Page 1586 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 86 Plasma Cell Neoplasms 1413

Among patients with relapsed myeloma following one to three lines
BOX 86.2 Treatment of Relapsed Multiple Myeloma
of prior therapy, bortezomib monotherapy had an ORR of 43%, a
• Ensure patient has had relapse requiring intervention. A negative median time to progression of 6.2 months, a duration of response of
immunofixation test becoming positive is not an indication to 8 months, and a median survival of 30 months. Bortezomib mono-
initiate salvage therapy. A clear clinical relapse occurs with new therapy is less effective in patients who have received more than one
or increased evidence of end-organ damage, and a substantial or line of prior therapy. Bortezomib is also synergistic when used in
aggressive biochemical relapse is defined by criteria for combination with other drugs, including alkylating agents, anthracy-
progressive disease. clines, immunomodulatory drugs, and dexamethasone. These com-
• Selection of treatment depends on prior therapy received binations generally produce higher ORRs in the range of 50% to
• Lenalidomide based 80%, with an increasing duration of response and OS. Bortezomib
• Initial treatment with bortezomib/thalidomide. plus pegylated liposomal doxorubicin was shown to be superior to
• Underlying peripheral neuropathy
• Lenalidomide used with caution in patients with renal monotherapy in a large randomized trial with an improved time to
dysfunction with appropriate dose adjustment progression (9.3 vs. 6.5 months) and OS. Bortezomib also was
• Bortezomib based recently administered as a subcutaneous injection. In a randomized
• Initial treatment with immunomodulatory agents trial comparing subcutaneous with intravenous administration,
• Renal dysfunction identical 42% response ratios were observed. The subcutaneous
• Poor hematopoietic reserve routes, however, had an improved safety profile, each with a reduced
• Long response (>12 mo) to prior bortezomib incidence of peripheral neuropathy (38% vs. 53% any grade,
• Thalidomide based p = .044; 6% vs. 16% grade 3 or worse, p = .026). 38
• Prior bortezomib/lenalidomide
• Renal impairment
• Poor hematopoietic reserve New Agents
• Chemotherapy with or without novel agent combination
• Progressed on novel agents
• Rapid, aggressive relapse with high lactate dehydrogenase Relapsed Myeloma
and/or extramedullary plasmacytomas
• Salvage transplant Several large phase II and phase III randomized clinical trials have
• In transplant-eligible patients, transplant needs to be been conducted in patients with relapsed myeloma. These studies
considered if stem cell transplant was deferred at initial have resulted in the approval of six new drugs for the treatment of
therapy or patient had a long remission (>3 yr) after first relapsed myeloma since 2012, including three new drugs (panobino-
transplant or has poor hematopoietic reserve and stem
cells are being stored. Transplant may also be considered stat, ixazomib, and elotuzumab) for patients with one to three relapses
as a way to reestablish hematopoiesis in select cases. and pomalidomide, carfilzomib, and daratumumab for those with
• Special considerations more than three relapses or refractory myeloma (Tables 86.23, 86.24).
• Rapid, or multiple sites, or extramedullary sites: chemotherapy Carfilzomib is a selective and irreversible proteasome inhibitor of
with or without novel agent combination the chymotrypsin-like activity of the proteasome. It is administered
• Central nervous system relapse - radiation therapy for intravenously. In a large, open-label, single-arm phase II study, 266
localized disease, intrathecal chemotherapy for positive patients with relapsed myeloma progressing on the last therapy were
cerebrospinal fluid cytology, along with systemic therapy as treated with carfilzomib at 20 mg/m during cycle 1 and thereafter
2
indicated at 27 mg/m intravenously twice weekly for three of four weeks.
2
• Poor performance status and hematopoietic reserve - oral
therapy with low-dose daily cyclophosphamide, thalidomide, Patients were refractory or intolerant to both bortezomib and
and prednisone lenalidomide. The ORR was 23.7% with a median duration of
• Prior drug exposure and associated toxicity: consider response of 7.8 months and a median OS of 15.6 months. Common
presence of neuropathy, cytopenias, and renal dysfunction to adverse events included fatigue, anemia, and thrombocytopenia. A
decide on agents, their schedule, and dose small proportion of patients (<5%) experienced grade 3 or 4 dyspnea,
• Clinical trials acute renal failure, and heart failure.
• Consider enrolling patient on a clinical trial with a new drug In the ENDEAVOR trial, dose-intense carfilzomib/dexamethasone
(Kd) was more efficacious than bortezomib/dexamethasone (VD)
with improvement in the ORR (77% vs. 63%) as well as doubling
of CR rate (13% vs. 6%) and median PFS (18.7 months vs. 9.4
months, duration of response of 16 months, and OS of 38 months. months). Because the median follow-up time was short (1 year), there
Patients who had received more than one line of prior therapy had was no survival advantage noted. Anemia, dyspnea, and cardiac
an ORR of 57%, and time to progression was 10.6 months. A median failure were the most common grade 3/4 adverse events in the Kd
PFS of 9.5 months and OS of 31 months were reported. Patients group, whereas diarrhea and peripheral neuropathy were more
with moderate or severe renal impairment developed more severe common in the VD arm.
thrombocytopenia, required more frequent dose modifications, and ASPIRE was a large, randomized phase III trial comparing
had inferior survival outcomes. Prior exposure to thalidomide did not carfilzomib, lenalidomide, and dexamethasone (KRd; 396 patients)
preclude responses to lenalidomide; however, patients who had with lenalidomide and dexamethasone (Rd; 396 patients) in patients
relapsed or progressed on thalidomide had a lower response rate with relapsed myeloma who had one to three prior treatments. PFS
(under 50%) and a shorter time to progression (7 months). Lenalido- was significantly improved in the KRd arm compared with the Rd
mide can easily be combined with conventional chemotherapy as well arm (26.3 months vs. 17.6 months; hazard ratio for progression
as bortezomib. Combination therapy results in a higher response rate or death, 0.69; p = .0001). The median OS was not reached in
and better disease control. either group at the time of the interim analysis, but the 2-year OS
survival rates were 73.3% in the KRd arm and 65.0% in the Rd arm
(hazard ratio for death, 0.79; p = .04). The KRd arm had an ORR
Bortezomib of 87.1% compared with 66.7% in the Rd arm (p < .001). There
was an increased incidence of grade 3/4 adverse events such as hypo-
In a large phase II trial (SUMMIT) conducted with patients with kalemia, thrombocytopenia, hypertension, and cardiac failure in the
relapsed and refractory MM, bortezomib monotherapy had an KRd arm.
impressive ORR of 28%, including 10% CR or near-CR. The PANORAMA1 was a large, multicenter, international, random-
median time to progression was 7 months, the duration of response ized, placebo-controlled, double-blind phase III trial for patients with
was 12.7 months, and the median survival time was 17 months. relapsed myeloma who had received between one and three regimens.