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ASH 2014 - Lymphoma & Multiple Myeloma

Hodgkin's Lymphoma
Upfront therapy
1. Brentuximab Vedotin instead of Bleomycin in ABVD (both share pulmonary toxicity): 96% 3-yr failure-free survival in advanced-stage Hodgkin's Lymphoma. Phase III studies are under way.

Relapsed / Refractory disease
1. Brentuximab + Bendamustine in preparation to autologous stem-cell transplantation: Small study, outpatient, ORR in the 90% range, and CR in the 80% range.

2. AETHERA trial shows higher 2-yr PFS in patients receiving consolidation with Brentuximab after Stem-Cell Transplantation for Hodgkin's Lymphoma (65% vs 45%), poised to become a new standard-of-care.

3. Nivolumab (anti PD-1 monoclonal antibody) in post-transplant relapse: Hodgkin's lymphoma is an ideal model for immune checkpoint modulation due to high immunocyte infiltration around the tumor cells. There is a Phase 1 study with up to 80% response rate in heavily pretreated patients (including patients previously treated with Brentuximab Vedotin). This is the most exciting result in lymphoma in this ASH 2014 (NEJM On-line first).

Low-grade lymphomas
1. Ibrutinib in follicular lymphoma: Ibrutinib showed only 30% response rate in relapse follicular lymphoma patients (somewhat disappointing). Whereas Idelalisib (PI3k inhibitor) shows 50% response rate with a median PFS of up to a year in chemo & rituximab refractory follicular lymphoma patients (and is FDA approved in that indication).

2. EFS12 as a prognostic marker in follicular lymphoma: A Mayo clinic dataset has shown that patients who have not had an event at 12 months after either initial treatment or observation have a life expectancy similar to age-matched controls. The converse is true, patients that have events within a year will not do well, and require a more aggressive approach.

Diffuse Large B-cell lymphoma (DLBCL)
1. Double-hit DLBCL: Abnormalities in both c-Myc and bcl-2 genes should be looked in high Ki67/proliferative DLCL. Some studies show that DA-EPOCH is effective with PFS in the 60% at 1-year.

2. Selenexor (a nuclear trafficking inhibitor): some 40% response rate in relapsed DLBCL, with some CRs, in phase-I trials.

Mantle-Cell lymphoma (MCL)
1. Intensive therapy is still disappointing in MCL: The current theme in MCL is highly aggressive upfront chemotherapy (R-CHOP alternating with DHAP, followed by transplant; R-CHOP followed by Bortezomib; Bortezomib + Rituximab + Bendamustine). All these trials are showing some relapses at the 3-year mark.

2. Chemo-free for MCL with Lenalidomide + Rituximab in 1-st line: Small study (38 patients) with median age of 65: 88% went into remission and 2-yr EFS in 80%.

Multiple Myeloma
Upfront therapy
1. Carfilzomib in 1st-line multiple myeloma patients: An italian trial showed very high response rate in the order of  >75% in patients receiving high-dose weekly Carfilzomib + Cyclophosphamide + Dexamethasone.

2. Ixazomib, an oral proteasome inhibitor, + Lenalidomide + Dexamethasone: The all oral combination chemotherapy was well tolerated and exhibited high response rate.

Relapsed  / Refractory disease
1. ASPIRE trial (Carfilzomib + Lenalidomide + Dexamethasone): Possibly the most outstanding result of the ASH 2014 (NEJM On-line first). Carfilzomib + Lenalidomide + Dexamethasone increases the PFS by 9 months over Lenalidomide + Dexamethasona in relapsed multiple myeloma patiens (26 months vs 17 months). The benefit was also seen in patients with high-risk cytogenetics. Quality-of-life was also superior in the Carfilzomib-based arm.

2. Oral proteasome inhibitors: Several presentations showed that both Ixazomib and Oprozomib are active in heavily-treated myeloma patients. Specifically, Oprozomib showed a single-agent activity with 30% response-rate in Carfilzomib-refractory patients. A change in formulation to tablet, and the use of antiemetic agents decreased its chemotherapy-induced nausea and vomiting. Still, not ready for prime time.

3. Anti CD38 monoclonal antibodies (MoAbs): CD38 is a surface marker in plasmocytes (and other blood cells). Daratumumab and SAR650984 are MoAbs that have shown activity in myeloma patients. In this ASH it was presented a combination of Daratumumab + Lenalidomide + Dexamethasone in relapsed myeloma patients. No added toxicity was found beyond a few infusion reactions.

4. Histone Deacetylase (HDAC) inhibitors (Panobinostat): Some interesting results with Panobinostat in relapsed/refractory myeloma. Further studies are required, especially to deal with its gastrointestinal toxicity.

5. Ibrutinib: The Bruton Tyrosine Kinase inhibitor, Ibrutinib has exhibited high clinical benefit rate of 50% with a median PFS of 6 months in heavily pre-treated myeloma patients. Another interesting agent that merits further investigation in this condition.

The longer exposure to anti-myeloma agents, the better. Post transplant lenalidomide maintenance is highly effective with responses that occur over several months. Some other trials have shown that Bortezomib maintenance is also highly effective.

1. Single-agent pomalidomide in heavily pre-treated myeloma: The newer imid Pomalidomide has shown to be effective as a single-agent, with a response rate of about 35%.

2. Pomalidomide in combination with other agents: In this ASH there are reports that show that Pomalidomide can be safely combined with Bortezomib + Dexamethasone, with Cyclophosphamide + Dexamethasone, also with Liposomal Doxorubicine + Dexamethasone with very good safety profile, and response rate in the range of 60-70%.

3. Safety of Pomalidomide in renal insufficiency: Some data were presented that show that Pomalidomide can be safely administered in pretty much any patient with any degree of renal dysfunction, provided they are not in dialysis.

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