicity with outcomes of umbilical cord blood transplantation (UCBT) is not well known. We analyzed the association between race/ethnicity and outcomes of unrelated single UCBT for leukemia and myelodysplastic syndromes. Our retrospective cohort study consisted of 885 adults and children (612 whites, 145 blacks, and 128 Hispanics) who received unrelated single UCBT for leukemia and myelodysplastic syndromes between 1995 and 2006 and were reported to the Center for International Blood and Marrow Transplant Research. A 5-6/6 HLA-matched unit with a total nucleated cell count infused of ≥2.5 × 10(7)/kg was given to 40% white and 42% Hispanic, but only 21% black patients. Overall survival at 2 years was 44% for whites, 34% for blacks, and 46% for Hispanics (P = .008). In multivariate analysis adjusting for patient, disease, and treatment factors (including HLA match and cell dose), blacks had inferior overall survival (relative risk of death, 1.31; P = .02), whereas overall survival of Hispanics was similar (relative risk, 1.03; P = .81) to that of whites. For all patients, younger age, early-stage disease, use of units with higher cell dose, and performance status ≥80 were independent predictors of improved survival. Black patients and white patients infused with well-matched cords had comparable survival; similarly, black and white patients receiving units with adequate cell dose had similar survival. These results suggest that blacks have inferior survival to whites after single UCBT, but outcomes are improved when units with a higher cell dose are used.

Pilot study of patient and caregiver out-of-pocket costs of allogeneic hematopoietic cell transplantation

Patient/caregiver out-of pocket costs associated with hematopoietic cell transplantation (HCT) are not well known. We conducted a pilot study to evaluate patient/caregiver out-of-pocket costs in the first 3 months after allogeneic HCT. Thirty patients were enrolled at three sites. Before HCT, participants completed a baseline survey regarding household income and insurance coverage. Subsequently, they maintained a paper-based diary to track daily out-of-pocket expenses for the first 3 months after HCT. Telephone interviews were conducted to follow-up on the missing/incomplete diaries and on study completion. Twenty-five patients/caregivers completed the baseline survey. Among these, the median pre-tax household income was

Effects of spleen status on early outcomes after hematopoietic cell transplantation

66 500 (range,

Consolidation and maintenance therapy for multiple myeloma after autologous transplantation: where do we stand?

30–