D Dingli

A practical guide to defining high-risk myeloma for clinical trials, patient counseling and choice of therapy

Clinical outcomes for multiple myeloma (MM) are highly heterogeneous and it is now clear that pivotal genetic events are the primary harbingers of such variation. These findings have broad implications for counseling, choice of therapy and the design and interpretation of clinical investigation. Indeed, as in acute leukemias and non-hodgkins lymphoma, we believe it is no longer acceptable to consider MM a single disease entity. As such, the accurate diagnosis of MM subtypes and the adoption of common criteria for the identification and stratification of MM patients has become critical. Herein, we provide a consensus high-risk definition and offer practical guidelines for the adoption of routine diagnostic testing. Although acknowledging that more refined classifications will continue to be developed, we propose that the definition of high-risk disease (any of the t(4;14), t(14;16), t(14;20), deletion 17q13, aneuploidy or deletion chromosome 13 by metaphase cytogenetics, or plasma cell labeling index >3.0) be adopted. This classification will identify most of the 25% of MM patients for whom current therapies are inadequate and for whom investigational regimens should be vigorously pursued. Conversely, the 75% of patients remaining have more favorable outcomes using existing – albeit non-curative – therapeutic options.

Refinement in patient selection to reduce treatment-related mortality from autologous stem cell transplantation in amyloidosis

This study sought to develop selection guidelines to determine the eligibility for SCT of patients with light-chain amyloidosis. Patients with biopsy-confirmed lightchain amyloidosis who underwent SCT between 8 March 1996 and 31 December 2011 were reviewed in two cohorts by date of transplantation: between 8 March 1996 and 30 June 2009 (n=410) and between 1 July 2009 and 31 December 2011 (n=89). Also evaluated were patients who died before post-transplant day 100 to determine the features predictive of early death. After 1 July 2009, fewer transplant recipients had Mayo stage III cardiac involvement. Mortality before post-transplant day 100 was 10.5% (43/410) in the earlier group and 1.1% (1/89) in the later group. In the earlier group, one-quarter of transplant recipients with N-terminal pro-brain natriuretic peptide (NT-proBNP) >5000 pg/mL died by 10.3 months. When serum troponin T was >0.06 ng/mL, 25% died at 3.7 months. The Mayo staging system is predictive for OS but not useful for selecting transplant recipients. Patients with serum troponin T >0.06 ng/mL or NT-proBNP >5000 pg/mL (not on dialysis) should not be considered candidates for SCT because of early mortality.

Comparison of high-dose CY and growth factor with growth factor alone for mobilization of stem cells for transplantation in patients with multiple myeloma.

We retrospectively analyzed outcomes of 716 patients with multiple myeloma who were mobilized using CY and growth factor (n=370) or growth factor alone (n=346) before SCT. Patients receiving CY had higher stem cell yields than the growth factor only group (median number of apheresis sessions needed to achieve stem cell collection goals, two vs four sessions, respectively (P=0.001)). However, patients treated with CY required more time for engraftment of platelets and neutrophils (P<0.001 for both). For patients receiving CY, 75% achieved engraftment (defined as a platelet count of 50 × 109/l) by day 39, whereas 75% of patients not receiving CY achieved engraftment by day 18. Similar results were observed for neutrophil engraftment. These differences did not affect the duration of hospitalization, but patients treated with CY had a higher incidence of post transplant nonstaphylococcal bacteremia. For CY-mobilized patients, considerably faster platelet engraftment (5 fewer days) resulted if stem cell reinfusion occurred more than 30 days after the first apheresis session. Our data suggested that CY damaged the microenvironment and slowed engraftment. By lengthening the period between the completion of apheresis and stem cell reinfusion, the microenvironment may recover and result in faster engraftment.

Predicting PBSC harvest failure using circulating CD34 levels: developing target-based cutoff points for early intervention

PBSCs are usually mobilized using G-CSF with or without chemotherapy. With the emergence of newer mobilizing agents, predicting poor mobilization may allow early intervention and prevent the costs and complications associated with remobilization. We retrospectively evaluated a cohort of 1556 patients seen between January 2000 and September 2008 with multiple myeloma (565; 36%), non-Hodgkins lymphoma (NHL) (562; 36%), amyloidosis (345; 22%) or Hodgkins disease (94; 6%), who were initially mobilized with single agent G-CSF. Sensitivity and specificity analysis was used to identify ideal peripheral blood CD34 count (PB-CD34) cutoff points that predicted successful collection. In patients with plasma cell disorders, a PB-CD34 count of 11, 17, 21 and 28/μL by day 4 or 5 was required to collect a target of 2, 4, 8 or 12 million cells/kg, respectively. A CD34 yield of <0.8 million cells/kg on first apheresis also predicted for <2 million CD34 cells/kg. For patients with NHL or Hodgkins disease, a PB-CD34 count of <6 and <15/μL on day 4 or 5 predicted failure to achieve a target collection of 2 and 4 million cells/kg, respectively. This study suggests that PB-CD34 thresholds should be based on collection target to allow for early intervention and to prevent collection failures.

Impact of early relapse after auto-SCT for multiple myeloma.

Auto-SCT is an effective therapy for patients with multiple myeloma (MM), but nearly a fifth of these patients relapse within a year of auto-SCT. We studied 494 patients, undergoing auto-SCT within 12 months of diagnosis of MM. Patients were divided into two groups: early relapse (relapse ⩽12 months from auto-SCT) and late relapse (either relapsed >12 months after auto-SCT or disease free at the last follow up). One hundred twenty patients (24%) were in the early relapse and 374 (76%) were in the late-relapse groups. The early relapse group had a significantly shorter median overall survival (OS) from diagnosis (26.6 vs 90.7 months; P<0.001) and from auto-SCT (20.1 vs 82.5 months; P<0.001). Among the 345 patients who have relapsed after auto-SCT, median OS from relapse was 10.8 months in the early relapse group compared to 41.8 months for the rest (P<0.001) and was longer with increasing duration of response to the SCT. In multivariate analyses, labeling index ⩾1% at transplant, greater than one treatment regimen prior to auto-SCT, and failure to achieve a complete response were predictive of early relapse. Patients who relapse within 12 months of an auto-SCT have a poor outcome and should be offered trials evaluating novel treatment approaches.

Trends in day 100 and 2-year survival after auto-SCT for AL amyloidosis: outcomes before and after 2006

The role of auto-SCT in the management of Ig light-chain (AL) amyloidosis remains undefined. In this study, we report 422 patients who received auto-SCT for AL amyloidosis to compare outcomes of patients treated before January 2006 with those treated from January 2006 to 1 December 2009. Day 100 all-cause mortality decreased over this time period from 12 to 7% (P=0.09). Survival at 2 years increased from 78 to 82%. The major determinants of early mortality (before day 100) were the presence of cardiac involvement by amyloid with increased levels of cardiac biomarkers, lower serum albumin, higher serum creatinine and a higher number of organs involved. On multivariate survival analysis, higher levels of serum troponin T and N-terminal pro-brain natriuretic peptide were the only predictors of early mortality after auto-SCT. Improved supportive care and refined patient selection have improved the safety margin of patients undergoing auto-SCT; short-term mortality showed a more than 40% decrease after 2005.

Patients with immunoglobulin light chain amyloidosis undergoing autologous stem cell transplantation have superior outcomes compared with patients with multiple myeloma: a retrospective review from a tertiary referral center.

The underlying plasma cell clones in multiple myeloma (MM) and Ig light-chain amyloidosis (AL) appear to be different not only in terms of ‘tumor burden’ but also in terms of their underlying biology. High-dose chemotherapy with auto-SCT is one method of reducing the clone size and thereby improving OS. Post-auto-SCT outcomes between the two diseases have never been formally compared. Among all patients with a diagnosis of AL or MM who received auto-SCT as primary therapy at the Mayo Clinic, Rochester, there were higher CR rates (40% versus 29%, P<0.0001) in the AL group. The respective median OS for the AL and MM patients was 113 and 59.5 months, respectively, P<0.0001. Among patients achieving CR, MM patients had a fivefold risk of death as compared with AL patients. Although auto-SCT cannot be offered to all patients with either AL or MM, it appears that for those well enough to be chosen for the procedure, greater benefit is derived among the AL patients. This difference in survival is most notable among those patients who achieve CR, suggesting very different plasma cell biology between the two diseases.

Second auto-SCT for treatment of relapsed multiple myeloma

High-dose therapy and auto-SCT remain integral in the initial treatment of multiple myeloma (MM), and are increasingly being applied for management of relapsed disease. We examined the outcomes in 98 patients undergoing salvage auto-SCT (auto-SCT2) for relapsed MM after receiving an initial transplant (auto-SCT1) between 1994 and 2009. The median age at auto-SCT2 was 60 years (range: 35–74). The median time between auto-SCT1 and auto-SCT2 was 46 months (range: 10–130). Treatment-related mortality was seen in 4%. The median PFS from auto-SCT2 was 10.3 (95% confidence interval (CI): 7–14) months and the median OS from auto-SCT2 was 33 months (95% CI: 28–51). In a multivariable analysis, shorter time to progression (TTP) after auto-SCT1, not achieving a CR after auto-SCT2, higher number of treatment regimens before auto-SCT2 and a higher plasma cell labeling index at auto-SCT2 predicted for shorter PFS. However, only a shorter TTP after auto-SCT1 predicted for a shorter OS post auto-SCT2. Hence, auto-SCT2 is an effective and feasible therapeutic option for MM patients relapsing after other treatments, especially in patients who had a TTP of at least 12 months after their auto-SCT1.

Positron emission tomography-computed tomography in the diagnostic evaluation of smoldering multiple myeloma: identification of patients needing therapy.

We studied 188 patients with a suspected smoldering multiple myeloma (MM) who had undergone a positron emission tomography-computed tomography (PET-CT) scan as part of their clinical evaluation. PET-CT was positive (clinical radiologist interpretation of increased bone uptake and/or evidence of lytic bone destruction) in 74 patients and negative in 114 patients. Of these, 25 patients with a positive PET-CT and 97 patients with a negative PET-CT were observed without therapy and formed the study cohort (n=122). The probability of progression to MM within 2 years was 75% in patients with a positive PET-CT observed without therapy compared with 30% in patients with a negative PET-CT; median time to progression was 21 months versus 60 months, respectively, P=0.0008. Of 25 patients with a positive PET-CT, the probability of progression was 87% at 2 years in those with evidence of underlying osteolysis (n=16) and 61% in patients with abnormal PET-CT uptake but no evidence of osteolysis (n=9). Patients with positive PET-CT and evidence of underlying osteolysis have a high risk of progression to MM within 2 years when observed without therapy. These observations support recent changes to imaging requirements in the International Myeloma Working Group updated diagnostic criteria for MM.

Abnormal FISH in patients with immunoglobulin light chain amyloidosis is a risk factor for cardiac involvement and for death

Importance of interphase fluorescent in situ hybridization (FISH) with cytoplasmic staining of immunoglobulin FISH (cIg-FISH) on bone marrow is not well understood in light chain amyloidosis (AL). This is in contrast with multiple myeloma where prognostic and treatment related decisions are dependent on cytogenetic testing. This retrospective study reviewed 401 AL patients with cIg-FISH testing performed at our institution between 2004 and 2012. Eighty-one percent of patients had an abnormal cIg-FISH. Common abnormalities involved translocations of chromosome 14q32 (52%), specifically: t(11;14) (43%), t(14;16) (3%) and t(4;14) (2%). Other common abnormalities include monosomy 13/deletion 13q (30%), trisomies 9 (20%), 15 (14%), 11 (10%) and 3 (10%). Median overall survival for this cohort of patients is 3.5 years. When plasma cell burden was greater than 10% trisomies predicted for worse survival (44 vs 19 months), and when it was ⩽10% t(11;14) predicted for worse survival (53 months vs not reached). Abnormal cIg-FISH was significantly associated with advanced cardiac involvement, and remained a prognostic factor on multivariate analysis. This large AL cohort demonstrates that abnormal FISH at diagnosis is prognostic for survival and advanced cardiac disease. Particularly, trisomies and t(11;14) affect survival when degree of plasma cell burden is considered.