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Combination therapy, HSCT extend PFS in primary plasma cell leukemia
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Hematopoietic stem cell transplantation preceded by induction therapy with bortezomib and dexamethasone plus doxorubicin or cyclophosphamide improved PFS and induced high response rates among patients with primary plasma cell leukemia, according to the results of a phase 2 study.
“Plasma cell leukemia (PCL) is a rare and aggressive form of symptomatic myeloma, either presenting as primary PCL (pPCL) in patients given a new diagnosis or as secondary PCL in patients with relapsed myeloma,” Bruno Royer, MD, of the hematology department at University Hospital in Amiens, France, and colleagues wrote. “pPCL accounts for 2% to 4% of patients with myeloma. All but one of the studies published so far have been small retrospective analyses.”
Patients with pPCL treated with conventional chemotherapy typically die within 1 year. Retrospective studies have shown improved survival with bortezomib (Velcade; Takeda, Millennium Pharmaceuticals) and lenalidomide (Revlimid, Celgene).
Royer and colleagues conducted a prospective study to assess the efficacy of an alternative combination treatment regimen comprised of standard chemotherapy, bortezomib, high-dose melphalan and autologous HSCT.
The researchers assigned 40 patients (median age, 57 years; range, 27-71) with newly diagnosed pPCL to four alternating cycles of bortezomib and dexamethasone, plus doxorubicin or cyclophosphamide. They collected peripheral blood stem cells from responding patients with less than 1% of circulating plasma cells prior to HSCT.
Patients with a minimum of stable disease and clearance of circulating plasma cells — defined as less than 1% of blood leukocytes — proceeded to treatment with high-dose melphalan and autologous HSCT; the remaining patients were excluded from the study.
Younger patients (< 66 years) with an HLA–matched donor and a very good partial response or better underwent a reduced-intensity conditioning allograft 3 months after first HSCT.
The remaining patients underwent a second course of high-dose melphalan and HSCT, followed by maintenance therapy with bortezomib, lenalidomide and dexamethasone for 1 year.
PFS served as the primary endpoint. Secondary endpoints included OS, response rate, safety and toxicity.
Median follow-up was 28.7 months (95% CI, 19.4-36.1).
Thirty-five patients (89%) completed the four planned induction cycles. The overall response rate was 69% (n = 27), which included four complete responses, 10 very good partial responses, nine partial responses and four cases of stable disease.
Seventeen patients died, 13 as a result of progressive disease. The remaining patients died of infection.
Median PFS in the intent-to-treat population was 15.1 months (95% CI, 8.4-not reached) and median OS was 36.3 months (95% CI, 25.6-not reached).
Fifty-eight percent (90% CI, 44-71) of patients achieved 12-months PFS, which was significantly higher than the 35% historical control value (P = .0088).
The 12-month OS rate was 75% (95% CI, 64-87).
Median OS in patients with primary refractory disease was 10.5 months (95% CI, 8.5-not reached), which was significantly shorter than that of patients who underwent effective HSCT (P = .0056).
Median PFS in the allograft group from the date of second transplantation was 11.3 months (95% CI, 7.6-not reached) and median OS was 28.6 months (95% CI, 16.2-not reached).
Thirteen patients experienced grade 1 or grade 2 neuropathy secondary to bortezomib, with no grade 3 or worse neuropathy observed. Seven patients experienced grade 3 or grade 4 infections, and four patients had grade 5 infections.
One patient developed a colon carcinoma in situ 2 months after HSCT; no other cancers were observed during follow-up.
“This approach significantly improved PFS,” Royer and colleagues wrote. “Nevertheless, relapses still occur, and further prospective studies are needed to investigate approaches to prolong the survival of patients who present with this ultra–high-risk multiple myeloma. … These approaches will be tested in future phase 2 trials.”
Limiting patients with pPCL to clinical trials only studying their specific disease may not be productive, Pellegrino Musto, MD, director of research at Scientific Institute of Research and Cure in Rionero in Vulture, Italy, wrote in an accompanying editorial.
“Patients with pPCL should be considered for clinical trials,” Musto wrote. “However, because of its rarity, pharmaceutical companies may not be interesting in investigating pPCL specifically. Therefore, it would be desirable to also enroll these patients in prospective studies designed for multiple myeloma, with a plan to extrapolate specific data, as well as ad hoc analyses and endpoints; this would extend novel strategies in patients with pPCL and allow availability of homogeneous clinical and biologic information.” – by Cameron Kelsall
Disclosure: Royer reports honoraria from Amgen and a consultant role with Octapharma Plasma. Please see the full study for a list of all other researchers’ relevant financial disclosures. Musto reports honoraria from Bristol-Myers Squibb, Celgene, Janssen-Cilag, Novartis and Sanofi.
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