S R Hayman

Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients

Therapy for multiple myeloma (MM) has markedly changed in the past decade with the introduction of new drugs, but it is not clear whether the improvements have been sustained. We studied 1038 patients diagnosed between 2001 and 2010, grouping patients into two 5-year periods by diagnosis, 2001–2005 and 2006–2010. The median estimated follow-up for the cohort was 5.9 years with 47% alive at the last follow-up. The median overall survival (OS) for the entire cohort was 5.2 years: 4.6 years for patients in the 2001–2005 group compared with 6.1 years for the 2006–2010 cohort (P=0.002). The improvement was primarily seen among patients over 65 years, the 6-year OS improving from 31 to 56%, P<0.001. Only 10% of patients died during the first year in the latter group, compared with 16% in the earlier cohort (P<0.01), suggesting improvement in early mortality. The improved outcomes were linked closely to the use of one or more new agents in initial therapy. The current results confirm continued survival improvement in MM and highlight the impact of initial therapy with novel agents. Most importantly, we demonstrate that the improved survival is benefitting older patients and that early mortality in this disease has reduced considerably.

Impact of lenalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with newly diagnosed myeloma

While initial therapies have become highly effective with introduction of lenalidomide and bortezomib and patients may opt for delayed stem cell transplantation, it is important to collect stem cells for future transplant. Given its increasing use as initial therapy, we examined if lenalidomide had any impact on the ability to collect peripheral blood stem cells (PBSC). We studied the entire cohort of patients with myeloma undergoing PBSC mobilization at our institution during a 5-year period, comparing the results between patients receiving different initial therapies. Among those mobilized with granulocyte-colony stimulating factor (G-CSF) alone, there was a significant decrease in total CD34+ cells collected (P<0.001), average daily collection (P<0.001), day 1 collection (P<0.001) and increased number of aphereses (P=0.004) in patients treated with lenalidomide compared to those receiving dexamethasone, thalidomide-dexamethasone or VAD. A similar trend was seen in those mobilized with chemotherapy and G-CSF. A trend was seen towards decreased PBSC yield with increasing duration of lenalidomide therapy as well as increasing age (P=0.002). There was no effect on quality of PBSC collected based on similar engraftment across all groups. We recommend collection of PBSC within 6 months of initiation of therapy with lenalidomide containing regimens to minimize the risk of mobilization failures.

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.

Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM)

Patients with multiple myeloma progressing on current therapies have limited treatment options. Pomalidomide (CC4047), an immunomodulatory drug, has significant activity in relapsed myeloma and previous studies suggest activity in lenalidomide refractory disease. To better define its efficacy in this group, we treated a cohort of lenalidomide refractory patients. Pomalidomide was given orally (2 mg) daily, continuously in 28-day cycles along with dexamethasone (40 mg) given weekly. Responses were assessed by the International Myeloma Working Group Criteria. Thirty-four patients were enrolled. The best response was very good partial response in 3 (9%), partial response (PR) in 8 (23%), best responses (MR) in 5 (15%), stable disease in 12 (35%) and progressive disease in 6 (18%), for an overall response rate of 47%. Of the 14 patients that were considered high risk, 8 (57%) had responses including 4 PR and 4 MR. The median time to response was 2 months and response duration was 9.1 months, respectively. The median overall survival was 13.9 months. Toxicity was primarily hematologic, with grade 3 or 4 toxicity seen in 18 patients (53%) consisting of anemia (12%), thrombocytopenia (9%) and neutropenia (26%). The combination of pomalidomide and dexamethasone (Pom/dex) is highly active and well tolerated in patients with lenalidomide-refractory myeloma.

Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains

Cast nephropathy is the most common cause of renal disease in multiple myeloma, however, treatment with plasma exchange remains controversial even after 3 randomized controlled studies. We sought to determine the importance of diagnostic confirmation and goal directed therapy in the treatment of cast nephropathy in forty patients with confirmed multiple myeloma and renal failure who underwent plasma exchange. A positive renal response was defined as a decrease by half in the presenting serum creatinine and dialysis independence. No baseline differences were noted between eventual renal responders and non-responders. Three quarters of the patients with biopsy proven cast nephropathy resolved their renal disease when the free light chains present in the serum were reduced by half or more but there was no significant response when the reduction was less. The median time to a response was about 2 months. In patients without cast nephropathy, renal recovery occurred despite reductions in free light chain levels of the serum. No association was found between free light chains in the serum, urinary monoclonal proteins, overall proteinuria and cast nephropathy. We found that the relationship between renal recovery and free light chain reduction was present only in patients with biopsy proven cast nephropathy showing the importance of extracorporeal light chain removal in this disease.

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.

Incidence of extramedullary disease in patients with multiple myeloma in the era of novel therapy, and the activity of pomalidomide on extramedullary myeloma

We studied 174 consecutive patients with relapsed refractory multiple myeloma (MM) enrolled on a phase II clinical trial of pomalidomide plus low-dose dexamethasone at Mayo Clinic. Extramedullary disease (EMD) was present at the time of trial entry in 7.5% (13 of 174 patients). The rate of EMD in the first 3 years following diagnosis of MM was 3%. The response of EMD to pomalidomide plus low-dose dexamethasone included two complete and two partial responses among the 13 patients (response rate, 31%). Overall survival measured from trial entry was significantly shorter for patients with treatment-emergent EMD compared with those who did not have EMD, (median 16 months versus not reached, P=0.002).

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.