Mutiple Myeloma management notes from training!
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Martha Q. Lacy, MD
Professor of Medicine
Division of Hematology
Mayo Clinic College of Medicine
Rochester, Minnesota

At diagnosis, if patient had no high-risk molecular markers and excellent renal function. In this setting, at Mayo, we prefer to start with lenalidomide and dexamethasone because it has high remission rates, is oral, well tolerated, and unlikely to induce peripheral neuropathy. When using lenalidomide in patients with no personal history of VTE, we favor prophylaxis with aspirin at 325 mg daily. We would use IV bisphosphonates monthly for 12 months and quarterly for 1 additional year. In patients with low-risk disease, we consider risks and benefits of maintenance therapy. If maintenance therapy is chosen, consider limiting the duration to 12-24 months. 

At relapse, if our patient had a good response and a long duration of remission (> 12 months), we favor re-introduction of the initial regimen. If the patient has suboptimal response or a short remission duration, we would change the class of drug used (eg, if initially treated with an immunomodulatory agent [thalidomide, lenalidomide], we would switch to proteasome inhibitor [bortezomib, carfilzomib]. If initially treated with a proteasome inhibitor, we would switch to an immunomodulatory agent). In this particular case, we would need to factor in that the patient now has renal failure and a new bone lesion. We generally re-introduce bisphosphonates quarterly at relapse in patients with new bone lesions. However, since this patient has renal failure, we would wait for renal improvement and favor pamidronate over zoledronic acid with a reduced dose of 30 mg (from 90 mg).¹ Also due to the renal status of this patient, full-dose lenalidomide should not be used. I would favor switching to bortezomib because it can be used at full dose. However, dose-adjusted lenalidomide is also an option.² A second ASCT may also be considered, especially if the initial remission was extremely long (eg, > 4 years).
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SECOND OPINION
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Thomas G. Martin III, MD
Clinical Professor of Medicine
Multiple Myeloma Translational Initiative
UCSF Medical Center, University of California, San Francisco
San Francisco, California

Mr Johnson's presentation was fairly typical and consistent with standard risk myeloma. At UCSF, we would consider this young (< 60 years), standard risk patient to be an excellent candidate for autologous transplantation at presentation. Therefore, we would avoid melphalan containing therapy and limit upfront lenalidomide therapy to 4-6 cycles thus allowing ample marrow reserve for stem cell collection. Lenalidomide/dexamethasone, bortezomib/dexamethasone, and/or lenalidomide with bortezomib would all be considered excellent upfront therapy options. Appropriate supportive care measures would be oral calcium and vitamin D and IV bisphosphonates. Patients receiving proteasome inhibition should receive anti-viral prophylaxis to prevent zoster reactivation and patients receiving immunomodulatory agents should receive venous thromboembolism (VTE) prophylaxis. Patients at increased risk for VTE should receive therapeutic warfarin, while low-risk patients, such as this one, can receive aspirin (325 mg) daily. In patients treated with autologous transplantation, we favor lenalidomide maintenance based on the CALGB 100104 and French randomized post-transplantation maintenance trials.^1,2 The median time to progression in the CALGB study was almost double for the lenalidomide arm (46 months) versus the placebo arm (27 months). The optimal duration of maintenance therapy remains unclear but we attempt to continue maintenance in this setting for at least 1 year and often for 2-3 years depending on tolerability and count suppression.

At relapse, Mr Johnson has developed significant renal insufficiency and this prevents the use of full-dose lenalidomide, as lenalidomide clearance is primarily renal. Since Mr Johnson's remission lasted 24 months, one could choose to use either dose-reduced lenalidomide, or a bortezomib-containing regimen. There are a number of reports describing improved renal function in patients receiving early bortezomib administration and no increased toxicity. Consequently, we would likely recommend a bortezomib-based regimen, like cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in this case. One should consider re-instituting bisphosphonate therapy once the renal function improves (unless the renal insufficiency is due to hypercalcemia for which bisphosphonates should be used right away). At relapse, one always needs to consider toxicity from prior therapy. Since the patient has a history of neuropathy, we would choose to administer bortezomib at weekly intervals and by subcutaneous injection. If the neuropathy increases, option would include switching to carfilzomib or lenalidomide-based therapy.

References

• ¹ McCarthy PL, et al. N Engl J Med. 2012;366(19):1770-1781.
• ² Attal M, et al. N Engl J Med. 2012;366(19):1782-1791.

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follow-up

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Once a patient has achieved remission following upfront therapy, it is important to follow their myeloma for evidence of relapse. Early recognition of disease relapse often can prevent morbid complications including hypercalcemia, compression fractures, and renal failure. For patients on maintenance therapy, we will follow their CBC including neutrophil and platelet counts every 4-6 weeks and adjust dosing accordingly. A history and physical exam and laboratories including serum protein electrophoresis, quantitative immunoglobulins, serum immunofixation electrophoresis, and serum free light chains can be followed every 12 weeks. We will follow 24-hour urine tests (TP, UPEP, UIFE) every 12 weeks if a patient has had disease that is only assessable by urine tests (this is rare). We perform bone marrow biopsies every 12-18 months unless the patient has truly nonsecretory disease for which BMB exams are performed every 3-6 months. We rarely performed routine skeletal surveys but prefer PET/CT or total body MRI exams, every 12-18 months.

Elizabeth Bilotti, MSN, RN, APN

For patients who have achieved a CR post-transplant, we would follow every 3 months or as clinically indicated for reported symptoms, with a change in the frequency of assessments at the time signs of relapse became present. Evaluation would include full laboratory assessment (CBC, chemistry panel, quantitative immunoglobulins, SPEP, free light chain analysis, serum immunofixation with 24-hour urine analysis as appropriate ‒ UTP, UPEP, and urine immunofixation on a 24-hour urine). Radiographic imaging and BM biopsy would be determined based upon medical necessity and only used routinely in patients with non-secretory disease. 

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Patients with the t(4;14) should receive bortezomib containing induction therapy. Often we will include lenalidomide and dexamethasone (thus RVD) as induction therapy in this setting. We would recommend transplantation and consider bortezomib maintenance following transplantation. The CALGB study has yet to evaluate lenalidomide maintenance therapy in the subset of t(4,14) patients, thus lenalidomide maintenance is also acceptable. 

Martha Q. Lacy, MD

I agree, t(4;14) patients have high remission rates with bortezomib. We would likely go with a bortezomib-based regimen and advocate bortezomib maintenance.

Elizabeth Bilotti, MSN, RN, APN

As the patient opted not to receive maintenance therapy, I would not recommend any changes in monitoring or assessments. However, had this cytogenetic information been available at the time of diagnosis, we would have likely recommended bortezomib as part of induction therapy. At relapse, we would opt for a combination regimen, with a bortezomib backbone, and, under the current renal circumstances, would choose VCD (bortezomib, cyclophosphamide, and dexamethasone).

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tougher case
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Martha Q. Lacy, MD
Professor of Medicine
Division of Hematology
Mayo Clinic College of Medicine
Rochester, Minnesota

This patient has intermediate/high-risk molecular markers consisting of the t(4;14), high beta-2 microglobulin, and a short duration of response following ASCT. Patients with the t(4;14) translocation have high response rates to bortezomib, so we prefer starting with a bortezomib-based regimen. If no maintenance therapy is given after the ASCT, remission duration is generally short. In addition, we would prefer bortezomib-based maintenance therapy for this patient. The choice to use bortezomib, 1 dose every other week, as maintenance is based on the HOVON-65/GMMG-HD4 trial that showed patients receiving bortezomib maintenance had improved PFS and OS.¹ Since the remission was a fairly short duration (< 12 months), we at Mayo favor switching class to an immunomodulatory agent-based regimen. A second ASCT generally would not be performed if the first remission was less than 12 months.

This patient is now dual refractory, and historical outcomes for this patient type are poor. Data by Kumar and colleagues found that in 286 multiple myeloma patients refractory to bortezomib and relapsing following, refractory to, or ineligible to receive lenalidomide or thalidomide, the median OS was 9 months and median event-free survival was only 5 months.² Recently, carfilzomib was approved for patients who have failed at least 2 prior therapies including bortezomib and an immunomodulatory agent. In a phase II trial of heavily pre-treated myeloma, carfilzomib monotherapy resulted in 20% overall response rate with a 7.4-month median duration of response in 214 bortezomib and lenalidomide refractory/intolerant patients. In addition to carfilzomib, a clinical trial would also be a reasonable approach for this patient.³ Agents in late stage trials include combination therapy and the immunomodulatory agent, pomalidomide, which produced a 26-29% response rate in patients refractory to both bortezomib and lenalidomide.⁴ Alkylating agents may also be considered for this dual refractory patient.

During treatment, Mrs Anderson developed peripheral neuropathy. There are a number of ways to reduce the risk of treatment-induced peripheral neuropathy. The randomized French trial found that subcutaneous bortezomib is not inferior to IV bortezomib and significantly reduced the risk of peripheral neuropathy.⁵ Efficacy with carfilzomib monotherapy is comparable to that of bortezomib but the risk of PN is greatly reduced.^3,6 Regimens containing melphalan or cyclophosphamide may be active and would not contribute to PN. Thalidomide can cause treatment-induced neuropathy and would not be an option to reduce the risk of neuropathy.

Thomas G. Martin III, MD
Clinical Professor of Medicine
Multiple Myeloma Translational Initiative
UCSF Medical Center, University of California, San Francisco
San Francisco, California

Mrs Anderson initially presented with high-risk disease based on high beta-2 microglubulin, complex cytogenetics, and FISH (+) for t(4,14). She was appropriately treated with a bortezomib-containing regimen and went on to receive an ASCT. Unfortunately, she relapsed within 1 year of transplant, which suggests very aggressive disease and poor OS. She was treated appropriately with salvage RVD but only enjoyed remission for approximately 5 months. At this point, one could consider using carfilzomib since the patient has received 2 prior regimens including both an immunomodulatory agent and proteasome inhibitor. Data recently published in Blood suggests an anticipated response rate of 23.7% and median duration of response of approximately 8 months.¹ A clinical trial would also be an excellent option for this patient. Aggressive chemotherapy including alkylator-based therapy like hyperCAD or PACE could also be considered in a robust patient.
  

When is a second transplant indicated?

Thomas G. Martin III, MD

Patients who clearly benefit from second autologous stem cell transplant (ASCT) are those who enjoy a remission duration longer than 24 months. Patients achieving a remission duration less than 12 months should not be considered for second transplant. Patients who achieved remission following ASCT between 12 and 24 months fall in the grey zone and should be considered for second transplant on a case by case basis. Obviously, patients should have good performance status and be in remission (chemoresponsive) at the time of second transplant.

Elizabeth Bilotti, MSN, RN, APN

At this time, the indication for a second transplant, outside of a novel conditioning regimen on protocol, would not be recommended. The patient got less than 12 months remission out of the first transplant, presumably when the disease would be more sensitive.

 

Martha Q. Lacy, MD

If you chose a clinical trial for this patient, what agents would you focus on?

Thomas G. Martin III, MD

The 2 most promising drugs on the horizon are carfilzomib and pomalidomide. I would focus on clinical trials that include one or both of these 2 agents. Impressive preliminary results were presented by Dr Richardson at ASCO 2012 utilizing a novel naked anti-CD38 monoclonal antibody.¹ To date monoclonal antibody therapy for myeloma has had limited success but these agents may be more potent when combined with immunomodulatory agents.² A number of phase II and III trials are now underway evaluating the potency of these new monoclonal antibodies. Additional studies combining proteasome inhibitors to mTOR, AKT, and HDAC inhibitors are underway and may demonstrate positive results.
 

References

Elizabeth Bilotti, MSN, RN, APN

In evaluating clinical trials we would focus on pomalidomide, a combination regimen that includes carfilzomib, monoclonal antibodies, and AKT inhibitors.¹

 

References

Katherine Sanvidge Shah, PharmD, BCOP

Our team would likely focus on novel agents with potential mechanisms differing from those she has seen previously such as the monoclonal antibody, elotuzumab (in combination with agents such as lenalidomide and dexamethasone). We would avoid agents known to cause or worsen PN as this patient has experienced grade 2 PN previously. Also, though now FDA-approved for the treatment of myeloma, I would also consider phase II or III carfilzomib combination trials (± lenalidomide, pomalidomide, dexamethasone, etc) trials as most patients do not experience new onset or worsening of their PN. One could also consider AKT or HDAC investigational agents.

Mrs Anderson - Idea Exchange #4

 

High-Risk Cytogenetics

Martha Q. Lacy, MD

What are options for patients who have or develop a deletion of 17p?

Thomas G. Martin III, MD

Those patients who develop del(17p) have a very poor prognosis. Transplantation has limited role as salvage therapy. The most promising agent is carfilzomib as the phase II data suggested that the 17p deleted patient responded equally as well as non-17p deleted subjects. I would treat with carfilzomib as a single agent or on a clinical trial in combination with other agents (ie, carfilzomib + cyclophosphamide, carfilzomib + pomalidomide, carfilzomib + histone deacetylase inhibitor).¹
 

References

Elizabeth Bilotti, MSN, RN, APN

del(17p) suggests poor prognosis at this point in time, but there is no evidence in this setting that it is clinically useful. Thus, with the current mature data, knowledge that the patient has developed a del(17p) would be purely scientific, as it would not provide any assistance in the determination of clinical intervention.

Katherine Sanvidge Shah, PharmD, BCOP

del(17p) confers an especially poor prognostic outcome (lower response rate and shorter PFS and OS). Currently there are no definitive treatments, and thus, would use agents with novel mechanisms of action or those not used previously.

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