Should treatment be started it should address both the paraprotein level and the lymphocytic B-cells.

In 2002, a panel at the International Workshop on Waldenström's Macroglobulinemia agreed on criteria for the initiation of therapy. They recommended starting therapy in patients with constitutional symptoms such as recurrent fever, night sweats, fatigue due to anemia, weight loss, progressive symptomatic lymphadenopathy or spleen enlargement, and anemia due to bone marrow infiltration. Complications such as hyperviscosity syndrome, symptomatic sensorimotor peripheral neuropathy, systemic amyloidosis, kidney failure, or symptomatic cryoglobulinemia were also suggested as indications for therapy.

Treatment includes the monoclonal antibody rituximab, sometimes in combination with chemotherapeutic drugs such as chlorambucil, cyclophosphamide, or vincristine or with thalidomide. Corticosteroids, such as prednisone, may also be used in combination. Plasmapheresis can be used to treat the hyperviscosity syndrome by removing the paraprotein from the blood, although it does not address the underlying disease. Ibrutinib is another agent that has been approved for use in this condition.

Recently, autologous bone marrow transplantation has been added to the available treatment options.

When primary or secondary resistance invariably develops, salvage therapy is considered. Allogeneic stem cell transplantation can induce durable remissions for heavily pre-treated patients.

The natural history of myeloma is of relapse following treatment. This may be attributed to tumor heterogeneity. Depending on the patient's condition, the prior treatment modalities used and the duration of remission, options for relapsed disease include re-treatment with the original agent, use of other agents (such as melphalan, cyclophosphamide, thalidomide or dexamethasone, alone or in combination), and a second autologous stem cell transplant.

Later in the course of the disease, "treatment resistance" occurs. This may be a reversible effect, and some new treatment modalities may re-sensitize the tumor to standard therapy. For patients with "relapsed disease", bortezomib is a recent addition to the therapeutic arsenal, especially as second line therapy, since 2005. Bortezomib is a proteasome inhibitor. Also, lenalidomide (Revlimid), a less toxic thalidomide analog, is showing promise for treating myeloma. The newly approved thalidomide derivative pomalidomide (Pomalyst in the U.S.) may be used for relapsed and refractory multiple myeloma.

In the 21st century, more patients have survived longer, as a result of stem cell transplant (with their own or a donor's) and treatments combining bortezomib (Velcade), dexamethasone and melphalan or cyclophosphamide. This seems to maintain the monoclonal peak at a reasonable level. Survival expectancy has risen. New treatments are under development.

Kidney failure in multiple myeloma can be acute (reversible) or chronic (irreversible). Acute kidney failure typically resolves when the calcium and paraprotein levels are brought under control. Treatment of chronic kidney failure is dependent on the type of kidney failure and may involve dialysis.

Several newer options are approved for the management of advanced disease:

- ixazomib — an orally available proteasome inhibitor indicated in combination with lenalidomide and dexamethasone in people who have received at least one prior therapy;

- panobinostat — an orally available histone deacetylase inhibitor used in combination with bortezomib and dexamethasone in people who have received at least 2 prior chemotherapy regimens, including bortezomib and an immunomodulatory agent (such as lenalidomide or pomalidomide);

- carfilzomib — a proteasome inhibitor that is indicated:

- as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy;

- in combination with dexamethasone or with lenalidomide+dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy;

- elotuzumab — an immunostimulatory humanized monoclonal antibody against SLAMF7 (also known as CD319). It is FDA-approved for the treatment of patients who have received one to three prior therapies (in combination with lenalidomide and dexamethasone);

- daratumumab — a monoclonal antibody against CD38 indicated for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who are double refractory to a proteasome inhibitor and an immunomodulatory agent.

Most people, including those treated with ASCT, will relapse after initial treatment. Maintenance therapy using a prolonged course of low toxicity medications is often used to prevent relapse. A 2017 meta-analysis showed that post ASCT maintenance therapy with lenalidomide improved progression free survival and overall survival in people at standard risk. A 2012 clinical trial showed that people with intermediate and high risk disease benefit from a bortezomib based maintenance regimen.

The protein electrophoresis test should be repeated annually, and if there is any concern for a rise in the level of monoclonal protein, then prompt referral to a hematologist is required. The hematologist, when first evaluating a case of MGUS, will usually perform a skeletal survey (X-rays of the proximal skeleton), check the blood for hypercalcemia and deterioration in renal function, check the urine for Bence Jones protein and perform a bone marrow biopsy. If none of these tests are abnormal, a patient with MGUS is followed up once every 6 months to a year with a blood test (serum protein electrophoresis). Although patients with MGUS have sometimes been reported to suffer from Small Fiber Neuropathy in monoclonal gammopathy of undetermined significance:a debilitating condition which causes bizarre sensory problems to painful sensory problems. peripheral neuropathy, no treatment is indicated.

The most effective treatment is autologous bone marrow transplants with stem cell rescues. However many patients are too weak to tolerate this approach.

Other treatments can involve application of chemotherapy similar to that used in multiple myeloma. A combination of melphalan and dexamethasone has been found effective in those who are ineligible for stem cell transplantation, and a combination of bortezomib and dexamethasone is now in widespread clinical use.

People affected by the severest, often life-threatening, complications of cryoglobulinemic disease require urgent plasmapharesis and/or plasma exchange in order to rapidly reduce the circulating levels of their cryoglobulins. Complications commonly requiring this intervention include: hyperviscosity disease with severe symptoms of neurological (e.g. stroke, mental impairment, and myelitis) and/or cardiovascular (e.g., congestive heart failure, myocardial infarction) disturbances; vasculitis-driven intestinal ischemia, intestinal perforation, cholecystitis, or pancreatitis, causing acute abdominal pain, general malaise, fever, and/or bloody bowel movements; vasculitis-driven pulmonary disturbances (e.g. coughing up blood, acute respiratory failure, X-ray evidence of diffuse pulmonary infiltrates caused by diffuse alveolar hemorrhage); and severe kidney dysfunction due to intravascular deposition of immunoglobulins or vasculitis. Along with this urgent treatment, severely symptomatic patients are commonly started on therapy to treat any underlying disease; this treatment is often supplemented with anti-inflammatory drugs such as corticosteroids (e.g., dexamethasone) and/or immunosuppressive drugs. Cases where no underlying disease is known are also often treated with the latter corticosteroid and immunosuppressive medications.

Treatment of Type I disease is generally directed towards treating the underlying pre-malignant or malignant disorder (see plasma cell dyscrasia, Waldenström's macroglobulinemia, and chronic lymphocytic leukemia). This involves appropriate chemotherapy regimens which may include bortezomib (promotes cell death by apoptosis in cells accumulating immunoglobulins) in patients with monoclonal immunoglobulin-induced renal failure and rituximab (antibody directed against CD20 surface antigen-bearing lymphocytes) in patients with Waldenstroms macroglobulonemia).

Autologous stem-cell transplants are shown to be an effective treatment. However, this should be only considered for certain people due to toxicity concerns. It is possible that the transplant may cause problems like septic shock.

Lastly, radiation is normally used as a rescue type treatment and is not recommended as a first line treatment. The doctor would perform localized radiation therapy at a dose of 30 to 40 Gy on the lesions. This is to limit the amount of radiation and prevent further damage to the nervous system, which could happen due to the toxicity of radiation therapy.

There is no standard treatment for LCDD. High-dose melphalan in conjunction with autologous stem cell transplantation has been used in some patients. A regimen of bortezomib and dexamethasone has also been examined.

Median survival for patients diagnosed with AL amyloidosis was 13 months in the early 1990s, but had improved to c. 40 months a decade later.

First-line treatment for CIDP is currently intravenous immunoglobulin (IVIG) and other treatments include corticosteroids (e.g. prednisone), and plasmapheresis (plasma exchange) which may be prescribed alone or in combination with an immunosuppressant drug. Recent controlled studies show subcutaneous immunoglobin (SCIG) appears to be as effective for CIDP treatment as IVIG in most patients, and with fewer systemic side effects.

IVIG and plasmapheresis have proven benefit in randomized, double-blind, placebo-controlled trials. Despite less definitive published evidence of efficacy, corticosteroids are considered standard therapies because of their long history of use and cost effectiveness. IVIG is probably the first-line CIDP treatment, but is extremely expensive. For example, in the U.S., a single 65 g dose of Gamunex brand in 2010 might be billed at the rate of $8,000 just for the immunoglobulin—not including other charges such as nurse administration. Gamunex brand IVIG is the only U.S. FDA approved treatment for CIDP, as in 2008 Talecris, the maker of Gamunex, received orphan drug status for this drug for the treatment of CIDP.

Immunosuppressive drugs are often of the cytotoxic (chemotherapy) class, including rituximab (Rituxan) which targets B cells, and cyclophosphamide, a drug which reduces the function of the immune system. Ciclosporin has also been used in CIDP but with less frequency as it is a newer approach. Ciclosporin is thought to bind to immunocompetent lymphocytes, especially T-lymphocytes.

Non-cytotoxic immunosuppressive treatments usually include the anti-rejection transplant drugs azathioprine (Imuran/Azoran) and mycophenolate mofetil (Cellcept). In the U.S., these drugs are used as "off-label" treatments for CIDP, meaning that their use here is accepted by the FDA, but that CIDP treatment is not explicitly indicated or approved in the drug literature. Before azathioprine is used, the patient should first have a blood test that ensures that azathioprine can safely be used.

Anti-thymocyte globulin (ATG), an immunosuppressive agent that selectively destroys T lymphocytes is being studied for use in CIDP. Anti-thymocyte globulin is the gamma globulin fraction of antiserum from animals that have been immunized against human thymocytes. It is a polyclonal antibody.

Although chemotherapeutic and immunosuppressive agents have shown to be effective in treating CIDP, significant evidence is lacking, mostly due to the heterogeneous nature of the disease in the patient population in addition to the lack of controlled trials.

A review of several treatments found that azathioprine, interferon alpha and methotrexate were not effective. Cyclophosphamide and rituximab seem to have some response. Mycophenolate mofetil may be of use in milder cases. Immunoglobulin and steroids are the first line choices for treatment. Rarely bone marrow transplantation has been performed.

Physical therapy and occupational therapy may improve muscle strength, activities of daily living, mobility, and minimize the shrinkage of muscles and tendons and distortions of the joints.

Studies on the treatment of cryofibrinoginemic disease have involved relatively few patients, are limited primarily to case reports, and differ based on whether the disease is primary or secondary. In all cases of cryofibrinogenemic disease, however, patients should avoid the exposure of afflicted body parts to cold weather or other environmental triggers of symptoms and avoid using cigarettes or other tobacco products. In severe cases, these individuals also risk developing serious thrombotic events which lead to tissue necrosis that may result in secondary bacterial infections and require intensive antimicrobial therapy and/or amputations. Careful treatment of these developments is required.

Plasmapheresis may be used to decrease viscosity in the case of myeloma, whereas leukapheresis or phlebotomy may be employed in a leukemic or polycythemic crisis, respectively. Blood transfusions should be used with caution as they can increase serum viscosity. Hydration is a temporizing measure to employ while preparing pheresis. Even after treatment, the condition will recur unless the underlying disorder is treated.

Several other illnesses can present with a monoclonal gammopathy, and the monoclonal protein may be the first discovery before a formal diagnosis is made:

Treatment of secondary cryofibrinoginemic disease may use the same methods used for treating the primary disease wherever necessary but focus on treating the associated infectious, malignant, premalignant, vasculitis, or autoimmune disorder with the methods prescribed for the associated disorder. Case report studies suggest that: corticosteroids and immunosuppressive drug regimens, antimicrobial therapy, and anti-neoplastic regimens can be effective treatments for controlling the cryfibrinoginemic disease in cases associated respectively with autoimmune, infectious, and premalignant/malignant disorders.

Causes of paraproteinemia include the following:

- Leukemias and lymphomas of various types, but usually B-cell Non-Hodgkin lymphomas with a plasma cell component.

- Myeloma

- Plasmacytoma

- Lymphoplasmacytic lymphoma

- Idiopathic (no discernible cause): some of these will be revealed as leukemias or lymphomas over the years.

- Monoclonal gammopathy of undetermined significance

- Primary AL amyloidosis (light chains only)

Paraproteinemia, also known as monoclonal gammopathy, is the presence of excessive amounts of paraprotein or single monoclonal gammaglobulin in the blood. It is usually due to an underlying immunoproliferative disorder or hematologic neoplasms, especially multiple myeloma. It is sometimes considered equivalent to plasma cell dyscrasia.

Antihistamines are not effective in treating the hives in this condition. It may respond to immunosuppressant drugs such as corticosteroids, cyclooxygenase inhibitors, interferon alpha, interleukin 1 receptor antagonists (Anakinra), perfloxacin, colchicine, cyclosporine or thalidomide. The hives may respond to treatment with PUVA, and the bone pain may respond to bisphosphonates.

Because Schnitzler's syndrome is so rare, the efficacy of different treatments cannot be compared using statistics. Nevertheless, case studies provide evidence that anakinra (otherwise known as kineret) is much more effective for Schnitzler's syndrome than any other drug, and that the improvement in symptoms associated with this treatment is dramatic. For example, Beseda and Nossent (2010) reviewed the literature concerning IL1-RA treatment (i.e. anakinra) for Schnitzler's syndrome. They concluded that, “Twenty-four patients with Schnitzler's syndrome... have been successfully treated with anakinra.” They add that “seven out of seven patients [with Schnitzler’s syndrome], that either interrupted or used anakinra every other day, had relapse of their symptoms within 24-48 h; anakinra was restarted in all patients with the same clinical efficiency.” Kluger et al. (2008) investigated the effectiveness of anakinra for a range of conditions. They searched MEDLINE for English-language trials of anakinra and abstracts from rheumatologial scientific meetings. They conclude that, “Over the last few years it has become increasingly evident that anakinra is highly effective and safe in patients with ... Schnitzler’s syndrome”. The year before, De Koning et al. (2007) reviewed the disease characteristics of Schnitzler syndrome and collected follow-up information to gain insight into long-term prognosis and treatment efficacy. They used data from 94 patients, and their conclusions about treatment for the condition are that, “There have been promising developments in therapeutic options, especially antiinterleukin-1 treatment, which induced complete remission in all 8 patients treated so far.”

Reports of individual patients treated with anakinra illustrate its effectiveness. Beseda and Nossent (ibid.) report treating a longstanding multidrug resistant Schnitzler’s syndrome patient with anakinra: “Within 24 h after the first injection, both the urticaria and the fever disappeared and have not recurred. For the past 6 months, the patient has been in clinical and biochemical remission.” Other authors report “a complete resolution of symptoms” (Dybowski et al., 2008). Crouch et al. (2007) report the effective treatment of a 52-year-old man who had been diagnosed with Schnitzler’s syndrome 8 years earlier: “On review, one week later, the patient’s systemic symptoms had resolved, and his previously elevated white cell count and inflammatory markers had normalised. The use of anakinra in our patient resulted in resolution of symptoms and has enabled cessation of oral prednisolone. Our patient remains symptom free on anakinra after 14 months of follow-up”. Similar stories are reported by Frischmeyer-Guerrerio et al. (2008), Wastiaux et al. (2007), and Eiling et al. (2007), Schneider et al. (2007). De Koning et al. (2006) treated three patients with Schnitzler’s syndrome with thalidomide and anakinra. Thalidomide was only effective for one of the three patients and was discontinued because of polyneuropathy. In contrast, for all three patients, anakinra “led to disappearance of fever and skin lesions within 24 hours. After a follow-up of 16-18 months, all patients are free of symptoms”. The authors concluded that anakinra as a treatment for Schnitzler’s syndrome “is preferable to thalidomide... as it has fewer side effects”.

As well as being more effective, anakinra is safer than the other treatments available for Schnitzler's syndrome. The Cochrane review entitled, ‘Anakinra for rheumatoid arthritis’ (Mertens and Singh, 2009 ) evaluates the (clinical effectiveness and) safety of anakinra in adult patients with rheumatoid arthritis, using data from 2876 patients, from five trials which constituted 781 randomized to placebo and 2065 to anakinra. The authors conclude, “There were no statistically significant differences noted in most safety outcomes with treatment with anakinra versus placebo - including number of withdrawals, deaths, adverse events (total and serious), and infections (total and serious). Injection site reactions were significantly increased, occurring in 1235/1729 (71%) versus 204/729 (28%) of patients treated with anakinra versus placebo, respectively”. These injection site reactions last for no more than four months, and are trivial compared to the very debilitating symptoms of Schnitzler's syndrome.

Macroglobulinemia is the presence of increased levels of macroglobulins in the circulating blood.

It is a plasma cell dyscrasia, resembling leukemia, with cells of lymphocytic, plasmacytic, or intermediate morphology, which secrete a monoclonal immunoglobulin M component. There is diffuse infiltration by the malignant cells of the bone marrow and also, in many cases, of the spleen, liver, or lymph nodes. The circulating macroglobulin can produce symptoms of hyperviscosity syndrome: weakness, fatigue, bleeding disorders, and visual disturbances. Peak incidence of macroglobulinemia is in the sixth and seventh decades of life. (Dorland, 28th ed)

Additionally, some researchers separate out lymphomas that appear to result from other immune system disorders, such as AIDS-related lymphoma.

Classic Hodgkin's lymphoma and nodular lymphocyte predominant Hodgkin's lymphoma are now considered forms of B-cell lymphoma.

The B-cell lymphomas are types of lymphoma affecting B cells. Lymphomas are "blood cancers" in the lymph nodes. They develop more frequently in older adults and in immunocompromised individuals.

B-cell lymphomas include both Hodgkin's lymphomas and most non-Hodgkin lymphomas. They are typically divided into low and high grade, typically corresponding to indolent (slow-growing) lymphomas and aggressive lymphomas, respectively. As a generalisation, indolent lymphomas respond to treatment and are kept under control (in remission) with long-term survival of many years, but are not cured. Aggressive lymphomas usually require intensive treatments, with some having a good prospect for a permanent cure.

Prognosis and treatment depends on the specific type of lymphoma as well as the stage and grade. Treatment includes radiation and chemotherapy. Early-stage indolent B-cell lymphomas can often be treated with radiation alone, with long-term non-recurrence. Early-stage aggressive disease is treated with chemotherapy and often radiation, with a 70-90% cure rate. Late-stage indolent lymphomas are sometimes left untreated and monitored until they progress. Late-stage aggressive disease is treated with chemotherapy, with cure rates of over 70%.

Splenectomy is usually ineffective for the treatment of cold agglutinin disease, because the liver is the predominant site of sequestration. However, if the patient has splenomegaly, then the disease may respond to splenectomy. More importantly, a lymphoma localized to the spleen may only be found after splenectomy.

Patients with cold agglutinin disease should include good sources of folic acid, such as fresh fruits and vegetables, in their diet. Activities for these individuals should be less strenuous than those for healthy people, particularly for patients with anemia. Jogging in the cold could be very hazardous because of the added windchill factor.