CLINICAL UPDATES: Thrombocytopenia and Multiple Myeloma

The first two clinical updates are based on information presented at “Emerging Therapies in Hematologic Malignancies,” a satellite symposium organized by PRIME Oncology and held in conjunction with the 13th Congress of the European Hematology Association, on June 12, 2008 in Copenhagen, Denmark. The entire symposium may be viewed as a webcast at www.primeoncology.org.

THROMBOCYTOPENIA:
Treatment with 2^nd Generation Thrombopoietic Growth Factors
The speaker for this topic was Adrian Newland, FRCP from The Royal London Hospital in London, United Kingdom.

Thrombopoietin (TPO) is involved in all stages of thrombopoiesis from the stem cell to the mature megakaryocytes that release platelets into the circulation. Thrombopoietic growth factors may stimulate platelet production by promoting proliferation, survival, and differentiation of megakaryocyte precursors into mature megakaryocytes, and by platelet release. The 2^nd generation thrombopoietic growth factors include TPO nonpeptide mimetics (eltrombopag, AKR 501), TPO peptide mimetics (romiplostim, AMG 531), and TPO agonist antibodies.

Eltrombopag is an orally bioavailable small molecule TPO-R (receptor) agonist that interacts with TPO-R differently than endogenous TPO. It stimulates megakaryocyte proliferation and differentiation, but does not prime platelets for activation. Given daily, eltrombopag increases platelet counts in a dose-dependent manner. In an early phase I trial in which daily doses of the drug were given, the platelet count started to increase at 7-10 days and continued to rise as long as eltrombopag was given. However, if the drug was stopped within 2 to 3 weeks the platelet count would drop to less than 10,000. A phase II dose-response study in which chronic ITP patients received daily eltrombopag (30mg, 50mg, or 75mg) resulted in progressive increase in platelet production and a steady decrease in bleeding as long as the drug was given.

Romiplostim (AMG 531) is a novel thrombopoiesis-stimulating peptibody (TPO peptide mimetic) that is structurally unrelated to TPO. It targets and affects the TPO-R and increases platelet production in a dose-responsive manner. It is administered subcutaneously once weekly. The median time to first response is 3.1 weeks, therefore, it is not an ideal candidate for use in acute, severe bleeding. When the ultimate platelet response did occur, the platelet count reached 350,000 to 450,000 in 60-70% of patients in a phase II trial; in fact if counts exceed 400,000 to 450,000 AMG 531 should be held to avoid risk of thrombosis. In a phase III chronic ITP trial, platelet responses were durable with long-term (up to 2 years) platelet counts double the baseline value and ≥50,000 in >50% of patients. The overall platelet response in this trial was 83% (splenectomized patients 79%; non-splenectomized patients 88%). Repeated treatment with AMG 531 is well tolerated and no antibodies to the drug have currently developed.

Thrombocytopenia associated with other clinical conditions has been treated in clinical trials with these agents with the following results:

• Hepatitis C virus associated – eltrombopag is effective at higher doses; 100% of patients able to complete their anti-viral therapy because thrombocytopenia improved or corrected.
  
• Chemotherapy-induced – will see a small response that only decreases the number of thrombocytopoenic days by 2 or 3; cost-effective??
  
• Myeloablative therapy – see very little response at all.
  
• MDS – romiplostim (AMG 531) effective in low and intermediate-1 risk, 41% durable response (median duration of response 23 weeks). No antibodies occurred; 3 deaths not related to thrombocytopoenia or AMG 531 therapy.

MULTIPLE MYELOMA
Front-Line Therapy
The speaker for this topic was Antonio Palumbo, MD from the University of Torino in Torino, Italy.

Over the last two decades three distinct groups of patients with newly diagnosed multiple myeloma have emerged. They are young patients (<65 years of age), elderly fit patients (≥ 65 years), and the elderly unfit patients (≥ 65 years) with concomitant medical illnesses. Improvements in our prognostic ability and in treatment options now make it possible to make appropriate therapeutic choices for patients in each group.

Several factors have contributed to our ability to better define these patient groups. First, increasing life span has resulted in an increased number of patients ≥65 years of age (the elderly group). Second, improved techniques for autologous stem cell transplantation (ASCT), improved supportive care options, and a group of novel anti-myeloma agents with impressive efficacy have resulted in improved survival for myeloma patients who are candidates for ASCT. These advances have made ASCT a viable option as front-line therapy for young patients and for some fit elderly patients as well. The final contributing factor is the influence of cytogenetics and beta-2-microglobulin (B₂MG) in defining risk and predicting outcomes in myeloma patients. Those with FISH(-), B₂MG <4 and some with del 13, B₂MG <4 have a 50% 5-year survival (S) of 80%. Those with FISH(-), B₂MG >4, del 13, B₂MG >4 and some with 4;14 or 17p, B₂MG <4 have a 50% 5-year S. All patients with 2 abnormal risk factors (4;14, 17p and B₂MG >4) have a poor prognosis even after tandem ASCT.

After that background information, Dr. Palumbo discussed his recommendations for management of the three patient groups. He stated that when you see a young patient, you generally think about ASCT and induction regimens used with that therapy. Lenalidomide (Len) + low-dose (LD) Dex has been proven to be more efficacious and less toxic (fewer severe A/Es and far fewer deaths) than Len + high-dose (HD) Dex – Len + LD-Dex is effective alone and as an induction therapy prior to ASCT. It is now proven in several trials to result in successful stem cell harvest in 97% to 100% of patients. Other induction regimens are Vel/Dex (bortezomib + Dex) and VTD (bortezomib + thalidomide + Dex).

The elderly fit patient group (≥65 years) certainly can be ASCT candidates with Len + LD-Dex or PAD (bortezomib + pegylated doxorubicin + Dex) induction. Non-ASCT patients in this group can benefit from regimens such as MPT (melphalan + prednisone + thalidomide) used in the IFM and Nordic Study Trials. VMP (bortezomib, melphalan + prednisone) was very effective in the VISTA registration trial.

The elderly unfit patients with concomitant illness should be evaluated perhaps for one of the non-ASCT regimens, but most will end up on best supportive care which is appropriate.

The speaker passed on two “clinical pearls” as take home messages:

• Aspirin is challenging low molecular weight heparin (LMWH) as the preferred prophylactic agent for thromboembolic events in myeloma patients.
  
• New effective regimens should be used early in the course of multiple myeloma.