Esha Kaul

Bortezomib Subcutaneous Injection in Combination Regimens for Myeloma or Systemic Light-Chain Amyloidosis: A Retrospective Chart Review of Response Rates and Toxicity in Newly Diagnosed Patients

BACKGROUND Bortezomib is a first-in-class proteasome inhibitor approved by the US Food and Drug Administration for the treatment of all phases of multiple myeloma (MM) and it is also used for the treatment of [corrected] light-chain amyloidosis (AL). The subcutaneous formulation of bortezomib was approved in 2012 based on data from Phase III studies in patients with relapsed MM. OBJECTIVE This article reports experience with subcutaneous bortezomib in patients with newly diagnosed MM or AL in a tertiary care center. METHODS This retrospective study analyzed data from all patients newly diagnosed with MM or AL and treated at our center between April 1, 2011, when the hospital pharmacy approved and implemented the option of subcutaneous bortezomib, and April 1, 2013. Patients who received subcutaneous bortezomib as a part of the first line of therapy were identified through the pharmacys database. Data were abstracted from electronic medical records, and data on demographic characteristics, disease profiles, toxicities, responses, and survival were collected. RESULTS Data from 29 patients (MM, 16; AL, 13; 62% male; median age, 66 years [range, 46-84]) were analyzed. Ninety percent of patients received cyclophosphamide, bortezomib, and dexamethasone (CyBorD) as the first line of treatment. None of the patients developed grade 3/4 peripheral neuropathy, whereas 1 patient experienced grade 3 diarrhea, and 2 patients developed grade 3 thrombocytopenia requiring dose reductions. The overall response rate was 93%, with 59% of patients achieving very good partial response or complete response. CONCLUSIONS With the use of subcutaneous bortezomib in combination regimens in patients with newly diagnosed MM or AL, there was a high overall response rate and minimal toxicity. These results are consistent with the findings from prior studies and provide a basis for further studies comparing new proteasome inhibitors to subcutaneous bortezomib in combination regimens for patients with newly diagnosed MM or AL.

Plerixafor and G-CSF for autologous stem cell mobilization in AL amyloidosis.

Risk-adapted melphalan and SCT (RA-SCT) is considered a standard therapy for selected patients with systemic AL amyloidosis (AL), with median OS exceeding 10 years when used as initial therapy. With this approach, peri-transplant mortality has been reduced but complications related to stem cell mobilization, particularly with high-dose G-CSF (16 mcg/kg), remain significant concerns. These concerns are amplified with the growing use of RA-SCT as consolidation post induction or as second-line therapy at relapse. Plerixafor is a small molecule that reversibly inhibits chemokine stromal cell-derived factor 1-α binding to its cognate CXC chemokine receptor, and its addition to G-CSF, compared to G-CSF alone, in patients with multiple myeloma was well tolerated and led to significantly increased CD34+ cell yields. Based on this experience we evaluated the use of plerixafor and G-CSF (10 mcg/ kg) for stem cell mobilization in 12 consecutive patients with AL (7 men, 5 women) between 4 June 2012 and 9 September 2013. Median age at mobilization was 58 years (range 46–72), time from diagnosis to mobilization 7.5 months (2–123) and number of organs involved 2 (1–4). The kidney (n= 9) and heart (n= 8, all stage 2) were most commonly involved. Nine patients had had prior bortezomib-based induction therapy (median 3 cycles). One had undergone SCT 10 years earlier and had relapsed, and two were untreated, including one who was a year post orthotopic heart transplant. Five patients had creatinine ⩾ 1.5 mg/dL, including two on hemodialysis (HD). G-CSF was started on the morning of day 1 at a dose of 10 mcg/ kg and plerixafor at 2100 hours on day 4; both were continued daily until collection was complete. For patients with a creatinine clearance (CrCl) >50mL/min, plerixafor was given at 0.24 mg/kg with a maximum of 40mg/day, while for those with a CrCl o50mL/min or on dialysis the dose was 0.16 mg/kg with a maximum of 27 mg/day. The target CD34+ cell collection goal was 10× 10 CD34+ cells/ kg. Leukapheresis was begun on day 4 if the circulating CD34+ cell count was ⩾ 5/μL and on day 5 otherwise. The median number of collections was 2 (range 2–3). With the first collection, a median of 3.6 × 10 CD34+ cells/kg (0.4–13.8 × 10) were procured and with the second 6.4 × 10 (2.7–19 × 10). Median total number of CD34+ cells/kg was 13.8 × 10 (5–18 × 10). Logistical and fluid balance issues slightly altered the schema for patients on HD. On day 4 of mobilization, HD preceded the daily injection of G-CSF. Apheresis followed if the circulating CD34 cell count was ⩾ 5/μL. On day 5, G-CSF was given followed by apheresis. This was done to avoid HD immediately after drug administration and fluid overload after apheresis. No significant toxicities were observed with plerixafor. Two patients had grade 1 bleeding from the catheter site during apheresis and one had dyspnea due to fluid overload that responded to furosemide. All patients went on to receive RA-SCT and there were no treatment-related deaths. Median number of CD34+ cells/kg infused was 7.7 × 10. Median number of days to ANC>500/μL was 11 (10–22), to platelets>20 000/μL untransfused 15 (9–34) and to lymphocytes>500/μL 14.5 (11–25). One patient developed veno-occlusive disease and persistent thrombocytopenia and was given the remaining stem cells on day +31 with subsequent normalization of the blood counts. Mobilization with G-CSF and plerixafor was well tolerated in this group of patients with significant organ impairment, including eight who had stage 2 cardiac involvement, two on HD, one with a previous SCT and one who was a year post orthotopic heart transplant. Limited leukaphereses were needed to achieve or exceed the target CD34+ cell dose. Plerixafor is excreted renally but is predicted to be easily dialyzable due to its small size and polarity. While the phase 3 study in myeloma excluded patients with creatinine ⩾ 2.2 mg/dL, studies of dose-adjusted use in myeloma and AL patients with severe renal impairment were not associated with additional toxicity. With an expanding role of SCT in patients with amyloidosis as initial therapy in selected patients, as consolidation after induction and as second-line therapy, the tolerability and efficacy of mobilization have become important issues. The use of plerixafor with G-CSF for mobilization can make the option of SCT available to patients who have been heavily pretreated or have multiple organs involved and might otherwise be bereft of effective treatment options. In this era of more effective initial therapies, an era in which many AL patients are living longer with moderate to severe organ damage and are receiving multiple lines of therapy including SCT, this approach allows not only the collection of sufficient CD34+ cells for optimal immediate use but also the cryopreservation of aliquots for future use, for a second SCT should it become necessary or for novel cell-based immunotherapies should they become available.

Twists and turns of determining amyloid type and amyloid-related organ damage: discordance and clinical skepticism in the era of proteomic typing.

Abstract Systemic immunoglobulin light-chain primary amyloidosis (AL) is the most common type of systemic amyloidosis. Recent advances in AL amyloidosis include the use of definitive proteomic typing, confirming the type of amyloid in patients with two possible amyloid-forming proteins. Laser microdissection followed by mass spectrometry (LMD/MS) can correctly identify the amyloid type with over 95% sensitivity and specificity. We report the case of a 68-year-old man with a history of IgA lambda monoclonal gammopathy and peripheral neuropathy who was diagnosed with pelvic nodal and psoas amyloidosis. The amyloid was found to be AL kappa type by LMD/MS. While LMD/MS has been effective in distinguishing among AL, secondary amyloidosis and hereditary forms of amyloidosis, our case demonstrates that typing can also identify unusual instances of discordance between light chain isotypes associated with clonal processes.

Multiple myeloma: Looking beyond standards

Multiple myeloma has been regarded as an incurable disease with frequent relapses. The diagnostic criteria have been revised multiple times to include early stage of the disease where treatment can be effective and can prolong the survival. Newer diagnostic criteria for myeloma have incorporated ≥60% plasma cells in the bone marrow and serum free light chain ratio (involved to uninvolved free light chains) of ≥100. The role of positron emission tomography-computed tomography scans has been recognized, and it has been increasingly utilized upfront in the management of multiple myeloma. Role of minimal residual disease monitoring has been studied in multiple trials and will in near future guide the treatment. Autologous stem cell transplant is still the preferred consolidation therapy after initial three or four drug induction. With the use of novel drugs combinations and with emerging treatment options the standard of care of myeloma patients will change.